US3726920A - 1,3-bis(4-chlorophenyl)-2-propen-1-one guanylhydrazone hydrochloride and analogs thereof useful as antimalarials - Google Patents

1,3-bis(4-chlorophenyl)-2-propen-1-one guanylhydrazone hydrochloride and analogs thereof useful as antimalarials Download PDF

Info

Publication number
US3726920A
US3726920A US00001061A US3726920DA US3726920A US 3726920 A US3726920 A US 3726920A US 00001061 A US00001061 A US 00001061A US 3726920D A US3726920D A US 3726920DA US 3726920 A US3726920 A US 3726920A
Authority
US
United States
Prior art keywords
chlorophenyl
bis
propen
hydrochloride
guanylhydrazone
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.)
Expired - Lifetime
Application number
US00001061A
Inventor
D Henry
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PMC SPECIALTIES GROUP Inc A CORP OF DE
US Department of Army
Original Assignee
US Department of Army
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by US Department of Army filed Critical US Department of Army
Application granted granted Critical
Publication of US3726920A publication Critical patent/US3726920A/en
Assigned to PMC SPECIALTIES GROUP, INC., A CORP. OF DE. reassignment PMC SPECIALTIES GROUP, INC., A CORP. OF DE. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: SHERWIN WILLIAMS COMPANY
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

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
    • C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine
    • C07C281/18—Compounds containing any of the groups, e.g. aminoguanidine the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to l,3-bis(4-chlorophenyl)-2- propen-l-one guanylhydrazone hydrochloride and analogs thereof, useful in the prevention and treatment of malaria.
  • l,3-bis-(4-chlorophenyl)-2- propen-l-one guanylhydrazone hydrochloride 1,3- bis(4-chlorophenyl)-2-buten-l-one guanylhydrazone hydrochloride, and l,3,3-tris(4-chlorophenyl)-2- propen-l-one guanylhydrazone hydrochloride.
  • Malaria is one of the most widespread of all human diseases; it has been estimated that over 200 million people are afflicted and over a million die each year from malaria. Furthermore, contrary to popular belief, malaria is not confined to the tropical and subtropical regions; outbreaks have occurred almost as far north as the Arctic Circle and to a corresponding latitude south. It is a protozoan disease caused by several species of the genus Plasmodium which forms one of the families of the sub-order Haemsporida. Plasmodium vivax and Plasmodium falciparum are the most common species causing malaria in humans.
  • This invention comprises the preparation of three new compounds and the discovery that these new compositions of matter are effective antimalarials.
  • compositions of matter that are analogs of l,3-bis( 4-chlorophenyl)-2-propen- 1 -one guanylhydrazone hydrochloride.
  • Another object of this invention is to prepare new compositions of matter that are analogs of l,3-bis(4- chlorophenyl )-2-propen- 1 -one guanylhydrazone hydrochloride and that possess antimalarial activity.
  • a further object of this invention is to provide new processes for the prevention and treatment of malaria in mammals, and particularly in humans, wherein the active ingredients are new analogs of 1,3-bis( 4- chlorophenyl )2-propen- 1 -one guanylhydrazone hydrochloride.
  • EXAMPLE 1 Preparation of 1,3-bis(4-ch1orophenyl)-2-propenl one guanylhydrazone hydrochloride
  • the first step in synthesizing the desired end product was to prepare the intermediate, 4,4- dichlorobenzalacetophenone.
  • This intermediate was prepared according to the general procedure of E. P. Kohler and H. M. Chadwell in Organic Synthesis, 2nd edition (1948), Collective vol. 1, page 78, by reacting 4-chloroacetophenone and 4-chlorobenzaldehyde.
  • the intermediate product was obtained in 83 percent yield and with a melting point of l53l55 C. which compares favorably with the melting point of l55-l57 C. reported by H. 0. House, Journal American Chemical Society, vol. 78 (1956), page 2298, for this intermediate compound.
  • the next step in the preparation of the desired end product was to slowly add amenoguiridine bicarbonate to a solution of 30 concentrated hydrochloric acid in 12 ml. of water. After the evolution of carbon dioxide had ceased, the intermediate 4,4- dichlorobenzalacetophenone and ethyl alcohol were added. This suspension was refluxed with stirring. The precipitate was the desired end product, 1,3-bis(4- chlorophenyl)-2-propen-l-one guanylhydrazone hydrochloride. It was recrystallized from ethyl alcohol and gave a melting point of l43153 C. The preparation resulted in a 14 percent yield. Thin-layer chromatography using silica gel and 10 percent methyl alcohol in chloroform revealed one component with an R, of 0.25.
  • aminoguanidine bicarbonate (3.0 g., 0.022 mole) was slowly added to a stirred solution of 32 ml. of water and 2.6 ml. of concentrated hydrochloric acid (0.031 mole).
  • 6.0 g. (0.022 mole) of the intermediate, l,3-bis(4-chlorophenyl)-2-buten-1- one was added along with 50 ml. of ethyl alcohol.
  • the mixture was refluxed overnight (solution attained) and then heated five hours longer. It was cooled and some of the ethyl alcohol was removed in vacuo.
  • EXAMPLE 3 Preparation of 1,3 ,3-tris(4-chlorophenyl)-2-propen-1- one guanylhydrazone hydrochloride
  • the first step in the preparation of 1,3,3-tris(4- chlorophenyl)-2-propen-l-one guanylhydrazone hydrochloride was to'prepare the first intermediate 1,1- bis(4-chlorophenyl)ethylene.
  • This first intermediate was prepared by the addition of methyl magnesium bromide to 4,4-dichlorobenzophenone and subsequent dehydration according to the procedure of O. Grummit et al. in Journal American Chemical Society, vol. 67 (1945), page 2265.
  • the first intermediate 1,1- bis(4-chlorophenyl)ethylene was obtained in an 80 percent yield with a melting point of 8388 C. which compared favorably with the results of Grummit et al., supra, who reported an percent yield with a melting point of 84-85 C.
  • the next step in the preparation of the desired end product was to prepare the second intermediate 1,3,3- tris(4-chlorophenyl)-2-propen-1-one.
  • the procedure used to prepare this second intermediate is a modification of the general method of F. Bergman et al. in Journal Chemical Society, 1952), page 2522.
  • the final step in the preparation of the desired end product was to slowly add aminoguanidine bicarbonate to a solution of concentrated hydrochloric acid in water. After the evolution of CO, had ceased, the second intermediate 1,3,3-tris(4-chlorophenyl)-2- propen-l-one and 46 ml. of ethyl alcohol were added. This suspension was refluxed with stirring for 16 hours. The initial preparation of this compound gave analytical samples of both a dehydrated (melting point -170 C.) and an unhydrated (melting point 210220 C.) product. A second preparation gave 1.5 g. (43 percent yield) of hydrated product.
  • mice 3.0 at 160 mg./kg. and 7.0 at 640 mgJkg. in this test.
  • a fraction followed by the letter G indicates cured mice over total mice in the treated group. Drug toxicity is assumed to be the cause of death when treated mice die before untreated controls. A dash indicates tests were not run at this dosage. Five mice were used in each test run at a specific dosage level. In some instances, repeat test runs were perform ed.
  • the Walter Reed Army Institute of Research uses the primary mouse screen with Plasmodium berghei for several reasons.
  • the Plasmodium species which cause malaria in humans i.e., Plasmodium falciparum and Plasmodium vivax
  • Plasmodium berghei is regarded as a good model for human malaria.
  • mice are easy to work with and the Plasmodium berghei infections show the same range of susceptibility to a variety of known antimalarial drugs as other malaria parasites used for evaluating antimalarial compounds. See for example Bull. Soc. Pathol. Exotique 42, 449 (1949); Ann. Trop. Med. Parasitol. 44, 291

Abstract

The disclosure describes three analogous compounds, 1,3-bis(4chlorophenyl)-2-propen-1-one guanylhydrazone hydrochloride, 1,3bis(4-chlorophenyl)-2-buten-1-one guanylhydrazone hydrochloride, and 1,3,3-tris(4-chlorophenyl)-2-propen-1-one guanylhydrazone hydrochloride. The compounds are useful in the prevention and treatment of malaria.

Description

United States Patent 1 Henry 51 Apr. 10, 1973 [54] 1,3-BIS(4-CHLOROPHENYL)-2- [56] References Cited PROPEN-l-ONE GUANYLHYDRAZONE UNITED STATES PATENTS HYDROCHLORIDE AND ANALOGS 2,815,377 12/1957 Mciser et a1 ..260/564 THEREOF USEFUL AS 2,952,677 9/1960 Birtwell et a1. ..260/564 F x ANTIMALARIALS 3,130,232 4/1964 Paquette ..260/564 [75] Inventor: David W. Henry, Menlo Park, Calif. Primary Examiner-Leon Zitver Assistant ExaminerGera1d A. Schwartz [73] Assignee Umted States 0f Amenca as Attorney-Charles K. Wright, Jr., William G. Gapcynrepresented by the Secretary of the ski and Lawrence A. Neureither Army [22] Filed: Jan. 6, 1970 ABSTRACT [21] Appl No: 1,061 The disclosure describes three analogous compounds,
1 ,3-bis( 4-chlorophenyl )-2-propen- 1 -one guanylhydrazone hydrochloride, l,3-bis(4-chlorophenyl)-2- [52] U.S. Cl. ..260/564 F, 424/326 buten-1- ne guanylhydrazone hydrochloride, and [51] Int. Cl ..C07c 129/00 1,3,3-tris(4-chlorophenyl)-2-propen1-one guanyl- [58] Field of Search ..260/564 F hydrazone hydrochloride. The compounds are useful in the prevention and treatment of malaria.
1 Claim, No Drawings l ,3-BIS(4-CHLOROPHENYL)-2-PROPEN-1-ONE GUANYLHYDRAZONE HYDROCHLORIDE AND ANALOGS THEREOF USEFUL AS ANTIMALARIALS The invention herein described was made in the course of or under a contract or subcontract thereunder with the Department of the Army.
BACKGROUND OF THE INVENTION Field of the Invention This invention relates to l,3-bis(4-chlorophenyl)-2- propen-l-one guanylhydrazone hydrochloride and analogs thereof, useful in the prevention and treatment of malaria. More specifically, it relates to three new antimalarial compounds, l,3-bis-(4-chlorophenyl)-2- propen-l-one guanylhydrazone hydrochloride, 1,3- bis(4-chlorophenyl)-2-buten-l-one guanylhydrazone hydrochloride, and l,3,3-tris(4-chlorophenyl)-2- propen-l-one guanylhydrazone hydrochloride.
Description of the Prior Art Malaria is one of the most widespread of all human diseases; it has been estimated that over 200 million people are afflicted and over a million die each year from malaria. Furthermore, contrary to popular belief, malaria is not confined to the tropical and subtropical regions; outbreaks have occurred almost as far north as the Arctic Circle and to a corresponding latitude south. It is a protozoan disease caused by several species of the genus Plasmodium which forms one of the families of the sub-order Haemsporida. Plasmodium vivax and Plasmodium falciparum are the most common species causing malaria in humans.
A number of antimalarial compounds have been prepared in the prior art, see for example the antimalarials section in Remingtons Pharmaceutical Sciences, 13th edition (1965), pages 1302-1306. Recently, however, the prior art antimalarials have proved to be ineffective in specific cases in various parts of the world. The World Health Organization Technical Report No. 296 1965 entitled Resistance of Malaria Parasites to Drugs, reports the following cases of drug resistance: quinine sulfate failed completely against strains of Plasmodium falciparum from New Guinea; chloroquine, amodiaquine, mepacrine, pyrimethamine and proguanil gave poor results against Plasmodium falciparum and Thailand; chloroquine, mepacrine, pyrimethamine and proguanil were ineffective against Plasmodium falciparum from Cambodia; Plasmodium falciparum from Vietnam proved resistant to chloroquine; and chloroquine gave poor results against malaria in Malaya. Further instances of drugresistant malaria may be seen in L. Bruce-Chwatt, Trans. Roy. Soc. Trop. Med. Hyg. 59, 105-144 (1965), in L. Legters et al., Military Med. 130, 168-176 (1965), and in A. Bourke et al., Trans. Roy. Soc. Trop. Med. Hyg. 60, 225-230 (1966 The only conclusion to be drawn from these reports is that there exists a great need for new antimalarial drugs.
SUMMARY OF THE INVENTION This invention comprises the preparation of three new compounds and the discovery that these new compositions of matter are effective antimalarials. The
three new compounds, 1,3-bis-(4-chlorophenyl)-2- compounds shown antimalarial activity that is completely unexpected.
Accordingly, it is an object of this invention to prepare new compositions of matter that are analogs of l,3-bis( 4-chlorophenyl)-2-propen- 1 -one guanylhydrazone hydrochloride.
Another object of this invention is to prepare new compositions of matter that are analogs of l,3-bis(4- chlorophenyl )-2-propen- 1 -one guanylhydrazone hydrochloride and that possess antimalarial activity.
A further object of this invention is to provide new processes for the prevention and treatment of malaria in mammals, and particularly in humans, wherein the active ingredients are new analogs of 1,3-bis( 4- chlorophenyl )2-propen- 1 -one guanylhydrazone hydrochloride.
Finally, it is an object of this invention to prepare new compositions of matter that will be active against drug resistant malaria.
DESCRIPTION OF THE PREFERRED EMBODIMENTS The new compositions of matter in this invention are prepared as follows:
EXAMPLE 1 Preparation of 1,3-bis(4-ch1orophenyl)-2-propenl one guanylhydrazone hydrochloride The first step in synthesizing the desired end product was to prepare the intermediate, 4,4- dichlorobenzalacetophenone. This intermediate was prepared according to the general procedure of E. P. Kohler and H. M. Chadwell in Organic Synthesis, 2nd edition (1948), Collective vol. 1, page 78, by reacting 4-chloroacetophenone and 4-chlorobenzaldehyde. The intermediate product was obtained in 83 percent yield and with a melting point of l53l55 C. which compares favorably with the melting point of l55-l57 C. reported by H. 0. House, Journal American Chemical Society, vol. 78 (1956), page 2298, for this intermediate compound.
The next step in the preparation of the desired end product was to slowly add amenoguiridine bicarbonate to a solution of 30 concentrated hydrochloric acid in 12 ml. of water. After the evolution of carbon dioxide had ceased, the intermediate 4,4- dichlorobenzalacetophenone and ethyl alcohol were added. This suspension was refluxed with stirring. The precipitate was the desired end product, 1,3-bis(4- chlorophenyl)-2-propen-l-one guanylhydrazone hydrochloride. It was recrystallized from ethyl alcohol and gave a melting point of l43153 C. The preparation resulted in a 14 percent yield. Thin-layer chromatography using silica gel and 10 percent methyl alcohol in chloroform revealed one component with an R, of 0.25.
An elemental analysis gave the following results: Analysis calculated for C I-I Cl,N -I-ICl: C, 52.0; H, 4.09; N, 15.2. Found: C, 51.9; H, 4.20; N, 15.2.
EXAMPLE 2 Preparation of 1,3-bis(4-chlorophenyl)-2-buten-1-one guanylhydrazone hydrochloride In the preparation of 1,3-bis(4-chlorophenyl)-2- buten-l-one guanylhydrazone hydrochloride, it was necessary to prepare the intermediate, 1,3-bis(4- chlorophenyl)-2-buten-l-one. This intermediate was prepared by the procedure of E. Ziegler and H. Schredt, in Monatsh. Chem., vol. 85 (1954), page 1191; Chemical Abstracts, vol. 50 (1956), page 321. 4- Chloroacetophenone (74 g., 0.51 mole) and 45 ml. of phosphorous oxychloride was held at 45 C. for hours and then at 25 C. for 10 hours. The brown solution was poured over cracked ice and the oily product was extracted with ether. The ethereal solution was washed with water and dilute sodium carbonate solution and concentrated to yield 70 g. of oil. The crude product was dissolved in 150 ml. of ethyl alcohol and the solution was seeded. The crude yellow l,3-bis(4- chlorophenyl-Z-buten-l-one melted at 75-l07 C. Two triturations with 500 ml. portions of methyl alcohol gave 16.5 g. (24 percent yield) of the intermediate, l,3-bis(4-chlorophenyl)-2-buten-l -one, melting at 75-80 C. This compares favorably with the report of Ziegler and Schredt, above, who gave a melting point of 80 C. for this compound.
Continuing in the preparation of the desired end product, aminoguanidine bicarbonate (3.0 g., 0.022 mole) was slowly added to a stirred solution of 32 ml. of water and 2.6 ml. of concentrated hydrochloric acid (0.031 mole). When the evolution of carbon dioxide ceased and the solution cleared, 6.0 g. (0.022 mole) of the intermediate, l,3-bis(4-chlorophenyl)-2-buten-1- one, was added along with 50 ml. of ethyl alcohol. The mixture was refluxed overnight (solution attained) and then heated five hours longer. It was cooled and some of the ethyl alcohol was removed in vacuo. The precipitated solid which resulted was collected and titrated with diethyl ether to give 4.93 g. (59 percent yield) of the desired end product, l,3-bis(4- chlorophenyl )-2-buten- 1 -one guanylhydrazone hydrochloride, melting at 235238 C. A portion of the product was recrystallized from 1:1 ethyl alcoholwater for an analytical sample melting at 245-246 C.
An ultraviolet spectrum analysis gave the following results: A f 207 my. (6 31,300), 274 m (c=31,300).
An elemental analysis gave the following results: Analysis calculated for C H Cl N -HClz C, 53.3; H, 4.47; N, 14.6. Found: C, 53.1; H, 4.53; N, 14.8.
EXAMPLE 3 Preparation of 1,3 ,3-tris(4-chlorophenyl)-2-propen-1- one guanylhydrazone hydrochloride The first step in the preparation of 1,3,3-tris(4- chlorophenyl)-2-propen-l-one guanylhydrazone hydrochloride was to'prepare the first intermediate 1,1- bis(4-chlorophenyl)ethylene. This first intermediate was prepared by the addition of methyl magnesium bromide to 4,4-dichlorobenzophenone and subsequent dehydration according to the procedure of O. Grummit et al. in Journal American Chemical Society, vol. 67 (1945), page 2265. The first intermediate 1,1- bis(4-chlorophenyl)ethylene was obtained in an 80 percent yield with a melting point of 8388 C. which compared favorably with the results of Grummit et al., supra, who reported an percent yield with a melting point of 84-85 C.
The next step in the preparation of the desired end product was to prepare the second intermediate 1,3,3- tris(4-chlorophenyl)-2-propen-1-one. The procedure used to prepare this second intermediate is a modification of the general method of F. Bergman et al. in Journal Chemical Society, 1952), page 2522.
A solution of 17 g. (0.0683 mole) of the first intermediate l,1-bis(4-chlorophenyl)ethylene and 13.15 g. (0.0751 mole) of 4-chlorobenzoyl chloride was heated to 240 C. At this temperature hydrogen chloride vapor evolved. The hydrogen chloride vapor was swept from the flask by a slow stream of nitrogen gas and monitored by bubbling through a sodium hydroxide solution containing phenolphthalein indicator. After about 18 hours, hydrogen chloride evolution ceased. The result ing black, solid reaction mixture was extracted with ethyl alcohol several times and the extracts were filtered. The solvent was removed from the combined filtrate and the residue was chromatographed on silica gel. Elution with carbon tetrachloride yielded starting materials and by-products. Elution with chloroform then gave 5.15 g. of moderately pure product, which was recrystallized several times from ethyl alcohol to yield 2.0 g. of pure product with a melting point of l40 C. Thin-layer chromatography using silica gel and carbon tetrachloride showed one component with an R,of0.l8.
An ultraviolet spectrum analysis gave the following results: A 233 mp. (e 22,000), 271 my. (e= 18,600), 318 mu (e= 14,000).
An elemental analysis gave these results: Analysis calculated for c,,u,,c1,o= C, 65.1; H, 3.38. Found: C, 65.6; H, 3.45.
The final step in the preparation of the desired end product was to slowly add aminoguanidine bicarbonate to a solution of concentrated hydrochloric acid in water. After the evolution of CO, had ceased, the second intermediate 1,3,3-tris(4-chlorophenyl)-2- propen-l-one and 46 ml. of ethyl alcohol were added. This suspension was refluxed with stirring for 16 hours. The initial preparation of this compound gave analytical samples of both a dehydrated (melting point -170 C.) and an unhydrated (melting point 210220 C.) product. A second preparation gave 1.5 g. (43 percent yield) of hydrated product.
An infrared spectrum analysis gave the following results: A 2.95 3.25u (NH functional group) and 5.96 (C=N functional group).
An elemental analysis gave the following results: Analysis calculated for C,,H Cl,N 'HCl-H,O: C, 53.0; H, 4.01; N, 11.2. Found: C, 52.8; H, 4.21; N, 11.4.
ANTIMALARIAL UTILITY The three new compositions of matter prepared in the above examples show unexpected and unobvious' Research primary mouse screen test on a series of analogs of 1,3-bis(4-chlorophenyl)-2-propen-l-one guanylhydrazone hydrochloride.
ANTIMALARIAL EVALUATION OF COMPOUNDS Antimalarial bionssay results '20 40 S 100 320 040 Example Structure lug/kg. nigJkg. lug/kg. nun/kg? Inga/kg. 1ng./kg.;
1 0.4 5.0 0.6 17.0 C -35 C C Gl- *CH=CH(|T -01 ll NNHONH2 .HCl
01 O=CHC -Cl l 1.0 4.6 14.9%C 19.4%0 23.9%(3 A0 CH3 I l NNH |I|1NHa CI (IJ=CHF Cl I NNHgNHz 1 Increase in survival time (in number of days) of treated mice beyond that of untreated controls after single subcutaneous dosages (three days post-infection) of 20, 40, 80, 160, 320 and 640 mg. of drug per kg. of body weight. Average survival time of untreated mice: 6.5 plus or minus 0.5 days.
Infecting organism: Plasmodium berghei. Quinine gives values of approximately 1.0 at 40 mg./kg.,
3.0 at 160 mg./kg. and 7.0 at 640 mgJkg. in this test. A fraction followed by the letter G indicates cured mice over total mice in the treated group. Drug toxicity is assumed to be the cause of death when treated mice die before untreated controls. A dash indicates tests were not run at this dosage. Five mice were used in each test run at a specific dosage level. In some instances, repeat test runs were perform ed.
1 Dosage in milligrams of drug per kilogram of mouse body weight.
The antimalarial evaluation reported in the above table reveals remarkable antimalarial activity in 1,3- bis(4-chlorophenyl)-2-pr0pen-l-one guanylhydrazone hydrochloride (Example 1), l,3-bis-(4-chlorophenyl)- 2-buten-l-one guanylhydrazone hydrochloride (Example 2) and in l,3,3-tris(4-chlorophenyl)-2-propen-lone guanylhydrazone hydrochloride (Example 3).
Testing antimalarial compounds in humans is obviously too dangerous for the first step in the development of antimalarials. Thus, animal tests have conventionally been used to test antimalarial compounds and animal tests have led to the development of many of the antimalarial compounds now available such as quinacrine, chloroquine, pamaquine, and proquanil.
The Walter Reed Army Institute of Research uses the primary mouse screen with Plasmodium berghei for several reasons. One reason is that the Plasmodium species which cause malaria in humans (i.e., Plasmodium falciparum and Plasmodium vivax) cannot live in animals. Another reason is that Plasmodium berghei is regarded as a good model for human malaria. Finally, mice are easy to work with and the Plasmodium berghei infections show the same range of susceptibility to a variety of known antimalarial drugs as other malaria parasites used for evaluating antimalarial compounds. See for example Bull. Soc. Pathol. Exotique 42, 449 (1949); Ann. Trop. Med. Parasitol. 44, 291
(1950); Brit. J. Pharmacol. 8, 162 (1953); Z. Tropenmed. U. Parasitol. 2, 471 (1951 I claim:
1. 1,3-Bis(4-chlorophenyl)-2-buten- 1 -one guanylhydrazone hydrochloride.
US00001061A 1970-01-06 1970-01-06 1,3-bis(4-chlorophenyl)-2-propen-1-one guanylhydrazone hydrochloride and analogs thereof useful as antimalarials Expired - Lifetime US3726920A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US106170A 1970-01-06 1970-01-06

Publications (1)

Publication Number Publication Date
US3726920A true US3726920A (en) 1973-04-10

Family

ID=21694193

Family Applications (1)

Application Number Title Priority Date Filing Date
US00001061A Expired - Lifetime US3726920A (en) 1970-01-06 1970-01-06 1,3-bis(4-chlorophenyl)-2-propen-1-one guanylhydrazone hydrochloride and analogs thereof useful as antimalarials

Country Status (1)

Country Link
US (1) US3726920A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0008854A1 (en) * 1978-08-17 1980-03-19 American Cyanamid Company Pentadienone hydrazone, and its use as insecticidal agent
EP0066943A1 (en) * 1981-05-12 1982-12-15 Imperial Chemical Industries Plc 1,1-Diphenylalkenes and a process for their preparation
DE102006028371A1 (en) * 2006-06-19 2007-12-20 Rheinische Friedrich-Wilhelms Universität Remedy for malaria

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2815377A (en) * 1953-03-30 1957-12-03 Schenley Ind Inc Di-guanyl hydrazones
US2952677A (en) * 1956-10-01 1960-09-13 Ici Ltd Aminoguanadine compounds
US3130232A (en) * 1963-02-12 1964-04-21 Upjohn Co Amidinohydrazones of cyclic halovinyl aldehydes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2815377A (en) * 1953-03-30 1957-12-03 Schenley Ind Inc Di-guanyl hydrazones
US2952677A (en) * 1956-10-01 1960-09-13 Ici Ltd Aminoguanadine compounds
US3130232A (en) * 1963-02-12 1964-04-21 Upjohn Co Amidinohydrazones of cyclic halovinyl aldehydes

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0008854A1 (en) * 1978-08-17 1980-03-19 American Cyanamid Company Pentadienone hydrazone, and its use as insecticidal agent
EP0066943A1 (en) * 1981-05-12 1982-12-15 Imperial Chemical Industries Plc 1,1-Diphenylalkenes and a process for their preparation
DE102006028371A1 (en) * 2006-06-19 2007-12-20 Rheinische Friedrich-Wilhelms Universität Remedy for malaria

Similar Documents

Publication Publication Date Title
Haller et al. The chemical composition of technical DDT1
DD204698A5 (en) PROCESS FOR THE PREPARATION OF 3,4-DIHYDRO-5H-2,3-BENZODIAZEPINE DERIVATIVES
US3726920A (en) 1,3-bis(4-chlorophenyl)-2-propen-1-one guanylhydrazone hydrochloride and analogs thereof useful as antimalarials
Alexander et al. Studies on the mechanism of Chugaev and acetate thermal decompositions. II. cis-and trans-2-Methyl-1-tetralol
EP0512502B1 (en) Process for removal of olefinic impurities from 1,1,1,2,3,3,3-heptafluoropropane
Lindquist et al. Some chemical and biological experiments with Thiodan
Spencer et al. 6-Deoxytetracyclines. V. 1a 7, 9-Disubstituted Products
DE2944295A1 (en) METHOD FOR PRODUCING RACEMIC P-HYDROXY ALMONIC ACID
DE1286047B (en) Process for the preparation of diaralkylamines and their acid addition salts
US3642899A (en) 2-phenyl-4-(1-adamantyl)-6-dimethylaminomethylphenol
Saito et al. Discoveries and syntheses of highly potent antimalarial troponoids
US3763167A (en) Process of purifying oripavines
Lee et al. Synthesis of Mustards from Putrescine, Cadaverine, and 1, 3-Diaminopropane1
DE69822503T2 (en) SULFONATED DERIVATIVES OF CYCLIC PHENOLSULFIDES, METHOD FOR THE PRODUCTION THEREOF, MEANS FOR THE SEPARATION AND RECOVERY THAT CONTAIN CYCLIC PHENOLSULFIDES, METHODS FOR THE SEPARATION OF THE SUBSTANCES AND MEDICAMENT COMPOSITIONS CONTAINING THESE SULFIDES
Kendrekar et al. Synthesis of some novel and potent anti-plasmodial aminoalkyl chalcone derivatives
US2791603A (en) Process for preparing carbamates of tertiary acetylenic carbinols
Singh et al. Antimalarials. 4-Proximal hydrazino derivatives of 7-chloroquinoline
Peng et al. The Synthesis of 4-Hydroxy-6-quinaldine Carbohydrazide1, 2
Benkeser et al. Reduction of Organic Compounds by Lithium in Low Molecular Weight Amines. IV. The Effect of Nitro and Amino Groups on the Course of the Reduction
US3244750A (en) Nu, nu'-disubstituted-aliphatic-bis-aminomethyl-cyclohexane derivatives
Paul et al. Synthesis of 1, 4-bis (6-methoxy-8-quinolylaminoalkyl) piperazines as potential prophylactic antimalarial agents
US3578682A (en) 2,5-bis-(2-n-lower alkyl amino isopropyl)-1,3,4-trithiolanes and process for the preparation thereof
US3694498A (en) Alpha, alpha-dimethyl-beta, beta-dimercapto-n-lower alkyl-(phenyl and substituted phenyl) ethylamines
DE2140765B2 (en) NEW 2- (4'-CHLOROBENZYL) -PHENOLS, METHOD FOR THEIR PRODUCTION, AND BACTERIOSTATIC AGENT
Deinzer et al. Synthesis of nonachloro-3-phenoxyphenol. Carbon-13 nuclear magnetic resonance spectra of polychlorinated intermediates

Legal Events

Date Code Title Description
AS Assignment

Owner name: PMC SPECIALTIES GROUP, INC., 12243 BRANFORD STREET

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:SHERWIN WILLIAMS COMPANY;REEL/FRAME:004447/0838

Effective date: 19850701