- Redesign of the Synthesis and Manufacture of an Azetidine-Bearing Pyrazine
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Commercial route definition for a glucokinase activator called for a re-evaluation of the synthesis and processes used to access multikilogram quantities of a pyrazine building block. The processes developed allowed a literature route to sodium 6-oxo-1H-pyrazine-3-carboxylate to be leveraged. One of these processes consisted of a highly selective decarboxylation that allowed the target building block to be accessed with complete regioselectivity in standard batch processing equipment. The presence of an azetidine ring in the target required the mitigation of impurity liabilities arising from the use of the hydrochloride salt of azetidine as an input material.
- Hose, David R. J.,Hopes, Phillip,Steven, Alan,Herber, Christian
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p. 241 - 246
(2018/02/23)
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- A Practical and Scalable Synthesis of a Glucokinase Activator via Diastereomeric Resolution and Palladium-Catalyzed C-N Coupling Reaction
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Here we describe the research and development of a process for the practical synthesis of glucokinase activator (R)-1 as a potential drug for treating type-2 diabetes. The key intermediate, chiral α-arylpropionic acid (R)-2, was synthesized in high diastereomeric excess through the diasteromeric resolution of 7 without the need for a chiral resolving agent. The counterpart 2-aminopyrazine derivative 3 was synthesized using a palladium-catalyzed C-N coupling reaction. This efficient process was demonstrated at the pilot scale and yielded 19.0 kg of (R)-1. Moreover, an epimerization process to obtain (R)-7 from the undesired (S)-7 was developed.
- Yamashita, Yohei,Morinaga, Yasuhiro,Kasai, Makoto,Hashimoto, Takao,Takahama, Yuji,Ohigashi, Atsushi,Yonishi, Satoshi,Akazome, Motohiro
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p. 346 - 356
(2017/03/24)
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- Design and synthesis of novel androgen receptor antagonists via molecular modeling
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Several androgen receptor (AR) antagonists are clinically prescribed to treat prostate cancer. Unfortunately, many patients become resistant to the existing AR antagonists. To overcome this, a novel AR antagonist candidate called DIMN was discovered by our research group in 2013. In order to develop compounds with improved potency, we designed novel DIMN derivatives based on a docking study and substituted carbons with heteroatom moieties. Encouraging in vitro results for compounds 1b, 1c, 1e, 3c, and 4c proved that the new design was successful. Among the newly synthesized compounds, 1e exhibited the strongest inhibitory effect on LNCaP cell growth (IC50= 0.35 μM) and also acted as a competitive AR antagonist with selectivity over the estrogen receptor (ER) and the glucocorticoid receptor (GR). A docking study of compound 1e fully supported these biological results. Compound 1e is considered to be a novel, potent and AR-specific antagonist for treating prostate cancer. Thus, our study successfully applied molecular modeling and bioisosteric replacement for hit optimization. The methods here provide a guide for future development of drug candidates through structure-based drug discovery and chemical modifications.
- Zhao, Chao,Choi, You Hee,Khadka, Daulat Bikram,Jin, Yifeng,Lee, Kwang-Youl,Cho, Won-Jea
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p. 789 - 801
(2016/05/24)
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- Combating highly resistant emerging pathogen Mycobacterium abscessus and Mycobacterium tuberculosis with novel salicylanilide esters and carbamates
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Abstract In the Mycobacterium genus over one hundred species are already described and new ones are periodically reported. Species that form colonies in a week are classified as rapid growers, those requiring longer periods (up to three months) are the mostly pathogenic slow growers. More recently, new emerging species have been identified to lengthen the list, all rapid growers. Of these, Mycobacterium abscessus is also an intracellular pathogen and it is the most chemotherapy-resistant rapid-growing mycobacterium. In addition, the cases of multidrug-resistant Mycobacterium tuberculosis infection are also increasing. Therefore there is an urgent need to find new active molecules against these threatening strains. Based on previous results, a series of salicylanilides, salicylanilide 5-chloropyrazinoates and carbamates was designed, synthesized and characterised. The compounds were evaluated for their in vitro activity on M. abscessus, susceptible M. tuberculosis H37Rv, multidrug-resistant (MDR) M. tuberculosis MDR A8, M. tuberculosis MDR 9449/2006 and on the extremely-resistant Praha 131 (XDR) strains. All derivatives exhibited a significant activity with minimum inhibitory concentrations (MICs) in the low micromolar range. Eight salicylanilide carbamates and two salicylanilide esters exhibited an excellent in vitro activity on M. abscessus with MICs from 0.2 to 2.1 μM, thus being more effective than ciprofloxacin and gentamicin. This finding is potentially promising, particularly, as M. abscessus is a threateningly chemotherapy-resistant species. M. tuberculosis H37Rv was inhibited with MICs from 0.2 μM, and eleven compounds have lower MICs than isoniazid. Salicylanilide esters and carbamates were found that they were effective also on MDR and XDR M. tuberculosis strains with MICs ≥1.0 μM. The in vitro cytotoxicity (IC50) was also determined on human MonoMac-6 cells, and selectivity index (SI) of the compounds was established. In general, salicylanilide derivatives substituted by halogens on both salicyl and aniline rings showed better activity, than 4-benzoylaniline derivatives. The ester or carbamate bond formation of parent salicylanilides mostly retained or improved antimycobacterial potency with moderate selectivity.
- Baranyai, Zsuzsa,Krátky, Martin,Vin?ová, Jarmila,Szabó, Nóra,Senoner, Zsuzsanna,Horváti, Kata,Stola?íková, Ji?ina,Dávid, Sándor,Bosze, Szilvia
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p. 692 - 704
(2015/08/03)
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- SELECTIVE OCTAHYDRO-CYCLOPENTA[C] PYRROLE NEGATIVE MODULATORS OF NR2B
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Compounds that selectively negatively modulate NMDA receptors containing an NR1/NR2B subunit, pharmaceutical compositions comprising the compounds, and methods of treating a disease using the compounds are disclosed. Such diseases include, without limitation, neurological dysfunction such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and seizure disorders; emotional disorders; depression; bipolar disorder; obsessive-compulsive disorder; and other anxiety disorders.
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Paragraph 0170
(2015/04/15)
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- [1,3]OXAZINES
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The present invention provides compounds of formula (I) having BACE1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer?s disease and type 2 diabetes. The invention further provides a radio-labelled derivative thereof
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Page/Page column 42-43
(2013/02/27)
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- ISOTHIOUREA DERIVATIVES OR ISOUREA DERIVATIVES HAVING BACE1 INHIBITORY ACTIVITY
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The present invention provides, for example, a compound of the following formula (I): wherein R1 is substituted amino and the like, R2 is halogen and the like, R3 is substituted or unsubstituted lower alkyl and the like, RA and RB are each independently hydrogen, substituted or unsubstituted lower alkyl and the like, RC and RD are each independently hydrogen, substituted or unsubstituted lower alkyl, or RC and RD together with the carbon atom to which they are attached may form a substituted or unsubstituted carbocycle, and ring A is a carbocycle or a heterocycle, its pharmaceutically acceptable salt, or a solvate thereof as a therapeutic agent for diseases induced by production, secretion and/or deposition of amyloid-βproteins.
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Page/Page column 49
(2012/02/01)
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- CRYSTALLINE POLYMORPHIC FORM 631
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A new polymorphic form of 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide, processes for making it and its use as an activator of glucokinase are described.
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- CHEMICAL PROCESS 632
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A process for preparing pharmaceutically active compounds of formula (I) or a salt thereof wherein R1, n, m, R3, R6, X1, X2, X3 and X4 are as defined in the specification, is described. Novel intermediates are also described and claimed.
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Page/Page column 18
(2010/08/22)
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- 2- (PIPERIDIN-1-YL) -4-HETEROCYCLYL-THIAZOLE-5-CARBOXYLIC ACID DERIVATIVES AGAINST BACTERIAL INFECTIONS
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Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described. Ring A is selected from formula (a), (b) or (b'):
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Page/Page column 183
(2010/07/02)
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- SUBSTITUTED PYRAZINYL AMIDE COMPOUNDS AS MODULATORS OF THE HISTAMINE H3 RECEPTOR
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Certain substituted pyrazinyl amide compounds are histamine H3 receptor modulators useful in the treatment of histamine H3 receptor-mediated diseases.
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Page/Page column 9
(2009/05/28)
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- CHEMICAL COMPOUNDS
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The invention relates to a novel group of compounds of Formula (I) or a salt thereof: wherein R1, A and HET-1 are as described in the specification, which may be useful in the treatment or prevention of a disease or medical condition mediated through glucokinase (GLK) such as type 2 diabetes. The invention also relates to pharmaceutical compositions comprising said compounds, methods of treatment of diseases mediated by GLK using said compounds and methods for preparing compounds of Formula (I).
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Page/Page column 45
(2008/12/06)
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- NOVEL CRYSTALLINE COMPOUND
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A novel crystalline form of 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-1H-pyrazol-3-ylbenzamide is described in the specification. This compound is a glucokinase (GLK or GK) activator and useful as a pharmaceutical agent in the treatment or prevention of a disease or medical condition mediated through GLK, leading to a decreased glucose threshold for insulin secretion. Processes for the manufacture of the crystalline form, pharmaceutical compositions comprising the crystalline form and the use of the crystalline form in medical treatment are also described.
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Page/Page column 6
(2008/12/06)
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- NOVEL MCH RECEPTOR ANTAGONISTS
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The present invention relates to a melanin concentrating hormone antagonist compound of formula (I); wherein Ar1, L1, R1, q, X, R2, R3, R4, and R5 are as defined, or a pharmaceutically acceptable salt, solvate, or enantiomer thereof useful in the treatment, prevention or amelioration of symptoms associated with obesity and related diseases.
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Page/Page column 71-72
(2008/06/13)
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- 2-PHENYL SUBSTITUTED IMIDAZOL [4 , 5B] PYRIDINE/ PYRAZINE AND PURINE DERIVATIVES AS GLUCOKINASE MODULATORS
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Compounds of Formula (I), wherein R1- R10, A and X1 to X3 are as described in the specification, and their salts and pro-drugs, are activators of glucokinase (GLK) and are thereby useful in the treatment of, for example, type 2 diabetes. Processes for preparing compounds of formula (I) are also described.
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Page/Page column 108
(2010/11/25)
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- ANTIBACTERIAL BENZOIC ACID DERIVATIVES
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The invention provides antimicrobial agents and methods of using the agents for sterilization, sanitation, antisepsis, disinfection, and treatment of infections in mammals.
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Page 350-351
(2010/02/06)
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- 5-SUBSTITUTED-PYRAZINE OR PYRIDINE GLUCOKINASE ACTIVATORS
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The present invention provides a compound according to formula (I) where the substituent designations are provided in the specification. Pharmaceutical compositions comprising a compound according to formula (I) are also provided, said compounds being glucokinase activators which are useful in the treatment of type II diabetes.
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Page 115 - 116
(2010/02/07)
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- Studies on Pyrazines. 7 (1). The Synthesis of 5-Chloropyrazinecarboxylic Acid
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The titled carboxylic acid (1) was prepared by condensation of 2-furylglyoxal with aminoacetamide followed by chlorination of the resulting 2-hydroxy-5-(2'-furyl)pyrazine (2) and permanganate oxidation.The acid was further converted into methyl ester and 5-hydroxypyrazinecarboxylic acid.
- Sato, Nobuhiro,Arai, Shinji
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p. 407 - 408
(2007/10/02)
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