- Rhodium(III)-Catalyzed Oxidative Intramolecular 1,1-Oxyamination of Alkenes with Protected Amino Acids to Produce Oxazoloisoindole-2,5-diones
-
It has been established that an electron-deficient bis(ethoxycarbonyl)-substituted cyclopentadienyl (CpE) rhodium(III) complex catalyzes the oxidative intramolecular 1,1-oxyamination of alkenes with N-benzoyl amino acids to produce oxazoloisoindole-2,5-diones. Experimental and theoretical mechanistic studies revealed that this oxidative 1,1-oxyamination proceeds via not the aza-Wacker reaction but the formation of a rhoda(III)oxazolidine initiated by the carboxylic acid-directed N?H bond cleavage.
- Takahashi, Hiroto,Nagashima, Yuki,Tanaka, Ken
-
supporting information
p. 1891 - 1895
(2021/04/05)
-
- MODIFIED COMPOUND OF ANDROGRAPHOLIDE
-
The present disclosure discloses a modified compound of andrographolide, and particularly discloses a compound shown in formula (I) and (II) or a pharmaceutically acceptable salt thereof.
- -
-
Paragraph 0184-0186
(2019/01/04)
-
- ASK1 INHIBITING AGENTS
-
Provided are compounds of Formulas (I'), (I), (II') and (II), or pharmaceutically acceptable salts thereof, and methods for their use and production.
- -
-
Page/Page column 176; 180
(2018/09/08)
-
- Vitamin Catalysis: Direct, Photocatalytic Synthesis of Benzocoumarins via (-)-Riboflavin-Mediated Electron Transfer
-
An operationally simple protocol is disclosed to facilitate entry to benzo-3,4-coumarins directly from biaryl carboxylic acids without the need for substrate prefunctionalization. Complementary to classic lactonization strategies, this disconnection relies on the oxidation competence of photoactivated (-)-riboflavin (vitamin B2) to generate the heterocyclic core via photoinduced single electron transfer. Collectively, the inexpensive nature of the catalyst, ease of execution, and absence of external metal additives are a convincing endorsement for the incorporation of simple vitamins in contemporary catalysis.
- Morack, Tobias,Metternich, Jan B.,Gilmour, Ryan
-
supporting information
p. 1316 - 1319
(2018/03/09)
-
- NEW ANTIBACTERIAL COMPOUNDS
-
The present invention relates to novel antibacterial compounds, pharmaceutical compositions containing them and their use as antimicrobials.
- -
-
Page/Page column 46
(2018/01/19)
-
- ANTIBACTERIAL COMPOUNDS HAVING BROAD SPECTRUM OF ACTIVITY
-
The present invention relates to novel antibacterial compounds, pharmaceutical compositions containing them and their use as antimicrobials.
- -
-
Page/Page column 83
(2016/07/05)
-
- 2-ARYLBENZOFURAN-7-FORMAMIDE COMPOUNDS, PREPARATION METHOD AND USE THEREOF
-
Provided in the present invention are a 2-arylbenzofuran-7-formamide compound as shown in general formula I or a pharmacologically or physiologically acceptable salt thereof, a preparation method thereof and use thereof in preparing anti-tumour drugs, whe
- -
-
Paragraph 0063; 0064; 0065
(2015/02/18)
-
- 2-ARYLBENZOFURAN-7-FORMAMIDE COMPOUNDS, PREPARATION METHOD AND USE THEREOF
-
Provided in the present invention are a 2-arylbenzofuran-7-formamide compound as shown in general formula I or a pharmacologically or physiologically acceptable salt thereof, a preparation method thereof and use thereof in preparing anti-tumour drugs, whe
- -
-
Paragraph 0016
(2015/01/18)
-
- Discovery and structure-activity relationship of novel 2,3- dihydrobenzofuran-7-carboxamide and 2,3-dihydrobenzofuran-3(2 h)-one-7-carboxamide derivatives as poly(ADP-ribose)polymerase-1 Inhibitors
-
Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3′,4′-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4′-hydroxyl/4′-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66-68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.
- Patel, Maulik R.,Bhatt, Aaditya,Steffen, Jamin D.,Chergui, Adel,Murai, Junko,Pommier, Yves,Pascal, John M.,Trombetta, Louis D.,Fronczek, Frank R.,Talele, Tanaji T.
-
p. 5579 - 5601
(2014/08/05)
-
- Discovery of (10 R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17- tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]- benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations
-
Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.
- Johnson, Ted W.,Richardson, Paul F.,Bailey, Simon,Brooun, Alexei,Burke, Benjamin J.,Collins, Michael R.,Cui, J. Jean,Deal, Judith G.,Deng, Ya-Li,Dinh, Dac,Engstrom, Lars D.,He, Mingying,Hoffman, Jacqui,Hoffman, Robert L.,Huang, Qinhua,Kania, Robert S.,Kath, John C.,Lam, Hieu,Lam, Justine L.,Le, Phuong T.,Lingardo, Laura,Liu, Wei,McTigue, Michele,Palmer, Cynthia L.,Sach, Neal W.,Smeal, Tod,Smith, Graham L.,Stewart, Albert E.,Timofeevski, Sergei,Zhu, Huichun,Zhu, Jinjiang,Zou, Helen Y.,Edwards, Martin P.
-
p. 4720 - 4744
(2014/07/07)
-
- BENZO-FUSED HETEROCYCLIC DERIVATIVES USEFUL AS AGONISTS OF GPR120
-
The present invention is directed to benzo-fused heterocyclic derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by GPR120. More particularly, the compounds of the present invention are agonists of GPR120, useful in the treatment of, such as for example, Type II diabetes mellitus.
- -
-
Paragraph 0400
(2014/09/30)
-
- MACROCYCLIC DERIVATIVES FOR THE TREATMENT OF PROLIFERATIVE DISEASES
-
The invention relates to compounds of formula (Φ) as further defined herein and to the pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to the uses thereof. The compounds and salts of the present invention inhibit anaplastic lymphoma kinase (ALK) and/or EML4-ALK and are useful for treating or ameliorating abnormal cell proliferative disorders, such as cancer.
- -
-
Page/Page column 181
(2013/09/26)
-
- BENZODIAZEPINE COMPOUNDS USEFUL FOR THE TREATMENT OF HEPATITIS C
-
The invention concerns benzodiazepine derivatives of Formula (I) wherein A, X, L1, L2, R1, R2, R3, R4, R5, R6 and R7 are as defined in the description. The present invention also relates to processes for the preparation of such compounds, pharmaceutical compositions containing them and their use in the treatment or prophylaxis of hepatitis C virus infection.
- -
-
Page/Page column 60
(2011/12/14)
-
- Leaving group assistance in the La3+-catalyzed cleavage of dimethyl (o-methoxycarbonyl)aryl phosphate triesters in methanol
-
The catalytic methanolysis of a series of dimethyl aryl phosphate triesters where the aryl groups contain an o-methoxycarbonyl (o-CO2Me) substituent (4a-i) was studied at 25°C in methanol containing La 3+ at various concentrations and sspH. Determination of the second-order rate constant for La3+ 2-catalyzed cleavage of substrate 4a (dimethyl (o-methoxycarbonyl) phenyl phosphate) as a function of sspH was assessed in terms of a speciation diagram that showed that the process was catalyzed by La3+ 2(-OCH3)x dimers, where x = 1-5, that exhibit only a 5-fold difference in activity between all the species. The second-order catalytic rate constants (k2La) for the catalyzed methanolysis of 4a-i at sspH 8.7 fit a Bronsted relationship of log k2La= (-0.82 ± 0.11)sspKalg + (11.61 ± 1.48), where the gradient is shallower than that determined for a series of dimethyl aryl phosphates that do not contain the o-CO2Me substituent, log k2La = (-1.25 ± 0.06)s spKalg + (16.23 ± 0.75). Two main observations are that (1) the o-CO2Me group preferentially accelerates the cleavage of the phosphate triesters with poor leaving groups relative to those with good leaving groups and (2) it provides an increase in cleavage rate relative to those of comparable substrates that do not have that functional group, e.g., k2La(dimethyl o-(methoxycarbonyl) phenyl phosphate)/k2La(dimethyl phenyl phosphate) = 60. Activation parameters for the La3+2-catalyzed methanolysis of 4a and dimethyl 4-nitrophenyl phosphate show respective ΔH? (ΔS?) values of 3.3 kcal/mol (-47 cal/mol·K) and 0.7 kcal/mol (-46.5 cal/mol·K). The data are analyzed in terms of a concerted reaction where the catalytic complex (La3+2( -OCH3)x-1) binds to the three components of a rather loose transition state composed of a nucleophile CH3O -, a nucleofuge -OAr, and a central (RO)2P 2+-O- in a way that provides leaving group assistance to the departing aryloxy group.
- Edwards, David R.,Liu, C. Tony,Garrett, Graham E.,Neverov, Alexei A.,Brown, R. Stan
-
supporting information; experimental part
p. 13738 - 13748
(2010/01/06)
-
- Heterocyclic compounds with carboxyl isostere groups and their use for the treatment of cardiovascular diseases
-
The present application relates to novel heterocyclic compounds, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, especia
- -
-
Page/Page column 44
(2009/09/25)
-
- Difluorophenol Derivatives and Their Use
-
The present application relates to novel difluorophenol derivatives, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prevention of cardiovascular disorders.
- -
-
Page/Page column 12; 22-23
(2009/12/05)
-
- Dissociative solvolytic cleavage of methyl (ortho-Carboxymethyl)Aryl phosphate diesters mediated by Yb3+ in methanol gives a 10 12-fold rate acceleration attributable to leaving group assistance
-
The Yb3+-catalyzed cleavage of a series of eight methyl aryl phosphates (2a-h) where the aryl groups all contain an ortho-methoxycarbonyl group was studied in acidic methanol from 1.34 ≤ spHs ≤ 3.34 at 25 °C. All substrates show saturation binding of the metal ion that is analyzed to provide a conditional binding constant (K)b for a 1:1 substrate/Yb3+ complex and catalytic rate constant (A cat) that varies between about 2 × 10-3 and 50 × 10-3 s-1 overthe range of substrates. Detailed analysis indicates that at very low c oncentration of Yb3+, 3 equiv of substrate are bound, and with increasing [Yb3+], the binding changes to a 1:1 complex which decomposes by a pathway independent of spHs over the range investigated. Control studies show that substrates without the o-methoxycarbonyl group still bind to the Yb 3+ with approximately the same strength as do the o-methoxycarbonyl containing substrates but have no observable reaction when bound. A Jaffe plot of the kcat vs substituent ?-values indicates that, during the catalyzed reactions of 2a-h, the phenoxy-O and C(O)OCH3 groups accommodate negative and positive charge respectively, the p phosphate and p c(o)OMe values being (1.84 ±0.11) and ( 0.85 ±0.14). For all these substrates, the final reaction products are dimethyl phosphate and the Yb3+ complex of the phenoxide. A study of the binding of the parent phenols to Yb3+ indicates that log(Kbind) = (0.84 ± 0.06)sspKa+ (3.4 ± 0.9), r2 = 0.9664 for phenols containing the o-methoxycarbonyl group; for those lacking that substituent log(Kb ind) = (0.96 ± 0.04)s spKa- (1.73 ± 0.4), (r2 = 0.99). For the catalyzed reacti on the βlg = -0.48, while the βeq = -0.95, leading to a Leffler parameter of α = 0.51. A mechanism is presented for the catalyzed reaction which is highly dissociative, having a transition state where the Yb3+ translocates during the cleavage reaction to assist the leaving group's departure with weak nucleophilic assistance by the solvent methanol. A comparison of the catalyzed rate of reaction with a computed rate of reaction attributable to solvent alone indicates that Yb3+ provides leaving group assistance on the order of 1012-fold, stabilizing the transition state for cleavage by some 16 kcal/mol.
- Edwards, David R.,Neverov, Alexei A.,Brown, R. Stan
-
supporting information; experimental part
p. 368 - 377
(2009/06/28)
-
- Enzyme-catalysed synthesis and reactions of benzene oxide/oxepine derivatives of methyl benzoates
-
A series of twelve benzoate esters was metabolised, by species of the Phellinus genus of wood-rotting fungi, to yield the corresponding benzyl alcohol derivatives and eight salicylates. The isolation of a stable oxepine metabolite, from methyl benzoate, allied to evidence of the migration and retention of a carbomethoxy group (the NIH Shift), during enzyme-catalysed ortho-hydroxylation of alkyl benzoates to form salicylates, is consistent with a mechanism involving an initial arene epoxidation step. This mechanism was confirmed by the isolation of a remarkably stable, optically active, substituted benzene oxide metabolite of methyl 2-(trifluoromethyl)benzoate, which slowly converted into the racemic form. The arene oxide was found to undergo a cycloaddition reaction with 4-phenyl-1,2,4-triazoline-3,5-dione to yield a crystalline cycloadduct whose structure and racemic nature was established by X-ray crystallography. The metabolite was also found to undergo some novel benzene oxide reactions, including epoxidation to give an anti-diepoxide, base-catalysed hydrolysis to form a trans-dihydrodiol and acid-catalysed aromatisation to yield a salicylate derivative via the NIH Shift of a carbomethoxy group. This journal is The Royal Society of Chemistry.
- Boyd, Derek R.,Sharma, Narain D.,Harrison, John S.,Malone, John. F.,McRoberts, W. Colin,Hamilton, John T. G.,Harper, David B.
-
experimental part
p. 1251 - 1259
(2008/10/09)
-
- Method of preparing poly(ADP-ribose) polymerases inhibitors
-
This invention relates to a new and convergent route to small molecule inhibitors of poly(ADP-ribose) polymerase, such as 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, via a key Sonogashira coupling reaction and a CuI-promoted indole formation.
- -
-
Page/Page column 5; 8
(2010/10/20)
-
- NOVEL SULPHONAMIDE DERIVATIVES AS GLUCOCORTICOID RECEPTOR MODULATORS FOR THE TREATMENT OF INFLAMMATORY DISEASES
-
Compounds of formula (I) or a pharmaceutically acceptable salt thereof; compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating the glucocorticoid receptor in a warm blooded animal).
- -
-
Page/Page column 55
(2008/06/13)
-
- Zatosetron, a Potent, Selective, and Long-Acting 5HT3 Receptor Antagonist: Synthesis and Structure-Activity Relationships
-
Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin.Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse.Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists.Simple benzoyl derivatives of tropine and 3α-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats.Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity.The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclooct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate).The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR.Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50=0.86 μg/kg iv).Low oral doses of zatosetron (30 μg/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats.Moreover, this compound did not produce hemodynamic effects after iv administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors.Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
- Robertson, David W.,Lacefield, William B.,Bloomquist, William,Pfeifer, William,Simon, Richard L.,Cohen, Marlene L.
-
p. 310 - 319
(2007/10/02)
-
- A Novel Electrophilic Fluorination of Activated Aromatic Rings Using Acetyl Hypofluorite, Suitable also for Introducing (18)F into Benzene Nuclei
-
Acetyl hypofluorite (1) is a new compound that serves as a novel electrophilic fluorinating agent.It is special in the sense that, while it is very reactive, it is still a milder reagent than other fluoroxy compounds such as CF3OF or CF3COOF.It is synthesized directly from elemental fluorine and is used without any isolation or purification.The hypofluorite 1 reacts efficiently and selectively with activated aromatic rings,particularly phenol and aniline derivatives after suitable protection of the hydroxyl and the amino groups.The net result of the reaction is partly according to classical aromatic electrophilic substitution.Unlike such a substitution, however, the electrophilic fluorine atom of 1 substitutes mainly an ortho hydrogen and only occasionally small amounts of p-fluoro derivatives are found.Evidence supports the mechanism for this aromatic fluorination as being mainly an addition-elimination one.In many cases the electrophilic aromatic fluorinations can replace the classical 60-year-old Balz-Schiemann method, which until today is probably the most used procedure.Since aromatic fluorination with 1 is a very fast reaction and since 1 is produced directly from elemental fluorine, this is probably one of the best ways for introduction of the short-living radioisotope (18)F into activated aromatic rings.This will greatly encourage the synthesis of compounds suitable for use in the rapidly developing field of positron emitting transaxial tomography, which in itself depends on the efficient and easy supply of compounds possessing positron emitting isotopes.
- Lerman, Ori,Yitzhak, Tor,Hebel, David,Rozen, Shlomo
-
p. 806 - 813
(2007/10/02)
-
- Acetyl Hypofluorite as a Taming Carrier of Elemental Fluorine for Novel Electrophilic Fluorination of Activated Aromatic Rings
-
The new fluorinating reagent CH3COOF, which is prepared in situ from F2, is used for electrophilic aromatic fluorinations of activated aromatic rings.
- Lerman, Ori,Tor, Yitzhak,Rozen, Shlomo
-
p. 4629 - 4631
(2007/10/02)
-