The preparation of a novel chemokine receptor type 2 (CCR-2) antagonist is described on a 135 g scale. The synthesis of an all-carbon bicyclic core was accomplished using a radical cyclization strategy using chiral precursors, wherein elaboration led to N-Boc carboxylic acid in good yield. After amidation using a traditional coupling reaction, a reductive amination using enantiomerically enriched 3-methoxy-4-pyranone led to the final compound. Although several steps of the syntheses involved reagents that would not be preferred in process and chromatography was used to provide the free-base diastereomer of the final succinate salt, the overall route went through stable intermediates that could be used for future scale-up. This lab-scale synthesis struck a balance between a quick scale-up and a more thorough process review of all possible methods and routes.

The preparation of a chemokine receptor type 2 (CCR-2) antagonist bearing a cyclopenta[b]furan core is described on a 600 g scale. Compared to our previously reported synthesis of the all-carbon core CCR-2 antagonist with a similar peripheral 3-methoxypyran appendage, our work required a redesign of the original Discovery Chemistry route and took advantage of a side product seen in the diastereoselective alkylation reaction. Elaboration by reduction and oxy-cyclization eventually led to the required N-Boc acid method. After amidation using a traditional coupling reaction, a reductive amination using enantiomerically enriched 3-methoxy-4-pyranone led to the final compound. Although several steps of the syntheses involved reagents such as selenium and chromium that would not be used in a large-scale process setting, the overall route went through intermediates that could certainly be used for future scale-up campaigns. The synthesis provided a method to make lab-scale quantities of the final succinate salt to support tox/toleration studies. Relative to the Discovery Chemistry route, this lab-scale route featured novel intermediates that could open new avenues for future research in this area.

As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).

Replacement of the methyl-thiazole moiety of GW501516 (a PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 21 which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. A structure-activity relationships study of 21 resulted in the identification of 40 as a potent and selective PPARalpha/delta dual agonist. Compound 40 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, high selectivity, significant gene induction, excellent PK profiles, low P450 inhibition or induction, and good in vivo efficacy in four animal models support 40 being selected as a pre-clinical study candidate, and may render 40 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists, and the potential usage for the treatment of metabolic syndrome.

The preparation of the selective VEGF-R2 kinase inhibitor 10 (JNJ-17029259) is described in which the key precursor, 4-(5-isoxazolyl)benzonitrile, undergoes clean transformation to the corresponding cumylamine derivative with CeCl(3)-MeLi in THF. This high-yielding cerium mediated transformation is robust, reproducible, and readily scalable based on a requirement for the anhydrous CeCl(3) to be milled and subjected to ultrasound treatment prior to addition of methyllithium.

An improved, reproducible nonchromatographic process for scale-up synthesis of 2,5,8-substituted 11,12-dihydro-5H-6,13-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene derivatives as selective estrogen receptor modulators (SERMs) is described. The titled compounds were prepared in 9-21% overall yield with high chemical purity (> 97%) after nine consecutive synthetic steps.

A novel series of 4-aryl-5-cyano-2-aminopyrimidines were synthesized and found to have potent VEGF-R2 kinase inhibitory activity. Structure-activity relationships were investigated and compound 14a was shown to be efficacious in a mouse model of corneal neovascularization. (c) 2007 Elsevier Ltd. All rights reserved.

The preparation of the PPAR alpha,delta agonist 2-methyl-2-(2-methyl-4-(3-(4-(trifluoromethyl)phenyl)[1,2,4]thiadiazol-5-ylmethoxy)phenoxy)propionic acid sodium salt (17) is described and compared with earlier in-house preparations of this important target compound. Key concerns around a large-scale synthesis of this thiadiazole derivative were a large number of purification steps, the use of dichlorobenzene as a solvent, and a possible large-scale Baeyer-Villiger oxidation. This paper describes a straightforward preparation of the target agonist using methylhydroquinone (MHQ) as an inexpensive precursor that eliminates the need of an oxidation step.

Cardiovascular disease is the most common cause of morbidity and mortality in developed nations. To effectively target dyslipidemia to reduce the risk of cardiovascular disease, it may be beneficial to activate the peroxisome proliferator-activated receptors (PPARs) PPARalpha and PPARdelta simultaneously through a single molecule. Replacement of the methylthiazole of 5 (the PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. Optimization of 13 led to the identification of 24 as a potent and selective PPARalpha/delta dual agonist. Compound 24 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficacies in three animal models may render compound 24 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists and as a potential treatment of the metabolic syndrome.

Unsymmetrical benzopyranobenzopyran compounds are novel selective estrogen receptor modulators (SERMs). A reproducible and nonchromatographic process was developed to prepare multihundred gram quantities of 5-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,11-dihydrochromeno[4,3-c]chromene-2,8-diyl-bis(2,2-dimethylpropanoate) (14). The overall yield of this 11-step synthesis was improved from 0.17% to 7.1% after three scale-up campaigns.

Inhibition of the p38 map kinase pathway has been shown to be beneficial in the treatment of inflammatory diseases. The first class of potent p38 kinase inhibitors was the pyridinylimidazole compounds from SKB. Since then several pyridinylimidazole-based compounds have been shown to inhibit activated p38 kinase in vitro and in vivo. We have developed a novel series of pyridinylimidazole-based compounds, which potently inhibit the p38 pathway by binding to unactivated p38 kinase and only weakly inhibiting activated p38 kinase activity in vitro.

Various substituents were introduced onto the methyl group in 4-methyl coumarins through lithiation, followed by reactions with a wide range of electrophiles. The presence of an alkoxy group on 6′-phenyl ring was found to be pivotal for the success of this reaction. This procedure provided a convenient synthetic pathway to elaborate the methyl group of 4-methylcoumarins. Application of this methodology was showcased with the synthesis of biologically important novel tetracyclic chromene ring systems (n=1–3).

Inhibition of angiogenesis may have wide use in the treatment of cancer; however, this approach alone will not cause tumor regression but may only slow the growth of solid tumors. The clinical potential of antiangiogenic agents may be increased by combining them with conventional chemotherapeutics. 4-[4-(1-Amino-1-methylethyl)phenyl]-2-[4-(2-morpholin-4-yl-ethyl)phenylamino]pyrimidine-5-carbonitrile (JNJ-17029259) represents a novel structural class of 5-cyanopyrimidines that are orally available, selective, nanomolar inhibitors of the vascular endothelial growth factor receptor-2 (VEGF-R2) and other tyrosine kinases involved in angiogenesis, such as platelet-derived growth factor receptor, fibroblast growth factor receptor, VEGF-R1, and VEGF-R3, but have little activity on other kinase families. At nanomolar levels, JNJ-17029259 blocks VEGF-stimulated mitogen-activated protein kinase signaling, proliferation/migration, and VEGF-R2 phosphorylation in human endothelial cells; inhibits the formation of vascular sprouting in the rat aortic ring model of angiogenesis; and interferes with the development of new veins and arteries in the chorioallantoic membrane assay. At higher concentrations of 1 to 3 microM, this compound shows antiproliferative activity on cells that may contribute to its antitumor effects. JNJ-17029259 delays the growth of a wide range of human tumor xenografts in nude mice when administered orally as single-agent therapy. Histological examination revealed that the tumors have evidence of reduced vascularity after treatment. In addition, JNJ-17029259 enhances the effects of the conventional chemotherapeutic drugs doxorubicin and paclitaxel in xenograft models when administered orally in combination therapy. An orally available angiogenesis inhibitor that can be used in conjunction with standard chemotherapeutic agents to augment their activity may have therapeutic benefit in stopping the progression of cancer and preventing metastasis.

AbstractQuinolone carboxylic acids are a class of totally synthetic antibacterial agents which encompass 4‐oxo‐3‐quinolinecarboxylic acids as well as the corresponding 1,8‐naphthyridines, cinnolines, and pyrido [2,3‐d]‐pyrimidines. These classes are illustrated by ciprofloxacin, nalidixic acid, cinoxacin, and piromidic acid, respectively. Established quinolone antibacterial agents are ciprofloxacin, ofloxacin, enoxacin, norfloxacin, and pefloxacin. Quinolones exert their antibacterial activity by interfering with the replication of bacterial DNA by inhibition of the enzyme DNA gyrase. The critical reaction is the negative supercoiling of bacterial DNA, a process involving the breaking and resealing of double‐stranded circular DNA. The general method by which most newer fluoro quinolones are prepared involves a ring closure reaction to form the quinolone nucleus. For the most part quinolones are well tolerated with few reports of adverse reactions, but because of a concern that they cause arthropathy in juvenile animals, quinolones are contraindicated for children and during pregnancy. A second problem is adverse side effects of the central nervous system (CNS) and adverse reactions with other drugs. Earlier quinolones have had little impact on the domestic antiinfective market as their utility was limited primarily to urinary tract infections. Newer quinolones, because of safety, seemingly low propensity toward bacterial resistance, and vastly improved therapeutic utility, enjoy a much greater market share.