- 1,5-Diaryl-2-alkylpyrrole-3-Substituted Nitro Esters, Selective COX-2 Inhibitors and Nitric Oxide Donors
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1,5-diaryl-2-alkylpyrrole-3-substituted nitro esters, of Formula (I) are provided. Such compounds are potent and selective COX-2 inhibitors which are able to release NO in concentrations that make it possible to counteract the side effects due to selective COX-2 inhibition, without giving rise to hypotensive effects. Formula (I) includes compounds wherein the groups R′ and R″ are: —H, —F, —Cl, —Br, —CH3, —CF3, —OCH3, —SCH3, R1 is methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl and the substituent in position ?3 of the pyrrole ring is a chain, where the groups X, Y, Z, W and R2 are: X is a carbonyl or a group —(CHR3)—, Y is an oxygen atom or the group —NR3— and Z is a carbonyl or a group —(CHR3)—, or a [—CH(COOH)—] group, or a group —(NR3)—, W is an aliphatic chain substituted with one or two (—O—NO2) groups, R2 is: —H, —OH, —OCH3, or —NHR3. R3 is: —H, —CH3, —CH2CH3, [—CH2(CH3)2]. R′″ is methylsulphonyl or sulphonamido. Pharmaceutical formulations and methods of making an using such formulations are also provided.
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Paragraph 0194; 0204
(2013/07/05)
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- L,5-DIARYL-2-ALKVLPVRROLE-3-SUBSTITUTED NITRO ESTERS, SELECTIVE COX-2 INHIBITORS AND NITRIC OXIDE DONORS
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The present invention relates to l,5-diaryl-2-alkylpyrrole-3-substituted nitro esters, of formula (I), which are potent and selective COX-2 inhibitors able to release NO in concentrations that make it possible to counteract the side effects due to selective COX-2 inhibition, without giving rise to hypotensive effects. (I). Where the groups R' and R" are: -H, -F, -CI, -Br, -CH3, -CF3, -OCH3, -SCH3, R1 is methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxymethyl and the substituent in position -3 of the pyrrole ring is a chain, where the groups X, Y, Z, W and R2 are: X is a carbonyl or a group -(CHR3)-, Y is an oxygen atom or the group -NR3- and Z is a carbonyl or a group - (CHR3)-, or a [-CH(COOH)-] group, or a group -(NR3)-, W is an aliphatic chain substituted with one or two (-O-NO2) groups, R2 is: -H, -OH, -OCH3, or -NHR3. R3 is: -H, -CH3, -CH2CH3, [-CH2(CH3)2]. R'" is methylsulphonyl or sulphonamido. The purpose of the invention includes: preparation of the compounds of formula (I), the respective pharmaceutical formulations and use thereof for treating acute and chronic pain, for treating inflammatory disorders and for drug treatment of some forms of tumours.
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Page/Page column 54
(2012/03/27)
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- Novel analgesic/anti-inflammatory agents: Diarylpyrrole acetic esters endowed with nitric oxide releasing properties
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The design of compounds that are able to inhibit cyclooxygenase (COX) and to release nitric oxide (NO) should give rise to drugs endowed with an overall safer profile for the gastrointestinal and cardiovascular systems. Herein we report a new class of pyrrole-derived nitrooxy esters (11a-j), cyclooxygenase-2 (COX-2) selective inhibitors endowed with NO releasing properties, with the goal of generating new molecules able to both strongly inhibit this isoform and reduce the related adverse side effects. Taking into account the metabolic conversion of nitrooxy esters into corresponding alcohols, we also studied derivatives 12a-j. All compounds proved to be very potent and selective COX-2 inhibitors; nitrooxy derivatives displayed interesting ex vivo NO-dependent vasorelaxing properties. Compounds 11c, 11d, 12c, and 12d were selected for further in vivo studies that highlited good anti-inflammatory and antinociceptive activities. Finally, two selected compounds (11c and 12c) tested in human whole blood (HWB) assay proved to be preferential inhibitors of COX-2.
- Biava, Mariangela,Porretta, Giulio Cesare,Poce, Giovanna,Battilocchio, Claudio,Alfonso, Salvatore,Rovini, Michele,Valenti, Salvatore,Giorgi, Gianluca,Calderone, Vincenzo,Martelli, Alma,Testai, Lara,Sautebin, Lidia,Rossi, Antonietta,Papa, Giuseppina,Ghelardini, Carla,Di Cesare Mannelli, Lorenzo,Giordani, Antonio,Anzellotti, Paola,Bruno, Annalisa,Patrignani, Paola,Anzini, Maurizio
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p. 7759 - 7771
(2012/01/03)
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