4-substituted-6-aryl-pyrimidine compounds

Details 4-substituted-6-aryl-pyrimidine compounds 4-substituted-6-aryl-pyrimidine compounds

1986-09-22

1989-01-03

Ramsuer, Robert W.

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

514908, 544330, C07D23942, C07D23948

Patent

active

047958120

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

Traditional treatments of cancer have utilized surgery, irradiation and chemotherapy. New classes of compounds are developed for use as chemotherapeutic agents. 5-Fluorouracil is a well known and widely used antineoplastic agent. Wierenga et al. disclose the use of 2-amino-6-aryl-5-substituted-4-pyrimidinols (pyrimidines) as interferon inducers, antiviral agents and for treatment of cancer in Belgium Pat. No. 882,315 and Great Britain Pat. No. 2,048,250.
The preparation of 4-chloro-6-phenyl-2-pyrimidinamine by the chlorination of 2-amino-6-phenyl-4(3H)-pyrimidinone with phosphorus oxychloride is described by Wierenga et al in Synthesis of 2-amino-6-phenyl-4(3H)-pyrimidinone-1-oxide, Heterocycles, 16(4), 563-71 (1981) and Chemical Abstracts 95 (5): 43025r.
4-Chloro-6-phenyl-2-pyrimidinamine is also disclosed in Heterocycles, 8, 229-305 (1977), Chemical Abstracts 88(15): 105255g and Izv. Akad. Nauk SSSR, Ser. Khim., 10, 2173-6 (1971), Chemical Abstracts 76(9): 45330t.
There are a number of examples of aziridine-containing anticancer agents, including triethylenemelamine, triethylenethiophosphoramide (thio-TEPA), aziridylbenzoquinone, mitomycins and 1-(2,3,5-tribenzoyl-.beta.-1)-ribofuranosyl)-4-aziridil-2-pyrimidinone. See W. B. Pratt and R. W. Ruddon, The Anti-Cancer Drugs, Oxford Univ. Press, N.Y., 1979 and S. K. Carter, et al (ed.), Recent Results in Cancer Research, Springer-Verlag, Berlin, 1977 for a review.


BRIEF DESCRIPTION OF THE INVENTION

This application relates to 4-substituted-5-substituted/unsubstituted-6-aryl-pyrimidine compounds represented by Formula I, wherein R.sub.4 is chloro, bromo, aziridyl or 2-(1-aziridyl)ethylamino and R.sub.5 and R.sub.6 are as defined below, and the use thereof to treat an animal or human hosting a neoplastic disease.


DETAILED DESCRIPTION OF THE INVENTION

The 4-substituted-6-aryl-pyrimidine compounds represented by Formula I, including the 4-aziridyl-6-aryl-pyrimidine compounds represented by Formula IA and the N'-[2-(1-aziridyl)ethyl]-6-aryl-2,4-pyrimidinediamine compounds represented by Formula IB wherein R.sub.5 is hydrogen, fluoro, chloro, bromo or iodo and R.sub.6 is a member selected from the group consisting of X.sub.1, X.sub.2, X.sub.3 or X.sub.4 is not hydrogen and is fluoro, chloro, bromo, iodo, alkyl of from 1 to 5 carbon atoms, inclusive, including isomeric forms, alkoxy of from 1 to 5 carbon atoms, inclusive, including isomeric forms, nitro or dialkylamino of from 1 to 3 carbon atoms, inclusive, including isomeric forms, and X.sub.2, X.sub.3 and X.sub.4 are not hydrogen and are the same or different and are fluoro, chloro, bromo, iodo, alkyl of from 1 to 5 carbon atoms, inclusive, including isomeric forms, alkoxy of from 1 to 5 carbon atoms, inclusive, including isomeric forms, nitro or dialkylamino of from 1 to 3 carbon atoms, inclusive, including isomeric forms, and procedures illustrated in Chart A.
The 6-aryl-pyrimidinol compounds are, however, tautomeric and can therefore also be drawn and/or named as isocytosines (Formula IIB), for example 2-amino-5-bromo-6-phenyl-4-pyrimidinol can also be named as 5-bromo-6-phenyl-isocytosine.
The 6-aryl-pyrimidinol compounds of Formula II can be obtained by the methods disclosed in Belgium Pat. No. 882,315 or Great Britain Pat. No. 2,048,250.
The starting 6-aryl-pyrimidinol (Formula II) is reacted with phosphorous oxychloride or phosphorous oxybromide, in the presence of heat to give the compound of Formula III where Z is chloro or bromo.
The compounds of Formula III, preferably where Z is chloro, is reacted with aziridine in the presence of an aprotic base, for example triethylamine, and carried out at 0.degree. to 50.degree..
If the compounds of Formula III are unsubstituted at the 5-position, the compounds of Formula IA or IB can be halogenated, if desired, by well known art methods. See, Preparation III or IV and Chart B.


DEFINITIONS

The definitions and explanations below are for the terms as used throughout the entire patent application including both the specification

REFERENCES:
patent: 3412094 (1968-11-01), Rorig et al.
Wierenga et al, Chemical Abstracts, vol. 95, No. 43025r (1981).

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