Pyrazolopyridine Derivatives Research Articles

One‐pot PTC synthesis of polyfused pyrazoles

AbstractThienopyrazole 2, 3, 5, or 6 and thienopyrazolothiazepine 7, 9, and 11 derivatives were prepared via the reaction of the 3‐aminopyrazoline‐5‐one 1 with CS2 and different molar ratio of a variety of halo compounds having an active methylene under PTC conditions. Also, treatment of 1 with CS2 and alcoholic KOH in 2:1:1 molar ratio afforded dipyrazolopyridine derivatives 12 and 14. On other hand, the pyrazolothiadiazineone derivative 13 was obtained by treating compound 1 with CS2 and alcoholic KOH in 1:2:2 molar ratio. Under PTC conditions, compound 1, CS2, and ethyl cyanoacetate or malononitrile to gave the pyrazolopyridine derivatives 16 and 17. Coupling of compound 1 with diazonium acetates afforded the hydrazone derivatives 18a,b, which were oxidized with bromine to give pyrazolotriazoles 19a,b or cyclized with aldehydes to give pyrazolotriazine derivatives 20a–e. Bromination of compound 1 afforded monobromopyrazole derivative 21, which could be condensed to a dipyrazolopyrazindione 23. Finally, the dibromopyrazole derivative 22 was cyclized with 2‐mercaptoethanol or o‐phenylenediamine to give the spiropyrazoles 24a,b. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:211–217, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10129

Synthesis of 2‐Thioxohydropyridine‐3‐Carbonitrile, 2‐Alkylthiopyridine, Thienopyridine, Pyrazolopyridine Derivatives and Their Theoretical Calculations

AbstractCyanothioacetamide (1) reacted with but‐2‐enal (2) to give the corresponding 4‐methyl‐2‐sulfanylpyridine‐3‐carbonitrile (7) which was used as a good starting material for the synthesis of 1‐(3‐amino‐4‐methylthieno[2,3‐b]pyridin‐2‐yl)ethan‐1‐one (10), 3‐amino‐4‐methylthieno[2,3‐b]pyridine‐2‐carboxamide (15), 3‐amino‐4‐methylthieno[2,3‐b]pyridine‐2‐carboxylate (18) and 3‐amino‐4‐methylthieno[2,3‐b]pyridin‐2‐ylarylketone 25a‐c through its reactions with each of (1‐chloroacetone (8), 3‐chloropentane‐2,4‐dione (11) or ethyl 2‐chloro‐3‐oxo‐butanoate (19)), 2‐chloroacetamide (13), ethyl 2‐chloroacetate (16) and 2‐bromo‐1‐arylethan‐1‐one 23a‐c, respectively. Considering the data of elemental analyses, IR, 1HNMR, mass spectra and theoretical calculations, structures of the newly synthesized heterocyclic compounds were elucidated.

Synthesis of Thiazole, Triazole, Pyrazolo[3,4-b]-Pyridinyl-3-Phenylthiourea, Aminopyrazolo[3,4-b]Pyridine Derivatives and Their Biological Evaluation

The pyrazolopyridine derivatives 1a,b reacted with phenylisothiocyanate (2), nitrous acid and cinnamonitrile derivatives 5a,b to afford the corresponded pyrazolo[3,4-b]-pyridinyl-3-phenylthiourea derivatives 3a,b, 3-diazotized aminopyrazolo[3,4-b]-pyridine derivatives 4a,b and Schiff bases 7a-d in a respective manner. Compounds 3a,b, 4a,b and 7a,d were taken as the starting materials for the present study owing to the presence of more than one active site. Compounds 3a,b reacted with the halogen-containing reagents e.g. 11a,b, 13 and 15 to give the corresponded thiazole derivatives 12a-d, 14a,b and 16a,b respectively. Compounds 4a,b coupled with the active hydrogen-containing reagents 17a,j to afford the corresponding 3-hydrazino derivatives 18a-t which could be cyclized to give the corresponding triazines 19a-t respectively. Compounds 7a-d reacted with thioglycolic acid (9) to give the corresponding thiazole derivative 10a-d in a good yield. The assigned structures of the newly synthesized compounds are based on their elemental analyses. IR. 1H NMR and mass spectra. The biological activity of some of these compounds was tested.

ChemInform Abstract: Coupling and Nucleophilic Reactions of a Diazotized Pyrazolopyridine Derivatives.

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Pyrazolopyridine derivatives act as competitive antagonists of brain adenosine A 1 receptors: [ [formula omitted]]GTPγS binding studies

The effects of adenosine receptor ligands and three novel pyrazolopyridine derivatives on guanosine-5′- O-(3-[ 35 S ]thio)triphosphate ([ 35 S ]GTPγS) binding to rat cerebral cortical membranes were examined. [ 35 S ]GTPγS binding was stimulated in a concentration dependent manner by several adenosine receptor agonists. The adenosine A 2a receptor selective agonist, 2- p-(2-carboxyethyl)phenethylamino-5′- N-ethylcarboxamidoadenosine (CGS 21680), was ineffective confirming specificity for adenosine A 1 receptor activation. 2-Chloro- N 6-cyclopentyladenosine (CCPA; 10 −7 M)-stimulated [ 35 S ]GTPγS binding was inhibited by xanthine and pyrazolopyridine based adenosine receptor antagonists. The concentration–response curve for CCPA-stimulated [ 35 S ]GTPγS binding was shifted to the right with increasing concentrations of antagonist without significant changes in maximal response. Schild analyses determined p K B values of 8.97, 8.88, 8.21, 8.16, 7.79 and 7.65 for 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), ( R)-1-[( E)-3-(2-phenylpyrazolo[1,5 a]pyridin-3-yl) acryloyl]-2-piperidine ethanol (FK453), 6-oxo-3-(2-phenylpyrazolo[1,5 a]pyridin-3-yl)-1(6 H)-pyridazinebutyric acid (FK838), 9-chloro-2-(2-furyl)[1,2,4]triazolo-[1,5 c]quinazolin-5-amine (CGS 15943), 8-cyclopentyl-1,3-methylxanthine (CPT) and ( R)-1-[( E)-3-(2-phenylpyrazolo[1,5 a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352), respectively. Schild slopes were close to unity, confirming that these novel pyrazolopyridine derivatives act as competitive antagonists at rat brain adenosine A 1 receptors.

Species differences in brain adenosine A1 receptor pharmacology revealed by use of xanthine and pyrazolopyridine based antagonists.

1. The pharmacological profile of adenosine A1 receptors in human, guinea-pig, rat and mouse brain membranes was characterized in a radioligand binding assay by use of the receptor selective antagonist, [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]-DPCPX). 2. The affinity of [3H]-DPCPX binding sites in rat cortical and hippocampal membranes was similar. Binding site affinity was higher in rat cortical membranes than in membranes prepared from guinea-pig cortex and hippocampus, mouse cortex and human cortex. pKD values (M) were 9.55, 9.44, 8.85, 8.94, 8.67, 9.39 and 8.67, respectively. The binding site density (Bmax) was lower in rat cortical membranes than in guinea-pig or human cortical membranes. 3. The rank order of potency of seven adenosine receptor agonists was identical in each species. With the exception of 5'-N-ethylcarboxamidoadenosine (NECA), agonist affinity was 3.5-26.2 fold higher in rat cortical membranes than in human and guinea-pig brain membranes; affinity in rat and mouse brain membranes was similar. While NECA exhibited 9.3 fold higher affinity in rat compared to human cortical membranes, affinity in other species was comparable. The stable GTP analogue, Gpp(NH)p (100 microM) reduced 2-chloro-N6-cyclopentyladenosine (CCPA) affinity 7-13.9 fold, whereas the affinity of DPCPX was unaffected. 4. The affinity of six xanthine-based adenosine receptor antagonists was 2.2-15.9 fold higher in rat cortical membranes compared with human or guinea-pig membranes. The rank order of potency was species-independent. In contrast, three pyrazolopyridine derivatives, (R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-2-piperidine ethanol (FK453), (R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352) and 6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinebutyric acid (FK838) exhibited similar affinity in human, guinea-pig, rat and mouse brain membranes. pKi values (M) for [3H]-DPCPX binding sites in human cortical membranes were 9.31, 7.52 and 7.92, respectively. 5. Drug affinity for adenosine A2A receptors was determined in a [3H]-2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido ade nosine ([3H]-CGS 21680) binding assay in rat striatal membranes. The pyrazolopyridine derivatives, FK453, FK838 and FK352 exhibited pKi values (M) of 5.90, 5.92 and 4.31, respectively, compared with pKi values of 9.31, 8.18 and 7.57 determined in the [3H]-DPCPX binding assay in rat cortical membranes. These novel pyrazolopyridine derivatives therefore represent high affinity, adenosine A1 receptor selective drugs that, in contrast to xanthine based antagonists, exhibit similar affinity for [3H]-DPCPX binding sites in human, rat, mouse and guinea-pig brain membranes.

FK453: A Novel Non‐Xanthine Adenosine A1 Receptor Antagonist as Diuretic

Adenosine is a purine nucleotide that is widely distributed throughout the body; it modulates a wide variety of physiological functions via extracellular receptors. Adenosine receptors, located on the cell membranes, are classified into two major subtypes, adenosine A, and A, receptors. This classification was originally based on the effects of a series of adenosine analogs on adenylate cyclase activity; activation of the adenosine A, receptor inhibits, while activation of the adenosine A2 receptor stimulates, adenylate cyclase (26,46). Many adenosine agonists that have a preferential affinity for adenosine A, receptors depress heart rate, myocardial contractility. and impulse conduction velocity (5,10,14). The agonists that have a greater affinity for adenosine A, receptors induce vasodilation ( 1 1.15,17,24,28). A number of workers have found that another adenosine receptor, which has been classified as an adenosine A , receptor, is present in many tissues. This receptor was recently subdivided into adenosine A, and A, receptor subtypes. As knowledge of the different types of adenosine receptors increases, these receptors may prove to be possible targets for novel pharmacologically active drugs. Adenosine itself is used in the acute treatment and diagnosis of supraventricular arrhythmias. To date, however, no selective adenosine receptor agonist or antagonist has been used therapeutically. FK453 is a novel pyrazolopyridine derivative that was synthesized at Fujisawa Pharmaceutical Co., Ltd. (Osaka, Japan). During a search for diuretics, FK453 was found to possess a potent diuretic activity with renal vasodilatory and uricosuric effects (40). In addition. FK453 markedly antagonized the negative inotropic effects of adenosine in isolated guinea pig atria, but was less potent in inhibiting the relaxation induced by adenosine in guinea pig aorta. These results suggested that FK453 is a potent and selective

Trimethylaluminum-Promoted Cyclization of Cyanoenaminones. A Versatile Synthesis of Substituted Pyrazolopyridines

Abstract Trimethylaluminum (TMA) promotes the cyclization of cyanoenaminones to form [b]-fused pyrazolopyridine derivatives.

Regulation between adenosine and excitatory aminoacids release “in vivo” in adult and old freely moving rats

The effects of adenosine receptor ligands and three novel pyrazolopyridine derivatives on guanosine-5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding to rat cerebral cortical membranes were examined. [35S]GTPγS binding was stimulated in a concentration dependent manner by several adenosine receptor agonists. The adenosine A2a receptor selective agonist, 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine (CGS 21680), was ineffective confirming specificity for adenosine A1 receptor activation. 2-Chloro-N6-cyclopentyladenosine (CCPA; 10−7 M)-stimulated [35S]GTPγS binding was inhibited by xanthine and pyrazolopyridine based adenosine receptor antagonists. The concentration–response curve for CCPA-stimulated [35S]GTPγS binding was shifted to the right with increasing concentrations of antagonist without significant changes in maximal response. Schild analyses determined pKB values of 8.97, 8.88, 8.21, 8.16, 7.79 and 7.65 for 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), (R)-1-[(E)-3-(2-phenylpyrazolo[1,5a]pyridin-3-yl) acryloyl]-2-piperidine ethanol (FK453), 6-oxo-3-(2-phenylpyrazolo[1,5a]pyridin-3-yl)-1(6H)-pyridazinebutyric acid (FK838), 9-chloro-2-(2-furyl)[1,2,4]triazolo-[1,5c]quinazolin-5-amine (CGS 15943), 8-cyclopentyl-1,3-methylxanthine (CPT) and (R)-1-[(E)-3-(2-phenylpyrazolo[1,5a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352), respectively. Schild slopes were close to unity, confirming that these novel pyrazolopyridine derivatives act as competitive antagonists at rat brain adenosine A1 receptors.

SYNTHESIS OF NEW THIENO-[2,3-b]-PYRIDINE AND PYRAZOLO-5,4-b-PYRIDINE DERIVATIVES

3-Cyano-4,6-dimethyl-2-pyridinethiol 1 was allowed to react with chloroacetone and hydrazine hydrate to give the corresponding thienopyridine derivative 2 and pyrazolopyridine derivative 5, respectively. Compound 2 reacted with aldehydes to yield 3a-3c. Reaction of compound 5 with thionyl chloride and arylidinemalononitriles gives 6 and 8a,b, respectively. Compound 6 reacted with benzil and p,p-dichlorobenzil to yield the corresponding benzilimine derivatives 7a,b.

ChemInform Abstract: Synthesis of Pyrazolo(3,4‐c)isoquinoline and Pyrazolo(3,4‐b)pyridine Derivatives from Azomethines and CH‐Acidic Compounds.

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ChemInform Abstract: Reactions with Cyanothioacetamide Derivatives: Synthesis and Reactions of Some Pyrazolo(3,4‐b)pyridine Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Characteristics of vasoinhibitory action of FK 453 (a pyrazolo-pyridine derivative), a new antihypertensive agent with diuretic action in isolated rabbit aorta.

The vasoinhibitory effect of FK 453 was examined in isolated rabbit aorta. FK 453 inhibited contractile responses to norepinephrine, angiotensin-I and KCl. Pretreatment of the tissue with FK 453 failed to affect the relaxing effect of verapamil on the KCl response and the inhibitory effect of prazosin on the phenylephrine response. FK 453 inhibited both the residual norepinephrine response and the subsequent Ca2+ response in a Ca(2+)-free medium containing EGTA and nifedipine. The inhibitory effect of a combined treatment with either FK 453 plus nitroglycerin or FK 453 plus theophylline, but not with FK 453 plus M & B 22,948 (2-o-propoxyphenyl-8-azapurine-6-one; May & Baker), was much greater than that of any single treatment. Pretreatment with FK 453 also potentiated relaxing effects of nitroglycerin and isoproterenol on the PGF2 alpha response. The effect of a combined treatment with FK 453 plus theophylline, but not with FK 453 plus M & B 22,948, was much greater than that of any single treatment. FK 453 also inhibited the activity of phosphodiesterase from canine aorta to convert cyclic [3H]-GMP and cyclic [3H]-AMP to 5'-GMP and 5'-AMP, respectively. These results suggest that the inhibitory action of FK 453 is not due to inhibition of voltage-operated Ca2+ channels or alpha-adrenoceptors, but due to increase in cyclic GMP level.

Tricyclic azaergoline analogues: synthesis, structural modifications, and pharmacological studies.

As an extension of previous investigations on synthesis and dopamine autoreceptor activity of bicyclic ergoline analogues the tricyclic azaergoline analogues 9a and 9b were synthesized. Furthermore, the geometry of the aromatic beta-ethylamine moiety of 9a,b was modified by stereoselective construction of the cycloheptenyl fused pyrazolopyridine derivative 7 and the aminomethyl substituted tricycle 10. Binding affinity of these compounds at dopamine (DA) receptor sites was investigated employing rat striatum homogenate: The compounds reveal modest to weak, but selective binding to a dopamine D-2 receptor when it is labelled with the DA-autoreceptor agonist [3H]-SND 919. In vivo studies with mice showed that 7, 9a,b, and 10 affect their CNS activity.

Reactions with activated nitriles: A new route for the synthesis of new pyridine and pyrazolopyridine derivatives

It has been found that α, β-unsaturated nitrile derivatives1–3 reacted with S-methylisothiourea to give the propene derivatives4–6 respectively. Cyclisation of4–6 using ethanolic hydrochloric acid afforded the pyridine derivatives7–9 in good yields. On the other hand, the reactions of hydrazine hydrate and of phenylhydrazine with each of7–9 gave the corresponding pyrazolopyridine derivatives10–15. The structures of the newly synthesised derivatives were assigned on the basis of elemental analyses, IR and1H-NMR spectral data studies.

ChemInform Abstract: Nitriles in Organic Synthesis: Synthesis of New Pyridazine, Pyridine and Pyrazolo(3,4‐b)pyridine Derivatives.

AbstractThe new nitrile (III), when coupled with the arenediazonium salts (IV), gives the highly stable hydrazones (V).

ChemInform Abstract: A Facile Synthesis of Pyrazolo(1,5‐a)pyridine Derivatives: Reaction of Cinnamonitriles with 5‐Amino‐4‐cyano‐3‐cyanomethylpyrazole.

ChemInform Abstract: A Facile Synthesis of Pyrazolo(1,5‐a)pyridine Derivatives: Reaction of Cinnamonitriles with 5‐Amino‐4‐cyano‐3‐cyanomethylpyrazole.

ChemInform Abstract: Synthesis of Aromatic Pyrazolo(4,5‐b)pyridine Derivatives.

AbstractThe aminopyrazole (I) reacts with the chalcones (II) to give the dihydropyrazolopyridines (III).

Effects of pyrazolopyridines and a triazolopyridazine on the pentobarbital discriminative stimulus.

Rats were trained to discriminate injections of racemic pentobarbital (5.0 mg/kg) from saline in a two-lever drug discrimination task. After stable discrimination performance was attained, stimulus generalization studies were conducted with another barbiturate (barbital), benzodiazepine derivatives (diazepam and chlordiazepoxide), pyrazolopyridine derivatives (etazolate, cartazolate, and tracazolate), and a triazolopyridazine (CL 218, 872). The pentobarbital stimulus generalized to all of these compounds, except cartazolate. In addition, the administration of the benzodiazepine receptor antagonist flumazepil prior to benzodiazepine or triazolopyridazine administration produced a dose-related antagonism of each generalization. In contrast, the administration of flumazepil before barbiturate or pyrazolopyridine (i.e., etazolate or tracazolate) injection resulted in no attenuation of these generalizations. The results indicate that while certain barbiturates, benzodiazepines, pyrazolopyridines and triazolopyridazines are capable of producing similar stimulus effects, the behavioral actions of these agents can be differentiated on the basis of their susceptibility to antagonism by flumazepil.

ChemInform Abstract: A Novel One‐Step Synthesis of Pyrazolo(1,5‐a)pyridine Derivatives.

ChemInformVolume 18, Issue 40 Heterocyclic Compounds ChemInform Abstract: A Novel One-Step Synthesis of Pyrazolo(1,5-a)pyridine Derivatives. R. C. PHADKE, R. C. PHADKE Dyes Res. Lab., Dep. Chem. Technol., Univ. Bombay, Matunga, Bombay-400019, IndiaSearch for more papers by this authorD. W. RANGNEKAR, D. W. RANGNEKAR Dyes Res. Lab., Dep. Chem. Technol., Univ. Bombay, Matunga, Bombay-400019, IndiaSearch for more papers by this author R. C. PHADKE, R. C. PHADKE Dyes Res. Lab., Dep. Chem. Technol., Univ. Bombay, Matunga, Bombay-400019, IndiaSearch for more papers by this authorD. W. RANGNEKAR, D. W. RANGNEKAR Dyes Res. Lab., Dep. Chem. Technol., Univ. Bombay, Matunga, Bombay-400019, IndiaSearch for more papers by this author First published: October 6, 1987 https://doi.org/10.1002/chin.198740194Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume18, Issue40October 6, 1987 RelatedInformation