- Sequential hydroaminomethylation/Pd-catalyzed hydrogenolysis as an atom efficient route to valuable primary and secondary amines
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The facile synthesis of valuable primary and secondary amines is reported using a sequential procedure of hydroaminomethylation and Pd-catalyzed hydrogenolysis. The hydroaminomethylation reaction was catalyzed by a cationic Rh(I) iminopyridyl complex and the N-alkylated benzylamines were produced with high chemoselectivity, albeit as mixtures of linear and branched products. Performing the hydrogenolysis reaction using 10% Pd/C, provided access to valuable primary and secondary amines which have applications in the surfactant, pharmaceutical and polymer industries.
- October, Jacquin,Mapolie, Selwyn F.
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supporting information
(2021/04/12)
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- Heterocyclization involving benzylic C(sp3)-H functionalization enabled by visible light photoredox catalysis
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A general and efficient method for heterocyclization involving benzylic C(sp3)-H functionalization enabled by visible light photoredox catalysis to access a wide range of structurally diverse oxygen as well as nitrogen heterocycles up to a gram scale is reported. The potential application of this new methodology is demonstrated by the total synthesis of (-)-codonopsinine and (+)-centrolobine. Herein it is proposed that selectfluor, unlike a fluorinating reagent, acts as an oxidative quencher and a hydrogen radical acceptor.
- Pandey, Ganesh,Laha, Ramkrishna,Mondal, Pradip Kumar
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p. 9689 - 9692
(2019/08/15)
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- HETEROCYCLIC MITOCHONDRIAL ACTIVITY INHIBITORS AND USES THEREOF
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Heterocyclic compounds of Formula (I) and pharmaceutically acceptable salt thereof are disclosed. The use of such heterocyclic compounds and pharmaceutically acceptable salt thereof for the treatment of cancers, and more particularly cancers sensitive to mitochondrial activity inhibition and increased reactive oxygen species (ROS) levels, is also disclosed. Such cancers include acute myeloid leukemia (AML), preferably AML characterized by certain features, such as high level of expression of one or more Homeobox (HOX)-network genes, high and/or low expression of specific genes, the presence of one or more cytogenetic or molecular risk factors such as intermediate cytogenetic risk, Normal Karyotype (A/K), mutated NPM1, mutated CEBPA, mutated FLT3, mutated DNMT3A, mutated TET2, mutated IDH1, mutated IDH2, mutated RUNX1, mutated WT1, mutated SRSF2, intermediate cytogenetic risk with abnormal karyotype (intern(abnK)), trisomy 8 (+8) and/or abnormal chromosome (5/7), and/or a high leukemic stem cell (LSC) frequency.
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- Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase
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Stearoyl-CoA desaturase (SCD) catalyzes the first step in the conversion of saturated fatty acids to unsaturated fatty acids. Unsaturated fatty acids are required for membrane integrity and for cell proliferation. For these reasons, inhibitors of SCD represent potential treatments for cancer. However, systemically active SCD inhibitors result in skin toxicity, which presents an obstacle to their development. We recently described a series of oxalic acid diamides that are converted into active SCD inhibitors within a subset of cancers by CYP4F11-mediated metabolism. Herein, we describe the optimization of the oxalic acid diamides and related N-acyl ureas and an analysis of the structure-activity relationships related to metabolic activation and SCD inhibition.
- Winterton, Sarah E.,Capota, Emanuela,Wang, Xiaoyu,Chen, Hong,Mallipeddi, Prema L.,Williams, Noelle S.,Posner, Bruce A.,Nijhawan, Deepak,Ready, Joseph M.
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p. 5199 - 5221
(2018/06/13)
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- SODIUM CHANNEL BLOCKERS
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The present invention relates to sodium channel blockers. The present invention also includes a variety of methods of treatment using these inventive sodium channel blockers.
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- Synthesis of 2-arylpyrroles via catalytic dehydrogenation of 2-aryl-1-pyrrolines in the presence of palladium-supported on alumina
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A convenient synthesis of 2-arylpyrroles from the catalytic dehydrogenation of 2-aryl-1-pyrrolines in the presence of commercial palladium-supported on alumina (Pd/Al2O3) is described. The reaction scope was tested for aryl substituents with different steric hindrances and electronic natures. The dehydrogenation reaction conditions such as temperature, reflux time and amount of catalyst, revealed to be highly dependent on the 2-aryl substituent group, moderate to high yields and selectivities being obtained in a reaction involving straightforward work-up and purification procedures. In addition, the synthesis of the corresponding 2-aryl-1-pyrroline starting materials, through the cyclisation reaction involving 4-chlorobutyronitrile and aryl Grignard reagents, is also reported.
- Figueira, Cláudia A.,Lopes, Patrícia S.,Gomes, Pedro T.
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p. 4362 - 4371
(2015/06/08)
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- COMPOUNDS FOR TREATMENT OF CYSTIC FIBROSIS
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Described herein are compounds, compositions, and methods of their use for the treatment of cystic fibrosis.
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Paragraph 00227
(2015/01/16)
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- Design, synthesis, and structure-activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: Drugs for cystic fibrosis and chronic bronchitis
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Amiloride (1), the prototypical epithelial sodium channel (ENaC) blocker, has been administered with limited success as aerosol therapy for improving pulmonary function in patients with the genetic disorder cystic fibrosis. This study was conducted to synthesize and identify more potent, less reversible ENaC blockers, targeted for aerosol therapy and possessing minimal systemic renal activity. A series of novel 2-substituted acylguanidine analogues of amiloride were synthesized and evaluated for potency and reversibility on bronchial ENaC. All compounds tested were more potent and less reversible at blocking sodium-dependent short-circuit current than amiloride. Compounds 30-34 showed the greatest potency on ENaC with IC50 values below 10 nM. A regioselective difference in potency was found (compounds 30, 39, and 40), whereas no stereospecific (compounds 33, 34) difference in potency on ENaC was displayed. Lead compound 32 was 102-fold more potent and 5-fold less reversible than amiloríde and displayed the lowest IC50 value ever reported for an ENaC blocker.
- Hirsh, Andrew J.,Molino, Bruce F.,Zhang, Jianzhong,Astakhova, Nadezhda,Geiss, William B.,Sargent, Bruce J.,Swenson, Brian D.,Usyatinsky, Alexander,Wyle, Michael J.,Boucher, Richard C.,Smith, Rick T.,Zamurs, Andra,Johnson, M. Ross
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p. 4098 - 4115
(2007/10/03)
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- Sodium channel blockers
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The present invention relates to sodium channel blockers. The present invention also relates to a variety of methods of treatment using these sodium channel blockers.
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- Sodium channel blockers
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The present invention relates to sodium channel blockers. The present invention also relates to a variety of methods of treatment using the sodium channel blockers.
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- N-phenpropylcuclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase
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The invention relates to compounds of formula (I) for treating for example sexual dysfunction, wherein R1 is optionally substituted C1-6alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, hydrogen, C1-6alkoxy, —NR2 R3 or —NR4SO2R5; X is the linkage —(CH2)n— or —(CH2)q—O— (wherein Y is attached to the oxygen); wherein one or more hydrogen atoms in linkage X may be replaced independently by C1-4alkoxy; hydroxy; hydroxy(C1-3alkyl); C3-7cycloalkyl; carbocyclyl; heterocyclyl; or by C1-4alkyl optionally substituted by one or more fluoro or phenyl groups; n is 3, 4, 5, 6 or 7; and q is 2, 3, 4, 5 or 6; and Y is phenyl or pyridyl, each of which may be substituted; or two R8 groups on adjacent carbon atoms together with the interconnecting carbon atoms may form a fused optionally substituted 5- or 6-membered carbocyclic or heterocyclyic ring.
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- Inhibitors of protein tyrosine phosphatase
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The present invention comprises small molecular weight, non-peptidic inhibitors of formulae I-VII of Protein Tyrosine Phosphatase 1 (PTP1) which are useful for the treatment and/or prevention of Non-Insulin Dependent Diabetes Mellitus (NIDDM).
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- Synthesis of potent non-imidazole histamine H3-receptor antagonists
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Histamine has been converted into a non-imidazole H3-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N(α)-position followed by removal of the imidazole ring. The resulting compound, N-ethyl- N-(4-phenylbutyl)amine, remarkably has a Ki = 1.3 μM as an H3 antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N- (5-phenoxypentyl)pyrrolidine (Ki = 0.18 ± 0.10 μM, for [3H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO2 into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (Ki= 39 ± 11 nM), ED50 = 1.1 ± 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.
- Ganellin, C. Robin,Leurquin, Fabien,Piripitsi, Antonia,Arrang, Jean-Michel,Garbarg, Monique,Ligneau, Xavier,Schunack, Walter,Schwartz, Jean-Charles
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p. 395 - 404
(2007/10/03)
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- Synthesis and pharmacological characterization of novel 6-fluorochroman derivatives as potential 5-HT(1A) receptor antagonists
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A series of novel 6-fluorochroman derivatives was prepared and evaluated as antagonists for the 5-HT(1A) receptor. N-2-[[(6-Fluorochroman-8- yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamine (3; J. Med. Chem. 1997, 40, 1252- 1257) was chosen as a lead, and structural modifications were done on the aliphatic portion of the chroman ring, the tether linking the middle amine and the terminal aromatic ring, the aromatic ring, and lastly the amine. Radioligand binding assays proved that the majority of the novel compounds behaved as good to excellent ligands at the 5-HT(1A) receptor, some of which were selective with respect to α1-adrenergic and D2-dopaminergic receptors. The antagonist activity of the compounds was assessed in the forskolinstimulated adenylate cyclase assays in CHO cells expressing the human 5-HT(1A) receptors. Among the modifications attempted, introduction of an oxo or an optically active hydroxy moiety at the chroman C-4 position was effective in ameliorating the receptor selectivity. Six analogues were selected through the in vitro screens and further evaluated for their in vivo activities. A 4-oxochroman derivative (31n), having a terminal 1,3- benzodioxole ring, demonstrated antagonist activities toward 8-OH-DPAT- induced behavioral and electrophysiological responses in rats.
- Yasunaga, Tomoyuki,Kimura, Takenori,Naito, Ryo,Kontani, Toru,Wanibuchi, Fumikazu,Yamashita, Hiroshi,Nomura, Tamako,Tsukamoto, Shin-Ichi,Yamaguchi, Tokio,Mase, Toshiyasu
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p. 2765 - 2778
(2007/10/03)
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- 7-oxabicycloheptyl substituted heterocyclic amide or ester prostaglandin analogs useful in the treatment of thrombotic and vasospastic disease
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7-Oxabicycloheptane substituted prostaglandin analogs useful in treating thrombotic and vasopastic disease have the structural formula STR1 wherein m is 1, 2 or 3; n is 1, 2, 3 or 4; Z is --(CH2)2 --, --CH=CH-- or STR2 wherein Y is O, a single bond or vinyl, with the proviso that when n is 0, if Z is STR3 then Y cannot be O, and Z is --CH=CH--, n is 1, 2, 3 or 4; and when Y=vinyl, n=0; R is CO2 H, CO2 lower alkyl, CH2 OH, CO2 alkali metal, CONHSOR3, CONHR3a or --CH2 --5-tetrazolyl, X is O, S or NH; and where R1, R2, R3 and R3a are as defined herein.
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- CONTROLLED REDUCTION OF NITROALKANES TO ALKYL HYDROXYLAMINES OR AMINES BY SAMARIUM DIIODIDE
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Alkyl hydroxylamines and alkyl amines have been prepared from nitroalkanes and SmI2 under mild conditions in moderate to good yields.
- Kende, Andrew S.,Mendoza, Jose S.
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p. 1699 - 1702
(2007/10/02)
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- Quaternary ammonium antiarrhythmic drugs
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Quaternary ammonium salts of certain phenylbutylamines are useful antiarrhythmic drugs. A method for treating arrhythmia and prolonging the action potential of cardiac tissue is provided. Pharmaceutical formulations containing such quaternary ammonium salts are disclosed.
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