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

2,4-diamino quinazoline derivatives Download PDF

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Publication number
US3853873A
US3853873A US00324276A US32427673A US3853873A US 3853873 A US3853873 A US 3853873A US 00324276 A US00324276 A US 00324276A US 32427673 A US32427673 A US 32427673A US 3853873 A US3853873 A US 3853873A
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diamino
quinazoline
compounds
thio
compound
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Edward Faith Elslager
Leslie Morton Werbel
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Parke Davis and Co LLC
United States Department of the Army
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Parke Davis and Co LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C329/00—Thiocarbonic acids; Halides, esters or anhydrides thereof

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  • 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
  • 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.
  • 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-
  • 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.
  • 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.
  • 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.
  • mammals Whenever the term mammals is used in the specification and claims it should be understood as including humans.
  • 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
  • Y is S, S0 or S0
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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";
  • '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.
  • 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.'
  • Aotus'trivirgatus also known as douracouli, owl monkey or night monkey
  • 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.
  • 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 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 0.25 lV FIG. 5 0.25 0.25 0.25 0.25 0.25 0.25

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US00324276A 1972-04-07 1973-01-17 2,4-diamino quinazoline derivatives Expired - Lifetime US3853873A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0028473A1 (en) * 1979-11-01 1981-05-13 Pfizer Inc. Chloro- and alkoxy-substituted-2,4-diaminoquinazolines and pharmaceutical compositions containing them
US6271415B1 (en) 1997-10-22 2001-08-07 Bayer Aktiengesellschaft S-(4-biphenyl)-thiosulphuric acids and their salts, method for producing the same and method for producing 4-mercaptobiphenyls
CN108938639A (zh) * 2017-05-17 2018-12-07 浙江立恩生物科技有限公司 化合物nsc305780在制备治疗或预防流感病毒的药物中的应用
WO2024157021A1 (en) * 2023-01-26 2024-08-02 De Montfort University 5,6,8-trifluoroquinazolines to treat parasitic infection

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2723247C2 (de) * 1977-05-24 1982-09-16 Hoechst Ag, 6000 Frankfurt Verfahren zur kontinuierlichen Herstellung von 3-Nitro-4-acetylaminotoluol
JPS5943478U (ja) * 1982-09-17 1984-03-22 株式会社東芝 エスカレ−タの踏段

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2953567A (en) * 1956-11-23 1960-09-20 Burroughs Wellcome Co 5-phenylmercaptopyrimidines and method
US3635979A (en) * 1969-09-29 1972-01-18 Pfizer Certain 6- and/or 7-alkoxy-substituted-2 4-bis(disubstituted amino) quinazolines

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1490622A (fr) * 1963-09-20 1967-08-04 Parke Davis & Co Nouveaux dérivés de 2, 4-diaminoqunazoline et procédés pour leur préparation
GB1143290A (en) * 1967-12-08 1969-02-19 Parke Davis & Co New 2,4-diamino-6-quinazolinesulfonamide compounds and methods for their production
DE1795271A1 (de) * 1968-08-31 1971-12-30 Bayer Ag Verfahren zur Herstellung von substituierten 4-Aminochinazolinen

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2953567A (en) * 1956-11-23 1960-09-20 Burroughs Wellcome Co 5-phenylmercaptopyrimidines and method
US3635979A (en) * 1969-09-29 1972-01-18 Pfizer Certain 6- and/or 7-alkoxy-substituted-2 4-bis(disubstituted amino) quinazolines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FALCO et al., Chem. Abstracts, 46:4675 b, (1949). *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0028473A1 (en) * 1979-11-01 1981-05-13 Pfizer Inc. Chloro- and alkoxy-substituted-2,4-diaminoquinazolines and pharmaceutical compositions containing them
US6271415B1 (en) 1997-10-22 2001-08-07 Bayer Aktiengesellschaft S-(4-biphenyl)-thiosulphuric acids and their salts, method for producing the same and method for producing 4-mercaptobiphenyls
CN108938639A (zh) * 2017-05-17 2018-12-07 浙江立恩生物科技有限公司 化合物nsc305780在制备治疗或预防流感病毒的药物中的应用
CN108938639B (zh) * 2017-05-17 2021-01-08 浙江立恩生物科技有限公司 化合物nsc305780在制备治疗或预防流感病毒的药物中的应用
WO2024157021A1 (en) * 2023-01-26 2024-08-02 De Montfort University 5,6,8-trifluoroquinazolines to treat parasitic infection

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ZA732393B (en) 1974-11-27
FR2182937A1 (is") 1973-12-14
BE797824A (fr) 1973-07-31
AU467250B2 (en) 1975-11-27
DE2317142A1 (de) 1973-10-18
NL7304751A (is") 1973-10-09
JPS4913188A (is") 1974-02-05
DE2317142B2 (de) 1979-02-08
AR196846A1 (es) 1974-02-19

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