Oxamates derived from 5‐aminopyrazoles

Abstract

Several oxamates were prepared from ethyl oxalyl chloride and 5-amino-4-cyanopyrazoles substituted in the 1-position with aryl, aroyl and arylsulfonyl groups. Both aroyl and arylsulfonyl groups suffered chlorideinduced cleavage during this process. The synthesis of 7-(6-chloro-3-pyridazinyl)-7H-pyrazolo[3,4-~-1,2,3-triazin-4(3H)-one (11) and its reaction with methanol to give 1-(6-chloro-3-pyridazinyl~5~methoxy-1H-pyrazole~4~ carboxamide (12) are also reported. A mechanism for this interesting transformation is presented. J. Heterocyclic Chem., 23, 193 (1986).There has been a great deal of recent interest in alkyl oxamates and oxamic acids or their salts as anti-allergy agents. Representative alkyl oxamates which reached later stages of drug development include Lodoxamide Ethyl (U-42,718) [1,2], WY-16,922 [3], AY-25,674 [4,5] and MTB [6]. Examples of oxamic acids and oxamic acid salts are 195 [7,8] and Lodoxamide Tromethamine (U-42,-585E) [9], respectively. Some of these agents have undergone extensive clinical evaluation. Q 00 II II NHCCOCH2CH3 0 AY -2 5 ~ 6 7 4 R" aR' NHCCOR ;fl R = H, R ' = CN, R" = NHCH3; WY-41,195 R = CH2CH3, R ' R = n-Bu, R ' = H , R" = 5 -1 e 1 r o r o 1 y 1 , M T B CONH2, A " = OCH3, WY-16,922 F N 00 fJ 00 II II NHCCOR II II ROCCNH C I R = C H 2 C H~, Lodoromide E t h y l ( U -4 2 , 7 1 8 ) R = NH3C(CH20H)3, Lodorarnide Tromslhorn!ne (U-42,585€)Most of these agents derive from anilines, and hence are also referred to as oxanilic acid derivatives [lo]. We decided to prepare oxamates of aminopyrazoles of the following general structure, in which the cyano group is ortho to R I R i OIhyI R I = a f y l , aroyl, ofylsulfonyl R4 = cyano the oxamate functionality. An ortho relationship of cyano and carboxamide groups to oxamate functionality is pre-193 sent in WY 922, respectively. A feature of the planned oxamates, not present in any of the existing oxamates with anti-allergic activity, was the electron-rich character of the aromatic (pyrazole) ring. It has been suggested that with Lodoxamide-like compounds, electronwithdrawing substituents on the aromatic ring are necessary for optimal activity [l]. A primary objective of the present study, then, was to explore the effect of an electronrich aromatic nucleus on the biological activity of oxamates.Two literature references exist on oxamates derived from aminopyrazoles. One described dioxamate 1, which was prepared from 4,5-diamino-lH-pyrazole and excess dimethyl oxalate, in a study describing lH-pyrazolo[3,4-h]pyrazines as purine antagonists [13]. The other describes 3-[(5-nitro-2-imidazolyl)pyrazol-5-yl)oxamic acid derivatives 2a-e as antibacterial agents [14]. I H 20. R =OCH3 b , R =OCH2CH3 C, R = OCgH5 d, R = NHNH2 8, R = NHOH Scheme I

Thermal Ring‐Opening of Pyrazolo[3,4‐d][1,2,3]triazin‐4‐ones: An Experimental and Theoretical Study

“…The structures of the 3 H ‐pyrazolotriazinone tautomers 4b – g were confirmed by NMR and IR spectroscopy, and the spectral data gave good agreement with those previously reported , , …”

“…Concerning the chemical reactivity of azole‐annulated 1,2,3‐triazinones, it has been found that modifications at the carbonyl group lead to 4‐substituted azolo‐triazines,, , alkylation at N‐3 and opening of the triazine ring with elimination of nitrogen afford pyrazole derivatives or pyrazolyl‐pyrazolo‐oxazinones by the dimerization of an iminoketene intermediate , . However, the study of nitrogen‐loss reactions of azolotriazines as an approach to preparing new heterocycles has not been so widely explored, despite the synthetic potential of the precursors.…”

Possible Rearrangements During the Synthesesof Di- and Trisubstituted Pyrazoles

“…Hydrolysis of the nitrile groups of 3a, b under mild conditions gave carbamoyl compounds 5a, b as expected [9]. However, migrations of the ester groups were not observed.…”

Synthesis of Some Pyrazolo[3, 4]pyrimidine Derivatives for Biological Evaluation

“…Experimental). Many reports 16,17 stated that nitrozation of compounds analogous to 4 gave the corresponding triazinone derivatives; however, our attempts to cyclize compound 4 to 5 by stirring with nitrous acid gave the unexpected 5-amino-1-(6-p-tolyl-pyridazin-3-yl)-1H-pyrazole-4-carboxylic acid alkyl esters 6a,b via formation of the diazonium chloride derivative, which on boiling in ethanol or methanol gave the corresponding esters 6a (R = C 2 H 5 ) or 6b (R = CH 3 ), respectively (Scheme 1). The formation of compounds 6a,b could be presumably explained by the formation of unstable diazonium salt on the amino of the amide moiety and not on the 5-amino group.…”