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PubMed1986

The effects of acidic and nonacidic pyrazoles on arachidonic acid metabolism in mouse peritoneal macrophages.

The effects of acidic and nonacidic pyrazole derivatives and their metabolites on arachidonic acid metabolism have been investigated in mouse peritoneal macrophages stimulated with the calcium ionophore A 23 187 (10(-6) Mol/l). In the group of the acidic compounds with anti-inflammatory properties, phenylbutazone and butyl malonic acid mono (1-phenylhydrazide), the hydrolysis product of mofebutazone, inhibited prostaglandin production in a dose-dependent manner (10(-4)-10(-6) Mol/l). In contrast, mofebutazone itself and its hydroxylation product, 4-OH-mofebutazone, failed to show any activity. Similarly, in the case of bumadizone, an anti-inflammatory drug structurally related to phenylbutazone, no inhibitory effect on prostaglandin release was found either. The nonacidic pyrazole derivatives with antipyretic and anti-inflammatory activity, antipyrine, isopropylaminophenazone, as well as metamizol and its active metabolites 4-methylaminophenazone and 4-aminophenazone, also inhibited prostaglandin release dose-dependently. This was found to be paralleled by an increased leukotriene C4 production. Neither of the main excretory metabolites of metamizol, acetyl- and formylaminophenazone, showed any effect. The concentration levels at which the nonacidic compounds affected arachidonic acid metabolism (approx. 10(-4) Mol/l) were high enough to elicit anti-inflammatory effects. They were far higher, though, than the plasma levels producing antipyretic and analgesic effects that are reached after therapeutic doses.

Aminopyrine↗
PubMed1986

Effect of anti-inflammatory and analgesic pyrazoles on arachidonic acid metabolism in isolated heart and gastric mucosa preparations.

The effects of acidic and nonacidic pyrazoles on the release of arachidonic acid-derived mediators from isolated perfused anaphylactic guinea pig hearts as well as rat and human gastric mucosa were investigated. High concentrations of the acidic drugs phenylbutazone and oxyphenbutazone as well as of the nonacidic metabolites of metamizol, i.e. 4-methylaminoantipyrine and 4-aminoantipyrine, inhibited the release of the cyclo-oxygenase products of arachidonic acid metabolism, TXB2 and 6-keto-PGF1 alpha, and simultaneously increased the release of LTC4-like immunoreactivity in hearts. By contrast, comparatively high concentrations of the metamizol metabolites 4-formylaminoantipyrine and 4-acetylaminoantipyrine were without effect. The comparable effects of acidic and nonacidic pyrazoles on eicosanoid release from anaphylactic hearts support the concept that hypersensitivity reactions to NSAIDs are related to their effect on arachidonic acid metabolism. The anti-inflammatory effects of phenylbutazone and oxyphenbutazone and of high concentrations of metamizol seem to be correlated with the inhibition of cyclo-oxygenase. On the other hand, lower concentrations of metamizol, which have analgesic and anti-pyretic effects, only marginally inhibit cardiac cyclo-oxygenase. It remains to be investigated whether the partial inhibition of the synthesis of PGI2, a major hyperalgesiccyclo-oxygenase product of arachidonic acid metabolism, at lower concentrations of the active metamizol metabolites contributes to the analgesic effect of metamizol. The acidic NSAID mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) had no effect on the cardiac release of arachidonic acid-derived cyclo-oxygenase and lipoxygenase products. The anti-inflammatory effect of these compounds requires further investigation. In isolated gastric mucosa, the active metabolite of metamizol 4-methylaminoantipyrine was found to inhibit fatty acid cyclo-oxygenase dose-dependently. Pharmacokinetic differences due to the nonacidic structure of metamizol and its metabolites as compared to acidic NSAIDs may be responsible for the fact that metamizol is better tolerated than e.g. indomethacin. In rat experiments, phenylbutazone was found to inhibit gastric mucosal cyclo-oxygenase like indomethacin. On the other hand, mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) did not affect gastric mucosal synthesis of 6-keto-PGF1 alpha. This lack of effect on gastric mucosal cyclo-oxygenase seems to be correlated with the considerably lower gastric toxicity of mofebutazone as compared to phenylbutazone.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

[Immediate-type reactions to pyrazole derivatives: results of skin tests and antibody determinations].

In a multicentric study by the European Study Group for Drug Allergy 58 patients suffering from an immediate type reaction after intake of pyrazol analgetics were examined with regard to allergy or pseudoallergy. Besides the scratch tests with the original substance we performed cutaneous tests with pyrazol conjugates and determined IgE and IgG antibodies by means of modified radioallergosorbent (RAST) method. Three groups could be distinguished: pseudoallergic reactions to nonsteroidal analgetics of the aspirin type (15 cases); IgE-mediated pyrazolone allergy verified by skin tests and/or IgE-RAST (21 cases), and pyrazolone idiosyncrasy (26 cases).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1986

Effect of the pretreatment with pyrazole, cystamine or diphenyl-P-phenylenediamine (DPPD) on the CCl4-promoted pentane evolution in rats.

CCl4 administration to Sprague-Dawley male rats promotes pentane evolution which is an index of lipid peroxidation (LP) occurrence in vivo. Pyrazole (150 mg/kg, ip) or cystamine (600 mg/kg, po) pretreatment do not prevent CCl4-induced increases in pentane evolution, while the prior administration of the powerful antioxidant DPPD (600 mg/kg, ip at 48, 24 and 10 minutes before CCl4) prevents most of it. Since previous studies evidenced that pyrazole and cystamine but not DPPD prevent several early effects of CCl4 and diminish the intensity of the covalent binding of CCl4 reactive metabolites to cellular constituents (CB), results suggest that CB and LP might be related to those deleterious effects of CCl4 on the liver.

Animals↗
PubMed1986

Chick embryonic development following exposure to ethanol and pyrazole.

The mechanism of alcohol-induced dysmorphogenesis is not clear. Pyrazole is a potent inhibitor of alcohol dehydrogenase. Treatment of chick embryos at 96 h incubation with pyrazole (0.1 mg) and ethanol (0.1 ml, 40-60% v/v) enhanced the embryopathic response, compared with individual treatments. The results suggest that ethanol itself is embryotoxic.

Animals↗
PubMed1982

Inhibition of methylazoxymethanol-induced intestinal tumors in the rat by pyrazole with paradoxical effects on skin and kidney.

Methylazoxymethanol is a potent carcinogen and induces tumors predominantly of the small intestine and colon following a single injection. Previous data indicated that alcohol dehydrogenase could convert this carcinogen to a reactive alkylating agent. Rats were treated with an inhibitor of this enzyme, pyrazole, 2 hr prior to their receiving the carcinogen. The development of intestinal and colonic tumors was prevented. The rats did, however, develop numerous tumors of the skin and kidney. Analyses of the complete autopsies are presented. The data indicate that intestinal and colonic alcohol dehydrogenase plays a role in the tumorigenic effects of methylazoxymethanol and that other non-pyrazole-sensitive enzymes exist in other organs that can also activate this carcinogen.

Alcohol Oxidoreductases↗
PubMed1993

Synthesis and dopamine receptor binding of 4-(2-aminoethyl)-1H-pyrazole and its N,N-dialkyl derivatives.

The agnostic activity of Quinpirole (3a) at the D2 dopamine (DA) receptor suggested that the dopaminergic pharmacophore embedded in 3a was the 4-(2-aminoethyl)-1H-pyrazole (5) moiety. On that basis we have synthesized some derivatives of 5 bearing on the amino group alkyl and alkylaryl substituents. The affinities of 5 and its derivatives for the D1 and D2 DA receptor subtypes were evaluated in rat striatum by binding assays. None of these compounds show affinity for the D1 receptor. In the D2 binding assay only the N,N-di-(2-phenylethyl) (5i) and N-n-propyl-N-[2-(3-hydroxyphenyl)ethyl] (5j) derivatives show affinities comparable to that of Quinpirole. These results do not support the postulate that the 4-(2-aminoethyl)-1H-pyrazole is a bioisostere of the catechol nucleus of DA.

Animals↗
PubMed1993

N-substituted 4-carboxy-1-phenyl-1H-pyrazole-5-propanamides with antiinflammatory, analgesic, antipyretic and platelet antiaggregating activities.

The synthesis of a series of N-substituted 4-carboxy-1-phenyl-1H-pyrazole-5-propanamides by reaction of 1-phenyl-1H-oxepino[4,3-c]pyrazole-4(8H),6(7H)-dione with aromatic primary amines is described. Some amides showed a platelet antiaggregating activity in vitro superior or comparable to that of acetylsalicylic acid, as well as moderate antiinflammatory, analgesic and antipyretic activities in rats or mice.

Amides↗
PubMed1995

New 2,3-substituted 4,7-dihydro-6-(1'H-pyrazol-3'-yl)pyrazolo[1,5-a] pyrimidin-7-ones and related compounds: synthesis and benzodiazepine receptor binding study.

The reaction between two series of 7-dimethylaminovinyl pyrazolo[1,5-a]pyrimidines 4(a-r) 7a, 7d, 7f, 7(h-j) and hydrazine in acetic acid is investigated. The structure of 4,7-dihydro-6-(1'H-pyrazol-3'-yl)pyrazolo[1,5-a]pyrimidin-7- ones 5(a-r) and 7-methyl-6-(1'H-pyrazol-3'-yl)pyrazolo[1,5-a]pyrimidines 8a, 8d, 8f, 8(h-j) are attributed to the isolated products and the pathway of this reaction is suggested. The in vitro benzodiazepine receptor (BzR) affinity of the title compounds are determined by testing their ability to displace 3H-flunitrazepam from its specific binding in bovine brain membranes. The IC50 and GABA (gamma-aminobutyric acid) ratio values give valuable indications about affinity and behavioural profile of these new BzR ligands. Included in this investigation are indicated several structure-affinity relationships of the title compounds.

Animals↗
PubMed1976

Inhibition of hepatic uptake of alpha aminoisobutyric acid by ethanol: effects of pyrazole and metabolites of ethanol.

Ethanol inhibits the uptake of AIB by the isolated perfused rat liver. However, if the metabolism of ethanol is blocked by pyrazole, there is no reduction in accumulation of AIB by the liver. Acetaldehyde and acetate, metabolites of ethanol have no effect on AIB uptake by the liver. The inhibition of urea synthesis by ethanol is also prevented by pyrazole. Neither of the metabolites of ethanol inhibit urea synthesis in the isolated liver.

Acetaldehyde↗
PubMed1997

Synthesis, solvolytic stability and cytotoxicity of a modified derivative of CPzI, a pyrazole analog of the alkylation subunit of the antitumor agent CC-1065: effect of the nitrogen substitution on the functional reactivity.

The synthesis and the comparative preliminary biological evaluation of a new pyrazole analog (16) of the CC-1065 alkylating unit (CPI) are described. This new derivative showed low cytotoxicity against L1210 murine leukemia (IC50 3064 nM) with respect to reference compound, but contrarily to literature data, was found to be more stable to solvolysis than the natural derivative (+/-)-N-Boc-CPI (pH 3, t1/2 = 212 h vs. 37 h). The results of such investigation showed that alkylation of the pyrazole nitrogen caused a loss of cytotoxic activity in vitro against tumor cells. This experimental observation allowed us to confirm the importance of free N-H for the anticellular activity.

Alkylation↗
PubMed1998

Synthesis of some novel pyrazole derivatives as potential antiinflammatory agents with minimum ulcerogenic activity.

Two novel isomeric series, N-substituted-5-amino-4-(3,4-dimethoxyphenyl)-3-hydroxy-1 H-pyrazole-1-carboxamides (or thiocarboxamides) 6a-e, 7a, b and N-substituted-3-amino-4-(3,4-dimethoxyphenyl)-5-hydroxy-1 H-pyrazole-1-carboxamides or (thiocarboxamides) 9a-c were synthesized. Moreover, the pyrazolo-[1,5-a]-1,3,5-triazine derivative 8 was also prepared. The new compounds were tested biologically for their in vivo antiinflammatory activity (AI) against carrageenan-induced rat paw oedema. All the investigated compounds exhibited significant AI activity in the range of 23-65%. The most potent compounds were further evaluated for their ulcerogenic liability and acute toxicity. They were found to be less toxic and nearly devoid of ulcerogenic activity as compared to phenylbutazone and indometacin.

Animals↗
PubMed2006

Heteropolynuclear palladium complexes with pyrazolate and its 3-tert-butyl derivatives: the effect of heterometal ions on the rate of isomerization.

The heteropolynuclear complexes [Pd(2)M'(2)(mu-pz)(6)] (M'=Ag (1), Au (2); pzH=pyrazole), HT-[Pd(2)M'(2)(mu-3-tBupz)(6)] (M'=Ag (3 a), Au (4 a); 3-tBupzH=3-tert-butylpyrazole), and HH-[Pd(2)Au(2)(mu-3-tBupz)(6)] (4 b) have been prepared and some of them were structurally characterized. When 3-tert-butylpyrazolate was employed as a bridging ligand, two linkage isomers (head-to-tail (HT) and head-to-head (HH)) arise from the difference in orientation of the substituent groups on the pyrazolate bridges between the two Pd atoms. (1)H NMR spectroscopy has been used to identify and to follow the reversible stereochemical rearrangement of the HH isomer of [Pd(2)Ag(2)(mu-3-tBupz)(6)] (3 b) to form the HT isomer 3 a in CDCl(3) and the HT isomer of [Pd(2)Au(2)(mu-3-tBupz)(6)] (4 a) to form the HH isomer 4 b in C(6)D(6). Kinetic studies of the reaction have established the rate law to be -d(HH)/dt=d(HT)/dt=k(2)[HH]-k(1)[HT] for 3 b and -d(HT)/dt=d(HH)/dt=k(1)[HT]-k(2)[HH] for 4 a, where k(1) and k(2) denote the rate of isomerization from the HT to the HH isomer and that from the HH to the HT isomer, respectively. For typical runs at 50 degrees C in C(6)D(6), k(1)=13.8x10(-5) s(-1), k(2)=18.6x10(-5) s(-1), and K(eq)=k(2)/k(1)=1.24 for 3 b, and k(1)=1.26x10(-5) s(-1), k(2)=3.52x10(-5) s(-1), and K(eq)=k(1)/k(2)=0.36 for 4 a. Temperature-dependent rate measurements reveal DeltaH(not equal) and DeltaS(not equal) to be 100(1) kJ mol(-1) and 0(3) J mol(-1) K(-1) for 3 b and 112(5) kJ mol(-1) and 20(17) J mol(-1) K(-1) for 4 a, respectively. The rate of isomerization is essentially unaffected by the concentration of the complex or by the presence of neutral bridging ligands. These data and observations imply that the isomerization involves an intramolecular exchange process.

Journal Article↗
PubMed2006

The structure of ammonium pyrazolates in the solid state.

The crystals obtained by mixing equimolar amounts of diethyl 1H-pyrazole-3,5-dicarboxylate and the primary amines phenethylamine and homoveratrylamine are ammonium pyrazolate salts as determined by 13C and 15N CPMAS NMR.

Journal Article↗
PubMed2000

New substituted 2-(pyrazol-1-yl) o-, m-, p-methylacetanilides with potential local anaesthetic and antiarrhythmic action. Part I.

Fifteen substituted 2-(pyrazol-1-yl)acetanilides were synthesized by N-alkylation of pyrazole and some of its derivatives with several 2-iodoacetanilides. The new compounds exhibited local anaesthetic and antiarrhythmic actions. The new compounds have been characterized by elemental chemical analysis, UV-Vis, IR, 1H, 13C NMR spectra and pharmacology research.

Acetanilides↗
PubMed2004

Novel eclipsed 2D cadmium(II) coordination polymers with open-channel structure constructed from terephthalate and 3-(2-pyridyl)pyrazole: crystal structures, emission properties, and inclusion of guest molecules.

Five new eclipsed two-dimensional (2D) coordination polymers, [[Cd(2)(TPT)(2)L(2)](GM(1))(3/2)(H(2)O)](infinity) (1) (TPT = terephthalate, L = 3-(2-pyridyl)pyrazole, GM(1) = terephthalic acid), [[Cd(TPT)L](GM(2))(H(2)O)(2)]( infinity) (2) (GM(2) = L = 3-(2-pyridyl)pyrazole), [[Cd(TPT)L](GM(3))(1/2)(H(2)O)](infinity) (3) (GM(3) = mesitylene), [[Cd(4)(TPT)(4)L(4)](GM(4))(7/2)](infinity) (4) (GM(4) = tetramethylbenzene), and [[Cd(TPT)L](GM(5))(1/2)](infinity) (5) (GM(5) = naphthalene), have been synthesized and characterized by X-ray diffraction. All the five complexes take the similar eclipsed 2D open-channel framework with different guest molecules included in the cavities of their channels. TGA analysis indicates that the eclipsed open-channel frameworks are thermally stable up to 300 degrees C. The porous property of the 2D framework of 5 was also investigated by the XRPD technique, which indicated that the guest molecules included in the open-channel frameworks are removable and the framework is maintained after the removal of the guest molecules. Moreover, complexes 1-5 also display strong blue emission in the solid state.

Journal Article↗
PubMed2006

Rhenium-mediated coupling of acetonitrile and pyrazoles. New molecular clefts for anion binding.

The reaction of fac-[ReBr(CO)3(NCMe)2] (1) with either pyrazole (Hpz) or 3,5-dimethylpyrazole (Hdmpz) in a 1:2 Re/pyrazole ratio affords the known complexes fac-[ReBr(CO)3(Hpz)2] (2) and [ReBr(CO)3(Hdmpz)2] (3). Using a 1:1 ratio, MeCN as solvent, and longer reaction times led to a mixture in which the major components are the pyrazolylamidino complexes fac-[ReBr(CO)3(HN=C(CH3)pz-kappa2N,N)] (4) and fac-[ReBr(CO)3(HN=C(CH3)dmpz-kappa2N,N)] (5). The complexes fac-[ReBr(CO)3(Hpz)(NCMe)] (6) and fac-[ReBr(CO)3(Hdmpz)(NCMe)] (7) (along with 2 and 3) were found to be minor components of these reactions. Analogous reactions of fac-[Re(OClO3)(CO)3(NCMe)2] yielded fac-[Re(NCCH3)(CO)3(HN=C(CH3)pz-kappa2N,N)]ClO4 (8), fac-[Re(NCCH3)(CO)3(HN=C(CH3)dmpz-kappa2N,N)]ClO4 (9), fac-[Re(Hpz)(CO)3(HN=C(CH3)pz-kappa2N,N)]ClO4 (10), and fac-[Re(Hdmpz)(CO)3(HN=C(CH3)dmpz-kappa2N,N)]ClO4 (11). The X-ray structure of 11 showed the perchlorate anion to be hydrogen-bonded by the N-H groups of the pyrazole and pyrazolylamidino ligands. The behavior of the compound fac-[Re(Hdmpz)(CO)3(HN=C(CH3)dmpz-kappa2N,N)]BAr'4 (13) (synthesized by reaction of [ReBr(CO)3(Hdmpz)2] (3) with (i) AgOTf and (ii) NaBAr'(4)/MeCN) as an anion receptor has been studied in CD3CN solution. In addition, the structure of the supramolecular adduct fac-[Re(CO)3(Hdmpz)(HN=C(CH3)dmpz-kappa2N,N)].Cl (14), featuring chloride binding by the two N-H groups, was determined by X-ray diffraction.

Journal Article↗