DE1180755B - Process for the preparation of trypanocidally active 4-melaminylphenylarsinodimercapto-succinates of 1,5-bis- (4'-amidinophenoxy) -pentane - Google Patents
Process for the preparation of trypanocidally active 4-melaminylphenylarsinodimercapto-succinates of 1,5-bis- (4'-amidinophenoxy) -pentaneInfo
- Publication number
- DE1180755B DE1180755B DER32035A DER0032035A DE1180755B DE 1180755 B DE1180755 B DE 1180755B DE R32035 A DER32035 A DE R32035A DE R0032035 A DER0032035 A DE R0032035A DE 1180755 B DE1180755 B DE 1180755B
- Authority
- DE
- Germany
- Prior art keywords
- bis
- amidinophenoxy
- pentane
- preparation
- active
- 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
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 3
- 150000003839 salts Chemical class 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000000047 product Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- -1 arsinodimercaptosuccinates Chemical class 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000000654 trypanocidal effect Effects 0.000 description 2
- WIJHFFBIVJGJJU-UHFFFAOYSA-N 4-[5-(4-carbamimidoylphenoxy)pentoxy]benzenecarboximidamide;hydrochloride Chemical compound Cl.C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 WIJHFFBIVJGJJU-UHFFFAOYSA-N 0.000 description 1
- 101000835998 Homo sapiens SRA stem-loop-interacting RNA-binding protein, mitochondrial Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000004554 Leishmaniasis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100025491 SRA stem-loop-interacting RNA-binding protein, mitochondrial Human genes 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000223104 Trypanosoma Species 0.000 description 1
- 241000223105 Trypanosoma brucei Species 0.000 description 1
- HWURPQUPKQFGJI-UHFFFAOYSA-N [amino-[4-[5-[4-[amino(azaniumylidene)methyl]phenoxy]pentoxy]phenyl]methylidene]azanium;dichloride Chemical compound [Cl-].[Cl-].C1=CC(C(=[NH2+])N)=CC=C1OCCCCCOC1=CC=C(C(N)=[NH2+])C=C1 HWURPQUPKQFGJI-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- XJLBFCVPIIFHQU-UHFFFAOYSA-N triazine;trihydrochloride Chemical compound Cl.Cl.Cl.C1=CN=NN=C1 XJLBFCVPIIFHQU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/66—Arsenic compounds
- C07F9/70—Organo-arsenic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Verfahren zur Herstellung von trypanocid wirksamen 4-Melaminylph enyl arsinodimercaptosuccinaten des 1 ,5-Bis-(4'-amidinoph enoxy)-pentans Die Erfindung betrifft die Herstellung von neuen, trypanocid wirksamen 4-Melaminylphenylarsinodimercaptosuccinaten des 1 ,5-Bis-(4'-amidinophenoxy)-pentans der Formel Die 4-Melaminylphenylarsinodimercaptobernsteinsäure, die zwei asymmetrische Kohlenstoffatome besitzt, kann wie die Weinsäure in vier stereoisomeren Formen existieren: zwei optisch aktive Formen, eine konstitutionsmäßig optisch inaktive Form (Meso-Form) und eine racemische Form. Die Erfindung betrifft die Herstellung der Salze aus jeder dieser beiden optisch inaktiven Formen, die man Formel und Form B nennt, mit l,5-Bis-(4'-amidinophenoxy)-pentan.Process for the preparation of trypanocidally effective 4-melaminylphenyl arsinodimercaptosuccinates of 1,5-bis (4'-amidinophenoxy) pentane The invention relates to the preparation of new, trypanocidally effective 4-melaminylphenylarsinodimercaptosuccinates of 1,5-bis- (4 ' -amidinophenoxy) pentanes of the formula Like tartaric acid, 4-melaminylphenylarsinodimercaptosuccinic acid, which has two asymmetric carbon atoms, can exist in four stereoisomeric forms: two optically active forms, a constitutionally optically inactive form (meso form) and a racemic form. The invention relates to the preparation of the salts from each of these two optically inactive forms, which are called formula and form B, with 1,5-bis (4'-amidinophenoxy) pentane.
Erfindungsgemäß können diese neuen Salze der Formel I dadurch hergestellt werden, daß man in an sich bekannter Weise 1,5-Bis-(4~amidinophenoxy) pentan mit einer4-Melaminylphenylarsinodimercaptobernsteinsäure entweder direkt oder durch doppelte Umsetzung zwischen je einem löslichen Salz dieser beiden Reaktionskomponenten umsetzt, das gebildete Salz isoliert und vorzugsweise im Vakuum trocknet. According to the invention, these new salts of the formula I can be prepared in this way be that in a known manner 1,5-bis- (4 ~ amidinophenoxy) pentane with a 4-melaminylphenylarsinodimercaptosuccinic acid either directly or through double conversion between a soluble salt of each of these two reaction components reacted, the salt formed isolated and preferably dried in vacuo.
Die doppelte Umsetzung erfolgt vorteilhafterweise in Wasser. Bei der direkten Umsetzung der 4-Melaminylphenylarsinodimercaptobernsteinsäure mit 1 ,5-Bis-(4'-amidinophenoxy)-pentan arbeitet man vorzugsweise in Gegenwart eines organischen Lösungsmittels, wie beispielsweise Dimethylsulfoxyd. The double conversion is advantageously carried out in water. at the direct reaction of 4-melaminylphenylarsinodimercaptosuccinic acid with 1 , 5-Bis (4'-amidinophenoxy) pentane is preferably carried out in the presence of an organic one Solvent, such as dimethyl sulfoxide.
Bei beiden Arbeitsweisen fällt das gebildete Salz sogleich aus oder verbleibt in Lösung, je nach dem Lösungsmittel: in letzterem Falle kann man es durch Zugabe einer mit dem Reaktionsmedium mischbaren organischen Flüssigkeit, in der jedoch das gewünschte Salz unlöslich oder wenig löslich ist, wie beispielsweise Aceton oder Äthanol, abtrennen. Man kann die Lösung auch einengen oder zur Trockne eindampfen, wobei man vorzugsweise unter vermindertem Druck arbeitet. In both modes of operation, the salt formed precipitates out immediately or remains in solution, depending on the solvent: in the latter case it can be through Addition of an organic liquid which is miscible with the reaction medium and in which however, the desired salt is insoluble or sparingly soluble, such as Separate acetone or ethanol. The solution can also be concentrated or dried evaporate, preferably working under reduced pressure.
Die erfindungsgemäßen Salze besitzen wertvolle chemotherapeutische Eigenschaften. Sie sind ins- besondere ausgezeichnete Trypanocide. Diese - Salze können zur Behandlung oder zur Prophylaxe von Infektionen durch Trypanosoma brncei - oder jedes andere Trypanosomen dieser Gruppe verwendet werden. Bezogen auf die Bestandteile, zeichnen sich diese Salze durch eine geringere Toxizität, eine bessere Verträglichkeit bei intramuskulärer Verabreichung und eine ausgesprochene Retardwirkung aus. Curativ sind diese Salze wirksamer als jede der Bestandteile; prophylaktisch ist ihre Wirkung zumindest ebenso lang wie die des 1 ,5-Bis-(4'-amidinophenoxy)-pentans und einwandfrei länger als die der 4 Melaminylphenylarsinodimercaptobernsteinsäure. The salts according to the invention have valuable chemotherapeutic properties Properties. They are mainly special excellent trypanocide. These - salts can be used for the treatment or prophylaxis of infections caused by Trypanosoma brncei - or any other trypanosome of this group can be used. Based on the Components, these salts are characterized by a lower toxicity, a better one Tolerance for intramuscular administration and a pronounced sustained release effect the end. Curatively, these salts are more effective than either of the ingredients; prophylactic its effect is at least as long as that of 1, 5-bis (4'-amidinophenoxy) pentane and perfectly longer than that of the 4 melaminylphenylarsinodimercaptosuccinic acid.
Diese Salze sind auch wertvolle Mittel gegen Leishmaniosen. Die die erfindungsgemäßen Salze enthaltenden therapeutischen Präparate können diese Salze einzeln oder im Gemisch enthalten.These salts are also valuable agents against leishmaniasis. The those Therapeutic preparations containing salts according to the invention can contain these salts contained individually or in a mixture.
Die folgenden Beispiele erläutern die Erfindung, ohne sie zu beschränken. The following examples illustrate the invention without restricting it.
Beispiel 1 Zu einer Lösung von 26,6 g Kalium4-melaminylphenylarsinodimercaptosuccinat (Form A) in 280 ccm Wasser setzt man unter Rühren innerhalb von 15 Minuten eine Lösung von 20,6 g 1 ,5-Bis-(4'-amidinophenoxy )-pentan-hydrochlorid in 780 ccm Wasser zu. Man rührt noch 80 Minuten weiter. Example 1 To a solution of 26.6 g of potassium 4-melaminylphenylarsinodimercaptosuccinate (Form A) in 280 ccm of water is set within 15 minutes with stirring Solution of 20.6 g of 1,5-bis- (4'-amidinophenoxy ) pentane hydrochloride in 780 cc of water. The mixture is stirred for a further 80 minutes.
Der gebildete Niederschlag wird abfiltriert, mit 250 ccm Wasser gewaschen und im Vakuum getrocknet. Man erhält so 33,8 g 4-Melaminylphenylarsinodimercaptosuccinat des 1,5-Bis-(4'-amidinophenoxy)-pentans (Form A). The precipitate formed is filtered off and washed with 250 cc of water and dried in vacuo. 33.8 g of 4-melaminylphenylarsinodimercaptosuccinate are thus obtained of 1,5-bis (4'-amidinophenoxy) pentane (Form A).
Beispiel 2 Zu einer Lösung von 5g Natrium4-melaminylphenylarsinodimercaptosuccinat (Form B) in 60 ccm Wasser setzt man unter Rühren innerhalb von 5 Minuten eine Lösung von 4,2 g 1,5-Bis-(4'-amidino phenoxy)-pentan-dihydrochlorid in 160 ccm Wasser zu. Man rührt noch 60 Minuten weiter. Der gebildete Niederschlag wird abfiltriert, mit 50 ccm Wasser gewaschen und im Vakuum getrocknet. Man erhält so 7,4 g 4-Melaminylphenylarsinodimercaptosuccinat des 1,5-Bis-(4'-amidinophenoxy>pentans (Form B). Example 2 To a solution of 5 g of sodium 4-melaminylphenylarsinodimercaptosuccinate (Form B) in 60 ccm of water, a solution is made with stirring over the course of 5 minutes of 4.2 g of 1,5-bis (4'-amidino phenoxy) pentane dihydrochloride in 160 cc of water. Stirring is continued for a further 60 minutes. The precipitate formed is filtered off with Washed 50 cc of water and dried in vacuo. 7.4 g of 4-melaminylphenylarsinodimercaptosuccinate are obtained in this way of 1,5-bis- (4'-amidinophenoxy> pentane (form B).
Vergleichsversuche Es wurde das Salz der 4Melaminylphenylarsinodimercaptobernsteinsäure
(Form A) mit dem 1,5-Bis-(4'-amidinophenoxy)-pentan (Produkt 1; Beispiel 1) und
das Salz der 4-Melaminylphenylarsinodimercaptobernsteinsäure (Form B) mit dem l,SBis-(4'-amidinophenoxyfipentan
(Produkt II; Beispiel 2) mit dem aus J. Chem. Soc., 1960, S. 4525 bis 4532, bekannten
2-Amino-4,6-di-p-amidino-anilino-s-triazin-trihydrochlorid (Produkt III) der Formel
verglichen. Folgender Vergleichsversuch wurde durchgeführt: Prüfung auf trypanozide
Wirksamkeit Man impft Mäusen subkutan 0,5 ccm einer Suspension ein, die aus dem
Blut von Mäusen hergestellt ist, welche 3 Tage vorher mit einem Stamm von Trypanosoma
brucei infiziert wurden, und die einen bis zwei Parasiten je mikroskopisches Feld
(G = 360) enthält. 2 Tage später verabreicht man subkutan das zu untersuchende Produkt
in verschiedenen Dosen. Die Mäuse werden dann während eines Zeitraums von 20 Tagen
beobachtet, wobei man alle 2 Tage eine mikroskopische Untersuchung auf
Trypanosomen
im Blut der Tiere durchführt. Man bestimmt dann diejenige Dosis (lKso) an Produkt,
welche während der Gesamtdauer des Versuchs das Erscheinen der Trypanosomen bei
5001o der Mäuse verhindert. Die Ergebnisse sind in der folgenden Tabelle zusammengefaßt,
wobei bei Produkt III das Resultat in Milligramm Base ausgedrückt ist.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1180755X | 1961-02-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1180755B true DE1180755B (en) | 1964-11-05 |
Family
ID=9661799
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DER32035A Pending DE1180755B (en) | 1961-02-08 | 1962-02-02 | Process for the preparation of trypanocidally active 4-melaminylphenylarsinodimercapto-succinates of 1,5-bis- (4'-amidinophenoxy) -pentane |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1180755B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2659723A (en) * | 1947-01-28 | 1953-11-17 | Ernst A H Friedheim | Triazine organometallic compounds and process for preparing same |
| GB824908A (en) * | 1958-06-03 | 1959-12-09 | May & Baker Ltd | Improvements in or relating to triazine derivatives |
-
1962
- 1962-02-02 DE DER32035A patent/DE1180755B/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2659723A (en) * | 1947-01-28 | 1953-11-17 | Ernst A H Friedheim | Triazine organometallic compounds and process for preparing same |
| GB824908A (en) * | 1958-06-03 | 1959-12-09 | May & Baker Ltd | Improvements in or relating to triazine derivatives |
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