- New hybrid pyrazole and imidazopyrazole antinflammatory agents able to reduce ROS production in different biological targets
-
Several anti-inflammatory agents based on pyrazole and imidazopyrazole scaffolds and a large library of substituted catechol PDE4D inhibitors were reported by us in the recent past. To obtain new molecules potentially able to act on different targets involved in inflammation onset we designed and synthesized a series of hybrid compounds by linking pyrazole and imidazo-pyrazole scaffolds to differently decorated catechol moieties through an acylhydrazone chain. Some compounds showed antioxidant activity, inhibiting reactive oxygen species (ROS) elevation in neutrophils, and a good inhibition of phosphodiesterases type 4D and, particularly, type 4B, the isoform most involved in inflammation. In addition, most compounds inhibited ROS production also in platelets, confirming their ability to exert an antiinflammatory response by two independent mechanism. Structure–activity relationship (SAR) analyses evidenced that both heterocyclic scaffolds (pyrazole and imidazopyrazole) and the substituted catechol moiety were determinant for the pharmacodynamic properties, even if hybrid molecules bearing to the pyrazole series were more active than the imidazopyrazole ones. In addition, the pivotal role of the catechol substituents has been analyzed. In conclusion the hybridization approach gave a new serie of multitarget antiinflammatory compounds, characterized by a strong antioxidant activity in different biological targets.
- Brullo, Chiara,Massa, Matteo,Rapetti, Federica,Alfei, Silvana,Bertolotto, Maria B.,Montecucco, Fabrizio,Signorello, Maria Grazia,Bruno, Olga
-
-
- Synthesis method of roflumilast key intermediate
-
The invention discloses a synthesis method of a roflumilast key intermediate. Specifically speaking, the synthesis method comprises the following steps: (1) preparing 3-methoxy-4-difluoro methoxybenzaldehyde; (2) preparing 3-hydroxy-4-difluoro methoxybenzaldehyde; (3) preparing 3-cyclopropyl methoxy-4-difluoro methoxybenzaldehyde; (4) preparing 3-cyclopropyl methoxy-4-difluoro methoxybenzoic acid. Compared with the existing synthesis method, the synthesis method disclosed in the invention has the advantages that low-price raw materials are adopted, thereby greatly reducing the production cost; vanillin serves as a starting material, thereby avoiding generation of similar impurities; column chromatography is replaced with recrystallization which serves as a purification way, thereby facilitating large-scale production application, and the yield and the purity are higher.
- -
-
Paragraph 0038-0042
(2017/07/21)
-
- SYNTHESIS OF DIFLUOROMETHYL ETHERS AND SULFIDES
-
The synthesis of difluoromethyl ethers and sulfides with a simple, non-ozone- depleting reagent is described. The difluoromethylation of phenols with this reagent occurs at room temperature within minutes with exceptional functional group tolerance. The mild conditions makes possible tandem processes for the conversion of aryl boronic acids, aryl halides and arenes to difluoromethyl ethers. Mechanistic studies support a reaction pathway involving nucleophilic attack of the phenolate to difluorocarbene.
- -
-
Paragraph 0078-0082; 00115-00118
(2014/07/22)
-
- 3′,4′-Bis-difluoromethoxycinnamoylanthranilate (FT061): An orally-active antifibrotic agent that reduces albuminuria in a rat model of progressive diabetic nephropathy
-
Cinnamoylanthranilates including tranilast have been identified as promising antifibrotics that can reduce fibrosis occurring in the kidney during diabetes, thereby delaying and/or preventing kidney dysfunction. Structure-activity relationships aimed at improving potency and metabolic stability have led to the discovery of FT061. This compound, which bears a bis-difluoromethoxy catechol, attenuates TGF-β-stimulated production of collagen in cultured renal mesangial cells (approx 50% at 3 μM). When dosed orally at 20 mg/kg to male Sprague Dawley rats, FT061 exhibited a high bioavailability (73%), Cmax of 200 μM and Tmax of 150 min, and a half-life of 5.4 h. FT061 reduced albuminuria when orally dosed in rats at 200 mg kg/day in a late intervention study of a rat model of progressive diabetic nephropathy.
- Williams, Spencer J.,Zammit, Steven C.,Cox, Alison J.,Shackleford, David M.,Morizzi, Julia,Zhang, Yuan,Powell, Andrew K.,Gilbert, Richard E.,Krum, Henry,Kelly, Darren J.
-
supporting information
p. 6868 - 6873
(2014/01/06)
-
- Synthesis and in vitro biological evaluation of novel 2-aminoimidazolone derivatives as anti-tumor agents
-
Novel 2-aminoimidazolone derivatives were synthesized. Most compounds displayed strong anticancer activities against human carcinoma cells in vitro. Compounds 8a, 8b and 8j exhibited optimal activity superior to 5-FU in most cancer cells tested. Especially, the IC50s of 8b (12.6-21.5 μmol/L) against five tumor cells were 1-4 fold less than those of 5-FU (18.4-56.1 μmol/L) in vitro. Furthermore, compound 8b could induce SMMC-7721 cell apoptosis in a dose-dependent manner. Therefore, our novel findings may provide a new framework for the design of new 2-aminoimidazolone derivatives for the treatment of cancer.
- Xiao, You-An,Wang, Zhi-Qiang,Wang, Xue-Min,Hui, Yi,Ling, Yong,Wang, Xin-Yang,He, Li-Qin
-
p. 727 - 730
(2013/07/26)
-
- HALOGENATED ANALOGUES OF ANTI-FIBROTIC AGENTS
-
The present invention relates to halogenated compounds of formula (I) with the substituents as described within the specification. The compounds may be useful as anti-fibrqtic agents. The present invention also relates to methods for their preparation.
- -
-
Page/Page column 37-38
(2009/07/25)
-
- (DIHYDRO)PYRROLO[2,1-A]ISOQUINOLINES
-
The invention relates to 5,6 - dihydropyrrolo [2,1-a] isoquinoline and pyrrolo[2,1-a] isoquinoline derivatives according to general formula (I) or a pharmaceutically acceptable salt thereof. The compounds can be used for the treatment of infertility.
- -
-
Page/Page column 131
(2009/10/09)
-
- Fluoroalkoxycombretastatin Derivatives, Method For Producing the Same and Use Thereof
-
Combretastatin derivatives of formula (I), preparation and use thereof are disclosed, wherein: Rf is alkyl with 1-8 carbon atoms and 1-17 fluorine atoms, R is amino, substituted amino, hydroxyl, nitro, halo, alkyloxy, phosphate or amino acid side chain. Said derivatives have a capability to inhibit the polymerization of microtubules and are useful in treatment against tumor and neovascularization.
- -
-
Page/Page column 8
(2009/01/20)
-
- 2, 6 BISHETEROARYL-4-AMINOPYRIMIDINES AS ADENOSINE RECEPTOR ANTAGONISTS
-
4-Aminopyrimidine derivatives of formula (I) FORMULA heteroaryl groups, including pharmaceutically acceptable salts thereof, wherein R1 and R2 are adenosine A2A receptor antagonists useful in the treatment of movement disorders such as Parkinson's disease.
- -
-
Page/Page column 131
(2010/02/12)
-
- FLUOROALKOXY-SUBSTITUTED BENZAMIDES AND THEIR USE AS CYCLIC NUCLEOTIDE PHOSPHODIESTERASE INHIBITORS
-
Compounds of formula (I), in which one of the substituents R1 or R2 stands for hydrogen, 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or totally or partially fluorine-substituted 1-4C-alkoxy, and the other stands for totally or partially fluorine-substituted 1-4C-alkoxy, and R3 stands for phenyl, pyridyl, R31, R32 and R33-substituted phenyl or R34, R35, R36 and R37-substituted pyridyl, in which R31 stands for hydroxy, halogen, cyano, carboxyl, trifluoromethyl 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, amino, mono- or di-1-4C-atkylamino or 1-4C-alkylcarbonylamino; R32 stands for hydrogen, hydroxy, halogen, amino, trifluoromethyl, 1-4C-alkyl or 1-4C-alkoxy; R33 stands for hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy; R34 stands for hydroxy, halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or amino; R35 stands for hydrogen, halogen, amino or 1-4C-alkyl; R36 stands for hydrogen or halogen; and R37 stands for hydrogen or halogen. These compounds constitute new effective bronchotherapeutic drugs
- -
-
-