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The pyrazolo[3,4-b]pyridine derivatives 3 could be prepared by condensing compounds 1 with the 3-aminopyrazolone derivative 2. The pyrazolo[5,2-b]-1,3-oxazine derivative 11 and polyfunctionally substituted 1,4-dihydropyridines 15, 18 were also synthesized. Some of the obtained compounds were tested for their antimicrobial activity.
The products obtained from the sequential reaction of [Ir2(mu-H)(mu-Pz)2H3(NCCH3)(PiPr3)2] (1) with diphenylacetylene and their subsequent reactions with hydrogen have been investigated in order to deduce the mechanisms operating in the hydrogenation reactions catalyzed by 1. The reaction of 1 with an excess of diphenylacetylene gives cis-stilbene and [Ir2(mu-H)(mu-Pz)2-[eta1-C6H4-2-[eta1-(Z)-C=CHPh]]((Z)-C(Ph) =CHPh](NCCH3)(PiPr3)2] (2), the structure of which has been determined by X-ray diffraction. The formation of 2 involves the intermediate species [Ir2(mu-H)(mu-Pz)2H2((Z)-C(Ph)=CHPh](NCCH3)-(PiPr3)2](3),[Ir2(mu-H)(mu-Pz)2H[(Z)-C(Ph)=CHPh]2(NCCH3)(PiPr3)2] (4), and [Ir2(mu-H)(mu-Pz)2H[eta1-C6H4-2-[eta1-(Z)-C=CHPh](NCCH3)(PiPr3)2] (5), which have been isolated and characterized. These three complexes react with hydrogen to give cis-stilbene and 1 and are possible intermediates of the diphenylacetylene hydrogenation under catalytic conditions. Nevertheless, the rate of formation of 5 is very slow compared with the rate of catalytic hydrogenation, which excludes its participation during catalysis. Compound 2 also reacts with hydrogen in benzene, but in this case the hydrogenation gives 1,2-diphenylethane as the sole organic product. The course of this reaction in acetone has been investigated, and deuteration experiments were carried out. The formation of [Ir2(mu-H)(mu-Pz)2H[eta1-C6H4-2-[eta1-(Z)-C=CHPh]](OC(CD3)2)(PiPr3)2] (6) and [Ir2(mu-H)(mu-Pz)2H[eta1-C6H4-2-[eta1-(Z)-C-CHPh]](NCCH3)(PiPr3)2] (7) was observed under these conditions. The experimental evidence obtained supports two alternative mechanisms for the alkyne hydrogenation catalyzed by 1, one of them being dinuclear and the other mononuclear. The experimental data suggest that the former is favored.
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Reaction of CuX(2) (X(-)=Cl(-), Br(-), NO(3) (-)), NaOH, and 3[5]-tert-butylpyrazole (Hpz(tBu)) in a 1:1:2 molar ratio in MeOH at 293 K for three days affords [[Cu(3)(Hpz(tBu))(6)(mu(3)-X)(mu(3)-OH)(3)](2)Cu]X(6) (X(-)=Cl(-), 1; X(-)=Br(-), 2; X(-)=NO(3)(-), 3) in moderate yields. These compounds contain a centrosymmetric, vertex-sharing double-cubane [[Cu(3)(Hpz(tBu))(6)(mu(3)-X)(mu(3)-OH)(3)](2)Cu](6+) core, surrounded by a belt of six hydrogen-bonded X(-) ions. For 1 and 2, the ring of guest anions has near C(3) symmetry, that is slightly distorted owing to the axis of Jahn-Teller elongation at the central Cu ion. For 3 only, the NO(3)(-) guest ions are crystallographically disordered, reflecting their poor complimentarity with complex host. A similar reaction employing CuF(2) yields [[Cu(3)(Hpz(tBu))(4)(mu-pz(tBu))(2)(mu-F)(2)(mu(3)-F)](2)]F(2) (4), whose structure contains a cyclic hexacopper core with approximate C(2v) symmetry. Finally, an analogous reaction using Cu(NCS)(2) gives a mixture of trans-[Cu(NCS)(2)(Hpz(tBu))(2)] (5) and [Cu(2)(NCS)(2)(mu-pz(tBu))(2)(mu-Hpz(tBu))(Hpz(tBu))(2)] (6). The latter compound contains a Hpzt(Bu) ligand bridging the two Cu ions in an unusual kappa(1),mu-coordination mode. The variable temperature magnetic properties of 1-3 show antiferromagnetic behavior, leading to a S=1/2 ground state in which the seven copper(II) ions are associated into three mutually independent distinct spin systems. In confirmation of this interpretation, Q-band EPR spectra of solid 1 and 2 at 5 K also demonstrate a S= 1/2 spin system and exhibit hyperfine coupling to three (63,65)Cu nuclei. Unusually, the coupling is manifest as an eight-line splitting of the parallel feature, rather than the usual 10 lines. This has been rationalized by a spin-projection calculation, and results from the relative magnitudes of coupling to the three Cu nuclei. UV/Vis and mass spectrometric data show that 1-4 decompose to lower nuclearity species in solution.
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Methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl-2H- pyrazolo[3,4-d]pyrimidine-2-carboxylate (AA-2379), a non-steroidal, non-acidic agent, markedly inhibits type III allergic (Arthus) reaction; the ID50 values of AA-2379 in the rat reversed passive Arthus pleurisy, the rat active Arthus pleurisy, and the reversed passive Arthus reaction in rat skin were 5-10 mg/kg, p.o., and 30 mg/kg of AA-2379 inhibited the active Arthus reaction in rabbit skin by about 50%. Dexamethasone, but not acidic non-steroidal anti-inflammatory drugs and aminopyrine, inhibited the Arthus reaction. The vascular permeability in the reversed passive Arthus pleurisy is enhanced biphasically in the early response mediated by physiologically active amines, prostaglandins, and leukotrienes, and in the late response mediated by complements and polymorphonuclear leukocytes (PMNs). AA-2379 inhibited the late response more potently than the early one. Furthermore, when given after the early response was reduced, AA-2379 obviously inhibited the late response. Rat zymosan-induced paw edema and mouse zymosan-activated serum-induced peritonitis, mediated by complements, were dose-dependently inhibited by AA-2379; the ID50 values were 11.4 and 10.2 mg/kg, p.o., respectively. The results suggest that AA-2379 differs from non-steroidal anti-inflammatory agents in strongly inhibiting the late response of the Arthus reaction, which associated with PMNs.
The antiinflammatory, analgesic, and antipyretic activities of methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl-2H-pyrazolo[ 3, 4-d]pyrimidine-2-carboxylate (AA-2379), a novel non-acidic agent, were examined. 1. AA-2379 had a potent antiinflammatory activity; 3-25 mg/kg, p.o. of the compound inhibited rat carrageenin-, bradykinin-, trypsin-, formalin-, dextran-, and nystatin-induced paw edema; mouse traumatic edema; and rat croton oil pouch inflammation by about 30%. The compound at 25-50 mg/kg, p.o. also inhibited the vascular permeability induced by histamine, serotonin, and bradykinin. 2. AA-2379 had an analgesic activity; the ID50 values in mouse phenylquinone-induced writhing were 10.1 mg/kg, p.o. and the compound at 12.5 mg/kg, p.o. inhibited dog urate arthritis. 3. AA-2379 at 3-10 mg/kg, p.o. showed antipyretic activity in febrile rats and rabbits. 4. AA-2379, at 500 mg/kg, p.o. was not ulcerogenic in rats. 5. These data show that AA-2379 is more active than non-acidic antiinflammatory agents, such as tiaramide and aminopyrine.
Malondialdehyde (MA) formed in linolenic acid, linoleic acid, corn oil and beef fat upon photoirradiation was determined by gas chromatography (GC). The MA produced was reacted with methylhydrazine to give 1-methylpyrazole and was subsequently analyzed on a GC equipped with a nitrogen-phosphorus specific detector and a fused silica capillary column. MA values determined by this method correspond to free or unbound MA levels. Linolenic and linoleic acids produced 867 micrograms MA/g and 106 micrograms MA/g, respectively. Oleic and stearic acids did not produce detectable levels of MA upon photoirradiation. Amounts of MA produced after eight hour irradiations of corn oil and beef fat were 56.24 micrograms/g and 25.01 micrograms/g, respectively. Some photoreaction products in irradiated corn oil also were identified as methylhydrazine derivatives.
Based on the principle of bioisosterism, a successful strategy in the planning of new drugs, we describe in this work the synthesis and the analgesic activity of the new functionalized arylcarbaldehyde 4-(1-phenyl-3-methylpyrazolo[3,4-b]pyridine) hydrazone derivatives 5a-m. These derivatives (5a-m) were synthesized in ca. 45% overall yield, using 4-(1-phenyl-3-methylpyrazolo[3,4-b]pyridinyl) hydrazine 6, as key intermediate. by applying classical synthetic methods to construct the aryl-hydrazone unit at C-4 of the heterocyclic system. Compound 6 was prepared from the corresponding 4-chloro-(N-phenyl-3-methylpyrazolo[3,4-b]pyridine) derivative 7 in very high yield. The antinociceptive activity of these new compounds 5a was evaluated by a test of abdominal contortions induced by 0.6% acetic acid solution i.p. in albino mice. The compounds 5f, 5g, 5j and 5k were strongly active showing a good analgesic profile.
Synthesis of prodrugs of orally active COX-2 inhibitor 3 involving sulfamoyl (SO(2)NH(2)) and hydroxymethyl (CH(2)OH) groups, and their biological evaluation are described. Of these prodrugs, the N-propionyl sulfonamide sodium 3k was found to be much superior to the parent compound 3 and other marketed COX-2 inhibitors in carrageenan induced rat paw edema model of inflammation due to highly elevated drug levels in systemic circulation. This prodrug has a potential both for oral as well as parenteral administration due to impressive analgesic activity, antipyretic potency, and extraordinary water solubility.
Structure-activity relationship (SAR) studies of 2-[3-di(and tri)fluoromethyl-5-arylpyrazol-1-yl]-5-methanesulfonylpyridine derivatives for canine COX enzymes are described. This led to the identification of 12a as a lead candidate for further progression. The in vitro and in vivo activity of 12a for the canine COX-2 enzyme as well as its in vivo efficacy and pharmacokinetic properties in dog are highlighted.
A series of tetrahydroacridines related to tacrine have been synthesized starting from 3-methylcyclohexananone, menthone, pulegone, carvone and dihydrocarvone (both racemic and chiral). In many cases, the yields and purity of the compounds have been improved by the use of a microwave oven. These compounds have been characterized by (1)H and (13)C NMR data. To establish their relative configuration, the structure of (1R,4R)-(+)-9-chloro-1-methyl-4-isopropyl-1,2,3,4-tetrahydroacridine (cis-10b), derived from (2S,5R)-(-)-menthone, has been determined by X-ray. The chemical shifts of cis-10b and trans-10b have been calculated at the GIAO/B3LYP/6-31G* level and compared successfully with the experimental data.
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A N-derivatized 3-dimethylaminopropyloxypyrazole library was prepared using solution-phase parallel synthesis. The library was designed using physicochemical constraints designed to remove non-membrane-permeable molecules. Cupric acetate-mediated N-arylation with aryl boronic acids proceeded regioselectively to form the N-2-substituted derivatives. The presence of the 3-dimethylaminopropyloxy group was found to completely control the regioselectivity of the arylation. Presence of a dimethylaminoethyloxy or dimethylaminobutyloxy group gave a lesser degree of regioselectivity. The scope of the method as applied to library synthesis is discussed.