- Practical, highly convergent, asymmetric synthesis of a selective PPARγ modulator
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A practical, highly convergent, asymmetric synthesis of a selective PPARγ modulator 1 is described. The inhibitor contains two key components, a 6-trifluoromethoxy-3-acylindole (6) and (R)-raryloxybutanoic acid derivative (10). Twomethods were developed to overcome the regioselectivity issues encountered in the preparation of the 6-substituted indole. The first involved an intramolecular Heck reaction of an iodoaryl enamine. The second involved application of a catalytic Meerwein arylation reaction between 2-nitro-4-trifluoromethoxyaniline and isopropenyl acetate and subsequent reductive cyclization. The α-aryloxybutanoic acid was prepared via an asymmetric hydrogenation of the corresponding α-aryloxy-α,β- unsaturated acid. Tetrabutylammonium iodidecatalyzed coupling of the two fragments and ester hydrolysis completed the convergent synthesis. The described convergent synthesis was used to prepare >3 kg of drug substance 1 in 50% overall yield and with >99.5% ee.
- Maligres, Peter E.,Humphrey, Guy R.,Marcoux, Jean-Francois,Hillier, Michael C.,Zhao, Dalian,Krska, Shane,Grabowski, Edward J.J.
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experimental part
p. 525 - 534
(2010/04/22)
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- Discovery of a peroxisome proliferator activated receptor γ (PPARγ) modulator with balanced PPARα activity for the treatment of type 2 diabetes and dyslipidemia
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A series of 3-acylindole-1-benzylcarboxylic acids were designed and synthesized while searching for a PPARγ modulator with additional moderate intrinsic PPARα agonistic activity. 2-[3-[[3-(4-Chlorobenzoyl)-2-methyl- 6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy]-(2R)-butanoic acid (12d) was identified as such an agent which demonstrated potent efficacy in lowering both glucose and lipids in multiple animal models with significantly attenuated side effects such as fluid retention and heart weight gain associated with PPARγ full agonists. The moderate PPARα activity of 12d not only contributed to the agent's ability to manage lipid profiles but also appears to have potentiated its PPARγ efficacy in lowering glucose levels in preclinical diabetic animal models.
- Liu, Weiguo,Liu, Kun,Wood, Harold B.,McCann, Margaret E.,Doebber, Thomas W.,Chang, Ching H.,Akiyama, Taro E.,Einstein, Monica,Berger, Joel P.,Meinke, Peter T.
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experimental part
p. 4443 - 4453
(2010/03/02)
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- Discovery of (2R)-2-(3-{3-[(4-methoxyphenyl)carbonyl]-2-methyl-6- (trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic acid (MK-0533): A novel selective peroxisome proliferator-activated receptor γ modulator for the treatment of type 2 diabetes mellitus with
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Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are used to treat type 2 diabetes mellitus (T2DM). Widespread use of PPARγ agonists has been prevented due to adverse effects including weight gain, edema, and increased risk of congestive
- Acton III, John J.,Akiyama, Taro E.,Chang, Ching H.,Colwell, Lawrence,Debenham, Sheryl,Doebber, Thomas,Einstein, Monica,Liu, Kun,McCann, Margaret E.,Moller, David E.,Muise, Eric S.,Tan, Yugen,Thompson, John R.,Wong, Kenny K.,Wu, Margaret,Xu, Libo,Meinke, Peter T.,Berger, Joel P.,Wood, Harold B.
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experimental part
p. 3846 - 3854
(2010/03/01)
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- INDOLES HAVING ANTI-DIABETIC ACTIVITY
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Indoles of Formula (I) having -X-aryl-(CH2)x#191-oxazolidinedione and -X-heteroaryl-(CH2)X-oxazolidinedione substituents on the N atom of the indole ring, where x is 0 or 1, and -X-is a bond or -CH2-, and their thiazolidinedione analogs, are PPAR gamma agonists or partial agonists and are useful in the treatment and control of type II diabetes, including hyperglycemia, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and obesity that are often associated with type 2 diabetes.
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Page/Page column 28
(2008/06/13)
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- NOVEL CRYSTALLINE FORMS OF ANTIDIABETIC COMPOUNDS
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Novel crystalline forms of two indole compounds connected to phenoxyalkylcarboxylic acid groups are selective PPAR gamma partial agonists that are useful in the treatment of type 2 diabetes, hyperglycemia, obesity, dyslipidemia, and the metabolic syndrome. The novel crystal forms include a crystalline free acid dihydrate and crystalline free acid anhydrate of one compound and several crystalline forms of the free acid and the sodium salt of the second compound. The invention also relates to pharmaceutical compositions comprising these novel crystal forms, processes to prepare the crystal forms and their pharmaceutical compositions, and uses of the crystal forms in the treatment of type 2 diabetes and other PPAR gamma modulated diseases.
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Page/Page column 8
(2010/11/23)
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- A highly active catalyst for the reductive cyclization of ortho-nitrostyrenes under mild conditions
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A mild and efficient method for the palladium-catalyzed reductive cyclization of ortho-nitrostyrenes to afford indoles is reported. Treatment of ortho-nitrostyrenes with 0.1 mol% palladium (II) trifluoroacetate [Pd(TFA) 2] and 0.7 mol% 3,4,7,8-tetramethyl-1,10-phenanthroline (tm-phen) in DMF at 15 psig CO and 80°C afforded indoles in good to excellent yields. When the reaction was conducted in toluene, the corresponding N-hydroxyindole was isolated. A mechanism that accounts for the formation of N-hydroxyindole is proposed.
- Davies, Ian W.,Smitrovich, Jacqueline H.,Sidler, Rick,Qu, Chuanxing,Gresham, Venita,Bazaral, Charles
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p. 6425 - 6437
(2007/10/03)
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- Selective PPARγ modulators with improved pharmacological profiles
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A series of metabolically robust N-benzyl-indole selective PPARγ modulators with either a 3-benzoyl or 3-benzisoxazoyl moiety have been identified. In vitro, these compounds are partial agonists and exhibit reduced adipogenesis in human adipocytes. In vivo, these SPPARγMs result in potent glucose lowering in db/db mice and attenuate increases in heart weight and brown adipose tissue that is typically observed in rats upon treatment with PPARγ full agonists.
- Liu, Kun,Black, Regina M.,Acton III, John J.,Mosley, Ralph,Debenham, Sheryl,Abola, Ramon,Yang, Meng,Tschirret-Guth, Richard,Colwell, Lawrence,Liu, Cherrie,Wu, Margaret,Wang, Chuanlin F.,MacNaul, Karen L.,McCann, Margaret E.,Moller, David E.,Berger, Joel P.,Meinke, Peter T.,Jones, A. Brian,Wood, Harold B.
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p. 2437 - 2440
(2007/10/03)
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- INDOLES HAVING ANTI-DIABETIC ACTIVITY
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Indoles having aryloxyalkanoic acid substituents or arylalkanoic acid substituents are agonists or partial agonists of PPAR gamma and are useful in the treatment and control of hyperglycemia that is symptomatic of type II diabetes, as well as dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and obesity that are often associated with type 2 diabetes.
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- OPHTHALMIC COMPOSITIONS FOR TREATING OCULAR HYPERTENSION
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This invention relates to the use of potent potassium channel blockers or a formulation thereof in the treatment of glaucoma and other conditions which leads to elevated intraoccular pressure in the eye of a patient. This invention also relates to the use
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- In pursuit of non narcotic analgetic and antiinflammatory agents. 1 carboxyalkyl 3 acylindoles
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The synthesis and study of different carboxyalcoyl 1 acyl 3 indoles has led to molecules endowed with analgesic properties associated with an anti inflammatory action of variable importance. In particular carboxymethyl 1 p chlorobenzoyl 3 methoxy 6 indole (RU 3959) has a strong analgesic activity and a remarkable tolerance which have been confirmed in clinical trials.
- Allais,Meier,Mathieu,et al.
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p. 187 - 199
(2007/10/08)
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