Pyrimidines pyrido

Reaction of 2-aininopyridine 59 with 3-keto-ester 60 in PPA provided pyrido-pyrimidine 61 in poor yield. Interestingly, upon heating isolated 61, rearrangement occurred to provide napthyridone 62 in good yield. 

Difficulty was experienced when repetition of this preparation was attempted, but conditions were soon found that enabled the pyrido-pyrimidine to be obtained in good yield. This product, however,... 

Triazanaphthalene (449) is the most unstable of the pyrido-pyrimidines to ring-degradation at pH 2 or pH 7.7 The 4-oxo derivative was converted into the 4-thioxo compound via nucleophilic displacement of the acyloxy intermediate formed with phosphorus pentasulfide. The 4-carboxymethylthio-pyridopyrimidine underwent some substitution by hydroxide ion but primarily gave the ring-opening reaction, which is facilitated by resonance activation of the 2-position by the 6-aza moiety. 

The final chapter by Istvan Hermecz (Chinoin, Ltd., Budapest, Hungary) deals with bicyclic systems containing one ring junction nitrogen and one heteroatom and their benzologs, i.e. pyrido-oxazines, pyrido-thiazines, pyrido-pyridazines, pyrido-pyrazines, pyrido-pyrimidines and their analogs. Much of this material has not been reviewed for forty years, during which time immense advances have occurred. 

When heated with bases, the 2-azidopyrido[l,2- ]pyrimidine (102) yields pyridyltetrazoles (269 R = CONR R2). This reaction is initiated by nucleophilic addition of the base to the carbonyl group it is followed by ring opening between the C-4 and N-5 atoms and formation of the tetrazole ring involving the azido group and the N-l atom of the starting pyrido-pyrimidine.166 291... 

Tsuge and Noguchi469 prepared the 3-benzamido-4-oxo-4//-pyrido-[l,2-a]pyrimidine and its methyl substituted derivatives from 2-amino-pyridines and 2-phenyl-4-ethoxymethylene-5-oxazolone in boiling ethanol, without the isolation of the condensation products of type 94. The pyrido-pyrimidine was formed from 2-amino-6-methylpyridine, but in a longer reaction period and in low percentage yield. Condensation product 94 was cyclized in ethanol or polyphosphoric acid or acetic acid. 3-Benzamido-2-methyl-4-oxo-4A/-pyrido[l,2- ]pyrimidine was synthetized from 2-amino-pyridine and the appropriate oxazolone derivative. 

Applications of MCR-Derived Heterocycles in Drug Discovery Table 6 Antibacterial activities of select pyrazolo-pyrido-pyrimidine-diones... 

Reactions having no parallel in any of the other systems of pyrido-pyrimidine are those syntheses utilizing methyl a-benzoylacetimidate... 

Analysis of the analgesic and anti-inflammatory effects of rimazolium, a pyrido-pyrimidine derivative, compared with that of prostaglandin synthesis inhibitors and morphine... 

Treatment of the pyrido-pyrimidines (346) with pyrrolidine gives the 1,8-naph-thyridines (347) (Scheme 133). The meso-ionic oxazines (349) that are formed by the reaction of chloroformyl-ketens with 2-pyridone undergo cycloaddition reactions with dimethyl acetylenedicarboxylate or with phenyl isocyanate, followed by loss of carbon dioxide, to yield quinolizines (350) and pyrido-pyrimidines (348), respectively (Scheme 134). Pyrido-pyrimidines (352) also result from the cycloaddition of anils of type (351) to ethyl vinyl ether (Scheme 135)."""... 

Piromidic acid (PA), 5,8-dihydro-8-ethyl-5-pyrrolidopyrido(2,3-carboxylic acid is a pyrido pyrimidine derivative, a congener of nalidixic acid. PA is widely used for its antibacterial activity against several gram negative pathogens. PA is very slightly water soluble [4, 5]. 

Zimmerman and coworkers studied the dimer formed from ureido pyrido-pyrimidine 6 and its tautomer (Scheme 10.2d) [21]. They pointed out that prototropy can be detrimental to hydrogen-bonded complex formation. Therefore, heterocycle 6 was designed to contain only one self-complementary hydrogen-bonding array (DDAA) eliminating others. They measured the self-association constant by employing H NMR dilution studies in chloroform, which was estimated to be more than 10 IVT. ... 

The use of acrolein in the technical gas-phase synthesis of pyridine derivatives has been reviewed, as has the formation of pyridines, pyrimidines, pyrido-pyrimidines, and pyrazolopyrimidines by ring-closure of jS -enol- and /3 -enamino-carbonyl compounds. ... 

Many patents have been issued on the use of pyrogaUol derivatives as pharmaceuticals. PyrogaUol has been used extemaUy in the form of an ointment or a solution in the treatment of skin diseases, eg, psoriasis, ringworm, and lupus erythematosus. GaUamine triethiodide (16) is an important muscle relaxant in surgery it also is used in convulsive-shock therapy. Trimethoprim (2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine) is an antimicrobial and is a component of Bactrin and Septra. Trimetazidine (l(2,3,4-trimethoxybenzyl)piperazine (Vastarel, Yosimilon) is used as a coronary vasodilator. l,2,3,4-Tetrahydro-6-methoxy-l-(3,4,5-trimethoxyphenyl)-9JT-pyrido[3,4- ]indole hydrochloride is useful as a tranquilizer (52) (see Hypnotics, sedatives, ANTICONVULSANTS, AND ANXIOLYTICS). Substituted indanones made from pyrogaUol trimethyl ether depress the central nervous system (CNS) (53). Tyrosine-and glycine(2,3,4-trihydroxybenzyl)hydrazides are characterized by antidepressant and anti-Parkinson activity (54). 

All four possible pyridopyrimidine systems, pyrido[2,3-Chemical Abstracts nomenclature is used throughout this Chapter. For the reasons given above (Section 2.15.1), the pyrido[2,3-fused systems, e.g. (5) and (6) (numbering shown), are also known. The linear benzo fused derivatives of pyrido[3,2-[Pg.201]

UV maxima in addition to those noted in (69AHC(10)149) have been recorded for pyrido[2,3-[Pg.204]

Many of these reactions occur in the course of synthesis of fully or partly unsaturated products after initial ring closure, giving rise to more unsaturated systems, e.g. in the pyrido[2,3-pipemidic acids (Section 2.15.4.1) and their derivatives, e.g. (16a) -> (17) (74JAP(K)7444000). Examples are also found in the pyrido[3,2-[Pg.205]

Enzymic oxidations at the 7-position of pyrido[2,3-oxygenated derivatives and of the 8-N-oxide have been observed in the metabolism of the pyrido[2,3-e/]pyrimidine analogues of the antiepileptic drug methaqualone (75MI21502, 74MI21500). 

In recent years most examples of ring opening of this type have been noted in the pyrido[2,3-[Pg.207]

Appropriate pyrido[2,3-d]pyrimidin-5-ones with formyl groups in the 6-position have been oxiized to piromidic (68) and pipemidic (69) acids, or to intermediates for these, using moist silver oxide, chromium trioxide (potassium dichromate), potassium permanganate or, alternatively, sodium chlorite/hydroxylamine-O-sulfonic acid. 6-Acetyl groups have been similarly oxidized using sodium hypobromite in aqueous dioxane, whilst 2-acetyl groups give dimethylaminomethylene derivatives en route to 2-pyrazolylpyrido[2,3-d]pyrimidines. 

In aqueous alkaline conditions with chloroacetic acid the pyrido[4,3- f]pyrimidinethione (80) undergoes facile ring opening, attributed to the resonance stabilization of a delocalized covalent hydrate dianion intermediate (81) (82). Pyrido[2,3- f]pyrimidine-4-thiones (and... 

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