- Boosting Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology
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Multitarget design offers access to bioactive small molecules with potentially superior efficacy and safety. Particularly multifactorial chronic inflammatory diseases demand multiple pharmacological interventions for stable treatment. By minor structural changes, we have developed a close analogue of the cysteinyl-leukotriene receptor antagonist zafirlukast that simultaneously inhibits soluble epoxide hydrolase and activates peroxisome proliferator-activated receptor γ. The triple modulator exhibits robust anti-inflammatory activity in vivo and highlights the therapeutic potential of designed multitarget agents.
- Schierle, Simone,Flauaus, Cathrin,Heitel, Pascal,Willems, Sabine,Schmidt, Jurema,Kaiser, Astrid,Weizel, Lilia,Goebel, Tamara,Kahnt, Astrid S.,Geisslinger, Gerd,Steinhilber, Dieter,Wurglics, Mario,Rovati, G. Enrico,Schmidtko, Achim,Proschak, Ewgenij,Merk, Daniel
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supporting information
p. 5758 - 5764
(2018/06/18)
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- CHROMONE INHIBITORS OF S-NITROSOGLUTATHIONE REDUCTASE
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The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
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Page/Page column 44
(2011/09/15)
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- An improved and scalable process for zafirlukast: An asthma drug
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An improved and scalable process for the large-scale production of zafirlukast (Accolate), an important drug for asthma, is discussed along with impurity and scale-up-related issues.
- Goverdhan, Gilla,Reddy, Anumula Raghupathi,Sampath, Aalla,Srinivas, Kurella,Himabindu, Vurimidi,Reddy, Ghanta Mahesh
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experimental part
p. 67 - 72
(2010/04/22)
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- PROCESSES FOR PREPARING ZAFIRLUKAST
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An improved process for the preparation of substantially pure zafirlukast and pharmaceutical compositions thereof.
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Page/Page column 8
(2009/06/27)
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- SUBSTITUTED INDOLES
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Disclosed herein are substituted indole cysteinyl leukotriene receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 51
(2009/08/14)
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- Antileishmanial activity screening of 5-nitro-2-heterocyclic benzylidene hydrazides
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A series of 53 nitro derivatives rationally designed were obtained by parallel synthesis and screened against Leishmania donovani. Six compounds exhibited IC50 values lower than standard drugs. Brief SAR analysis revealed that substitution is important to the activity. Nitrothiophene analogues were more potent than the nitrofuran ones. This was attributed to the ability of sulfur atoms in accommodating electrons from nitro group, which facilitate its reduction and therefore the formation of free radicals lethal to parasites.
- Rando, Daniela G.,Avery, Mitchell A.,Tekwani, Babu L.,Khan, Shabana I.,Ferreira, Elizabeth I.
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p. 6724 - 6731
(2008/12/22)
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- Stereoselective syntheses of (±)-komaroviquinone and (±)-faveline methyl ether through intramolecular Heck reaction
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An efficient, flexible, and stereoselective convergent route for constructing the trans-10-hydroxy-1,1-dimethyloctahydrodibenzo[a,d]cyclohepten- 7-ones (5a-c) was achieved via intramolecular Heck reaction. This strategy has been successfully implemented for the syntheses of (±)-komaroviquinone (3) through (±)-coulterone dimethyl ether (5c) and (±)-faveline methyl ether (1a).
- Sengupta, Sujaya,Drew, Michael G. B.,Mukhopadhyay, Ranjan,Achari, Basudeb,Banerjee, Asish Kr
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p. 7694 - 7700
(2007/10/03)
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- Oxidant scavengers
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The present invention relates, in general, to a method of modulating physiological and pathological processes and, in particular, to a method of modulating intra- and extracellular levels of oxidants and thereby processes in which such oxidants are a participant. The invention also relates to compounds and compositions suitable for use in such methods.
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- CONDENSED PYRAZOLE DERIVATIVES, METHOD OF MANUFACTURING THE SAME, AND ANDROGEN INHIBITOR
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This invention provides a condensed pyrazole derivative of the Formula (1): STR1 (where A denotes CH or N, R 0 and R 3 denote same or different, a hydrogen atom or a lower alkyl group, R 1 and R 2 denote same or different, a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a nitro group or a halogen atom, m denotes 1 or 2, and n denotes 1, 2 or 3, provided that, when n is 2, two R 2 may be connected to each other to form a lower alkylenedioxy group), or its pharmaceutically acceptable salt. This derivative or its salt is excellent in the effect of inhibiting the expression of action of androgen, thereby being excellent in therapeutical effect of benign prostatic hypertrophy, prostatic carcinoma, etc., and has a long lasting of efficacy and high oral absorption.
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- Process for the preparation of aromatic methyl methoxycarboxylates
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The invention relates to a preparation process for aromatic methyl methoxycarboxylates by reaction of aromatic hydroxycarboxylic acids in the form of a mixture with the methoxycarboxylic acids with dimethyl sulphate in water.
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- Bicyclic carbamates and methods of treating inflammatory diseases using the same
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A compound of the formula STR1 wherein R is defined herein is useful as an anti-inflammatory agent.
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- Heter-aliphatic carboxamides
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This invention provides a series of novel heter-aliphatic carboxamides of formula I in which the group >Z--Y--XC=CH--NN--CH=CC=N--NN--N=C and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds; pharmaceutical compositions containing the formula I compound, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processes for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture.
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- Cyclic amides as medicaments
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This invention provides a series of novel cyclic amides of formula I in which the group >Z--Y--XC=CH--NN-CH=CHC=N--NN--N=C and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds; pharmaceutical compositions containing the formula I compound, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processs for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture.
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- Aliphatic carboxamides
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This invention provides a series of novel heterocyclic aliphatic carboxamides of formula I in which the group >Z--Y--XC=CH--NN--CH=CC=N--NN--N=C and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds; pharmaceutical compositions containing the formula I compound, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processes for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture.
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- Evolution of a Series of Peptidoleukotriene Antagonists: Synthesis and Structure-Activity Relationships of 1,6-Disubstituted Indoles and Indazoles
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A perception of structural similarities between two independent series of leukotriene antagonists (one emanating from FPL 55712 and one based upon the leukotrienes themselves) led to the discovery of a novel class of indole and indazole derived antagonists of peptidoleukotrienes.A systematic exploration of C-6 substituted 4-(indol-1-ylmethyl)-3-methoxybenzoic acids identified cyclopentylacetamide and cyclopentylurethane as preferred substituents.The corresponding indazoles were equipotent.These compounds are selective leukotriene antagonists with pKB values of 7.5-7.8 vs LTE4 on guinea pig trachea.
- Brown, Frederick J.,Yee, Ying K.,Cronk, Laura A.,Hebbel, Kevin C.,Krell, Robert D.,Snyder, David W.
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p. 1771 - 1781
(2007/10/02)
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- Indole and indazole keto sulphones as leukotriene antagonists
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This invention provides a series of novel keto sulfones of formula I STR1 in which the group =A-- is selected from =C(Ra)-- and =N-- and the other radicals have the meanings defined in the following specification. The compounds of formula I are leukotriene antagonists. The invention also provides pharmaceutically acceptable salts of the formula I compounds; pharmaceutical compositions containing the formula I compound, or their salts, for use in the treatment of, for example, allergic or inflammatory diseases, or endotoxic or traumatic shock conditions; and processes for the manufacture of the formula I compounds, as well as intermediates for use in such manufacture.
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- Heterocyclic amide derivatives and pharmaceutical use
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The invention concerns novel, pharmaceutically useful, amide derivatives of certain benzoheterocyclylalkanoic acids (and related tetrazoles and acylsulphonamides) of the formula I and salts thereof, wherein the radicals R1, R2, L, X, Y, Z, A1, Q, A2 and M have the meanings set out in the specification. The invention also includes pharmaceutical compositions incorporating a formula I compound or a salt thereof, a process for the manufacture of the said compound, together with intermediates for use in the latter process. STR1
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- Diels-Alder Reactions with 2H-Pyran-2-ones: Reactivity and Selectivity
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2H-Pyran-2-ones 1 react with maleic anhydride (2) in a double Diels-Alder reaction to give bicyclooct-2-ene-5,6:7,8-tetracarboxylic dianhydrides 5; the syn/syn structure was established.As expected, the reactivity of 1 was increased by electron donor substituents (OR, alkyl) and diminished by electron withdrawing substituents (CO2R).The steric influence of substituents at C-6 also decrease the reactivity of 1. - Methyl propiolate (6) and phenylacetylene (9) react with 1 to form the Diels-Alder products 7 which suffer CO2 elimination to yield methyl benzoates 8 with low and biphenyls 10 with high regioselectivity, respectively.
- Effenberger, Franz,Ziegler, Thomas
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p. 1339 - 1346
(2007/10/02)
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- Aromatic retinoic acid analogues
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Aromatic retinoic acid analogues of the formula STR1 where X is hydrogen or fluorine, Y is hydrogen, halogen of atomic number 9 or 17, hydroxy, alkyl of 1 to 2 carbon atoms or alkoxy of 1 to 2 carbon atoms and R is hydroxy, alkoxy, aroxy, or NR 1 R 2 where R 1 is hydrogen, alkyl, or aryl and R 2 is alkyl or aryl, with the proviso that when Y is hydrogen, X is fluorine. These retinoids are useful as chemopreventive agents for inhibiting tumor promotion in epithelial cells and for treating nonmalignant skin disorders.
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- Aromatic Retinoic Acid Analogues. 2. Synthesis and Pharmacological Activity
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Aromatic analogues of (E)-1-(4-carboxyphenyl)-2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)butadiene (1b) and its ethyl ester (1a) were synthesized as potential chemopreventive agents for the treatment of epithelial cancer and such skin diseases as psoriasis and cystic acne.The phenyl ring of 1 was replaced by 2-fluorophenyl, 2-methoxyphenyl, thienyl, furanyl, and pyridyl groups.The 1-fluorobutadiene analogue of 1 was also synthesized.With exception for the furanyl analogue, these compounds demonstrated good activity in reversing keratinization in hamster tracheal organ culture and in inhibiting the induction of ornithine decarboxylase in mouse epidermis by a tumor promoter.
- Dawson, Marcia I.,Chan, Rebecca,Hobbs, Peter D.,Chao, Wan-ru,Schiff, Leonard J.
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p. 1282 - 1293
(2007/10/02)
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- ipso Nitration. XXIII. Reactions of cyclohexadiene adducts from nitration of 4-ethyltoluene in acetic anhydride
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The diastereoisomers of 4-ethyl-1-methyl-4-nitrocyclohexa-2,5-dienyl acetate (1) and 1-ethyl-4-methyl-4-nitrocyclohexa-2,5-dienyl acetate (2) are stereospecifically reduced to the corresponding nitrocyclohexadienols with aluminum hydride.Each dienol is stereospecifically methylated to the corresponding methyl ether with methyl iodide, silver oxide, and potassium hydroxide.Acid-catalysed solvolysis of the acetates 1 and 2 results in the substitution of the acetate moiety by other nucleophiles and these reactions are not stereospecific.The products of rearomatization of dienyl acetates, dienols and dienyl methyl ethers depend on the acidity and ionizing power of the solvents and are readily explained in terms of reactions involving a nitrocyclohexadienyl cation or acetoxy- (hydroxy-, methoxy-)cyclohexadienyl cation as key intermediates.In the 4-acetoxy-4-alkylcyclohexadienyl cation 1,2-migration of the acetoxyl group is more rapid then alkyl migration, but 1,2-alkyl migration is faster then migration of the hydroxyl or methoxyl groups in the corresponding cations. 1-Ethyl-4-methoxy-4-methylcyclohexa-2,5-dien-1-ol and 4-ethyl-3-nitrotoluene are significant minor products in the solvolysis of 1-ethyl-4-methyl-4-nitrocyclohexa-2,5-dien-1-ol in aqueous methanol.Nitration of p-ethyltoluene in the presence of sulfuric acid or in trifluoracetic anhydride gives a mixture of 4-ethyl-2-nitro- and 4-ethyl-3-nitrotoluene in a 2:1 ratio.
- Fischer, Alfred,Henderson, George N.
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p. 2314 - 2327
(2007/10/02)
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