US2656357A - 1-piperazyl-4-methylthioxanthones and method of preparing same - Google Patents

1-piperazyl-4-methylthioxanthones and method of preparing same Download PDF

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Publication number
US2656357A
US2656357A US303400A US30340052A US2656357A US 2656357 A US2656357 A US 2656357A US 303400 A US303400 A US 303400A US 30340052 A US30340052 A US 30340052A US 2656357 A US2656357 A US 2656357A
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Prior art keywords
piperazyl
methylthioxanthones
worms
compounds
methylthioxanthone
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Expired - Lifetime
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US303400A
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Kushner Samuel
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Wyeth Holdings LLC
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American Cyanamid Co
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Priority to US303400A priority Critical patent/US2656357A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
    • C07D335/12—Thioxanthenes
    • C07D335/14—Thioxanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D335/16—Oxygen atoms, e.g. thioxanthones

Definitions

  • the compounds of the present, invention may be: illustrated by the following EStIU'QtHI'BJl formula:
  • reaction is ⁇ preferably carried out in: a hydrocarbon solvent such as toluene, benzene, xylene, and the like.
  • a hydrocarbon solvent such as toluene, benzene, xylene, and the like.
  • a desirable method is one in which. the intermediates are heatedin a solvent at refluxing-temperatures for a period of from 4 to Zi'hours. In general the preferred temperature maybe from to 150 C.
  • the products of the present invention are ac.- tive against schistosomiasis.
  • the activity of the compounds is determined-by inoculating mice intraperitoneally with a suspension of viable cercariae and allowing 6-170 8 weeks forthe de+ velopment of adulti'worms-inthe mesenteric and portal veins or liver.” Treatment is started when adult worms are present and is continued for various periods of time thereafter. The effect of the treatment on the schistosomes is determined by killing the mice, necropsy and counting the number of living and dead worms in the mesentery or liver. In untreated mice about of the worms are found in the mesentery and dead worms are seldom found in the liver.
  • Schistosomacidal compounds cause a pronounced shift of worms from the mesentery to the liver and within a short period of time most of the worms in the liver are dead.
  • the following table shows the results obtained using the compound 1-[1'(4'-methylpiperazyl)l 4 methylthioxanthone against Schistosoma mansoni:
  • the compounds of the present invention are toxic to the agents causing schistosomiasis while being relatively non-toxic to the host.
  • the compounds also are more active and less toxic than antimonial compounds such as tartar emetic.
  • the compounds of the present invention may be prepared by the following method which illustrates the preparation of 1-[1'(4t-methy1piperazyl) li-methylthioxanthone.
  • the compound 1- (1 '-piperazyl) -4-methylthioxanthone can be prepared by the same process illustrated above with the exception that a carbalkoxy piperazine, such as carbethoxy-p-iperazine, is used instead of 'l-methylpiperazine and the carbalkoxy or carbethoxy group removed by acid hydrolysis.
  • a carbalkoxy piperazine such as carbethoxy-p-iperazine
  • R is a member of the group consisting of hydrogen and methyl radicals.
  • R is a member of the group consisting 15 of hydrogen and methyl radicals which comprises reacting l-chloro-4-methylthioxanthone with a member of the group consisting of carboxalkylated piperazines and N-methylpiperazine in a hydrocarbon solvent and recovering said prod- 20 not therefrom.
  • a method of preparing 1-[1(4-methylpiperazyl)l-4-methylthioxanthone which comprises reacting 1-chloro--methylthioxanthone with l-methylpiperazine in a hydrocarbon sol- 25 vent and recovering said product therefrom.

Description

Patented Oct. 20, 1953 1-PIPERAZYL-4-METHYLTHIOXANTHONES. AND METHOD OF PREPARING" SAME Samuel. Kushner, Nanuet,i N.' Y, assignor' to American Cyanamid Company, New.Xork; N. Y:;. a corporation of Maine No Drawing. Application August 8, 1952," Serial No. 303,400
4 Claims (Cl..260-268 )J This .invention relates-.-tonew organic com.-
pounds. More particularly, it relates to l-piperazyl-i methylthioxanthones and their method of preparation.
The compounds of the present, invention may be: illustrated by the following EStIU'QtHI'BJl formula:
Thereaction is {preferably carried out in: a hydrocarbon solvent such as toluene, benzene, xylene, and the like. A desirable methodis one in which. the intermediates are heatedin a solvent at refluxing-temperatures for a period of from 4 to Zi'hours. In general the preferred temperature maybe from to 150 C.
The products of the present invention are ac.- tive against schistosomiasis. The activity of the compounds is determined-by inoculating mice intraperitoneally with a suspension of viable cercariae and allowing 6-170 8 weeks forthe de+ velopment of adulti'worms-inthe mesenteric and portal veins or liver." Treatment is started when adult worms are present and is continued for various periods of time thereafter. The effect of the treatment on the schistosomes is determined by killing the mice, necropsy and counting the number of living and dead worms in the mesentery or liver. In untreated mice about of the worms are found in the mesentery and dead worms are seldom found in the liver. Schistosomacidal compounds cause a pronounced shift of worms from the mesentery to the liver and within a short period of time most of the worms in the liver are dead. The following table shows the results obtained using the compound 1-[1'(4'-methylpiperazyl)l 4 methylthioxanthone against Schistosoma mansoni:
Activity of 1-[1 (4'-methylpiperazyl) ]-4-methylthioxanthone against Schistosoma mansoni in mice . Total No. of Worms Found No. Mice Necropsy at Necropsy Average Percent zsiriod Il:{o. Percent Dof d ays we ea Dosage after Mesentery Liver Worms gg Worms Actwlty tree per in Used Survived ment) M ouse Liver Liver Alive Deed Alive Dead 10 Ip. B. I. D.X12 10 9 24 72 0 7 2+ 9 11. 1+ 22. 2+ 25 11). B. I. D.Xl2 10 8 24 6 0 1 1 1 25.0 50.0 50 Ip. B. I. D.Xl2 10 3 24 0 0 0 1+ 0 100. 0 100. O 50 Or. B. I. D. l2.. l0 3 24 1 1 0 1 50. 0+ 50. 0+ Or. B. I. D. 6 l0 7 24 0 0 0 30 0 100.0 100.0 Or. 0. D. 6 l0 7 25 0 0 1 3+ 1 100. 0 75. 0+ Or.1 dose. 10 9 23 33 0 8 29 3 52. 8 78. 3 300 Or.1 dose 10 9 23 6 l 1 5+ 1 46. 0+ 83. 3+
Ip. =Intraperitoneally.
B. I. D.=Twice a day. tion they may be chemically linked together in some manner. The 4-chloro isomer is less reactive than the 1-ch1oro compound and under the conditions of the present process, does not combine with the alkylated or carboxalkylated piperazine. The unreacted 4-chloro compound, lacking basic properties, is not extracted when using an aqueous acid solution. The desired product, on the other hand, is basic and is extracted by the aqueous acid solution and subsequently precipitated by neutralization with an alkaline substance.
The compounds of the present invention are toxic to the agents causing schistosomiasis while being relatively non-toxic to the host. The compounds also are more active and less toxic than antimonial compounds such as tartar emetic.
The compounds of the present invention may be prepared by the following method which illustrates the preparation of 1-[1'(4t-methy1piperazyl) li-methylthioxanthone.
An isomeric mixture of 20 g. of 1-ch1oro-4- methyl thioxanthone and its isomer 4-chloro-lmethylthioxanthone, 10 g. of sodium bicarbonate,
yield of 11 g. of 1-[1(4'-methylpiperazyl)1-4- methylthioxanthone, having a melting point of 133-134 C. was obtained.
The compound 1- (1 '-piperazyl) -4-methylthioxanthone can be prepared by the same process illustrated above with the exception that a carbalkoxy piperazine, such as carbethoxy-p-iperazine, is used instead of 'l-methylpiperazine and the carbalkoxy or carbethoxy group removed by acid hydrolysis.
I claim:
1. Compounds having the general formula:
0 in which R is a member of the group consisting of hydrogen and methyl radicals.
4 2. 1-[l(4'-methylpiperazyl)1-4 methylthioxanthone.
3. A method of preparing compounds having the general formula:
in which R is a member of the group consisting 15 of hydrogen and methyl radicals which comprises reacting l-chloro-4-methylthioxanthone with a member of the group consisting of carboxalkylated piperazines and N-methylpiperazine in a hydrocarbon solvent and recovering said prod- 20 not therefrom.
4. A method of preparing 1-[1(4-methylpiperazyl)l-4-methylthioxanthone which comprises reacting 1-chloro--methylthioxanthone with l-methylpiperazine in a hydrocarbon sol- 25 vent and recovering said product therefrom.
SAMUEL KUSHNER.
No references cited.

Claims (2)

1. COMPOUNDS HAVING THE GENERAL FORMULA:
3. A METHOD OF PREPARING COMPOUNDS HAVING THE GENERAL FORMULA:
US303400A 1952-08-08 1952-08-08 1-piperazyl-4-methylthioxanthones and method of preparing same Expired - Lifetime US2656357A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1057120B (en) * 1955-10-29 1959-05-14 Hoechst Ag Process for the preparation of 1,4-disubstituted piperazines effective against schistosomiasis
DE1060401B (en) * 1956-11-02 1959-07-02 Hoechst Ag Process for the preparation of 1- (carboxyalkyl) -piperazines and their esters effective against schistosomiasis
US3904631A (en) * 1973-05-29 1975-09-09 Parke Davis & Co Novel thioxanthenone compounds and means of producing the same
FR2282890A1 (en) * 1974-08-30 1976-03-26 Parke Davis & Co 6-Chloro-4-methyl-1-(4-methyl-1-piperazinyl)thio-xanthen-9-ones - their 4-hydro xymethyl derivs and N-oxides, schistosomicides
WO2005077899A2 (en) * 2004-02-04 2005-08-25 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use
US20050234031A1 (en) * 2004-02-04 2005-10-20 Schrimpf Michael R Amino-substituted tricyclic derivatives and methods of use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1057120B (en) * 1955-10-29 1959-05-14 Hoechst Ag Process for the preparation of 1,4-disubstituted piperazines effective against schistosomiasis
DE1060401B (en) * 1956-11-02 1959-07-02 Hoechst Ag Process for the preparation of 1- (carboxyalkyl) -piperazines and their esters effective against schistosomiasis
US3904631A (en) * 1973-05-29 1975-09-09 Parke Davis & Co Novel thioxanthenone compounds and means of producing the same
FR2282890A1 (en) * 1974-08-30 1976-03-26 Parke Davis & Co 6-Chloro-4-methyl-1-(4-methyl-1-piperazinyl)thio-xanthen-9-ones - their 4-hydro xymethyl derivs and N-oxides, schistosomicides
WO2005077899A2 (en) * 2004-02-04 2005-08-25 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use
US20050234031A1 (en) * 2004-02-04 2005-10-20 Schrimpf Michael R Amino-substituted tricyclic derivatives and methods of use
WO2005077899A3 (en) * 2004-02-04 2005-12-01 Abbott Lab Amino-substituted tricyclic derivatives and methods of use
EP2258682A3 (en) * 2004-02-04 2011-03-09 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use
US7951791B2 (en) 2004-02-04 2011-05-31 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use

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