- INHIBITORS OF NOTCH SIGNALLING PATHWAY AND USE THEREOF IN TREATMENT OF CANCERS
-
The present invention relates to new inhibitors of Notch signalling pathway and its use in the treatment and/or prevention of cancers.
- -
-
Page/Page column 147-148
(2020/10/21)
-
- Scalable 9-Step Synthesis of the Splicing Modulator NVS-SM2
-
NVS-SM2, the first activator of pre-mRNA splicing, displays remarkable pharmacological in vivo activities in models of spinal muscular atrophy. Herein we describe an improved approach to the synthesis of this compound, which features a convenient introduction of sterically encumbered amine moiety onto a fluoropyridazine intermediate.
- Abou-Hamdan, Hussein,Désaubry, Laurent
-
p. 2954 - 2958
(2018/03/09)
-
- Identification and Profiling of Hydantoins - A Novel Class of Potent Antimycobacterial DprE1 Inhibitors
-
Tuberculosis is the leading cause of death worldwide from infectious diseases. With the development of drug-resistant strains of Mycobacterium tuberculosis, there is an acute need for new medicines with novel modes of action. Herein, we report the discovery and profiling of a novel hydantoin-based family of antimycobacterial inhibitors of the decaprenylphospho-β-d-ribofuranose 2-oxidase (DprE1). In this study, we have prepared a library of more than a 100 compounds and evaluated them for their biological and physicochemical properties. The series is characterized by high enzymatic and whole-cell activity, low cytotoxicity, and a good overall physicochemical profile. In addition, we show that the series acts via reversible inhibition of the DprE1 enzyme. Overall, the novel compound family forms an attractive base for progression to further stages of optimization and may provide a promising drug candidate in the future.
- Rogacki, Maciej K.,Pitta, Eleni,Balabon, Olga,Huss, Sophie,Lopez-Roman, Eva Maria,Argyrou, Argyrides,Blanco-Ruano, Delia,Cacho, Monica,Vande Velde, Christophe M. L.,Augustyns, Koen,Ballell, Lluis,Barros, David,Bates, Robert H.,Cunningham, Fraser,Van Der Veken, Pieter
-
p. 11221 - 11249
(2019/01/08)
-
- Efficient and chromatography-free methodology for the modular synthesis of oligo-(1H-pyrazol-4-yl)-arenes with controllable size, shape and steric bulk
-
A novel methodology to synthesise oligo-(1H-pyrazol-4-yl)-arenes with controllable size, shape and steric bulk from 1-trityl-1H-pyrazol-4-ylboronate pinacol esters. This straightforward and efficient procedure can be applied to a variety of brominated aro
- Kershaw Cook, Laurence J.,Kearsey, Rachel,Lamb, Jessica V.,Pace, Edward J.,Gould, Jamie A.
-
supporting information
p. 895 - 898
(2016/02/05)
-
- Rhodium/chiral diene complexes in the catalytic asymmetric arylation of β-pyrazol-1-yl acrylates
-
The asymmetric conjugate addition of arylboronic acids to substituted and unsubstituted β-pyrazol-1-yl (E)-tert-butyl acrylates 4 catalyzed by 5 mol % of the Rh(I)/diene 2a catalyst provided the corresponding addition products in 44-98% yield and 91->99.5
- Gopula, Balraj,Tsai, Yun-Fan,Kuo, Ting-Shen,Wu, Ping-Yu,Henschke, Julian P.,Wu, Hsyueh-Liang
-
supporting information
p. 1142 - 1145
(2015/03/14)
-
- Inverse electron demand diels-alder reactions of 1,2,3-triazines: Pronounced substituent effects on reactivity and cycloaddition scope
-
A systematic study of the inverse electron demand Diels-Alder reactions of 1,2,3-triazines is disclosed, including an examination of the impact of a C5 substituent. Such substituents were found to exhibit a remarkable impact on the cycloaddition reactivity of the 1,2,3-triazine without altering, and perhaps even enhancing, the intrinsic cycloaddition regioselectivity. The study revealed not only that the reactivity may be predictably modulated by a C5 substituent (R = CO2Me > Ph > H) but also that the impact is of a magnitude to convert 1,2,3-triazine (1) and its modest cycloaddition scope into a heterocyclic azadiene system with a reaction scope that portends extensive synthetic utility, expanding the range of participating dienophiles. Significantly, the studies define a now powerful additional heterocyclic azadiene, complementary to the isomeric 1,2,4-triazines and 1,3,5-triazines, capable of dependable participation in inverse electron demand Diels-Alder reactions, extending the number of complementary heterocyclic ring systems accessible with implementation of the methodology.
- Anderson, Erin D.,Boger, Dale L.
-
supporting information; experimental part
p. 12285 - 12292
(2011/09/16)
-
- Synthesis of 4-aryl-1H-pyrazoles by Suzuki-Miyaura cross coupling reaction between 4-bromo-1H-1-trityl-pyrazole and arylboronic acids
-
A general procedure for the synthesis of 4-aryl-1H-pyrazoles by the Suzuki-Miyaura cross coupling reaction between 4-bromo-1H-1-tritylpyrazole and commercially available arylboronic acids was developed. Using this procedure, a direct synthesis of 4-aryl-1H-pyrazoles possessing functional groups, such as hydroxyl, nitro, and amino groups, on the aryl ring was realized. Those molecules could not be prepared by our previous synthesis of 4-aryl-1H-pyrazoles via the Kumada cross coupling reaction.
- Ichikawa, Hayato,Nishioka, Miho,Arimoto, Masao,Usami, Yoshihide
-
experimental part
p. 1509 - 1516
(2010/12/24)
-
- PYRIDINE DERIVATIVES SUBSTITUTED BY HETEROCYCLIC RING AND PHOSPHONOAMINO GROUP, AND ANTI-FUNGAL AGENT CONTAINING SAME
-
Anti-fungal agent having excellent anti-fungal action physicochemical properties including safety and water solubility. Compound represented by formula (I), or salt thereof: wherein R1 represents hydrogen, halogen, amino, R11-NH- wherein R11 represents C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, or C1-6alkoxycarbonyl C1-6 alkyl, R12-(CO)-NH- wherein R12 represents C1-6 alkyl group or C1-6 alkoxy C1-6 alkyl, C1-6 alkyl, hydroxy C1-6 alkyl, cyano C1-6 alkyl, C1-6 alkoxy, or C1-6 alkoxy C1-6 alkyl or a phosphonoamino group; R2 represents hydrogen, C1-6 alkyl, amino, or a di C1-6 alkylamino group or a phosphonoamino group; one of X and Y is nitrogen while the other is nitrogen or oxygen; ring A represents a 5- or 6-member heteroaryl ring or a benzene ring which may have a halogen atom or 1 or 2 C1-6 alkyl groups; Z represents a single bond, a methylene group, an ethylene group, oxygen, sulfur, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S-, or -SCH2-; R3 represents hydrogen or halogen or C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, a 5- or 6-member heteroaryl group or a 5- or 6-member nonaromatic heterocyclic group which may have 1 or 2 substituents; and R4 represents hydrogen or halogen; provided that either R1 or R2 represents a phosphonoamino group.
- -
-
Page/Page column 81
(2009/04/24)
-
- Tec Kinase Inhibitors
-
Disclosed are compounds of formula (I): wherein Q, R1, R2, R3, R4 and R5 are defined herein. The compounds of the invention inhibit Itk kinase and are therefore useful for treating diseases and pathological conditions involving inflammation, immunological disorders and allergic disorders. Also disclosed are processes for preparing these compounds and to pharmaceutical compositions comprising these compounds.
- -
-
Page/Page column 12
(2008/12/04)
-
- Novel Antifungal Triazole Derivatives
-
Disclosed herein are antifungal triazole derivatives or pharmaceutically acceptable salts thereof, a preparation method thereof, and a pharmaceutical composition comprising the same. The triazole derivatives of Chemical Formula 1 or pharmaceutically accep
- -
-
Page/Page column 5
(2008/12/09)
-
- Heterocycles substituted pyridine derivatives and antifungal agent containing thereof
-
An object of the present invention is to provide an antifungal agent which has excellent antifungal effects and is superior in terms of its physical properties, safety and metabolic stability. According to the present invention, there is disclosed a compound represented by the following formula (I), or a salt thereof: wherein R1 represents a hydrogen atom, a halogen atom, an amino group, a C1-6 alkyl group, a C1-6 alkoxy group or a C1-6 alkoxy C1-6 alkyl group; R2 represents a hydrogen atom, a C1-6 alkyl group, an amino group or a di C1-6 alkylamino group; one of X and Y is a nitrogen atom while the other is a nitrogen atom or an oxygen atom; ring A represents a 5- or 6-member heteroaryl ring or a benzene ring which may have a halogen atom, or 1 or 2 C1-6 alkyl groups; Z represents a single bond, a methylene group, an ethylene group, an oxygen atom, a sulfur atom, —CH2O—, —OCH2—, —NH—, —CH2NH—, —NHCH2—, —CH2S—, or —SCH2—; R3 represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C6-10 aryl group, a 5- or 6-member heteroaryl group, or 5- or 6-member non-aromatic heterocyclic group which may have 1 or 2 substituents; and R4 represents a hydrogen atom or a halogen atom.
- -
-
Page/Page column 78
(2010/11/27)
-
- NOVEL ANTIFUNGAL TRIAZOLE DERIVATIVES
-
Disclosed herein are antifungal triazole derivatives or pharmaceutically acceptable salts thereof, a preparation method thereof, and a pharmaceutical composition comprising the same. The triazole derivatives of Chemical Formula 1 or pharmaceutically accep
- -
-
Page/Page column 20-21
(2010/11/27)
-
- N-MERCAPTOACYL PHENYALANINE DERIVATIVES, PROCESS FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
-
The invention relates to compounds of formula (I); wherein R1 represents C1-6alkyl; R2 represents pyrazole or pyrimidine; or a pharmaceutically acceptable derivative thereof. The invention also relates to pharmaceutical co
- -
-
-
- COMPOUNDS
-
The invention relates to compounds of formula (I) wherein R1 represents benzyl; R2 represents pyrazole; or a pharmaceutically acceptable derivative thereof. The invention also relates to pharmaceutical compositions containing compounds of formula (I) and to the use of compounds of formula (I) in medicine, particularly in the amelioration of a clinical condition for which a ACE and/or NEP inhibitor is indicated.
- -
-
-
- 4,5-diaryl-3(2H)-furanone derivatives as cyclooxygenase-2 inhibitors
-
The present invention provides a novel class of 4,5-diaryl-3(2H)-furanone derivatives, which inhibit strongly and selectively COX-2 over COX-1. They are useful to treat inflammation, inflammation-associated disorders, and COX-2 mediated diseases.
- -
-
-
- Compounds as delta opioid agonists
-
Compounds of the formula (I)—shown below—are described. The compounds are useful in the manufacture of a pharmaceutical composition for preventing or treating inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, disorders of respiratory function, gastrointestinal disorders such as functional bowel disease, functional GI disorders such as irritable bowel syndrome, functional diarrhoea, functional distension, functional pain, non-ulcerogenic dyspepsia or others associated with disorders of motility or secretion, urogenital tract disorders such as incontinence, as analgesics for treating pain including non-somatic pain, or as immunosuppressants to prevent rejection in organ transplant and skin graft.
- -
-
-
- Inhibitors of acyl-coA:cholesterol O-acyltransferase. 2. Identification and structure-activity relationships of a novel series of N-alkyl-N- (heteroaryl-substituted benzyl)-N'-arylureas
-
A series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylurea and related derivatives represented by 2 and 3 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Among these novel compounds, the type 3 series was superior. A pyrazol-3-yl group on the N-benzyl group of this trisubstituted urea (i.e. 3, Ar1 = pyrazol-3- yl) was identified as a heteroaromatic ring providing a good profile of biological activity. As a result of optimization of the combination with the N-alkyl group (R) and N-aryl group (At3), compound 3aq (FR186054) was identified as a new, orally efficacious ACAT inhibitor, which exhibited potent in vitro ACAT inhibitory activity (rabbit intestinal microsomes IC50 = 99 nM) and excellent hypocholesterolemic effects in cholesterol-fed rats, irrespective of administration mode (ED50 = 0.046 mg/kg dosed via the diet, ED50 = 0.44 mg/kg administered by gavage in PEG400 vehicle). Moreover, a toxicological study revealed compound 3aq to be nontoxic to the adrenal glands of dogs when tested at a single dose of 10 mg/kg po.
- Tanaka, Akira,Terasawa, Takeshi,Hagihara, Hiroyuki,Sakuma, Yuri,Ishibe, Noriko,Sawada, Masae,Takasugi, Hisashi,Tanaka, Hirokazu
-
p. 2390 - 2410
(2007/10/03)
-
- Palladium(0)-catalyzed preparation of 4-arylpyrazoles
-
A general method for the palladium(0)-catalyzed preparation of 4- arylpyrazoles 2, by coupling of either 4-halopyrazoles 3 with arylstannanes 4 or 4-tributylstannyl-1-tritylpyrazole 5 with aryl iodides 6, is reported. Deprotection of trityl and/or methyl
- Elguero, Jose?,Jaramillo, Carlos,Pardo, Carmen
-
p. 563 - 566
(2007/10/03)
-
- 2-Amino-5-heterocyclic-substituted-1,4-benzodiazepines and their use in the treatment of aids
-
The benzodiazepines of formula where, X and Y are each independently selected from H, halogen, and lower alkyl; R10 and R11 are both H, or one of R10 and R11 is H and the other is methyl, or R10 and R11 together are -(CHs
- -
-
-