Synthesis of new 2,4‐diamino‐7H‐pyrrolo[2,3‐d]pyrimidines via the Taylor ring transformation/ring annulation strategy

Abstract

Selected examples 2,4-diamino-7H-pyrrolo [2,3-d]pyrimidines with a phenyl or benzyl group at the 5-position were synthesized as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii and Toxoplasma gondii, two potentially life-threatening opportunistic pathogens associated with AIDS and other disorders of the immune system. Aldol condensation of paraformaldehyde with substituted benzaldehydes or with phenylacetaldehyde afforded α-hydroxyketones with a phenyl or benzyl group at the 4-position. Further reaction of the hydroxyketones with malononitrile afforded 2-aminofuran-3-carbonitriles, which upon heating with guanidine underwent ring transformation/ring annulation to produce 2,4-diamino-7H-pyrrolo[2,3-d]pyrimidines rather than 2,4-diaminofuro[2,3-d]pyrimidines. One of the target compounds obtained in this manner, 2,4-diamino-5-(3,4,5-trimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (1d), may be viewed as a conformationally restricted analogue of trimethoprim, an antimicrobial agent widely used in combination with a sulfa drug to treat P. carinii and T. gondii opportunistic infections in patients with AIDS. Compound 1d inhibited P. carinii and T. gondii DHFR with IC 50 values of 8.3 and 14 µM, respectively. This potency was somewhat greater than that of trimethoprim. However, because this compound was also more potent than trimethoprim against mammalian (rat liver) DHFR rat liver it lacked species selectivity. The other 2,4-diamino-7H-pyrrolo[2,3-d]pyrimidines synthesized were neither potent nor selective.

Towards Species-specific Antifolates

“…(3)), provides the starting point for the structure-based drug design process. [92,93], pyrido[2,3-d]pyrimidines [86,88,[94][95][96][97][98], pyrrolo[2,3-d]pyrimidines [99,100], thieno[2,3-d]pyrimidines [101][102][103], purines [104], furo[2,3-d]pyrimidines [105][106][107], quinazolines [55, 73, 88, 98, 101, Therapeutic options for PCP have been comprehensively reviewed by Queener [69] in 1995 and Fishman [70,71] in 1998. A review by Gangjee et al, focused specifically on antifolates, was published in 1996 [72].…”

The Effect of 5-Alkyl Modification on the Biological Activity of Pyrrolo[2,3-d]pyrimidine Containing Classical and Nonclassical Antifolates as Inhibitors of Dihydrofolate Reductase and as Antitumor and/or Antiopportunistic Infection Agents

“…These furans were in turn obtained by the condensation of suitable α-hydroxy ketones with malonodinitrile in the presence of a suitable base such as triethylamine. Gangjee et al 12,14,15,22 and Rosowsky et al 23,24 have also successfully adopted this methodology in their synthesis of pyrrolo[2,3- d ]pyrimidine containing antifolates. Extending this general methodology to the synthesis of 31 required the synthesis of 1-hydroxy-2-pentanone, 29 (Scheme 1).…”