US3853873A - 2,4-diamino quinazoline derivatives - Google Patents

Abstract

Compounds having the structure shown in FIG. 1 where Y is S, SO or SO2, and Ar is p-chlorophenyl, Alpha , Alpha , Alpha trifluoro-m-tolyl or 2-naphthyl. Specific compounds disclosed are: 2,4-diamino-6-((p-chlorophenyl)thio) quinazoline (FIG. 2); 2,4-diamino-6-(( Alpha , Alpha , Alpha -trifluoro-mtolyl)thio)quinazoline (FIG. 3); 2,4-diamino-6-(2-naphthylthio) quinazoline (FIG. 4); 2,4-diamino-6-(-naphthylsulfinyl)quinazoline (FIG. 5); (FIG. 6). These compounds are useful for antimalarial and antibacterial purposes. The thio compounds are synthesized according to the following process: And the sulfinyl and sulfonyl compounds are synthesized according to this process:

Description

United States Patent [191 Elslager et al.

[ 2,4-DIAMINO QUINAZOLINE DERIVATIVES [75] Inventors: Edward F. Elslager; Leslie M.

Werbel, both of Ann Arbor, Mich.

[73] Assignee: The United States of America as represented by the Secretary of the Army, Washington, DC.

[22] Filed: Jan. 17, 1973 [21] Appl. No.: 324,276

[30] Foreign Application Priority Data Apr. 7, 1972 Great Britain 16230/72 [52] US. Cl.... 260/256.5 R, 260/465 R, 260/465 F,

' Y 424/251 [51] Int. Cl.... C07d 51/48 [58] Field of Search 260/256.5 R

[56] References Cited UNITED STATES PATENTS 2.953.567 9/l960 Hitchings et al. 260/256.5 R 3.635979 l/l972 OTHER PUBLICATIONS FALCO et al., Chem. Abstracts, 46:4675 b, (1949).

Primary Examiner-Richard J. Gallagher Attorney, Agenl, 0r Firm-James E. Noble; William G. Gapcynski; Lawrence A. Neureither [57] ABSTRACT Compounds having the structure'shown in Fig. 1 where Y is S, S0 or S0 and Ar is p-chlorophenyl, a, a, a-trifluoro-m-tolyl or Z-naphthyl. Specific com- Hess 260/256.5 R

[111 3,853,873 45] Dec. 10,1974

And the sulfinyl and sulfonyl compounds are synthesized according to this process:

6 Claims, 7 Drawing Figures PATENTEL M 3.853.873

SHEET 1 2.

Cl 8 Y I v NH PATENTEL I 3.853.873

' sum 2 or 2 FIG.4

1 2,4- DIA MINQ QUINAZOL INE DERIVATIVES 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 INVENTION 1. Field of the Invention This invention relates to 2,4-diamino-6-[(arylthio) substituted]quinazoline compounds, and the use of compounds of this type for antibacterial purposes and antimalarial purposes.

2. Description of the Prior Art The prior art includes the compound 2,4-diamino-6- (3,4-dichlorobenzylamino)quinazoline which has the structure shown in FIG. 7. This prior art compound is disclosed in British Pat. No. 1,045,180 (Oct. 12, 1966) (inventor: I. Davoll) and use of the compound as an antimalarial chemotherapeutic agent is taught by Thompson et al., Experimental Parasitology, 25: 32-49 (1969). This prior art compound is sometimes designated as PAM 1392.

The Thompson et al. publication, above, states on p.

47: The approximate potency of the drug [PAM 1392] relative to quinine on a weight basis was deter mined in mice under several test conditions. These studies indicated PAM 1392 to have the following orders of greater activity than quinine: 6- to 9-fold with drug-diet treatment, 4-fold with eight doses by gavage, and 1 l-fold with eight subcutaneous doses."

The novel compounds of the instant invention have some structural similarity to PAM 1392. However, what is completely unexpected concerning the novel compounds of the instant invention is that they have antimalarial activity which vastly exceeds that of PAM 1392. Whereas the prior art teaches that PAM 1392 has a quinine equivalent on the order of 4 to l 1, de-

pending on theparticular mode of administration, the compounds of this invention have quinine equivalents on the order of 300 to 800. This far greater activity from structurally similar compounds is unexpected and unpredictable to a person of ordinary skill in the art.

SUMMARY OF THE INVENTION This invention comprises the creation of new compounds having the general formula shown in FIG. 1 wherein Y is S, S0, or S and Ar is 4-chlorophenyl, a,a,a-trifluoro-m-tolyl, or Z-naphthyl. specific compounds invented include the following: 2,4-diamino-6- [(p-chlorophenyl)thio]quinazoline (FIG. 2); 2,4- diamino-6 [a,a,a-trifluoro-m-tolyl)thio]quinazoline (FIG. 3); 2,4-diamino-6-( Z-naphthylthio )quinazoline (FIG. 4); 2,4-diamino-6-(2-naphthylsulfinyl)quinazoline (FIG. 5); and 2,4-diamino-6-(2-naphthylsulfonyl)- quinazoline (FIG. 6). These compounds are highly active antimalarial and antibacterial agents.

Accordingly, another aspect of this invention comprises providing new processes for the prevention and treatment of malaria in mammals and new'processes' for the prevention and treatment of bacterial infections. Whenever the term mammals is used in the specification and claims it should be understood as including humans.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is the structural fonnula for the compounds of this invention wherein Y is S, S0 or S0 and Ar is p- DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds of this invention may be prepared by the processes described above in the Abstract of the Disclosure. Specific examples showing the preparation of each compound will now be given. All temperatures are given in degrees Celsius (C) and metric units are employed for weights and measures.

EXAMPLE I Preparation of 2,4-Diamino-6-[(p-chlorophenyl)thio]-quinazoline, one-third Hydrate 2-Nitro5- p-c hlorophenyl )thio]benzonitrile was prepared from p-chlorobenzenethiol, potassium carbonate and 5-chloro-2-nitrobenzonitrile. Reduction with stannous chloride afforded 2-amino-5-[(pchlorophenyl)thio]benzonitrile which was condensed with chloroformamidine hydrochloride (see A. Hantzsch and A. Vagt, Ann., 314, 366 (1900)) to give the end-product compound having the structure shown in FIG. 2.

2-Nitro-5-[(p-chlorophenyl)thio]benzonitrile A mixture of 6.4 g (0.044 mole) of pchlorobenzenethiol, 8.0 g (0.044 mole) of 5-chloro-2- nitrobenzonitrile and 6.7 g (0.048 mole) of potassium carbonate in 120 ml acetone was heated under reflux for 3 hr. The salt present was removed by filtration and the solvent was removed from the filtrate under reduced pressure. The oily residue was dissolved in hot ethanol and allowed to cool. The yellow solid obtained was recrystallized from acetonitrile to give 6.2 g (49%) of the desired product, mp 107-109.

Anal. Calcd for C,;,H ClN- O S: C. 53.70; H. 2.43; N, 9.

Found: C. 53.65; H. 2.50; N, 9.63.

2-Amino-5-[(p-chlorophenyl)thio]benzonitrile To astirred solution of 18 g (0.08 mole) of stannous chloride dihydrate in a mixture of 60 ml of concentrated hydrochloric acid and 10 ml of glacial acetic acid was added a warm solution of 7.5 g (0.0258 mole) of 2-nitr0-5-[(p-chlorophenyl)thio]benzonitrile in 50 ml of glacial acetic acid. The stirred mixture was heated at 50 for 2 hr, stirred for 2 hr at room temperature and then poured into 1 l. of ice-water containing 110 ml of 50% sodium hydroxide. The crude product was collected, washed with water and air-dried. Recrystallization from 70% aqueous ethanol (charcoai) gave 4.5 g (67%) of product, mp 123l25.

Anal. Caled for CmH ClNgSZ C. 59.88

Found: C. 59.82;

2,4-Diamino-6-[ (p-ehlorophenyl)thio]quinazoline,

one-third Hydrate.

A mixture of 4.5 g (0.0173 mole) of 2-amino-5-[(pchlorophenyl)thio]-benzonitrile, 2.2g (0.019 mole) of chloroformamidine hydrochloride and 10.5 ml of dry diglyme was heated to 145 C. A brisk evolution of hydrogen chloride occurred producing a clear solution which solidified rapidly. The mixture was maintained for 1 hr at 145, cooled and diluted with ether. The

Anal. Calcd for C H ClN S' H O: c.5445; H, 3.91;

Found: C. 54.53; H, 4.03;

N, 18.34. H O. 2.15.

EXAMPLE 11 Preparation of 2,4-Diamino-6-[ a,a,a-trifluoro-m-tolyl )thio quinazoline 2-Nitro-5-[(a,a,a-trifluoro-m-tolyl )thio lbenzonitrile was prepared from m-trifluoromethylthiophenol and -chlor0-2-nitrobenzonitrile. Reduction with stannous chloride afforded 2-amino-5-[(a,a,o:-trifluoro-mtolyl)thio]benzonitrile which was condensed with chloroformamidine hydrochloride to give the desired endproduct compound having the structure shown in FIG.

2-Nitro-5- a,a,a-trifluoro-m-tolyl )thio 1 benzonitrile A mixture of 11.6 g (0.065 mole) of m-trifluoromethylthiophenol, 11.9 g (0.065 mole) of 5-chloro-2- nitrobenzonitrile and 10.0 g (0.072 mole) of anhydrous potassium carbonate in 160 ml of acetone was stirred v under reflux for 3 hr, cooled and filtered. The fitrate was concentrated to dryness and the oily residue was triturated several times with hot iso-octane. On cooling the residue solidified forming yellow crystals. The solid was recrystallized from anhydrous ethanol to give 15.3 g (72.5%) of the desired product. mp 96-98.5.

Anal. Calcd for C H F N O S: C. 51.86; Found; C. 51.86;

2-Amino-5[ a,a,atrifluoro-m-tolyl )thio benzonitrile.

To a stirred solution of 34.4 g (0.153 mole) of stannous chloride dihydrate in a mixture of 50 ml of concentrated hydrochloric acid and 20 ml of glacial acetic acid was added slowly a warm solution of 15. l g (0.0465 mole) of 2-nitro-5-[(a,a,cx-trifluoro-mtolyl)thio}benzonitrile in 50 ml of glacial acetic acid. The temperature was held below 25 during the 1.5 hr addition period. After stirring at room temperature for 18 hr, the clear solution was poured slowly into 600 ml of ice water containing ml of 50% sodium hydroxide solution. The white solid which precipitated was collected and dried. The crude product was triturated with 250 ml of hot 95% ethanol and filtered. The filtrate was concentrated to ml and chilled. The white crystals which formed were collected and dried to give 1 l .l g (81%) of the desired product, mp l l4l 16.

Anal. Calcd for C H F N Sz C, 57.13; H. 3.09; N. 9.52. Found. C, 56.97; H, 318; N. 9.34.

2,4-Diamino-6-[ cx,a,a-trifluoro-m-tolyl )thio lquinazoline A stirred mixture of 10.0 g (0.0371 mole) of 2- amino-5- a,a,a-trifluoro-m-tolyl )thio lbe nzonitrile and 4.7 g (0.0408 mole) of chloroformamidine hydrochloride in 20 ml of diglyme was placed in an oil bath at l50l55. A homogeneous solution soon formed. hydrogen chloride was evolved and then a new yellow solid began to precipitate. After 0.5 hr the mixture was cooled to room temperature and the solid was collected. washed first with diglyme and then with ethyl acetate and dried. The solid was recrystallized from 70% aqueous ethanol containing excess ammonium hydroxide. After drying in vacuo 7.8 g (62.5%) of the desired end-product. mp 229230.5 was obtained.

Anal. Calcd for C H F N S: C. 53.57; H. 3.31); N. 16.66. Found: C, 53.58; H. 3.45; N, 16.83.

EXAMPLE 11] Preparation of 2,4-Diamino-6-( Z-naphthylthio )quinazoline 2-Nitro-5-(Z-naphthylthio)benzonitrile was prepared from B-thionaphthol and 5-chloro-Z-nitrobenzonitrile. Reduction with stannous chloride afforded 2-amino-5- (Z-naphthylthio)benzonitrile which was condensed with chloroformamidine hydrochloride to give the desired end-product having the structure shown in FIG. 4.

2-Nitro-5-( 2-naphthylthio)benzonitrile A mixture of 20.5 g (0.128 mole) of B-thionaphthol. 24.5 g (0.134 mole) of 5-chloro-2-nitrobenzonitrile and 19.5 g (0.141 mole) of anhydrous potassium carbonate in 300 ml of benzene was stirred under reflux for 4 hr and filtered hot to remove the salt. The benzene solution was concentrated and cooled. The brittle yellow solid which precipitated was collected and dried. After recrystallization from acetonitrile 18.1 g (46%) of the desired product, mp 139141, was obtained.

Anal. Calcd for C H N O S: C, Found: C,

2-Amino-5-(2-naphthylthio)benzonitrile To a well stirred solution of 14.8 g (0.066 mole) of stannous chloride dihydrate in a mixture of 40 ml of concentrated hydrochloric acid and ml of glacial acetic acid was added slowly a warm solution of 6.0 (0.02 mole) of 2-nitro-5-(Z-naphthylthio)benzonitrile in 60 ml of glacial acetic acid. External cooling kept the temperature of the reaction mixture below 20 C during the addition. The resulting yellow suspension was stirred for 18 hr at room temperature producing a white suspension which was poured into a stirred icewater mixture containing 110 ml of 50% sodium hydroxide solution. The white solid which precipitated was collected, washed with water and dried. The crude product was treated with hot 95% ethanol, and filtered to remove the insoluble inorganic material. The chilled filtrate yielded a white crystalline solid which was collected and dried to give 3.3 g (59%) of the desired product, mp 140.5-142.5.

Anal. Calcd for C H N S: C, 73.88, H, 4.35; N, 10.14. Found: C, 74.05; H, 4.45; N, 10.18.

2,4-Diamino-6-(2-napthylthio)quinazoline with 7 ml of diglyme and the solid was collected,

washed with ethyl acetate and dried. The solid was recrystallized once from aqueous ethanol containing excess ammonium hydroxide and once from anhydrous ethanol. After drying in vacuo (50) 1.4 g (38%) of the desired product, mp 2265-2281 was obtained.

Anal. Calcd for C H N S: C,

67.90, H, 4. Found: C, 67.87; H, 4.

EXAMPLE IV Preparation of 2,4-Diamino-6-( Z-naphthylsulfinyl )quinazoline, one-eighth hydrate Brief treatment of 2,4-diamino-6-(2-naphthylthio)- quinazoline (Example 111 above) in acetic acid with hydrogen peroxide afforded the desired end-product compound having the structure shown in FIG. 5.

2,4-Diamino-6-(Z-naphthylsulfinyl)quinazoline, one-eighth hydrate To a stirred suspension of 1.59 g (0.005 mole) of 2,4- diamino-6-(2-naphthylthio)quinazoline in 32 ml of glacial acetic acid was added 13.0 ml (0.13 mole) of 30% hydrogen peroxide solution. The mixture was allowed to stir at room temperature until a clear solution formed 0.50.75 hr). The solution was then poured into a stirred ice-water mixture containing 28.5 ml of 50% aqueous sodium hydroxide. The white solid which precipitated was collected, washed with water and dried in vacuo (50). The solid was reprecipitated twice from dimethylformamide with water and dried in vacuo (50) to give 1.2 g (71.5%) of the desired end-product compound, mp 312314 with preliminary softening.

Anal. Calcd for C H N OS'1/8H O: C, 64.22; H, 4.24; N, 16.65; H O, 0.67.

Found: C, 64.22; H, 4.26;

EXAMPLE V Preparation of 2,4-Diamino-6-( 2-naphthylsulfonyl)quinazoline, 0.9

hydrate Oxidation of quinazoline (Example 111 above) in acetic acid with aqueous hydrogen peroxide gave the desired endproduct compound having the structure shown in FIG. 6.

2,4-Diamino-6-( 2-naphthylsu1fonyl )quinazoline, 0.9 hydrate To a stirred suspension of 1.59 g (0.005 mole) of 2,4- diamino-6-(2-naphthylthio)quinazoline in 25 ml of glacial acetic acid was added ml (0.13 mole) of 30% hydrogen peroxide solution. The mixture was stirred at room temperature for 23 hr. The pale yellow solution was poured slowly into a stirred ice-water mixture containing 24 m1 of 50% aqueous sodium hydroxide. The prepcipitate which formed was collected and washed with water. The sticky white solid was suspended in 200 ml of hot absolute ethanol. The mixture was cooled and the solid was collected and dried in vacuo (50) to give 1.6 g (91.5%) of the desired end-product compound, mp 310.

2,4-diamino-6-( 2-naphthylthio Anal. Calcd for C H N O S09H O: C. 58.97; H, 4.31

N, 15.29; H O, 4.42.

Found: C, 58.91; H, 4.13;

N, 15.40; H O, 4.40.

The infrared spectrum revealed new absorption at 1 155 cm and at 131 1 cm to confirm the presence of S ANTIMALARIAL UT1 LlTY The five new compounds prepared in the above examples show unexpectedly high antimalarial activity. This fact can be seen in Table l which gives the results of antimalarial evaluations against Plasnwdr'um berghei in mice and Plasmodium gallinaceum in chicks.

This test system is based on comparisons of response to test compounds by Plasmodium berghei malaria in mice as expressed in maximum survival times as compared to survival times of untreated control mice. Thus, compounds noted as active produce increases in the survival times of the treated mice that are significant when compared with the survival times of the untreated control mice. Since an established disease is less sensi tive to treatment than a disease in the early stages of development, treatment is withheld until the parasitemia is relatively high in order to insure a more reliable assay of activity and the selection of appropriate compounds for intensive preclinical studies.

Utilizing young lCR/HA Swiss mice and a standard inoculum of Plasmodium berghei, it is possible to produce a uniform disease fatal to 100% of untreated animals within 6 to 8 days with a mean survival time of 6.2

days.

test are approximately of the same age. Animals on test are house in metal-topped plastic cages, given a standard laboratory diet and water ad lib.

Test animals receive an intraperitoneal injection of 0.5 ml. of a 1:100 dilution of heparinized hearts blood with a minimum of 90% parasitized cells drawn from donor mice infected 1 week earlier with Plasmodium berghei. The donor strain is maintained by weekly passages in separate groups of mice inoculated with a 0.5 ml. of 1:500 dilution of heparinized hearts blood.

Test compounds are usually administered after solution or suspension in sesame or peanut oil. A single dose is given subcutaneously 72 hours after the mice are infected with Plasmodium berghei. At this time a 10-15% parasitemia has developed; the disease is well established but has not produced sufficient debility to alter the response of the host to toxic effects of the drug on test. Since treatment is withheld for three days to permit the infection to become well established and death occurs in untreated controls within 6 to 8 days, it is felt that this system prevents a candidate compound with the maximum challenge. Treated animals are kept under observation for days. Survivors at the end of this period of time are considered as cured. In order to check factors such as changes in the infectivity of Plasmodium berghei or in the susceptibility of the host or to detect technical errors a group of infected animals treated with pyrimethamine at dose levels producing definite increases in survival time is included as a positive control in every experiment. In each experiment test compounds are administered in graded dosages. With highly active compounds, increases in dose levels are usually followed by increases in the survival time of the treated mice. However, if an active drug is toxic for the host, its toxicity may become a limiting factor; continued increases in dose levels also increase the toxic effects and may result in the diminution of survival times. Deaths prior to the sixth day, when untreated controls begin to die, are regarded as non parasitic and become the basis for toxicity evaluations.

Table 1 Antimalarial Evaluation Against Plasmodium berghei in Mice and Plasmodium gallinat'eum in Chicks Com ound (Ex amp e No. and Figure Showing P. bergher' Sm 1e Subcutaneous dose KfiS 1; C after mglhgz 1?. allinaceum Single 5. c. dose Structure) 640 320 160 40 20 10 5 2 5 1.25 mg/kg AMST;C

C5 C5 C5 258 13.1;C2 9.2 10.1 6.8 3.6 1.7 320 C5 1 (FIG. 2) C5 C5 :C4 13.1;C2 11.1 10.1 6.8 2.5 1.7 22.2;C2

141-,C4 E11 80 16.7 15.8;C4

C5 C5 C5 C5 14.9;C3 12.7 9.1 8.7 2.7 0.5 160 15.4 11 (F16 3) C5 C5 C5 15.9;C3 13.1 9.3

C4 (5 C5 C5 C5 C5 C5 11 1 6 5 5.3 2 9 320 16.0;

C5 C5 C5 C5 C5 11.3 160 15.0;C4 111 (FIG. 4) C5 C5 80 16.2 40 12.4 20 7.8 10 6.2

C5 C5 C5 C5 C5 C5 C5 142 10.9 6 7 1V (FIG. 5) C5 C5 C5 C5 C5 31.9 ,C2

C5 C5 ;C4

C5 C5 C5 C5 C5 C5 C5 15.6;C2 12 1 10.9 40 16.4 C5 C5 C5 C5 C5 C5 9.9;C4 5.9 4.5 20 11.0 V (FIG. 6) C5 C5 C5 10 9.0 5 7.8 2.5 4.8 1.25 2.0

"AMS'l' is the mean survival time (days) of treated mice tMSll') minus the mean survival time (days) of control mice from 6.1 to (1.5 days. L indicates the number 01' mice surviving at 60 days post infection and termed "cured";

sub-inoculation is unavailable.

'AMS'l' is the mean survival time (days) of treated chick MSl'l) minus the mean survival time (days) f Cmttrol chicks t MSTC 1. 1n the present study the MS'l'C ranged from 3.0 to 4.0 days. C designates the number 01' chic s surviving to 30 days post infection and termed "cured"; data to establish parasitological care based on sub-inoculation is unavailable. Each entry at each dose level represents results with a 5 animal group.

[MSTC 1. 1n the present study the MSTC ranged data to cstahlish parasitnlogical cure based on Two compounds were also tested for their oral suppressive antimalarial effects against another normal drug-sensitive strain of Plasmodium berghei (KEG-173) in mice utilizing published test procedures [P. E. Thompson et al., Exp. Parasitol, 25:32 (1969)]. The SD (the daily dose in mg/kg of body weight required for 90% suppression of the parasitemia in treated mice relative to control mice) for the compound 2,4- diamino-6- I p-chlorophenyl )thio ]quinazoline (Example I: FIG. 2) is 0.22 mg/kg/day as estimated graphically using semi-logarithmic paper. The SD for the compound 2,4-diamino-6-(2-naphthylio)quinazoline (Example III, FIG. 4) is 0.085 mg/kg/day as estimated graphically. The quinine equivalent Q (the ratio of the SD of quinine hydrochloride 74.5 mg base/kg/day to the SD of the test compound under comparable conditions) for the compound of Example I (FIG. 2) is 338 and the Q of the compound of Example III (FIG.'

It has been established that the New World monkey, Aotus'trivirgatus (also known as douracouli, owl monkey or night monkey) is especially susceptible to the parasites of human malaria when splenectomized or given immune-suppressant agents. Monkeys so prepared were first used in developing laboratory models for human Plasmodium vivax [M. D. Young, J. A. Forter, Jr., and C. M. Johnson, Science, 153, 1006 (1966); J. A. Porter, Jr., and M. D. Young, Military Med, 131, supplement, 952 (1966); D. C. Baerg, J. A. Porter, Jr., and M. D. Young, Amer. J. Trop. Med. Hyg., 18. 346 (1969); D. C. Baerg and M. D. Young, Military Med., 134, special issue, 772 (1969)] and for Plasmodiumfalciparum [Q. M. Geiman and M. J. Meagher, Nature, 215, 437 (1967); Q. M. Geiman, W. A. Siddiqui, and

(1969); P. G. Contaeos and W. E. Collins, Science. 161, 56 (1968)]. In particular, such work has constituted a noteworthy advance in malariology in the latter instance, for there are numerous strains of malignant tertain malaria which pose marked medical problems because the strains are resistant to most antimalarial drugs now available. Earlier, Old World monkeys infected with simian malaria parasites had been found to be valuable for laboratory models of malarias [ef., W. Peters, Chemotherapy and Drug Resistance in Malaria. Academic Press. Inc.. New York. 1970]. Through detailed study of aspects of such infections [cf.. G. R. Coatney, W. E. Collins, McW. Warren, and P. G. Contacos, The Primate Malarias, US. Government Printing Office. 1972], a reproducible and standardized system for the testing of chemotherapeutic agents against several strains of Plasnwdium falciparum in intact Aotustrivirgatus has been developed [L. H. Schmidt, Bulletin of Southern Research Institute, vol. 24, no. 1, page 9 J. V. Scheel, Military Med., 134, special issue, 780

The standardized Aotus test system (Schmidt, loc. cit.) has rendered it possible to determine the efficacy of antimalarials under circumstances akin to those in clinical cases of falciparum malaria. This significant advance eliminated the potential of hazards to man through use of volunteers to evaluate candidate drugs against strains of Plasmodiumfalciparum following successful trials in malarial infections-of lesser creatures. Response in the secondary test system has closely paralleled those shown in man by antimalarials. This provides firm basis for development of antimalarial agents which are safe and more broadly effective than those now in use, and which may be taken into the clinic with greater assurances of success than hitherto.

Tables 2 and 3 give the results of the antimalarial evaluation using the Aotus test system.

Table 2 Antimalarial Evaluation Using the Aotus Test System with the Chloroquine-Susceptible Malayan Camp-CH/Q and Chloroquine-Resistant Vietnam Oak Knoll Strains of Plasmudium falciparum Daily Response to Treatment use No. Suppressed/No. No. Parasite Clearances/ No. Cures lNo. Mg/kg Infected with Strain No. Infected with Strain Infected with Strain Body Malayan Vietnam Malayan Vietnam Malayan Vietnam Compound Weight Camp-CH/Q Oak Knoll Camp-CH/O Oak Knoll Camp CH/Q Oak Knoll Examplcl 0.31 0/2 3/3 0/2 3/3 0/2 3/3 (FIG. 2) 1.25 3/3 3/3 3/3 3/3 0/2 3/3 5.0 3/3 3/3 3/3 3/3 3/3 3/3 0.19 0/2 2/2 0/ 2 2/2 0/2 0/2 0.78 5/5 5/5 l/5 5/5 0/5 2/5 Example III 1.56 3/3 3/3 2/3 3/3 0/3 3/3 (FIG. 4) 3.125 6/6 6/6 6/6 6/6 4/6 5/5 6.25 3/3 3/3 3/3 3/3 3/3 3/3 12.5 2/2 l/l 2/2 l/l 2/2 l/l 50.0, 2/2 l/l 2/2 I/l 2/2 1/1 0.025 3/3 6/6 0/3 3/6 0/3 0/4 0.098 3/3 6/6 l/3 6/6 0/3 1/3 0.19 2/2 2/2 2/2 2/2 1/2 l/2 Example IV 0.39 6/6 7/7 6/6 7/7 2/5 5/5 (FIG. 5) 0.78 5/5 5/5 5/5 S/5 4/5 5/5 1.56 6/6 6/6 6/6 6/6 5/6 6/6 3.125 3/3 6/6 3/3 6/6 2/2 5/5 12.5 2/2 2/2 2/2 2/2 2/2 2/2 50.0 III III III III I/l l/l 0.025 0/3 4/4 0/3 4/4 2/3 2/3 Example V 0.098 3/3 4/4 0/3 4/4 0/3 2/2 (FIG 6) 0.39 6/6 8/8 6/6 8/8 5/6 6/6 1.56 0/6 9/9 6/6 9/9 6/6 6/6 6.25 3/3 3/3 3/3 3/3 3/3 /3 Table 3 SUMMARY OF COMPARATIVE ACTIVITIES OF THE COMPOUNDS OF EXAMPLE IV (FIG. 5) AND EXAMPLE V (FIG. 6) AGAINST ESTABLISHED INFECTIONS WITH THE CHLOROQL'INE SUSCEPTIBLE MALAYAN CAMP ZH/O AND CHLOROOUINF RESISTANT VIETNAM MONTEREY STRAINS OF PLASMUDIUM FALCJPARUM Daily Responses of Infections Dose No. No. Cures/No, Infected Parasites Clearances/No. Infected Strain Mg/Kg Thera eutic A ent Therapeutic Agent Body Wt Compound of Example 1 Compound of Example V Compound ot Example lV Compound of EXumpIc V X 7 (FIG. 5) (F106) (FIG. 5) (FIG. 6)

Malayan 0.00625 -Camp- 00125 /2 0/2 Cl'l/Q 0.025 3/6 0/6 0/6 0/6 0.049 2/5 0/7 0/4 0/7 0.098 7/9 3/12 4/9 U12 0196 5/7 6/11 7 4/11 0.39 /9 13/15 6/9 10/13 0.78 7/7 2/2 4/7 2/2 1.56 12/12 9/10 11/12 9/10 3.125 8/8 1/1 7/7 l/l Vietnam 0.00625 0/1 0/1 Oak 0.0125 Knoll 0.025 3/6 /9 0/6 7/9 0.049 4/4 0/1 1/4 0/1 0.098 6/6 11/11 3/6 10/11 0.196 2/3 1/3 0139 7/7 11111 7/7 ll/ll 0.78 5/5 5/5 ANTIBACTERIAL UTILITY Three of the compound prepared in the above examples show antibacterial utility as demonstrated by the evaluation results shown in Table 4.

Table 4 Compound (Example No. and Figure Showing Structure) Antibacterial Evaluation Inhibitory drug concentration, ug/ml" Sire tucocc'us Slaphy/woccus Slaphylococcus Escherichia S/uge/la j ecalis aurcus aureus cu/i summ' MGH-2 UC-76 518713 Vogcl C l 0 I FIG. 2 0.25 0.25 0.25 1.0 5.0 Ill FIG. 4 0.25 O.25 0.25 0.25 lV FIG. 5 0.25 0.25 0.25 0.25

"Grandient plate in vitro antibacterial test employed.

ications at several dose levels has been tabulated, with 1 claim:

indications given from suppression of signs and symptoms and parasitological status to cures of the malaria infections. All of the novel compounds produced satisfactory response in the infections caused by either chloroquine-sensitive or chloroquine-resistant strains of parasites. Remarkably, there was even suggestion that those of the latter type responded somewhat better than the former. The most effective compounds were found to be 2,4-diamino-6-(Z-naphthylsulfinyl)- quinazoline (FIG. 5) and 2,4-diarnino-6-(2-naphthylsulfonyl)quinazo1ine (FIG. 6). More detailed study of the profiles of potency for those two was indicated, and results thereof have been summarized in Table 3. On the basis of the fact that 2,4-diamino-6-( Z-naphthylsulfonyl)quinazoline had the greater levels of effectiveness against chloroquine-resistant Plasmoa'ium falciparum (Vietnam Oak Knoll Strain), that compound has been considered to be the best representative of the present series.

l. A compound having the structural formula N OYNII: A r-Y wherein Y is S, SO, or S0 and Ar is p-chlorophenyl,

a,a,a-trifluoro-m-tolyl, or Z-naphthyl.

2. 2,4-diamino-6-I p-chlorophenyl )thio lquinazoline.

3. 2,4-diamino-6-[ (a,0z,o:-trifluoro-m-tolyl )thio 1- quinazoline.

4. 2,4-diamino-6-( Z-naphthylthio )quinazoline. 5. 2,4diamino-6-( Z-naphthylsulfinyl )quinazoline. 6. 2,4-diamino-6-( 2-naphthylsulfonyl )quinazoline. =l=

Claims (6)

1. A COMPOUND HAVING THE STRUCTURAL FORMULA

2. 2,4-diamino-6-((p-chlorophenyl)thio)quinazoline.

3. 2,4-diamino-6-(( Alpha , Alpha , Alpha -trifluoro-m-tolyl)thio)quinazoline.

4. 2,4-diamino-6-(2-naphthylthio)quinazoline.

5. 2,4-diamino-6-(2-naphthylsulfinyl)quinazoline.

6. 2,4-diamino-6-(2-naphthylsulfonyl)quinazoline.

Images