DE1091575B - Process for the preparation of amoebicidally active N-dichloroacet-p-oxy-anilide esters - Google Patents
Process for the preparation of amoebicidally active N-dichloroacet-p-oxy-anilide estersInfo
- Publication number
- DE1091575B DE1091575B DEB50336A DEB0050336A DE1091575B DE 1091575 B DE1091575 B DE 1091575B DE B50336 A DEB50336 A DE B50336A DE B0050336 A DEB0050336 A DE B0050336A DE 1091575 B DE1091575 B DE 1091575B
- Authority
- DE
- Germany
- Prior art keywords
- dichloroacet
- oxy
- anilide
- preparation
- amoebicidally
- 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 7
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052717 sulfur Chemical group 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 10
- 241000700159 Rattus Species 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 230000003569 amebicidal effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 2
- 241000224489 Amoeba Species 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 241000224432 Entamoeba histolytica Species 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940007078 entamoeba histolytica Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000003812 trophozoite Anatomy 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
- C07F9/165—Esters of thiophosphoric acids
- C07F9/18—Esters of thiophosphoric acids with hydroxyaryl compounds
-
- 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
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DEUTSCHESGERMAN
Die Erfindung betrifft ein Verfahren zur Herstellung therapeutisch wertvoller, nämlich amoebicid wirkender N-Dichloracet-p-oxy-anilid-Ester der allgemeinen FormelThe invention relates to a method for the production of therapeutically valuable, namely amoebicidally active substances N-dichloroacet-p-oxy-anilide ester of the general formula
/· Ii '\ / Ii '\
— O-C-O— ( \- OCO— ( \
Cl2CHCON-Cl 2 CHCON-
jJ—NCOCHCLjJ-NCOCHCL
(I)(I)
Cl2CHCON-,Cl 2 CHCON-,
-OH-OH
(Π)(Π)
worin R die oben angegebene Bedeutung hat, mit Phosgen oder Thiophosgen.wherein R has the meaning given above, with phosgene or thiophosgene.
Die amoebicide Wirksamkeit der erfindungsgemäßen Verbindungen wurde bei Tieren in der folgenden Weise nachgewiesen. Die Technik ist im wesentlichen diejenige, wie sie von Jones (Annals of Tropical Medicine and Parasitology, 1946, 40, S. 130) beschrieben wurde, wobei soeben entwöhnte Ratten intracaecal mit Trophozoiten von Entamoeba histolytica geimpft werden. Beginnend mit dem Tage nach der Impfung werden jedem Tier aus einer Gruppe von Ratten fünf Tagesdosen der zu prüfenden Droge mittels einer Magensonde verabfolgt; die Tiere werden 1 Tag nach Verabfolgung der letzten Dosis getötet. Der Blinddarm jeder Ratte wird sowohl mikroskopisch als auch makroskopisch untersucht, und bei jeder Ratte wird der Grad der Infektion nach einer willkürlich gewählten Skala bewertet. Für jede Gruppe wird dann der durchschnittliche Infektionsgrad berechnet, nachstehend als A. D. I. bezeichnet. Man sieht eineThe amoebicidal activity of the compounds of the invention was determined in animals in the following manner proven. The technique is essentially that described by Jones (Annals of Tropical Medicine and Parasitology, 1946, 40, p. 130), with rats that have just been weaned intracaecally with trophozoites be vaccinated by Entamoeba histolytica. Starting the day after vaccination, each animal will be out administered five daily doses of the drug to be tested to a group of rats by means of a gastric tube; the animals are sacrificed 1 day after administration of the last dose. Each rat's appendix will have both examined microscopically as well as macroscopically, and in each rat the degree of infection is determined after one arbitrarily chosen scale rated. The average degree of infection is then calculated for each group, hereinafter referred to as A. D. I. You see one
worin R niedere Alkylgruppen und X Sauerstoff oder Schwefel bedeuten.where R is lower alkyl groups and X is oxygen or sulfur.
Es ist zwar schon bekannt, daß N-acylierte m-Oxyanilinverbindungen amoebicide Wirkungen aufweisen. Hieraus konnte jedoch nicht gefolgert werden, daß auch die erfindungsgemäß hergestellten Verbindungen solche Wirkungen besitzen.It is already known that N-acylated m-oxyaniline compounds have amoebicidal effects. From this, however, it could not be concluded that either the compounds prepared according to the invention have such effects.
Verbindungen der vorgenannten allgemeinen Formel I werden erfindungsgemäß hergestellt durch Umsatz eines Phenols der allgemeinen FormelCompounds of the aforementioned general formula I are prepared according to the invention by reacting a Phenol of the general formula
Verfahren zur HerstellungMethod of manufacture
amoebicid wirksamer
N-Dichloracet-p-oxy-anilid-Esteramoebicid more effective
N-dichloroacet-p-oxy-anilide ester
Anmelder:Applicant:
Boots Pure Drug Company Limited,
Nottingham (Großbritannien)Boots Pure Drug Company Limited,
Nottingham (Great Britain)
Vertreter: Dr. M. Eule, Patentanwalt,
München 13, Kurfürstenplatz 2Representative: Dr. M. Eule, patent attorney,
Munich 13, Kurfürstenplatz 2
Beanspruchte Priorität:
Großbritannien vom 3. November 1955Claimed priority:
Great Britain 3 November 1955
Peter Oxley, Gerald Woolfe,
Norman William Bristow, James Fräser,Peter Oxley, Gerald Woolfe,
Norman William Bristow, James Millers,
George Alfred Harrison Williams
und Eric Charles Wilmshurst, NottinghamGeorge Alfred Harrison Williams
and Eric Charles Wilmshurst, Nottingham
(Großbritannien),
sind als Erfinder genannt worden(Great Britain),
have been named as inventors
Verbindung als amoebenabtötend an, wenn der A. D. I. der behandelten Gruppe geringer ist als die Hälfte des A. D. I. der nicht behandelten Kontrollgruppe. Bei hochwirksamen Drogen werden die Ratten völlig von den Amoeben befreit, und der A. D. I. ist dann gleich Null. In der nachstehenden Tabelle sind die bei dem obigen Test mit den Verbindungen bis-[4-(Dichloracet-N-methylamido)-phenyl]-carbonat und bis-[4-(Dichloracet-N-methylamido) -phenyl] -thionocarbonat erhaltenen Ergebnisse verzeichnet. Es werden hierbei Einzelheiten über die Höhe der Tagesdosen der Testverbindung sowie der Wirksamkeit angegeben. Die »Wirksamkeit« wird hierbei definiert als die Zahl, welche man erhält, wenn man den bei der Kontrollgruppe erhaltenen A. D. I. dividiert durch den A. D. I. der behandelten Gruppe (wobei jede Zahl das Ergebnis eines Versuches darstellt).Compound as amoebic if the A.DI of the treated group is less than half of the A. D. I. of the untreated control group. With highly potent drugs, the rats will be completely off frees the amoeba, and the ADI is then zero. The table below shows the above test with the compounds bis- [4- (dichloroacet-N-methylamido) -phenyl] -carbonate and bis- [4- (dichloroacet-N-methylamido) phenyl] thionocarbonate Results recorded. There will be details about the amount of daily doses of the test compound as well indicated the effectiveness. The "effectiveness" is defined here as the number one receives when the A.D.I. obtained in the control group is divided by the A.D.I. of the treated group (where each number represents the result of an experiment).
(mg/kg)Daily dose
(mg / kg)
2. bis-[4-(Dichloracet-N-methylamido)-phenyl]-thionocarbonat j1. bis- [4- (dichloroacet-N-methylamido) phenyl] carbonate I
2. bis- [4- (dichloroacet-N-methylamido) phenyl] thionocarbonate j
50
200
50200
50
200
50
3,5
3,3
1,94.0
3.5
3.3
1.9
009 629/416009 629/416
Eine auf diese Weise erhaltene Zahl, welche größer ist als 1, bedeutet also, daß die Testverbindung eine amoebicide Wirkung zeigt. Je größer diese Zahl ist, desto höher ist auch die Wirksamkeit. Im Falle einer vollständigen Austreibung der Amoeben durch die Testverbindung kann man daher die »Wirksamkeit« als unendlich groß bezeichnen.Thus, a number obtained in this way which is greater than 1 means that the test compound is a shows amoebicidal effect. The larger this number, the higher the effectiveness. In case of a complete expulsion of the amoeba by the test compound can therefore be considered the "effectiveness" as call infinitely large.
Verbindungen von der allgemeinen Formel II sowie Verfahren zu deren Herstellung sind in dem älteren Patent 1 046 063 beschrieben.Compounds of the general formula II and processes for their preparation are in the older U.S. Patent 1,046,063.
Das nachstehende Beispiel dient zur Erläuterung der vorliegenden Erfindung:The following example serves to illustrate the present invention:
Bei der Herstellung von bis-[4-(Dichloracet-N-methylamido)-phenyl]-carbonat wird eine Lösung von 23,4 g Dichloracet-^-oxy-N-methylanilid in einem Gemisch aus 22 cm3 5n-Natronlauge, 5 cm3 gesättigter Natriumbisulfitlösung von 200 cm3 Wasser bei Zimmertemperatur gerührt und mit Phosgen gesättigt. Es bildet sich ein Niederschlag, welcher abfiltriert und mit 100 cm3 η-Natronlauge verrieben wird. Der feste Körper wird aufgesammelt und aus 15 cm3 Äthylglykol und nochmals aus 10 cm3 Äthylglykol umkristallisiert. Man erhält auf diese Weise bis-[4-(Dichloracet-N-methylamido)-phenyl]-carbonat in der Form eines kristallinen festen Körpers mit einem Schmelzpunkt von 164 bis 1650C. (Die Analyse ergab 46,3 °/0 C sowie 3,5 H; C19H16O5N2Cl4 erfordert 46.2C sowie 3,2% N.)In the preparation of bis- [4- (dichloroacet-N-methylamido) -phenyl] -carbonate, a solution of 23.4 g of dichloroacet - ^ - oxy-N-methylanilide in a mixture of 22 cm 3 of 5N sodium hydroxide solution, 5 cm 3 of saturated sodium bisulfite solution of 200 cm 3 of water was stirred at room temperature and saturated with phosgene. A precipitate forms, which is filtered off and triturated with 100 cm 3 of η-sodium hydroxide solution. The solid body is collected and recrystallized from 15 cm 3 of ethyl glycol and again from 10 cm 3 of ethyl glycol. Obtained in this way bis- [4- (N-methylamido Dichloracet-) phenyl] carbonate in the form of a crystalline solid substance having a melting point 164-165 0 C. (Analysis showed 46.3 ° / 0 C and 3.5 H; C 19 H 16 O 5 N 2 Cl 4 requires 46.2C and 3.2% N.)
In genau der gleichen Weise erhält man bei Verwendung von Thiophosgen an Stelle von Phosgen die Verbindung bis-[4-(Dichloracet-N-methylamido)-phenyl]-thiocarbonat in Form eines kristallinen festen Körpers mit einem Schmelzpunkt von 174 bis 177°C. (Die Analyse ergab 44,4% C, 3,2% H, 5,5% N; C19H16O4N2Cl4S erfordert 44,3% C, 3,1% H, 5,5% N.)If thiophosgene is used instead of phosgene, the compound bis- [4- (dichloroacet-N-methylamido) -phenyl] -thiocarbonate is obtained in exactly the same way in the form of a crystalline solid with a melting point of 174 to 177 ° C. (Analysis found 44.4% C, 3.2% H, 5.5% N; C 19 H 16 O 4 N 2 Cl 4 S requires 44.3% C, 3.1% H, 5.5% N.)
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB356471X | 1955-11-03 | ||
| GB90356X | 1956-03-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1091575B true DE1091575B (en) | 1960-10-27 |
Family
ID=26242602
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEB50246A Pending DE1095844B (en) | 1955-11-03 | 1956-10-27 | Process for the preparation of amoebicidally active esters of p-oxy-N-dichloroacet-N-alkyl-anilides and their salts |
| DEB42293A Pending DE1092932B (en) | 1955-11-03 | 1956-10-27 | Process for the preparation of amoebicidally active N-dichloroacet-oxy-anilide esters |
| DEB50336A Pending DE1091575B (en) | 1955-11-03 | 1956-10-27 | Process for the preparation of amoebicidally active N-dichloroacet-p-oxy-anilide esters |
| DEB50245A Pending DE1092933B (en) | 1955-11-03 | 1956-10-27 | Process for the preparation of amoebicidally active esters of p-oxy-N-dichloroacet-N-alkyl-anilides |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEB50246A Pending DE1095844B (en) | 1955-11-03 | 1956-10-27 | Process for the preparation of amoebicidally active esters of p-oxy-N-dichloroacet-N-alkyl-anilides and their salts |
| DEB42293A Pending DE1092932B (en) | 1955-11-03 | 1956-10-27 | Process for the preparation of amoebicidally active N-dichloroacet-oxy-anilide esters |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEB50245A Pending DE1092933B (en) | 1955-11-03 | 1956-10-27 | Process for the preparation of amoebicidally active esters of p-oxy-N-dichloroacet-N-alkyl-anilides |
Country Status (5)
| Country | Link |
|---|---|
| BE (1) | BE552250A (en) |
| CH (1) | CH356471A (en) |
| DE (4) | DE1095844B (en) |
| GB (1) | GB794762A (en) |
| NL (2) | NL96977C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB855556A (en) * | 1958-05-06 | 1960-12-07 | Boots Pure Drug Co Ltd | New acetanilide derivatives |
| CH1085667A4 (en) * | 1967-08-01 | 1969-03-14 | ||
| DE2714440C2 (en) * | 1977-03-31 | 1982-10-21 | Siemens AG, 1000 Berlin und 8000 München | Process for the production of titanate ceramic |
| FR2649977B1 (en) * | 1989-07-18 | 1991-10-04 | Cird | BI-AROMATIC ESTERS, THEIR PREPARATION PROCESS AND THEIR USE IN HUMAN OR VETERINARY MEDICINE AND IN COSMETICS |
-
0
- BE BE552250D patent/BE552250A/xx unknown
- NL NL211890D patent/NL211890A/xx unknown
- NL NL96977D patent/NL96977C/xx active
-
1955
- 1955-11-03 GB GB31482/55A patent/GB794762A/en not_active Expired
-
1956
- 1956-10-27 DE DEB50246A patent/DE1095844B/en active Pending
- 1956-10-27 DE DEB42293A patent/DE1092932B/en active Pending
- 1956-10-27 DE DEB50336A patent/DE1091575B/en active Pending
- 1956-10-27 DE DEB50245A patent/DE1092933B/en active Pending
- 1956-11-02 CH CH356471D patent/CH356471A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL211890A (en) | |
| DE1092932B (en) | 1960-11-17 |
| BE552250A (en) | |
| DE1092933B (en) | 1960-11-17 |
| GB794762A (en) | 1958-05-07 |
| NL96977C (en) | |
| DE1095844B (en) | 1960-12-29 |
| CH356471A (en) | 1961-08-31 |
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