Synthesis of Novel Heterocyclic Systems from a-(2-R-5-halogenopyrimidin-4-yl)-2-azahetarylacetonitriles. New Potential Anticancer Agents
Tamara Fursy, Alexei Nemazany and Kenner C. Rice
Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive
and Kidney Diseases, Bldg. 8, Rm. B1-23, Bethesda, MD 20892, U.S.A.
Introduction
Pyrimidines have been the subject of substantial attention by synthetic and
medicinal chemists because of the role of this heteroaromatic ring in many
biological systems. The extent of this interest is reflected in the reviews by
Brown [1]. Recently we have reported the synthesis of moleculs which contain
new heterocyclic ring systens, such as pyrido[1,2:1,6]pyrrolo[3,2-d]pyrimidine
and pyrimido[4',5':4,5]pyrrolo[1,2-a]quinoline (3) [2]. As part of our
studies on new planar condensed heterocyclic compounds as new potential
antitumor agents, we synthesized a series of compounds containing new
heterocyclic ring systems pyrimido[4',5':4,5]pyrrolo[2,1-b]benzimidazole
(22) and pyrimido[4',5':4,5]pyrrolo[2,1-b]benzthiazole (23),
which are delivered from substituted hetarylacetonitriles 5-14 by the
reaction of intramolecular nucleophilic cyclization. The electron deficient
nature of the pyrimidine ring facilitates the synthesis of a large number of
pyrimidine derivatives through nucleophilic aromatic substitution. The halogens
at 2, 4 and 6 positions have been especially useful in this regard [3]. Because
of the differences in reactivity in nucleophilic reactions between a halogen
atom at these position and at C-5, nucleophilic reactions of 1 were
investigated. We were interested in studies of nucleophilic aromatic
intramolecular substitution of the halogen atoms at the C-5 position by the
nitrogen atom of hetaryl ring systems and synthesis of new condensed
pyrimidines with a bridgehead nitrogen atom and their biological activity.
Results and Discussion
We recently reported [2] that 4,5-dihalogeno substituted pyrimidines 1
react with 2-tosylmethylpyridine or -quinoline (2) in the presence
of base to give condensed pyrazolo derivatives 3 in high yields (Scheme
1).
Utilizing an intermolecular nucleophilic substitution approach, we discovered
that the reaction between 2-R-6-R1-5-halogenopyrimidines (1)
and 2-azahetarylacetonitriles (4, a-f) produced
a-(2-R-6-R1-5-halogenopyrimidin-4-yl)-2-azahetarylacetonitriles
(5-14, a-f) with yields of 89-96%. Since the halogen at the C-4 position
of pyrimidine ring reacts with nucleophiles easily, the reaction was carried
out under mild conditions in acetonitrile at 80oC in the presence of
K2CO3 (Scheme 2).
These compounds also undergo a further reaction of chlorine substitution at
position C-2 by secondary amines in DMF at 130oC in the presence of
a base yielding the amino analogs (15 - 19, a-f). The latter were
transformed to their salts by treatment of hydrochloric acid in 76-82% overall
yield (Scheme 2).
The compounds 5-14, a-f were found to undergo intramolecular
nucleophilic hetarylation upon long heating in DMF or dimethylacetamide in the
presence of K2CO3, Cs2CO3 or
dimethylbenzylamine (Scheme 3) with formation of new heterocyclic systems
pyrimido[4',5':4,5]pyrrolo[2,1-b]benzimidazole (22) and
pyrimido[4',5':4,5]pyrrolo[2,1-b]benzthiazole (23) as well as new
derivatives of compounds 3 (20 and 21).
The type of substituted halogen atoms (F, Cl or Br) plays a key role in the
cyclization to the condensed system. The cyclization time for the 5-fluoro-,
5-chloro- and 5-bromo substituted compounds are about 10, 48 and 24 h,
correspondingly. The type of substitution at the C-2 position in pyrimidine
ring does not significantly influence the cyclization time.
Synthesized compounds have been evaluated as anticancer agents at the National
Cancer Institute's Drug Discovery Program againts leukemia, non-small cell lung
cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal, prostate and
breast cancer, and some of these compounds demonstrated in vitro
activity.
Summary
In conclusion, the synthesis of novel condensed pyrimidine systems systems
pyrimido[4',5':4,5]pyrrolo[2,1-b]benzimidazole (22) and
pyrimido[4',5':4,5]pyrrolo[2,1-b]benzthiazole (23) as well as new
derivatives of pyrido[1,2:1,6]pyrrolo[3,2-d]pyrimidine (20) and
pyrimido[4',5':4,5]pyrrolo[1,2-a]quinoline (21) with a bridgehead
nitrogen atom has been achieved from their precursors 5-14. Nucleophilic
substitution at C-4 in the pyrimidine ring of 1, a-f yielded novel
2-substituted 5-halogeno pyrimidines 5-19, a-f. Our results indicate
that the studied compounds are potential anticancer agents againts leukemia,
non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer,
renal, prostate and breast cancer.
Acnowledgment
The authors thank Mr. Noel Whittaker at LAC, NIDDK for mass spectra data,
NIDDK, NIH for support this work, the National Cancer Institute, Drug
Development Program for biological results and Dr. Bonnie L. Robeson, Starks
C.P. for the fruitful discussion.
References
1. D. J. Brown, in "The Pyrimidines", Wiley-Interscience, New York, NY,
1994.
2. Yu. M. Volovenko, F.S. Babichev, T.A. Fursy, S.V. Litvinenko, Khim.
Geterotsikl. Soedin., 6, 852, 1991; CA 116:6510.
3. D. J. Brown, in "The Pyrimidines; Supplement II" Interscience, New
York, NY, 183 -240, 1985.
4. J. A. Benvenuto, K. Lu, S. W. Hall, R. S. Benjamin and T. L. Loo, Cancer
Res., 38, 3867-3870, 1978.
