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KOtBu/DMSO Catalytic System for Isomerization of Allylic Alcohols to Ketones
The isomerization of allylic alcohols is an important reaction because it can afford carbonyl compounds in an atom-economical manner. Although base-catalyzed methods are more desirable than those using transition-metal catalysts from both the economic and environmental points of view, these methods have several drawbacks, such as narrow substrate scope and high catalyst loading. This paper reports the development of an efficient KOtBu/DMSO catalytic system suitable for the isomerization of a broad range of allylic alcohols with good yields, to which previously reported systems could not be applied. This catalytic system was successfully applied to a tandem allylic isomerization/electrophilic trapping reaction, thereby highlighting its synthetic utility.
Sai, Masahiro
(2022/04/03)

Photoredox/nickel-catalyzed hydroacylation of ethylene with aromatic acids
We report a general, practical and scalable hydroacylation reaction of ethylene with aromatic carboxylic acids with the synergistic combination of nickel and photoredox catalysis. Under ambient temperature and pressure, feedstock chemicals such as ethylene can be converted into high-value-added aromatic ketones in moderate to good yields (up to 92%) with reaction time of 2-6 hours.
Chen, Shuai,He, Hengchi,Li, Weipeng,Xie, Jin,Zhang, Lili,Zhu, Chengjian
supporting information
p. 9064 - 9067
(2021/09/15)

A facile and versatile electro-reductive system for hydrodefunctionalization under ambient conditions
A general electrochemical system for reductive hydrodefunctionalization is described, employing the inexpensive and easily available triethylamine (Et3N) as a sacrificial reductant. This protocol is characterized by facile operation, sustainable conditions, and exceptionally wide substrate scope covering the cleavage of C-halogen, N-S, N-C, O-S, O-C, C-C and C-N bonds. Notably, the selectivity and capability of reduction can be conveniently switched by simple incorporation or removal of an alcohol as a co-solvent.
Huang, Binbin,Guo, Lin,Xia, Wujiong
supporting information
p. 2095 - 2103
(2021/03/26)

Synthesis, Antiproliferative Effect, and Topoisomerase II Inhibitory Activity of 3-Methyl-2-phenyl-1 H-indoles
A series of 3-methyl-2-phenyl-1H-indoles was prepared and investigated for antiproliferative activity on three human tumor cell lines, HeLa, A2780, and MSTO-211H, and some structure-activity relationships were drawn up. The GI50 values of the most potent compounds (32 and 33) were lower than 5 μM in all tested cell lines. For the most biologically relevant derivatives, the effect on human DNA topoisomerase II relaxation activity was investigated, which highlighted the good correlation between the antiproliferative effect and topoisomerase II inhibition. The most potent derivative, 32, was shown to induce the apoptosis pathway. The obtained results highlight 3-methyl-2-phenyl-1H-indole as a promising scaffold for further optimization of compounds with potent antiproliferative and antitopoisomerase II activities.
Argaez, Aida Nelly Garcia,Dalla Via, Lisa,Hyeraci, Mariafrancesca,Kikelj, Danijel,Ma?i?, Lucija Peterlin,Passarella, Daniele,Secci, Daniela,Toma?i?, Tihomir,Zidar, Nace
p. 691 - 697
(2020/07/14)

Heteroaryl estrogen receptor regulating agent and application thereof
The invention provides a compound as shown in a formula (I) and a heteroaryl estrogen receptor regulating agent including the same, belonging to the technical field of medicines. The heteroaryl estrogen receptor regulating agent further comprises a calcium phosphosilicate microsphere carrier, wherein the carrier includes silicon oxide, calcium oxide and phosphorus pentoxide in a weight ratio of 20: 4: 1, and the diameters of the microspheres are in a range of 300 to 1100 nm. The compound and the regulating agent provided by the invention can be used as estrogen receptor degrading agents, AKR1C3 inhibitors and bone resorption inhibitors for treating estrogen receptor related diseases or illnesses of patients and can be applied to the treatment of breast cancer, endometriosis and osteoporosis. The preparation method for the regulating agent can prolong the shelf life of the compound, increase the loading amount of a microsphere product, and enhance the stability and sustained release performance of the regulating agent; and the regulating agent provides a supersaturation amount of Ca in a biological fluid environment for binding to bone tissue nucleation sites so as to promote regeneration or repairing of bone tissue.
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Paragraph 0065; 0070; 0072

(2019/10/04)

PROCESS FOR THE PREPARATION OF BAZEDOXIFENE
The invention relates to a process for preparation of the compound 3-methyl-5-benzyloxy-2-(4-benzyloxyphenyl)-1H-indole 5, an intermediate for the synthesis of bazedoxifene and bazedoxifene acetate.
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Paragraph 0058

(2020/01/12)

BETA-HYDROXYETHYLAMINES FOR USE IN THE TREATMENT OR PREVENTION OF NON-ALCOHOLIC FATTY LIVER DISEASES
There is herein provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a non-alcoholic fatty liver disease (NAFLD), such as non-alcoholic steatohepatitis (NASH), wherein X, R1, R2, R3 and n have meanings as provided in the description.
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(2019/04/11)

INDOLE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
The present disclosure relates to compounds and a pharmaceutically acceptable salt thereof, compositions, combinations and medicaments containing the compounds, and processes for their preparation. The disclosure also relates to the use of the compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of the estrogen receptor, including degrading the estrogen receptor, the treatment of diseases and conditions mediated by the estrogen receptor.
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Paragraph 0432; 0433

(2018/04/21)

COMPOUNDS FOR THE TREATMENT OF HYPERGLYCAEMIA
There is herein provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycaemia or a disorder characterized by hyperglycaemia, such as type 2 diabetes, wherein X, R1, R2, R3 and n have meanings as provided in the description.
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(2017/09/28)

Toxicity of the amphetamine metabolites 4-hydroxyamphetamine and 4-hydroxynorephedrine in human dopaminergic differentiated SH-SY5Y cells
Amphetamine (AMPH) is a psychostimulant used worldwide by millions of patients in the clinical treatment of attention deficit hyperactivity disorder, narcolepsy or even obesity, and is also a drug of abuse. 4-Hydroxynorephedrine (4-OHNE) and 4-hydroxyamphetamine (4-OHAMPH) are two major metabolites known to persist in the brain longer than AMPH. The contribution of AMPH metabolites for its neurotoxicity is undetermined. We evaluated the toxicity of AMPH and its metabolites 4-OHNE and 4-OHAMPH, obtained by chemical synthesis, in human dopaminergic differentiated SH-SY5Y neurons. Cells were exposed to AMPH (concentration range 0–5 mM) or 4-OHAMPH or 4-OHNE (concentration range 0–10 mM) for 24 or 48 h, and the viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) leakage assays. Results showed that for both AMPH and the metabolites a concentration-dependent toxicity was observed. The toxic concentration 50% (TC50) for AMPH and 4-OHNE following 24 h exposure was circa 3.5 mM and 8 mM, respectively. For 4-OHAMPH the TC50 was not reached in the tested concentration range. N-acetyl cysteine, cycloheximide, L-carnitine, and methylphenidate were able to reduce cell death induced by AMPH TC50. Acridine orange/ethidium bromide staining showed evident signs of late apoptotic cells and necrotic cells following 24 h exposure to AMPH 3.50 mM. The 4-OHAMPH metabolite at 8.00 mM originated few late apoptotic cells, whereas 4-OHNE at 8.00 mM resulted in late apoptotic cells and necrotic cells, in a scenario similar to AMPH. In conclusion, the AMPH metabolite 4-OHNE is more toxic than 4-OHAMPH, nonetheless both are less toxic than the parent compound in vitro. The most toxic metabolite 4-OHNE has longer permanence in the brain, rendering likely its contribution for AMPH neurotoxicity.
Feio-Azevedo,Costa,Ferreira,Branco,Pereira,Bastos,Carvalho,Capela
p. 65 - 76
(2017/02/19)

Piperazinone compounds and application thereof
The invention belongs to the technical field of medicine and relates to 1-ethyl-4-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole-1-yl]butyl]piperazine-2,3-dione as well as a medical application, a stereoisomer and pharmaceutically acceptable salt thereof. The structural formula of 1-ethyl-4-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole-1-yl] butyl]piperazine-2,3-dione is represented in the specification; 1-ethyl-4-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole-1-yl]butyl]piperazine-2,3-dione and pharmaceutically acceptable acid addition salt of the compound can be combined with existing drugs or can be independently used as an estrogen receptor modulator for treating or preventing various estrogen function related diseases such as bone loss, fracture, osteoporosis, hectic fever, LDL cholesterol level rise, cardiovascular disease, cognitive impairment, brain degeneration disease and anxiety, as well as depression, sexual dysfunction, hypertension, retinal degeneration and cancer caused by estrogen deficiency, especially osteoporosis.
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Paragraph 0026; 0030; 0035; 0036

(2016/10/09)

Synthesis, antiproliferative and pro-apoptotic activity of 2-phenylindoles
Breast cancer is the second most common cancer worldwide after lung cancer with the vast majority of early stage breast cancers being hormone-dependent. One of the major therapeutic advances in the clinical treatment of breast cancer has been the introduction of selective estrogen receptor modulators (SERMs). We describe the design and synthesis of novel SERM type ligands based on the 2-arylindole scaffold to selectively target the estrogen receptor in hormone dependent breast cancers. Some of these novel compounds are designed as bisindole type structures, while others are conjugated to a cytotoxic agent based on combretastatin A4 (CA4) which is a potent inhibitor of tubulin polymerisation. The indole compounds synthesised within this project such as 31 and 86 demonstrate estrogen receptor (ER) binding and strong antiproliferative activity in the ER positive MCF-7 breast cancer cell line with IC50values of 2.71?μM and 1.86?μM respectively. These active compounds induce apoptotic activity in MCF-7 cells with minimal effects on normal peripheral blood cells. Their strong anti-cancer effect is likely mediated by the presence of two ER binding ligands for 31 and an ER binding ligand combined with a cytotoxic agent for 86.
Kelly, Patrick M.,Bright, Sandra A.,Fayne, Darren,Pollock, Jade K.,Zisterer, Daniela M.,Williams, D. Clive,Meegan, Mary J.
p. 4075 - 4099
(2016/08/23)

Iodine promoted α-hydroxylation of ketones
A novel method for α-hydroxylation of ketones using substoichiometric amount of iodine under metal-free conditions is described. This method has been successfully employed in synthesizing a variety of heterocyclic compounds, which are useful precursors. α-Hydroxylation of diketones and triketones are illustrated. This strategy provides a novel, efficient, mild and inexpensive method for α-hydroxylation of aryl ketones using a sub-stoichiometric amount of molecular iodine.
Siddaraju, Yogesh,Prabhu, Kandikere Ramaiah
supporting information
p. 6749 - 6753
(2015/06/25)

Bazedoxifene-scaffold-based mimetics of solomonsterols A and B as novel pregnane x receptor antagonists
Pregnane X receptor (PXR), a member of the NR1I nuclear receptor family, acts as a xenobiotic sensor and a paramount transcriptional regulator of drug-metabolizing enzymes and transporters. The overexpression of PXR in various cancer cells indicates the importance of PXR as a drug target for countering multidrug resistance in anticancer treatments. We describe the discovery of novel bazedoxifene-scaffold-based PXR antagonists inspired by the marine sulfated steroids solomonsterol A and B as natural leads. A luciferase reporter assay on a PXR-transfected HepG2 cell line identified compounds 19-24 as promising PXR antagonists. Further structure-activity relationship studies of the most active PXR antagonist from the series (compound 20, IC50 = 11 μM) revealed the importance of hydroxyl groups as hydrogen-bond donors for PXR antagonistic activity. PXR antagonists 20 and 24 (IC50 = 14 μM), in addition to the downregulation of PXR expression, exhibited inhibition of PXR-induced CYP3A4 expression, which illustrates their potential to suppress PXR-regulated phase-I drug metabolism.
Hodnik, ?iga,Peterlin Ma?i?, Lucija,Toma?i?, Tihomir,Smodi?, Domen,D'Amore, Claudio,Fiorucci, Stefano,Kikelj, Danijel
p. 4819 - 4833
(2014/07/07)

Ring-opening reactions of 1,4-diazabicyclo[2.2.2]octane (DABCO) derived quaternary ammonium salts with phenols and related nucleophiles
1,4-Diazabicyclo[2.2.2]octane (DABCO) has been evaluated as a starting material for the synthesis of 1-alkyl-4-(2-phenoxyethyl)piperazines and related derivatives. We found that 1-alkyl-1,4-diazabicyclo[2.2.2]octan-1-ium salts, resulting from the alkylation of DABCO, efficiently react with a variety of nucleophiles in polyethyleneglycol (PEG) or diglyme at high temperatures to give piperazine products resulting from the nucleophilic ring-opening reaction. The benzylation side reaction was found to be relevant with softer nucleophiles when using 1-benzyl-1,4-diazabicyclo[2.2.2]octan-1-ium salts, while other types of alkylations were not observed. One-pot methodologies allow for the synthesis of piperazines directly from primary alcohols, alkyl halides or sulfonates, using phenols, or other nucleophile sources, and DABCO. The Royal Society of Chemistry 2012.
Mara, Nenad,Polanc, Slovenko,Koevar, Marijan
experimental part
p. 1300 - 1310
(2012/03/07)

In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1H- indol-5-ol in human liver microsomes
Bazedoxifene is a selective estrogen receptor modulator (SERM) that has been developed for use in post-menopausal osteoporosis. However, it contains a potentially toxic 5-hydroxy-3-methylindole moiety. Previous studies on the 5-hydroxyindole and the 3-alkylindole-containing drugs indometacine, zafirlukast and MK-0524 structural analogs have shown that they are bioactivated by cytochrome P450s through a dehydrogenation process to form quinoneimine or 3-methyleneindolenine electrophilic species. In the present study, bazedoxifene was synthesized and then evaluated, together with raloxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol (13), a 3-methyl-5-hydroxyindole- based structural fragment of bazedoxifene, for its ability to form reactive electrophilic species when incubated with human liver microsomes (HLMs) or recombinant CYP isozymes. We showed that bazedoxifene was bioactivated only in trace amounts with recombinant CYP isozymes. In contrast, the N-dealkylated fragment of bazedoxifene (2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol) was bioactivated in considerable amounts to an electrophilic intermediate, which was trapped with glutathione and identified by LC-MS/MS. This suggests that bazedoxifene would require initial N-dealkylation, which could subsequently lead to the formation of the reactive intermediate. However, such an N-dealkylated metabolite of bazedoxifene was not detected after the incubation of bazedoxifene in HLM or recombinant CYP isozymes.
Lu?in, Tina Trdan,Toma?i?, Tihomir,Trontelj, Jurij,Mrhar, Ale?,Peterlin-Ma?i?, Lucija
experimental part
p. 8 - 15
(2012/07/28)

Synthesis of aryl alkyl ethers by alkylation of phenols with quaternary ammonium salts
Phenolic compounds can be efficiently O-methylated with tetramethylammonium chloride in diglyme or polyethyleneglycol (PEG) at temperatures of 150-160 °C and in the presence of either K2CO3 or NaOH. When applying benzyl-trimethylammonium chloride as a reagent, the benzylation and methylation of phenols occurs, with the benzylation product always predominating. With allyl-substituted phenols as substrates and using NaOH as a base it was possible to achieve both the alkylation and the double-bond isomerization of the allyl group to obtain (E/Z)-propenyl-substituted methyl and benzyl aryl ethers in a single preparative step.
Maras, Nenad,Polanc, Slovenko,Kocevar, Marijan
experimental part
p. 29 - 36
(2010/09/05)

Ruthenium-catalyzed tandem allylic substitution/isomerization: A direct route to propiophenones from cinnamyl chloride derivatives
A tandem nucleophilic substitution/redox isomerization catalyzed by a single ruthenium catalyst leads to the direct transformation of allylic chlorides into propiophenones. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.
Helou, Marion,Renaud, Jean-Luc,Demerseman, Bernard,Carreaux, Francois,Bruneau, Christian
p. 929 - 931
(2008/12/20)

Ruthenium-catalyzed synthesis of allylic alcohols: Boronic acid as a hydroxide source
Secondary allylic alcohols were synthesized from linear allylic halides or carbonates using a catalytic amount of a ruthenium complex in the presence of boronic acid. The effects of solvent, base, ruthenium precursor, and boronic acid were fully explored, and the scope of the reaction was extended to various sub-strates. We also describe a preliminary investigation towards an enantioselective process.
Bouziane, Asmae,Helou, Marion,Carboni, Bertrand,Carreaux, Francois,Demerseman, Bernard,Bruneau, Christian,Renaud, Jean-Luc
experimental part
p. 5630 - 5637
(2009/05/27)

5-Aryl-imidazolin-2-ones as a scaffold for potent antioxidant and memory-improving activity
A series of 5-phenyl-substituted-N-alkyl-imidazolin-2-ones with potent radical-scavenging activity and lipid peroxidation inhibitory activity was synthesized. Many of the compounds showed memory-improving effect in animal models independent of the inhibitory activity on lipid peroxidation.
Watanabe, Kazutoshi,Morinaka, Yasuhiro,Hayashi, Yoshio,Shinoda, Masaki,Nishi, Hiroyoshi,Fukushima, Nobuko,Watanabe, Toshiaki,Ishibashi, Akira,Yuki, Satoshi,Tanaka, Masahiko
p. 1478 - 1483
(2008/09/18)

PYRAZOLE DERIVATIVES AS THERAPEUTIC AGENTS
Salts of 1,5-diarylpyrazole-3-carboxamides and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.
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Page/Page column 35; 54

(2010/11/26)

THERAPEUTIC AGENTS
The present invention relates to compounds of formula (I) and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.
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Page/Page column 28

(2008/06/13)

PYRAZOLE DERIVATIVES AS CBl MODULATORS
The present invention relates to compounds of formula (I) wherein R1 represents a group R5O- in which R5 represents a C3-7alkyl group substituted by one or more fluoro or R5 represents a C3-7alkylsulphonyl group which is optionally substituted by one or more fluoro; R2 represents a C1-4alkyl group, hydroxy, fluoro, chloro or cyano wherein each R2 is independently selected when n is >1; R3 represents a) cyclohexyl optionally substituted by one or more of the following: hydroxy, fluoro, amino, mono or diC1-3alkylamino, carboxy or a C1-4alkoxycarbonyl group b) piperidino substituted by one or more hydroxy c) unsubstituted piperidino but only when one of the following applies: R4 represents cyano or R1 represents 3-fluoropropylsulphonyloxy or R1 represents 3,3,3-trifluoropropoxy or R1 represents 3-fluoropropoxy or R2 is methyl d) phenyl substituted by one or more of the following: hydroxy, halo or a C1-4alkyl group e) pyridyl substituted by a C1-4alkyl group or f) a C4-9alkyl group; R4 represents cyano or methyl; and n is 1, 2 or 3 and pharmaceutically acceptable salts thereof and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.
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Page/Page column 32; 40

(2010/11/25)

Synthesis and evaluation of uterine relaxant activity for a novel series of substituted p-hydroxyphenylethanolamines
Novel racemic 1-(4-hydroxyphenyl)-2-[3-(substituted phenoxy)-2-hydroxy-1-propyl]aminopropan-1-ol hydrochlorides (9a-h) were synthesized by condensing racemic 1-(p-hydroxyphenyl)-2-aminopropan-1-ol hydrochloride (6) with substituted aryloxymethyloxiranes (8a-h) in DMF in presence of anhydrous potassium carbonate and then reacting with dry hydrogen chloride gas. They were evaluated for uterine relaxant activity in vitro on isolated rat uterus and in vivo in pregnant rats. Their cAMP releasing potential was studied using rat uterus tissue homogenates by cAMP [3H] assay and cardiac stimulant potential was evaluated in dog. All compounds exhibited potent uterine relaxant activity in vitro and produced a significant delay in the onset of labour in pregnant rats; their cAMP releasing potential was higher than isoxsuprine hydrochloride except for 9b and 9c. Finally insignificant cardiac stimulant potential was noted for these compounds when compared to isoxsuprine hydrochloride.
Viswanathan,Chaudhari
p. 6581 - 6585
(2007/10/03)

THERAPEUTIC AGENTS
The present invention relates to 1,5-diphenylpyrazole compounds of formula I (A chemical formula should be inserted here - please see paper copy enclosed herewith) and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.
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Page/Page column 38

(2008/06/13)

Design, synthesis and evaluation of racemic 1-(4-hydroxyphenyl)-2-[3- (substituted phenoxy)-2-hydroxy-1-propyl]amino-1-propanol hydrochlorides as novel uterine relaxants
Novel 1-(4-hydroxyphenyl)-2-[3-(substituted phenoxy)-2-hydroxy-1-propyl] amino-1-propanol hydrochlorides were designed based on the pharmacophore for potent uterine relaxant activity and by utilizing the principles of structural hybridization. The designed molecules were synthesized as racemates by a novel route and were evaluated for uterine relaxant activity in vitro on isolated rat uterus and in vivo in pregnant rats. Their cAMP-releasing potential was studied using rat uterus tissue homogenates by the cAMP [3H] assay, and cardiac stimulant potential was evaluated on isolated guinea pig right atrium. All compounds exhibited potent uterine relaxant activity in vitro and produced a significant delay in the onset of labour in pregnant rats; their cAMP-releasing potential was slightly less, while their cardiac stimulant potential was insignificant as compared to isoxsuprine hydrochloride.
Viswanathan,Kodgule,Chaudhari
p. 3532 - 3535
(2007/10/03)

THERAPEUTIC AGENTS
The present invention relates to compounds of formula (I) and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.
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Page/Page column 20; 36

(2008/06/13)

Studies in Potential Antifertility Agents: Part XXIV - Synthesis of 2,3-Disubstituted 4'-(&β-dialkylaminoethoxy)propiophenones
A number of 2,3-disubstituted 4'-(β-dialkylaminoethoxy)propiophenones (32-41) have been synthesized as the structural analogs of a potent antifertility agent erythro-2,3-diphenyl-4'-(β-pyrrolidinoethoxy)valerophenone (1).Compounds 34, 35, 38 and 40 show cent per cent activity at dose levels of 2.5, 10, 10, 10 and 1 mg/kg, respectively.The structure activity relationship has also been discussed.
Rao, K. V. B.,Iyer, R. N.
p. 54 - 58
(2007/10/02)