Imidazo[1,2-a]pyrimidines are a class of compounds with antiinflammatory potential.

No abstract

We have studied the effects of some hexahydroimidazo[1,2-c]pyrimidine derivatives (HIPs) on leucocyte functions in-vitro and we have assayed the anti-inflammatory activity of these compounds in two models of inflammation. All HIPs inhibited the human neutrophil degranulation process and superoxide generation at concentrations in the microM range. In mouse peritoneal macrophages stimulated with lipopolysaccharide, HIP-4 and HIP-5 inhibited nitrite production without affecting prostaglandin E2 (PGE2) accumulation. HIP-4 was also active in the zymosan-injected mouse air pouch model (at 100 nmol/pouch), with significant reductions in leucocyte migration and PGE2 and leukotriene B4 levels in the air pouch exudate. To confirm the anti-inflammatory effects of this compound, we tested HIP-4 orally (10-40 mg kg(-1)) on carrageenan mouse-paw oedema where it exerted a dose-dependent inhibition of paw swelling with significant reductions of myeloperoxidase and elastase activity and PGE2 levels in paw homogenates. This study demonstrates that some HIPs inhibit leucocyte functions and one of these derivatives (HIP-4) shows anti-inflammatory activity when administered by the oral route, which can be related to inhibition of leucocyte migration.

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Hexahydromidazo[1,pyrimidines 6 were prepared by the reaction of tosylpyrimidines 2 with bromoacetamides 3 in one step. The stereoselectivity of the reaction has been confirmed by Xray analysis. Imidazo[1,2-a]pyrimidines 5 were obtained on heating hexahydroimidazo[1,2-c]pyrimidines 6 with trifluoroacetic anhydride.During the preparation of a series of imidazo[1,2-a]pyrimidines 5 for a study of pharmacological activity, we found that the reaction of 2-aminopyrimidine (1A) with ptoluenesulfonyl chloride and further alkylation of the sulfonamidopyrimidine 2A formed with the bromoacetamides 3a-f 1 afforded the alkylated products 4Aa-f.Heating 4Aa-f with trifluoroacetic anhydride afforded the expected imidazo[1,2-a]pyrimidines 5Aa-c,f. Similar results occur with the 5-substituted 2-aminopyrimidines 1B,C as starting materials when the bromoacetamide 3a was used for alkylation. However, when the 2-aminopyrimidines 1B,C, were tosylated and the derivatives 2B,C were alkylated with 3b-f, the hexahydroimidazo[1,2-c] pyrimidines 6, (R 1 = B,C; R 2 = b-f) were isolated as the major products along with minor amounts of the corresponding alkylated derivatives 4. Hexahydroimidazo[1,2-c]pyrimidines 6 were converted to the imidazo[1,2-a]pyrimidines 5 by refluxing with trifluoroacetic anhydride similar to the reaction of the alkylated products 4. (Scheme).The procedure used for the preparation of the imidazo [1,2-a]pyrimidines 5 was based on the literature using 2-aminopyridines as starting material. 2 In the first step the tosylation of the 2-aminopyrimidines 1A,B afforded the sulfonamidopyrimidines 2A,B as solid compounds in very high yields. The 1 H NMR and 13 C NMR data are shown in Tables 1 and 2. The tosylation of 1C was a slower reaction and when it was heated to completion, the ditosylated derivative 7C was obtained (14%) along with 2C (76%).The tosylation of 2-aminopyrimidines having electronwithdrawing substituents at C-5 was not successful. 2-Amino-5-formylpyrimidine did not react even under forced conditions and 2-amino-5-ethoxycarbonylpyrimidine gave only small amounts (8%) of the corresponding tosylated derivative.In the reaction of 2A with bromoacetamides 3a-f and 2B,C, alkylation occurred on the endocyclic nitrogen in the reaction with the bromoacetamide (3a) affording the derivatives 4. The products 4, showed in the 1 H NMR spectra typical AMX patterns (three doublets of doublets) where R 1 = H (4Aa-f) and an AB pattern where R 1 π H (4Ba, 4Ca) for pyrimidine ring hydrogen atoms, because of the asymmetry of the molecule. The chemical shift of H-4 was always at lower field than H-6 (Tables 3 and 4). An NOE effect (26%) on the H-6 signal appeared for 4Aa Scheme Downloaded by: Rutgers University. Copyrighted material.