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Showing papers on "Pyrazole published in 1997"


Journal ArticleDOI
TL;DR: 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis, is identified.
Abstract: A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.

1,895 citations


Journal ArticleDOI
TL;DR: In this article, the σ-donor/π-acceptor characteristics of imidazole carbenes are compared with those of phosphines, and an in situ forted rhodium ethoxide complex acts as deprotonating agent.

173 citations


Journal ArticleDOI
TL;DR: The tripodal bis(thioimidazolyl)(pyrazolyl)hydroborato [NSS] donor ligand, [HB(timMe)2pz]-, has been synthesized by the sequential reaction of LiBH4 with methimazole and pyrazole.
Abstract: The tripodal bis(thioimidazolyl)(pyrazolyl)hydroborato [NSS] donor ligand, [HB(timMe)2pz]-, has been synthesized by the sequential reaction of LiBH4 with methimazole and pyrazole. Importantly, the ...

163 citations


Journal ArticleDOI
TL;DR: Results clearly indicate that complex 1 is a good model for superoxide dismutase, which catalyzes the dismutation of superoxide at biological pH.
Abstract: A new dinucleating ligand, 1,5-bis(1-pyrazolyl)-3-[bis(2-imidazolyl)methyl] azapentane (Hbpzbiap), containing pyrazoles and imidazoles has been designed and synthesized. The synthesis and characterization of the copper complexes with the ligand Hbpzbiap and its dehydronated form are described. This study is aimed at modeling the active site of copper−zinc superoxide dismutase (SOD). Single crystals of the imidazolato-bridged complex [Cu2(bpzbiap)Cl3] (1) and non-imidazolato-bridged complex [Cu2(Hbpzbiap)Cl4] (2) were obtained and their structures determined by X-ray diffraction. Both structures show two copper centers in two different coordination environments: a distorted square pyramid and a distorted tetrahedron. The Cu−nitrogen bond lengths range from 1.919(4) to 2.039(3) A and are as expected. The copper−copper distances from 5.566(1) to 6.104(1) A being only slightly shorter than that found in bovine erythrocyte SOD. Temperature-dependent magnetic susceptibility study of 1 shows antiferromagnetic b...

133 citations


Patent
14 Nov 1997
TL;DR: In this article, substituted pyrazole derivatives are used as a medicament to treat cardiocirculatory diseases, and a method for the production and use of such derivatives as a medicine is described.
Abstract: The present invention relates to novel substituted pyrazole derivatives, a method for the production and the use thereof as a medicament, specially as a medicament to treat cardiocirculatory diseases.

88 citations


Journal ArticleDOI
TL;DR: Compound 14n, a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists, shows high potency both in vitro and in vivo and is selection for clinical evaluation as an antihypertensive agent.
Abstract: The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure−activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2‘-(1H-tetrazol-5-yl)-1,1‘-biphenyl-4-yl]methyl]-1H-pyrazole-4-carbo...

82 citations


Journal ArticleDOI
TL;DR: A series of new rhodium complexes with chiral ferrocenyl chelating ligands containing a tertiary phosphine and a pyrazole moiety have been obtained in good yields from the reaction of the corresponding P,N ligand (1a−p) with [Rh(1,5-COD)2]BF4, [Rh (CO)2Cl]2, and [RH(COE)2CL]2] as discussed by the authors.

75 citations


Journal ArticleDOI
TL;DR: The discovery that 5-(4-chlorophenyl)-4-methyl-3-(1-2-phenylethyl)piperidin-4-yl)iso xazole is a nanomolar antagonist at human dopamine D4 receptors with > 500-fold selectivity over hD2 and > 200- fold selectivityover hD3.
Abstract: 5-(4-Chlorophenyl)-3-(1-(4-chlorobenzyl)piperidin-4-yl)pyrazole (3) was identified from screening of the Merck sample collection as a human dopamine D4 (hD4) receptor ligand with moderate affinity ...

66 citations


Journal ArticleDOI
TL;DR: A series of novel 1,5-diarylpyrazole derivatives was synthesized and tested for anti-inflammatory and analgesic activities to develop anti- inflammatory agents with fewer side effects than existing nonsteroidal anti- inflammation drugs.
Abstract: A series of novel 1,5-diarylpyrazole derivatives was synthesized and tested for anti-inflammatory and analgesic activities to develop anti-inflammatory agents with fewer side effects than existing nonsteroidal anti-inflammatory drugs. The structure-activity relationships in this series were extensively studied. Electron-withdrawing substituents such as CN and CF3 were optimal at the 3-position of the pyrazole ring. Replacement of these substituents with bulky ones gave less active compounds. The 4-(methylsulfonyl)phenyl group seemed to be the optimal group at the 5-position of the pyrazole ring. The most potent compound was 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyrazole-3-carbonitrile (19a), with oral ED50 value of 0.030 and 0.47 mg/kg on adjuvant-induced arthritis and collagen-induced arthritis, respectively, and an ED30 value of 7.4 mg/kg in the yeast-induced hyperalgesia (Randall-Selitto) assay. Compound 19a also showed potent inducible cyclooxygenase (COX-2)-inhibitory activity (IC50 = 0.24 microM) with no COX-1 inhibition even at 100 microM.

65 citations


Journal ArticleDOI
TL;DR: A comparison of guanylating agents 1 and 2 was performed on a series of primary, secondary and aromatic amines in solution and on solid phase resins as mentioned in this paper, and Pyrazole 2 performed well in each case, except one aniline which failed to react.

64 citations


Journal ArticleDOI
TL;DR: A variety of α-cyanoketene S,S-acetals, readily prepared by the reaction of cyanoacetanilides or cyanothioacetamide with carbon disulfide, followed by alkylation, react smoothly with nucleophiles to afford variously substituted methylthio derivatives of pyrrole, pyrazole, pyridine and pyrimidine as discussed by the authors.
Abstract: A variety of novel α-cyanoketene S,S-acetals, readily prepared by the reaction of cyanoacetanilides or cyanothioacetamide with carbon disulfide, followed by alkylation, react smoothly with nucleophiles to afford variously substituted methylthio derivatives of pyrrole, pyrazole, pyridine and pyrimidine.

Journal ArticleDOI
TL;DR: The X-ray crystal structure and 1H NMR and electronic spectroscopic properties of {[Ru(py-pz)3]2Cu3}(ClO4) are reported.
Abstract: Reaction between [Ru(py-pzH)3](ClO4)2 (where py-pzH = 3-(pyridin-2-yl)pyrazole) and Cu(II) or Cu(I) in methanol, in the presence of excess NEt3, affords the triple-strand helical supramolecular {[Ru(py-pz)3]2Cu3}(ClO4). The X-ray crystal structure and 1H NMR and electronic spectroscopic properties of {[Ru(py-pz)3]2Cu3}(ClO4) are reported.

Journal ArticleDOI
TL;DR: The 1H-pyrazole-3-carboxylic acid or its remarkably stable acid chloride 3 can easily be converted into the corresponding ester or amide derivatives 4 or 5, respectively, from reaction with alcohols or N-nucleophiles.

Journal ArticleDOI
TL;DR: In this paper, an achiral pyrazole template has been evaluated in enantioselective conjugate radical additions and it was shown that it is inferior to those obtained from an oxazolidinone template.

Journal ArticleDOI
TL;DR: The crystal structures of Fe 4 III (HL) 2 (L) 6 (μ-O) 2 [PF 6 ] 2 ·4MeCN ( 1 ·4MECN) and [Fe 2 III(HL) 4 (OSO 3 ) 2 (μ -O)]·2MeOH·3H 2 O ( 2 ·MeOH ·3H2 O) have been determined.

Journal ArticleDOI
TL;DR: In this article, the 2 × 2grid-like architectures are a result of the preference of the nodes for elongated square-pyramidal coordination, in which the deprotonated====== pyrazolyl groups act as bridging ligands and the 2× 2gridlike structures are a consequence of the preferences of nodes.

Journal ArticleDOI
TL;DR: A series of potential ligands bearing polydentate amine substituents in the 3 and 5 positions of the heterocycle has been synthesized in this paper, which can be viewed as dinuclear linked versions of tran-type complexes with distorted trigonal-bipyramidal coordination spheres around cobalt(II).
Abstract: A series of pyrazole-based potential ligands bearing polydentate amine substituents in the 3- and 5-positions of the heterocycle has been synthesized [3,5-bis(R2NCH2)-pyzH R2N = Me2N(CH2)3NMe (2aH), [Me2N(CH2)3]2N (2bH), (Et2NCH2CH2)2N (2cH)]. Upon reaction with two equivalents of CoCl2 they form complexes LCo2Cl3 (3a–c; L = 2a–c, respectively) which are shown crystallographically to contain a dinuclear metal core bridged by both the pyrazolate unit and a chlorine atom, with each cobalt center carrying a further terminal chlorine atom. Two of the ligand side arms in 3b, c are dangling, thus leading to five-coordination of the cobalt(II) centers in all cases. Addition of two equivalents of NaBPh4 to solutions of 3b, c induced coordination of the formerly dangling side arms to the metal centers by substitution of the terminal chlorine atoms. The resulting compounds [LCo2Cl](BPh4)2 (4b, c, respectively) were characterized by X-ray structure analyses. They can be viewed as dinuclear linked versions of tran-type complexes [(tran = tris(aminoalkyl)amine] with distorted trigonal-bipyramidal coordination spheres around cobalt(II). Conformational analyses employing force-field calculations were carried out for 4b, c in order to rationalize the conformations observed in the solid state with regard to the accessible conformational space.

Journal ArticleDOI
TL;DR: A series of pyrazole derivatives with two and three alkylating sites were prepared and their cytotoxicity against cancer cells as well as antitumor activity against L1210 was investigated.
Abstract: A series of pyrazole derivatives with two and three alkylating sites were prepared and their cytotoxicity against cancer cells as well as antitumor activity against L1210 was investigated. The best result of cytotoxicity was obtained with the trichloride 5 and the best antitumor activity (ILS 33%) with the dibromide 3. These results can provide valuable information for further study of the more effective antitumor agent. Keywords: pyrazole, synthesis, cytotoxicity, antitumor activity, polyalkylator.

Journal ArticleDOI
TL;DR: In this paper, the structure-activity relationship of eight chiral compounds having either a pyrazole (series P) or an isoxazole ring as a central bridge in the mesogenic core was studied.
Abstract: A study has been undertaken of the structure-activity relationship of eight new chiral compounds having either a pyrazole (series P) or an isoxazole (series I) ring as a central bridge in the mesogenic core. The presence of dimers in the pyrazole compounds accounts for their lower P s values in comparison with the isoxazole analogues. The corresponding four beta-diketone precursors have also been studied and these, as expected given their bent molecular shape, show much worse mesomorphic and ferroelectric behaviour. In order to complete the study, the molecular dipoles of the three types of derivative have been determined using AM1 calculations. Two types of chiral tail have been incorporated into the compounds: alkoxy and alkanoyloxy. The latter tail gives rise to the best mesomorphic and ferroelectric properties. A study of the tail conformations by MM2 calculations provides an explanation of these results. The highest P s value (137 nC cm) has been obtained for the isoxazole derivative with the (2S)-2-...

Journal ArticleDOI
TL;DR: In this article, a model has been used to design novel pyrazole methanesulfonates with high levels of insecticidal activity and very low levels of acute mammalian toxicity.
Abstract: A model has been used to design novel pyrazole methanesulfonates. The pyrazole carboxamide methanesulfonates demonstrated insecticidal activity with low levels of acute mammalian toxicity. The amides formed from amines with α-branching (e.g. isopropyl and sec-butyl) demonstrated the highest level of activity. The model has also been used to design novel pyrazole sulfonamide methanesulfonates with very high levels of insecticidal activity. Most of the sulfonamides also possessed significant acute mammalian toxicity. Rice paddy field testing of the carboxamides on field population hoppers gave poor results.

Patent
30 Sep 1997
TL;DR: In this paper, 4-Amino-1H-pyrazolo[3,4-d]pyrimidine derivatives of formula (I) are described. The compounds inhibit the tyrosine kinase activity of the receptor for epidermal growth factor.
Abstract: 4-Amino-1H-pyrazolo[3,4-d]pyrimidine derivatives of formula (I) in which m, n and v are each, independently of one another, 0 or 1, R is hydrogen or methyl, R1 is chlorine or methyl which is in each case located in position 3 of the phenyl radical, X is the group NH(CH-R7)t in which t is 0, 1 or 2 and R7 is hydrogen, or the group (C[R3]-R4)q, in which q is 0, and R2 is nitro, cyano, amino, dimethylamino-lower-alkyleneamino, 4-pyridylcarbonylamino, 2-methylpropanoylamino, tert-butyloxycarbonylamino, or methyl which is substituted by amino, C1-C5-alkanoylamino, tert-butyloxycarbonylamino or benzoylamino, with the exception of 3-(3-aminobenzylamino)-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine are described. The compounds of formula (I) inhibit in particular the tyrosine kinase activity of the receptor for epidermal growth factor and can be used, for example, for epidermal hyperproliferation (psoriasis) and as antitumor agents.

Journal ArticleDOI
TL;DR: In this paper, the coordination mode of the title ligand, HMPzSB (synthesized for the first time and characterised by elemental analysis, mass, IR and PMR spectral parameters), is reported by solid state isolation and physicochemical identification of cobalt(III) complexes.

Journal ArticleDOI
TL;DR: The cycloaddition reaction of the pyrrol-2,3-diones 1a-e to equimolar amount of diazomethane gave 2-aryl(methyl)-2-azabicyclo[3.1.0]hexane 3a−e together with 5,6-dioxo-1H-pyrrolo[2, 3-d]pyrazole derivatives 4a −e.

Journal ArticleDOI
TL;DR: In this article, the liquid crystalline behavior of 1-(4n-decyloxyphenyl)-3-(4-X-phenyl)propan-1,3-diones and their pyrazole and isoxazole derivatives has been studied by optical microscopy, DSC and X-ray techniques.
Abstract: The liquid crystalline behaviour of 1-(4-n-decyloxyphenyl)-3-(4-X-phenyl)propan-1,3-diones and their pyrazole and isoxazole derivatives has been studied by optical microscopy, DSC and X-ray techniques. The 4-substituents (X) were chosen to include a range of different polar and non-polar substituents: H, OCH3, Cl, Br and CN. A monotropic SA phase is observed for the beta-diketone derivative in which X CN and this is the first example of this phase found in a 1,3-diphenylpropan-1,3-dione derivative. The majority of the pyrazole and isoxazole compounds show SA phases. As regards the cyano-substituted compounds, X-ray diffraction studies on the mesophase show that the layer spacing is consistent with a partial bilayer SA mesophase. The first hyperpolarizabilities of the cyano-derivatives due to their push-pull structure have been measured by the EFISH method. Values for these compounds were found to be comparable to those for other conjugated CH3O-pi-CN systems.

Journal ArticleDOI
TL;DR: In this article, the molecular structures of 2,6-bis-(2′-methoxyphenyl)pyridine 1, the tetrafluoroborate salt of 2.6-bis-(2.6)-methoxide-mithoxy-polymorphic pyridine 2 and 3,5-bimodal pyrazole 4 have been determined by X-ray analysis.

Journal ArticleDOI
TL;DR: In this article, the crystal structures of two of these atoms show electronic interaction between the tetrazine rings and the amino groups, but none between the pyrazine and pyrazole rings.
Abstract: Reaction of 3,6-bis(3,5-dimethylpyrazolyl)-1,2,4,5-tetrazine with mono- and di-amines gives rise to nucleophilic substitution of one or both of the pyrazolyl substituents, and reaction with diamines under appropriate conditions can lead to bis(3-amino-1,2,4,5-tetrazines), e.g. 12a, 12b and 13. The crystal structures of two of these (12a and 13) show electronic interaction between the tetrazine rings and the amino groups, but none between the tetrazine and pyrazole rings. In 12a there is an extensive network of N–H · · · N hydrogen bonds.

Patent
23 Dec 1997
TL;DR: In this paper, the concept of compounds of formula (I) was introduced, where Ar represents a mono-, di- or trisubstituted aryl group where at least one position on Ar ortho to the point of attachment to the pyrazole ring is substituted.
Abstract: This invention encompasses compounds of formula (I), wherein Ar represents a mono-, di- or trisubstituted aryl group where at least one position on Ar ortho to the point of attachment to the pyrazole ring is substituted; and R1 represents lower alkyl; R2 is hydrogen or lower alkyl; and R3 and R4 independently represent organic and inorganic substituents, which compounds are highly selective partial agonists or antagonists at human CRF1 receptors and are useful in the diagnosis and treatment of treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.

Journal ArticleDOI
TL;DR: In this article, the Tpx ligands hydrotris(5-methyl-3-py*-pyrazolyl)borate Tp3Py,Me (py* = 3-pyridyl) with zinc halides or with Zn(ClO4)2 and KOH.
Abstract: Treatment of the potassium salts of the Tpx ligands hydrotris(5-methyl-3-py*-pyrazolyl)borate Tp3Py,Me (py* = 3-pyridyl) and TpPic,Me (py* = 5-α-picolyl) with zinc halides or with Zn(ClO4)2 and KOH yields the halide complexes Tp3Py,MeZn−Hal (Hal = F, Cl, Br, I) and the hydroxide complexes Tp3Py,MeZn−OH and TpPic,MeZn−OH, as well as the bis(ligand) complex (Tp3Py,Me)2Zn. All Tp3Py,MeZn−X complexes show a tendency for dimerization, using one pyridyl group each of the two Tp3Py,Me units to coordinate to the zinc ion of the opposite Tp3Py,MeZn fragment, as evidenced by the solid state structures of Tp3Py,MeZn−F (strong interaction) and Tp3Py,MeZn−I (weak interaction) and by a variable-temperature NMR study of Tp3Py,MeZn−OH. Despite the steric bulk of the Tp3Py,Me ligands, the bis(ligand) complex (Tp3Py,Me)2Zn contains zinc bound to all pyrazole nitrogen donor atoms in an octahedral fashion. Tp3Py,MeZn−F crystallizes in the triclinic space group P1 with a = 11.123(5) A, b = 11.638(7) A, c = 13.793(4) A, α = 7...

Journal ArticleDOI
TL;DR: In this paper, the total or partial hydrolysis of selected heterocycles afforded the dicarboxylic acids 8, 9 and 10 and the DICARBOXylic acid monoesters 11 and 12.

Journal ArticleDOI
TL;DR: In this article, the 2-(benzothiazol-2-yl)-1-bromo-1,2-ethanedione-1-arylhydrazones 3 were prepared and their behavior toward some nucleophiles was investigated.
Abstract: The novel, highly versatile 2-(benzothiazol-2-yl)-1-bromo-1,2-ethanedione-1-arylhydrazones 3 were prepared and their behavior toward some nucleophiles was investigated. Thus, reaction of 3 with the sodium salt of malononitrile afforded the aminopyrazolecarbonitriles 5 that undergo cyclocondensation with hydrazine, formic acid, and formamide to give the corresponding pyrazolo[3,4-d]pyridazine 6, pyrazolo[3,4-d]pyrimidinone 7, and pyrazolo[3,4-d]pyrimidine 8 derivatives, respectively. Similarly, reactions of 3 with each of acetylacetone, dibenzoylmethane, and benzoylacetonitrile afforded the corresponding pyrazole derivatives 9, 10, and 11, respectively. The latter products undergo cyclocondensation with hydrazine to afford the corresponding pyrazolo[3,4-d]pyridazines 12, 13, and 14, respectively. © 1997 John Wiley & Sons, Inc.