Improvements in corticosteroid 21-acetoxy-17α-hydroxy-16α-methyl-pregna-1,4,9(11)-triene-3,20-dione synthesis and its use as common intermediate in the synthesis of some impurities related to dexamethasone and mometasone.

There are quite substantial number of impurities related to dexamethasone or mometasone which cannot be made from respective Active Pharmaceutical Ingredients but from common intermediate 21-acetoxy-17α-hydroxy-16α-methyl-pregna-1,4,9(11)-triene-3,20-dione (12). As such, a robust and economical synthesis of this key intermediate is important for delivering a resilient and economically viable supply chain for these impurities. Therefore, it is critical to have a robust and economically viable process to synthesize the intermediate 12 in good yield and quality. We report here an improved synthesis of 12 and eight impurities related to dexamethasone and mometasone from this common intermediate.

Total synthesis of phenylpropanoid glycosides, grayanoside A and syringalide B, through a common intermediate.

Phenylpropanoid glycosides are known as bioactive natural products. Two of them, grayanoside A (1) and syringalide B (2), were synthesized through a common intermediate, using benzyl as temporary protecting group following a shorter route.

Advances in antithrombotic agents.

Thrombosis is the condition where an imbalance in the homeostatic mechanism results in unwanted intravascular thrombus formation. Imbalances in this highly regulated process of coagulation and anticoagulation can lead to a variety of pathophysiological conditions leading to stroke, pulmonary heart attack and other serious conditions. In the western world, thromboembolic diseases are the leading cause of morbidity and mortality. Remarkable progress has occurred over the last decade in the development of antithrombotic drugs, which can be classified into 3 major categories - Anticoagulants, Antiplatelets and thrombolytics. Increased understanding of the pathobiology of thrombotic and vascular disorders has helped researchers to target novel pathways involving the coagulation, thrombolytic, fibrinolytic and integrin systems. Traditionally aspirin and unfractionated heparin was used for myocardial infarction. Newer antiplatelet agents such as, clopidogrel, GP IIb/IIIa inhibitors, low molecular weight heparin, direct thrombin inhibitors and several improved thrombolytic agents have been introduced for clinical use. This review will discuss different important drugs, which have been launched in recent years and also some new targets pursued by different companies.

Antiobesity therapy: emerging drugs and targets.

Obesity and its associated morbidities and mortalities are the effects of imbalance between energy intake and expenditure. The healthcare burden for the treatment of obesity is significantly high, due to increased risk of secondary chronic diseases such as hypertension and associated co-morbidities such as diabetes and cardiovascular disease. Lack of physical activity, high fat diets and sedentary life styles are major factors contributing to obesity. However, genetic predisposition and ethnicity are increasingly found to cause obesity. Till date, approved therapeutics have addressed excess energy intake by acting on central neural circuits that regulate feeding or on peripheral mechanisms to reduce nutrient absorption from the gut. These approaches have met with moderate success; and recently with safety concerns, leaving an unmet medical need for effective and safe pharmacotherapy for obesity thereby posing a significant challenge to pharmaceutical industry. Potential antiobesity drugs, which are being investigated by different companies, can be classified in 4 broad categories: 1) Agents that primarily decrease appetite through central action; 2) Agents that primarily increase metabolic rate or affect metabolism through peripheral action; 3) Agents that act on gastrointestinal tract; and 4) Agents that not only affect obesity but also overall Metabolic Syndrome. The current review will deal mainly with different molecules, which are under development for the above-mentioned targets and also their potential benefits and disadvantages.

Role of PPAR in cardiovascular diseases.

Cardiovascular disease (CVD) is the most critical global health threat, which contributes more than one third of global morbidity. CVD includes heart disease, vascular disease, atherosclerosis, stroke and hypertension. The most important independent risk factors for CVD include dyslipidemia along with hypertension, obesity, sedentary lifestyle, diabetes and chronic inflammation. These factors are directly regulated by diet, metabolism and physical activity. Diets rich in fat and carbohydrate coupled to sedentary lifestyles have contributed to the increase in dyslipidemia, type 2 diabetes, obesity and CVD in the world. Discovery of Peroxisome Proliferator Activated Receptors (PPARs) as a key regulator of metabolic pathways has led to significant insight into the mechanisms regulating these processes. Three PPAR subtypes, encoded by distinct genes, are designated as PPAR-alpha, PPAR-delta (also know as beta) and PPAR-gamma. PPARs act as nutritional sensors that regulate a variety of homeostatic functions including metabolism, inflammation and development. PPAR-alpha is the main metabolic regulator for catabolism whereas PPAR-gamma regulates anabolism or storage. PPARs are expressed in the cardiovascular system such as endothelial cells, vascular smooth muscle cells and monocytes/macrophages. It has been shown that they play an important role in the modulation of inflammatory, fibrotic and hypertrophic responses. In 1997, a Glaxo patent described that Troglitazone (first PPAR-gamma ligand to reach market) reduced TNF-induced VCAM1 expression in HUVECs indicating the potential benefit in atherosclerosis. A series of patents from Eli Lilly and Dr. Reddy's Laboratories Ltd. between 1999 and 2005 described a variety of PPAR-alpha and -alpha,gamma dual ligands in a number of patents having glucose, triglyceride, cholesterol lowering, HDL elevating and body weight reducing activity. Patents from Metabolex and Tularik in 2001 and 2002 described the beneficial effects of SPPARM molecules for insulin resistance and diabetes, without showing concern on PPAR-gamma related side effects such as edema and body weight. GSK and Takeda described the potential effects of PPAR-delta modulators during 2001 to 2004 in few patents. Several clinical and preclinical studies have demonstrated the beneficial effects of PPAR ligands on various cardiovascular risk factors. This review intends to capture some of the key studies in this area as is described in some recent patents and literature.

Non-insulin dependent diabetes mellitus: present therapies and new drug targets.

Type 2 Diabetes Mellitus (DM) or Non-Insulin Dependent Diabetes Mellitus (NIDDM) accounts for 90-95% of all diabetes cases and has become a major health concern over the years. This disease has assumed frightening proportions due to unhealthy food habits and sedentary life style. About a decade ago, due to the absence of defined molecular targets or an understanding of disease pathophysiology, treatment of this disease was mostly focused on insulin secretion or administration of external insulin. During the past decade however, advent of genomics and proteomics has helped in understanding the molecular alteration characteristics of NIDDM. Untreated type 2 diabetes leads to several complications such as hyperlipidemia, hypertension and atherosclerosis--collectively known as Syndrome X. Though United Kingdom Prospective Diabetes Study (UKPDS) showed that normalization of hyperglycemia could prevent majority of diabetes complications, the available treatment regime does not adequately normalize the blood glucose level in type 2 diabetic patients. Currently, four distinct classes of oral hypoglycemic agents are available, some of which can act as lipid lowering agents as well. The efficacy and side effect profiles of these drugs are still to be optimized, so there is an unmet need for better candidates. Several new targets as well as better drugs for old targets are under investigation across the world. Availability of such drugs, based on the validated targets, may lead to a new therapeutic paradigm for the prevention of diabetes as well as complications arising out of it. The current review will deal with existing oral therapies for type 2 diabetes as well as the emerging therapeutic targets.

Endothelin receptor antagonists: an overview of their synthesis and structure-activity relationship.

Endothelins (ETs) are potent vasoconstrictor peptides and are associated with several disease states like pulmonary hypertension, systemic hypertension and heart failure. Endothelin-1 (ET-1) is the first member of the family and it has the receptor subtypes known as ETA and ETB. The receptors ETA and ETB are attractive new therapeutic targets for diseases associated with elevated ET-1 levels. Several studies have thus led to the discovery of selective ETA receptor antagonists as well as non-selective ETA/ETB antagonists. The preclinical and clinical studies have clearly established that these antagonists are effective in the treatment of essential hypertension, pulmonary hypertension, heart failure and atherosclerosis. The advances in this area have resulted in the FDA approval of the orally active dual antagonist Bosentan for pulmonary hypertension in 2001. This review highlights the synthesis and structure-activity of the endothelin receptor antagonists and covers the literature in this area up to 2001.

InCl3 as a powerful catalyst for the acetylation of carbohydrate alcohols under microwave irradiation.

Indium(III) chloride catalyzed microwave assisted acetylation of different carbohydrates is an efficient synthesis of per-O-acetyl derivatives and provides the products in good to excellent yields.

A mild and convenient indium(III) chloride-catalyzed synthesis of thioglycosides.

The efficiency of glycosidation reactions generally involves a high chemical yield, as well as high/complete stereo- and regioselectivity. All these depend on the compatibility of the reactivity of glycosyl donors and acceptors. Among glycosyl donors, thioglycosides are widely used because of their high degree of stability in many organic reactions. Although there are number of methods available for the preparation of thioglycosides, all of them have one or more disadvantages, especially concerning the time factor and cumbersome workup procedures. Here we report a convenient and high-yielding method for the preparation of thioglycosides.

Montmorillonite K10 clay: an efficient catalyst for the one-pot stereoselective synthesis of beta-acetamido ketones.

An efficient one-pot three-component coupling process for the synthesis of beta-acetamido ketones catalyzed by montmorillonite K10 clay is described. The reaction is highly stereoselective and the catalyst can be recycled.

Cobalt-catalyzed one-pot three-component coupling route to beta-acetamido carbonyl compounds: a general synthetic protocol for gamma-lactams.

An efficient improved procedure for the synthesis of beta-acetamido carbonyl compounds is developed by a cobalt(II) chloride-catalyzed three-component coupling protocol. The procedure is also amenable to the synthesis of gamma-lactams by a three-component coupling reaction with use of 2-carbomethoxybenzaldehyde. The beta-acetamido carbonyl compounds derived from 2-carbomethoxybenzaldehyde are useful intermediates as they can be transformed to the corresponding gamma-lactams on treatment with base.

Novel thieno oxazine analogues as antihyperglycemic and lipid modulating agents.

A series of phenyl acetic acid and alpha-hydroxy propionic acid derivatives were synthesized. In vivo studies of the compounds indicated compound 2c as the most potent in one of the series, which has both glucose and lipid lowering properties. The syntheses and biological studies have been discussed.

Synthetic studies of cis-4-Amino-L-proline derivatives as novel lipid lowering agents.

cis-4-Amino-L-proline derivatives 1 and 2 derived from quinazolinone and pyrazolo pyrimidone respectively were designed as novel lipid lowering agents. A preliminary in vivo screening indicates that 1b and 2a have moderate triglyceride lowering activity.