Heterocyclic Acids Research Articles

Hypervalent Iodine Oxidation of Acid Hydrazides: A New Synthesis of N,N′-Diacylhydrazines

Hypervalent iodine oxidation of p-substituted benzohydrazides (1a-h), phenylacetohydrazide (1i) and heterocyclic acid hydrazides (1j-I) using one equivalent of iodobenzene diacetate in dry dichloromethane or acetonitrile leads to dimerization thereby providing a new and facile method for the synthesis of N,N-diacylhydrazines 2.

On the Mesomorphic Properties of New Aryl Esters of Carbocyclic and Heterocyclic Acids

This paper presents a number of laterally substituted liquid crystalline compounds which have been synthesized by systematically varying both the position and the type of the lateral substituent.

ChemInform Abstract: Synthesis and Angiotensin II Receptor Antagonistic Activities of Benzimidazole Derivatives Bearing Acidic Heterocycles as Novel Tetrazole Bioisosteres.

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Carboxyamidation of Purine Nucleosides: New Secondary 8-Carboxamidopurine Nucleosides

Palladium catalyzed carboxyamidation at the 8-position of 8-bromoadenosine and 8-bromoguanosine nucleosides is a versatile reaction, which allows primary, secondary, heterocyclic, aromatic mine and amino acids to be incorporated into purine nucleosides.

Structure-activity relationships in a series of 2(1H)-quinolones bearing different acidic function in the 3-position: 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid, a new potent and selective AMPA/kainate antagonist with neuroprotective properties.

Recently, we reported the synthesis of 3-(sulfonylamino)-2(1H)-quinolones, a new series of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate and N-methyl-D-aspartic acid (NMDA)/glycine antagonists. By exploring the structure-activity relationships (SAR) in this series, we were able to identify the 6,7-dinitro derivative 6 as a potent and balanced antagonist at both receptors. Unfortunately, compound 6 was devoid of in vivo activity in mice anticonvulsant testing. To overcome this critical limitation, new compounds bearing various acidic moieties at the 3-position of the quinolone skeleton were synthesized and evaluated. The SAR of these new analogues indicated that not all acidic groups are acceptable at the 3-position: A rank order of potency going from carboxylic approximately phosphonic > tetrazole > mercaptoacetic > hydroxamic >> other heterocyclic acids was defined. In addition, the selectivity between the AMPA/kainate and NMDA/glycine sites is dependent on the nature of the substitution (nitro > chloro for AMPA selectivity), its position (5,7- > 6,7-pattern for glycine selectivity), and the distance between the quinolone moiety and the heteroatom bearing the acidic hydrogen (the longer the distance the more AMPA selective the compound). Among these new AMPA antagonists, we have identified 6,7-dichloro-2(1H)-oxoquinoline-3-phosphonic acid (24c) as a water soluble and selective compound endowed with an appealing pharmacological profile. Compared with the reference AMPA antagonist NBQX, the phosphonic acid 24c is much less potent in vitro but almost equipotent in vivo in the audiogenic seizures model after intraperitoneal administration. Moreover, unlike NBQX, compound 24c is also active after oral administration. In the gerbil global ischemia model, compound 24c shows a neuroprotective effect at 10 mg/kg/ip, equivalent to the reference NBQX.

Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres.

The design, synthesis, and biological activity of benzimidazole-7-carboxylic acids bearing 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, 5-thioxo-1,2,4-oxadiazole, and 2-oxo-1,2,3,5-oxathiadiazole rings are described. These compounds were efficiently prepared from the key intermediates, the amidoximes 4. The synthesized compounds were evaluated for in vitro and in vivo angiotensin II (AII) receptor antagonistic activities. Most were found to have high affinity for the AT1 receptor (IC50 value, 10(-6)-10(-7)M) and to inhibit the AII-induced pressor response (more than 50% inhibition at 1 mg/kg po). The 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, and 5-thioxo-1,2,4-oxadiazole derivatives showed stronger inhibitory effects than the corresponding tetrazole derivatives, while their binding affinities were weaker. This might be ascribed to their improved bioavailability by increased lipophilicity. The 5-oxo-1,2,4-oxadiazole derivative 2 (TAK-536) and 5-oxo-1,2,4-thiadiazole derivative 8f showed efficient oral bioavailability without prodrug formation. This study showed that the 5-oxo-1,2,4-oxadiazole ring and its thio analog, the 5-oxo-1,2,4-thiadiazole ring, could be lipophilic bioisosteres for the tetrazole ring in nonpeptide AII receptor antagonists.

Synthesis of a series ofcis-diamminedichloro-platinum (II) complexes linked to uracil and uridine as candidate antitumor agents

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diamminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore undescribed uracil and uridine-platinum (II) complexes are; [N-(2-aminoethyl)uracil-5-carboxamide]dichloroplatinum (II) (3a), [N-(2-aminoethyl)uracil-6-carboxamide]dichloroplatinum (II) (3b), [5-(2-aminoethyl)carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl) carbamoylu-carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7a), [6-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-carboxyuracil (1a) and 6-carboxyuracil (1b) which were reacted with ethylenediamine to afford the respective N-(2-aminoethyl)uracil-5-carboxamide (2a) and N-(2-aminoethyl)uracil-6-carboxamide (2b). The cisplatin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatinate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannicchloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-carboxy-2′,3′,5′-tri-0-acetyluridine (4a) and 6-carboxy-2′,3′,5′-tri-0-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5a) and 6-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH3ONa. The antitumor activities were evaluated against three cell lines (K-562, FM-3A and P-388).

Synthesis of Heterocyclic α-Aminophosphonic Acids

Abstract Heterocyclic α-aminophosphonic acids derivatives were easily obtained by 1,3 dipolar cycloaddition of acetylenic compounds on azido α-aminophosphonic esters.

Evaluation of heterocyclic acid equivalents as tetrazole replacements in imidazopyridine-based nonpeptide angiotensin II receptor antagonists

A series of imidazol[4,5- b] pyridine AII antagonists incorporating heterocyclic acid equivalents, e.g., oxathiadiazoles, thiatriazoles, and dioxobenzothiadiazines, are exemplified as novel non-peptide AII receptor antagonists. The most potent antagonist in this series, L-161,177 (IC 50 = 0.7 nM, rabbit aorta), bearing the oxathiadiazole, exhibited in vivo profile after both iv and oral administration to conscious rats.

Development of tetrazole bioisosteres in angiotensin II antagonists

The application of acidic heterocycles as a substitute for tetrazole in the synthesis of potent non-peptide Angiotensin II AT1 receptor antagonists is described.

Derivatives of heterocyclic ?-iminocarboxylic acids. 4. Reduction of N-alkoxycarbonyl derivatives of ?-iminocarboxylic acids

When N-methoxycarbonyl and N-benzoxycarbonyl derivatives of methyl esters of aziridine-2-carboxylic acid, L-proline, L-thioproline, and pipecolic acid interact with NaBH4 in tert-butanol/methanol, the products of reduction of the C-methoxycarbonyl group of the original compounds are accompanied by bicyclic urethanes and oxazolidines. Reduction of N-maleates and N-fumarates of heterocyclic α-iminocarboxylic acids leads to the formation of α-hydroxymethyl-N-[4-(2-oxo-2,5-dihydrofuryl)] derivatives of pyrrolidine, piperidine, 1,3-thiazolidine, and 1,4-thiazan. In the latter case, 1-aza-2-hydroxymethyl-4-oxo-5-oxa-9-thiabicyclo [5.4.0]undecene-2 is also obtained. The N-maleates and fumarates of aziridine-2-carboxylic acid are reduced anomalously by sodium borohydride, forming 2-hydroxymethyl-2-(β-hydroxyethyl)-3-oxa-1-azabicyclo[3.1.0]hexanes.

1,3,4-Oxadiazole, 1,3,4-thiadiazole, and 1,2,4-triazole analogs of the fenamates: in vitro inhibition of cyclooxygenase and 5-lipoxygenase activities.

N-Arylanthranilic acids, known generically as the fenamates, are nonsteroidal antiinflammatory drugs (NSAIDs) that block the metabolism of arachidonic acid by the enzyme cyclooxygenase (CO). Substitution of the carboxylic acid functionality of several fenamates with acidic heterocycles provided dual inhibitors of CO and 5-lipoxygenase (5-LO) activities when tested in an intact rat basophilic leukemia (RBL-1) cell line. Compound 5b (IC50 = 0.77 microM (5-LO), 0.27 microM (CO)) which contains an 1,3,4-oxadiazole-2-thione replacement and 10b (IC50 = 0.87 microM (5-LO), 0.85 microM (CO)) which contains a 1,3,4-thiadiazole-2-thione are the most potent inhibitors of 5-LO and CO activities from these series. Both of these heterocyclic analogs of flufenamic acid are also active in carageenin-induced rat footpad edema (CFE), a model of acute inflammation. When dosed orally the ID50s for 5b and 10b in CFE are 8.5 and 4.7 mg/kg, respectively.

A convenient method for the synthesis of dinitrosylmolybdenum(0) complexes of heterocyclic acids

A simple procedure is described for the synthesis of dinitrosylmolybdenum(0) complexes of picolinic acid and its derivatives by the reaction of Mo(NO) 2(acac) 2 (where acacH = acetylacetone) with the respective ligand in methanol under aerobic conditions.

Acetylenic chemistry. Part 24. N‐vinylation of N‐H acid heterocycles

AbstractThe vinylation of 9H‐carbazole (1), 1H‐indole (3a), and 1H‐pyrrolo[2,3‐b]pyridine (3b) with propiolic acid ethyl ester resulting in N‐acrylic esters is reported here.

5034409 Pyrrole carboxylic acids and esters for blood platelet aggregation inhibition

Heterocyclic acids and esters useful as inhibitors of mammalian blood platelet aggregation characterized by Formula I are disclosed. HET.sub.1 --(CH.sub.2).sub.n CO.sub.2 R (I) Formula I compounds are those wherein n is 6-9, R is hydrogen, lower alkyl or an alkali metal ion, and HET 1 is the heterocyclic radical 3,4-diphenyl-1H-pyrrol-1-yl.

Synthesis of 3‐hetaryl‐4,5,6,7‐tetrahydrobenzo[b]thiophenes

AbstractA novel efficient synthesis of 3‐hetaryl‐4,5,6,7‐tetrahydrobenzo[b]thiophenes was achieved by the cyclocondensation of ethyl 2‐amino‐4,5,6,7‐tetrahydrobenzo[6]thiophene‐3‐carboxylate with selected o‐substituted aromatic amines or with alifatic, aromatic and heterocyclic acid hydrazides in the presence of polyphosphoric acid.

Solvent extraction, spectrophotometric, and atomic absorption spectrophotometric determination of beryllium with heterocyclic hydroxamic acids

A simple, rapid, and selective method for extraction spectrophotometric determination of beryllium(II) is described. Beryllium is extracted with a chloroform solution of N-phenyl-2-furohydroxamic acid (PFHA) at pH 9.0. The beryllium(II)-hydroxamate complex extract is colorless and hence morin is added to the extract, which gives an intensely yellow-colored complex having a maximum absorbance at 420 nm with a molar absorptivity of 2.7 × 104 1 mol−1 cm−1. Common anions and cations do not interfere in the determination of beryllium. The spectral characteristics of beryllium complexes with eight beterocyclic hydroxamic acids are recorded. Beryllium is also determined by AAS and the results obtained are in agreement with those of the spectrophotometric method. The method is applied to the determination of beryllium in standard samples.

Acidic isostere design: Synthetic strategies and recent progress in understanding electronic properties and metabolic stability

AbstractThe efficient synthesis of a family of twelve acidic heterocycles of varying acidity from a single common intermediate facilitates the search for new acidic bioisosteres. An extension of this chemical approach led to a new family of phosphonate replacements in prototypes related to the N‐methyl Dasparate (NMDA) antagonist 2‐amino‐7‐phosphonoheptanoic acid (AP7). Acidic isostere design may be facilitated by grouping hydroxylic heterocyclic carboxylic isosteres into one of two electronic classes based on the Gandour hypothesis. The limitations of normal hydroxamic acids as carboxylic acid surrogates suggest that the excellent metabolic stability of reverse hydroxamic acids may be useful in prospective acidic isostere design.

Picolinic acid: a mobile phase additive for improved chromatography of metal-chelating heterocyclic acids and β-diketones

La chromatographie des acides heterocycliques et des β-dicetones est realisee sur colonne Zorbax C 8 ou Spherisorb C, en utilisant comme phase mobile de l'acetonitrile, de l'acide phosphorique, de la butylamine et/ou de l'acide picolinique comme modificateur organique

Synthesis of 4,12‐dihydro‐4‐oxoquino‐[1,8a,8‐a,b]quinoxaline‐5‐carboxylic acid derivatives

AbstractThe synthesis and antibacterial activity of 1‐substituted amino‐2‐fluoro‐4,12‐dihydro‐4‐oxoquino[1,8a,8‐a,b]quinoxaline‐5‐carboxylic acid derivatives are described. The synthetic route includes a carbon homologation and two intramolecular nucleophilic displacement cyclization reactions leading to the novel 4,12‐dihydro‐4‐oxoquino[1,8a,8‐a,b]quinoxaline‐5‐carboxylic acid heterocycle.