DE1203781B - Process for the preparation of trypanocidally active phenanthridinium derivatives - Google Patents
Process for the preparation of trypanocidally active phenanthridinium derivativesInfo
- Publication number
- DE1203781B DE1203781B DEM42015A DEM0042015A DE1203781B DE 1203781 B DE1203781 B DE 1203781B DE M42015 A DEM42015 A DE M42015A DE M0042015 A DEM0042015 A DE M0042015A DE 1203781 B DE1203781 B DE 1203781B
- Authority
- DE
- Germany
- Prior art keywords
- phenanthridinium
- known per
- manner known
- preparation
- salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000003839 salts Chemical class 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 8
- 150000001450 anions Chemical class 0.000 claims description 5
- 150000008049 diazo compounds Chemical class 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000005349 anion exchange Methods 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- PLOCPSZUSGEEMU-UHFFFAOYSA-N phenanthridin-1-amine Chemical class C1=CC=CC2=C3C(N)=CC=CC3=NC=C21 PLOCPSZUSGEEMU-UHFFFAOYSA-N 0.000 claims description 2
- 239000012429 reaction media Substances 0.000 claims description 2
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 239000000243 solution Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZINFXAROCISAEQ-UHFFFAOYSA-N 3-amino-4-methoxybenzenecarboximidamide dihydrochloride Chemical compound Cl.Cl.NC=1C=C(C(=N)N)C=CC1OC ZINFXAROCISAEQ-UHFFFAOYSA-N 0.000 description 2
- BITVSRNAFFZUFW-UHFFFAOYSA-N 5-ethyl-6-phenylphenanthridin-5-ium-3,8-diamine;chloride Chemical compound [Cl-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 BITVSRNAFFZUFW-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- XNYZHCFCZNMTFY-UHFFFAOYSA-N diminazene Chemical compound C1=CC(C(=N)N)=CC=C1N\N=N\C1=CC=C(C(N)=N)C=C1 XNYZHCFCZNMTFY-UHFFFAOYSA-N 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- COJLEDKJRFSDTQ-UHFFFAOYSA-N 3-amino-4-chlorobenzenecarboximidamide Chemical compound NC(=N)C1=CC=C(Cl)C(N)=C1 COJLEDKJRFSDTQ-UHFFFAOYSA-N 0.000 description 1
- KRBRYJLBILJHAS-UHFFFAOYSA-N 3-amino-4-chlorobenzonitrile Chemical compound NC1=CC(C#N)=CC=C1Cl KRBRYJLBILJHAS-UHFFFAOYSA-N 0.000 description 1
- XBLPHYSLHRGMNW-UHFFFAOYSA-N 4-chloro-3-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC(C#N)=CC=C1Cl XBLPHYSLHRGMNW-UHFFFAOYSA-N 0.000 description 1
- DQZCAYQQTVQSLM-UHFFFAOYSA-N Cl.Cl.NC=1C=C(C(=N)N)C=CC1Cl Chemical compound Cl.Cl.NC=1C=C(C(=N)N)C=CC1Cl DQZCAYQQTVQSLM-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000223107 Trypanosoma congolense Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethanedisulfonate group Chemical class C(CS(=O)(=O)[O-])S(=O)(=O)[O-] AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- -1 m-aminobenzoyl-m-aminop - methylbenzoyl -1- naphthylamino Chemical group 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 239000013081 microcrystal Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- CUGZEDSDRBMZMY-UHFFFAOYSA-N trihydrate;hydrochloride Chemical class O.O.O.Cl CUGZEDSDRBMZMY-UHFFFAOYSA-N 0.000 description 1
- 230000000654 trypanocidal effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
- C07D221/12—Phenanthridines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Verfahren zur Herstellung von trypanocid wirksamen Phenanthridiniumderivaten Zahlreiche Phenanthridiniumsalze wurden bereits als trypanocide Mittel vorgeschlagen, doch wurden nur wenige von ihnen auf diesem Gebiet praktisch verwendet. Die Wirksamkeit und die Toxizität dieser Derivate schwanken beträchtlich mit der Anzahl und der Art der Aubstituenten, und es ist unmöglich, vorherzusagen, wie die Wirksamkeit eines neuen Phenanthridiniumsalzes sein wird.Process for the preparation of trypanocidally active phenanthridinium derivatives Numerous phenanthridinium salts have already been proposed as trypanocide agents, however, few of them have been put to practical use in this field. The effectiveness and the toxicity of these derivatives vary considerably with number and amount Type of aubstituent and it is impossible to predict how effective it is of a new phenanthridinium salt will be.
Es wurden nun neue Phenanthridiniumsalze gefunden, die eine erhöhte Wirksamkeit gegen die Blutparasiten, wie beispielsweise die Trypanosomen, besitzen. Außerdem weisen die neuen Salze eine sehr viel niedrigere Toxizität als die bis jetzt bekannten Phenanthridiniumsalze mit trypanocider Wirksamkeit auf. Ihr chemotherapeutischer Index ist daher im Verhältnis viel höher als derjenige anderer bekannter Produkte dieser Familie. New phenanthridinium salts have now been found which increase a Effectiveness against blood parasites, such as the trypanosomes, have. In addition, the new salts have a much lower toxicity than the bis now known phenanthridinium salts with trypanocider activity. Your chemotherapeutic The index is therefore proportionally much higher than that of other well-known products this family.
Erfindungsgemäß werden die neuen, trypanocid wirksamen Phenanthridiniumderivate hergestellt, indem man in an sich bekannter Weise ein substituiertes Anilin der Strukturformel worin R1 ein Halogenatom oder einen Methoxylrest darstellt, diazotiert und danach die erhaltene Diazoverbindung mit der äquimolaren Menge eines AminophenanthridiniumsalzPsderallgemeinen Formel worin Y ein pharmazeutisch verträgliches An ion, wie die Anionen Cl oder Br-, darstellt, in an sich bekannter Weise umsetzt, wobei man isomere Phenanthridiniumverbindungen erhält, die anschließend aus dem Reaktionsmedium in an sich bekannter Weise isoliert und gegebenenfalls durch Anionenaustausch in andere Salze übergeführt werden.According to the invention, the new, trypanocidally active phenanthridinium derivatives are prepared by adding a substituted aniline of the structural formula in a manner known per se wherein R1 represents a halogen atom or a methoxyl radical, diazotized and then the diazo compound obtained with the equimolar amount of an aminophenanthridinium salt Ps of the general formula in which Y is a pharmaceutically acceptable anion, such as the anions Cl or Br-, is reacted in a manner known per se to obtain isomeric phenanthridinium compounds which are then isolated from the reaction medium in a manner known per se and optionally converted into other salts by anion exchange will.
Die Kupplungsreaktion führt zur Bildung von zwei isomeren Verbindungen, von denen die eine rot und die andere purpurfarbig ist. Jedes dieser Isomeren kann nach den üblichen Fraktionierungsverfahren abgetrennt werden. Im übrigen kann man sich damit begnügen, die Mischung der beiden Isomeren zu isolieren, da beide therapeutisch wirksam sind. The coupling reaction leads to the formation of two isomeric compounds, one of which is red and the other is purple. Any of these isomers can are separated according to the usual fractionation processes. Otherwise you can content themselves with isolating the mixture of the two isomers, since both are therapeutic are effective.
Die neuen Phenanthridiniumverbindungen können in Form verschiedener Salze hergestellt werden. Als Beispiele für solche verwendbaren Salze seien die Salze der Halogenwasserstoffsäuren, z. B, die Hydrochloride, die Phosphate, Nitrate, Sulfate, Maleate, Fumarate, Citrate, Tartrate, Methansulfonate und Äthandisulfonate, genannt. Diese Salze können nach üblichen Arbeitsweisen erhalten werden, beispielsweise durch Durchleiten einer Lösung des Hydrochlorids des Chlorids in einem geeigneten Lösungsmittel durch eine lonenaustauschersäule, die das gewünschte Anion enthält, und Isolierung des so gebildeten Salzes durch Verdampfen des gesamten oder eines Teils des Lösungsmittels. Man kann auch beispielsweise eine doppelte Umsetzung zwischen dem Hydrochlorid des Chlorids und einer wäßrigen Lösung des Natriumsalzes einer nichttoxischen Säure durchführen. The new phenanthridinium compounds can be in the form of various Salts are produced. Examples of such salts that can be used are the Salts of hydrohalic acids, e.g. B, the hydrochloride, the phosphates, the nitrates, Sulfates, maleates, fumarates, citrates, tartrates, methanesulfonates and ethane disulfonates, called. These salts can be obtained by conventional procedures, for example by passing through a solution of the hydrochloride of the chloride in a suitable one Solvent through an ion exchange column, which the desired Containing anion, and isolating the salt so formed by evaporating the whole or part of the solvent. For example, you can also do a double Reaction between the hydrochloride of the chloride and an aqueous solution of the sodium salt a non-toxic acid.
In gleicher Weise können die neuen Verbindungen in Form von unlöslichen Salzen hergestellt werden, beispielsweise als Salze der 4*4'-Diaminostilben-2,2'-disulfonsäure, der 2,2'-Dihydroxy-l,1'-dinaphthylmethan-3,3'-dicarbonsäure und des symmetrischen Harnstoffs der m-Aminobenzoyl-m-aminop - methylbenzoyl -1- naphthylamino - 4,6,8- trisulfonsäure. In the same way, the new compounds can be in the form of insoluble Salts are produced, for example as salts of 4 * 4'-diaminostilbene-2,2'-disulfonic acid, the 2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylic acid and the symmetrical one Urea of m-aminobenzoyl-m-aminop - methylbenzoyl -1- naphthylamino - 4,6,8- trisulfonic acid.
Die folgenden Beispiele erläutern die Erfindung, ohne sie zu beschränken. The following examples illustrate the invention without restricting it.
Beispiel 1 Eine Lösung von 16,7 g 3-Amino4-chlorbenzamidin in 89 ml Wasser und 15 ml konzentrierter Salzsäure wird bei 5 bis 8"C mit 4,85 g Natriumnitrit diazotiert. Nach Filtrieren und Zerstören der überschüssigen salpetrigen Säure mittels Sulfaminsäure wird die Lösung der Diazoverbindung auf einmal in eine Lösung von 18,4 g 2,7-Diamino-10-äthyl-9-phenylphenanthridiniumchlorid in 100 ml Wasser von 5 bis 10°C eingegossen. Dann setzt man 27 g wasserfreies Natriumacetat, gelöst in 81 ml Wasser zu, rührt 1112 Stunden bei 5 bis 15"C, filtriert die gebildete dunkelblaue Festsubstanz ab, wäscht sie mit einer gesättigten Natriumchloridlösung und trocknet über Kieselxerogel. Die Papierelektrophorese zeigt das Vorliegen von zwei Haupthestandteilen. Ein Gemisch der Hydrochloridtrihydrate der isomeren Verbindungen des Phenanthridiniumchlorides scheidet sich durch Zugabe von Äther zu einer methanolischen Lösung des rohen Gemisches in Form von purpurfarbenen Mikrokristallen ab, die sich bei 265 bis 270°C zersetzen. Example 1 A solution of 16.7 g of 3-amino4-chlorobenzamidine in 89 ml of water and 15 ml of concentrated hydrochloric acid is mixed with 4.85 g of sodium nitrite at 5 to 8 "C diazotized. After filtering and destroying the excess nitrous acid using Sulfamic acid turns the solution of the diazo compound into a solution of at one time 18.4 g of 2,7-diamino-10-ethyl-9-phenylphenanthridinium chloride in 100 ml of water Poured in at 5 to 10 ° C. 27 g of anhydrous sodium acetate, dissolved in 81 ml of water are added, the mixture is stirred for 1112 hours at 5 to 15 ° C., and the dark blue that has formed is filtered off Solid matter off, washed with a saturated sodium chloride solution and dried about Kieselxerogel. Paper electrophoresis shows the presence of two main components. A mixture of the hydrochloride trihydrates of the isomeric compounds of phenanthridinium chloride separates by adding ether to a methanolic solution of the crude mixture in the form of purple microcrystals that decompose at 265 to 270 ° C.
Das als Ausgangssubstanz verwendete 3-Amino-4-chlor-benzamidin-dihydrochlorid, das sich bei 265"C zersetzt, wird aus 3-Amino-4-chlorbenzonitril vom F. 93 bis 94"C hergestellt, welch letzteres seinerseits durch Reduktion von 4-Chlor-3-nitrobenzonitril erhalten wird (Le Fevre und Turner, Journ. The 3-amino-4-chlorobenzamidine dihydrochloride used as the starting substance, which decomposes at 265 "C, becomes 3-amino-4-chlorobenzonitrile with a melting point of 93 to 94" C produced, the latter in turn by reducing 4-chloro-3-nitrobenzonitrile is obtained (Le Fevre and Turner, Journ.
Chem. Soc., 1927, S. 1118).Chem. Soc., 1927, p. 1118).
Beispiel 2 Aus 6,4 g 3-Amino-4-methoxybenzamidin-dihydrochlorid. 24,2 ml Wasser, 6 ml konzentrierter Salzsäure und 1,9 g Natriumnitrit stellt man bei 0 bis 5 C eine Lösung des Diazoniumsalzes her. Nach Zerstörung überschüssiger salpetriger Säure durch Zugabe von Sulfaminsäure gießt man die Lösung der Diazoverbindung auf einmal in eine Lösung von 10,8 g 2,7 -Diamino - 10-äthyl -9 -phenylphenanthridiniumchlorid in 6,5 ml Wasser von 5 bis 10°C unter Rühren ein. Hierauf setzt man 15,4g wasserfreies Natriumacetat, gelöst in 48,4 ml Wasser, zu und rührt die rote Lösung 2Stunden bei 10 bis 15"C. Example 2 From 6.4 g of 3-amino-4-methoxybenzamidine dihydrochloride. 24.2 ml of water, 6 ml of concentrated hydrochloric acid and 1.9 g of sodium nitrite are provided a solution of the diazonium salt at 0 to 5 ° C. After destroying excess nitrous acid by adding sulfamic acid, the solution of the diazo compound is poured at once in a solution of 10.8 g of 2,7-diamino-10-ethyl-9-phenylphenanthridinium chloride in 6.5 ml of water at 5 to 10 ° C with stirring. 15.4g of anhydrous is put on this Sodium acetate, dissolved in 48.4 ml of water, and the red solution is stirred for 2 hours 10 to 15 "C.
Dann versetzt man mit 40 g Natriumchlorid und verreibt die gebildete schmierige Masse in Gegenwart von Salzlösung bis zur Bildung eines festen Produkts.40 g of sodium chloride are then added and the resultant triturated greasy mass in the presence of saline solution until the formation of a solid product.
Die purpurfarbene Festsubstanz wird dann abfiltriert, mit Salzwasser gewaschen und dann über Kiesel- xerogel getrocknet. Die Papierelektrophorese zeigt das Vorliegen eines Hauptbestandteils, den man durch fraktionierte Kristallisation aus Methanol abtrennt. Durch Umkristallisation aus wäßrigem Sithanol erhält man ein Hydrochloridmonohydrat einer Verbindung des Phenanthridiniumchlorids, das in Form von Nadeln anfällt, die sich bei 264"C zersetzen.The purple colored solid is then filtered off with salt water washed and then over silica Dried xerogel. The paper electrophoresis shows the presence of a major ingredient identified by fractional crystallization separated from methanol. Recrystallization from aqueous sithanol is obtained a hydrochloride monohydrate of a compound of phenanthridinium chloride found in In the form of needles which decompose at 264 "C.
Das als Ausgangssubstanz verwendete 3-Amino-4-methoxybenzamidin-dihydrochlorid, das sich bei 277"C zersetzt, wird aus 3-AminoXmethoxybenzonitril hergestellt (Blankama und Petri, Rec. trav. chim., 1947, Bd. 66, S. 365). The 3-amino-4-methoxybenzamidine dihydrochloride used as the starting substance, which decomposes at 277 "C, is made from 3-AminoXmethoxybenzonitrile (Blankama and Petri, Rec. trav. chim., 1947, vol. 66, p. 365).
Therapeutische Testergebnisse Es wurde die therapeutische Wirksamkeit und die Toxizität der nach den Beispielen 1 und 2 hergestellten Produkte A bzw. B im Vergleich zu dem aus der britischen Patentschrift 735 438 bekannten, ähnlich gebauten 2,7-Diamino-9-phenyl- 1 Oäthylphenanthridiniumchlorid C und zu 4,4'-Diamidino-diazoaminobenzol D (Arzneimittelforschung, 5, S. 6341635 19551) geprüft. Therapeutic test results It was therapeutic effectiveness and the toxicity of products A and 2 prepared according to Examples 1 and 2, respectively. B compared to that known from British Patent 735,438 built 2,7-diamino-9-phenyl-1 Oäthylphenanthridiniumchlorid C and to 4,4'-diamidino-diazoaminobenzene D (Arzneimittelforschung, 5, p. 6341635 19551) checked.
Die Toxizität wurde durch subkutane Injektion festgestellt, die therapeutische Wirksamkeit nach folgender Methode: Therapeutische Wirksamkeit Die therapeutische Wirksamkeit wurde an Mäusen bestimmt, die mit einem Trypanosoma-Congolense-Laboratoriumsstamm infiziert waren, wodurch eine heftige Infektion hervorgerufen wird. Man verabreicht diesen so infizierten Mäusen, deren peripheres Blut unter starker Vergrößerung im Gesichtsfeld ein bis zehn Trypanosomen zeigt, subkutan das zu prüfende Produkt (eine einzige Dosis pro Maus). The toxicity was determined by subcutaneous injection, the therapeutic Effectiveness according to the following method: Therapeutic effectiveness The therapeutic Efficacy was determined in mice exposed to a laboratory Trypanosoma congolense strain infected, causing severe infection. Man administered these infected mice, whose peripheral blood is under high magnification in the Visual field shows one to ten trypanosomes, subcutaneously the product to be tested (one single dose per mouse).
Es wurden verschieden starke Dosen angewandt und die Wirkung jeder Dosis an zehn Mäusen bestimmt. Eine Bestimmung an fünf unbehandelten Mäusen in jeder Versuchsreihe dient zum Vergleich; diese Vergleichsmäuse starben 5 bis 7 Tage nach der Infizierung.Doses of different strengths were used and the effects of each one Dose determined on ten mice. A determination on five untreated mice in each The test series is used for comparison; these control mice died 5 to 7 days later the infection.
Abstriche aus frischem Blut wurden 4 Wochen lang dreimal pro Woche geprüft und die Zahl der Tiere festgestellt, die frei von Trypanosomen waren. Fresh blood smears were taken three times a week for 4 weeks and the number of animals free from trypanosomes was determined.
Man bestimmt dann graphisch die therapeutische Dosis 50°/o (Das), die 500/0 geheilten Tieren entspricht.The therapeutic dose is then determined graphically 50% (Das), which corresponds to 500/0 cured animals.
Die Ergebnisse sind in der folgenden Tabelle zusammengestellt:
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2124058A GB901643A (en) | 1958-07-02 | 1958-07-02 | Phenanthridinium salts and their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1203781B true DE1203781B (en) | 1965-10-28 |
Family
ID=10159566
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEM42015A Pending DE1203781B (en) | 1958-07-02 | 1959-07-02 | Process for the preparation of trypanocidally active phenanthridinium derivatives |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE1203781B (en) |
| GB (1) | GB901643A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0492570A1 (en) * | 1990-12-24 | 1992-07-01 | Enzo Diagnostics, Inc. | Method for detecting a target polynucleotide in a sample using a background reducing reagent and composition and kit comprising such a reagent |
| CN105153032A (en) * | 2015-10-13 | 2015-12-16 | 遵义医学院 | Preparation method of 6-H-phenanthridine compounds by one-pot process |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB735438A (en) * | 1952-07-24 | 1955-08-24 | May & Baker Ltd | Improvements in or relating to phenanthridinium salts |
-
1958
- 1958-07-02 GB GB2124058A patent/GB901643A/en not_active Expired
-
1959
- 1959-07-02 DE DEM42015A patent/DE1203781B/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB735438A (en) * | 1952-07-24 | 1955-08-24 | May & Baker Ltd | Improvements in or relating to phenanthridinium salts |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0492570A1 (en) * | 1990-12-24 | 1992-07-01 | Enzo Diagnostics, Inc. | Method for detecting a target polynucleotide in a sample using a background reducing reagent and composition and kit comprising such a reagent |
| US5989809A (en) * | 1990-12-24 | 1999-11-23 | Enzo Diagnostics, Inc. | Methods for detecting a polynucleotide using an inactivating reagent and composition and kit comprising same |
| CN105153032A (en) * | 2015-10-13 | 2015-12-16 | 遵义医学院 | Preparation method of 6-H-phenanthridine compounds by one-pot process |
Also Published As
| Publication number | Publication date |
|---|---|
| GB901643A (en) | 1962-07-25 |
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