Preparation of Novel Bridged Bicyclic Thiomorpholines as Potentially Useful Building Blocks in Medicinal Chemistry

Walker D.P., Bedore M.W.

Bridged bicyclic piperazines are important building blocks in medicinal chemistry research. The bicyclic piperazine 3,6-diazabicylo[3.1.1]heptane is of particular interest as a piperazine isostere because it is achiral and shows similar lipophilicity to that of piperazine based on the c Log P of a derived analog. A concise synthesis of N3- and N6-monoprotected 3,6-diazabicyclo[3.1.1]heptanes 2d and 2e, respectively, is described. The seven step sequence begins with inexpensive starting materials and uses straightforward chemistry.

Villemagne B., Crauste C., Flipo M., Baulard A.R., Déprez B., Willand N.

Tuberculosis is a major disease causing every year 1.8 million deaths worldwide and represents the leading cause of mortality resulting from a bacterial infection. Introduction in the 60's of first-line drug regimen resulted in the control of the disease and TB was perceived as defeating. However, since the progression of HIV leading to co-infection with AIDS and the emergence of drug resistant strains, the need of new anti-tuberculosis drugs was not overstated. However in the past 40 years any new molecule did succeed in reaching the market. Today, the pipeline of potential new treatments has been fulfilled with several compounds in clinical trials or preclinical development with promising activities against sensitive and resistant Mycobacterium tuberculosis strains. Compounds as gatifloxacin, moxifloxacin, metronidazole or linezolid already used against other bacterial infections are currently evaluated in clinical phases 2 or 3 for treating tuberculosis. In addition, analogues of known TB drugs (PA-824, OPC-67683, PNU-100480, AZD5847, SQ609, SQ109, DC-159a) and new chemical entities (TMC207, BTZ043, DNB1, BDM31343) are under development. In this review, we report the chemical synthesis, mode of action when known, in vitro and in vivo activities and clinical data of all current small molecules targeting tuberculosis.

Ravula S.B., Yu J., Tran J.A., Arellano M., Tucci F.C., Moree W.J., Li B., Petroski R.E., Wen J., Malany S., Hoare S.R., Madan A., Crowe P.D., Beaton G.

The structure–activity relationships of 2-(piperidin-3-yl)-1 H -benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1 H -benzimidazoles are described. In the lead optimization process, the p K a and/or log P of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics. The structure–activity relationships of 2-(piperidin-3-yl)-1 H -benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1 H -benzimidazoles are described. In the lead optimization process, the p K a and/or log P of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.

Trujillo J.I., Huang W., Hughes R.O., Joseph Rogier D., Turner S.R., Devraj R., Morton P.A., Xue C., Chao G., Covington M.B., Newton R.C., Metcalf B.

This report describes the design and synthesis of a series of CCR2 antagonists incorporating novel non-aryl/heteroaryl RHS (right hand side) motifs. Previous SAR in the area has suggested an aryl/heteroaryl substituent as a necessary structural feature for binding to the CCR2 receptor. Herein we describe the SAR with regards to potency (binding to hCCR2), dofetilide activity and metabolic stability (in vitro HLM) for this series. The resulting outcome was the identification of compounds with excellent properties for the investigation of the role of CCR2 in disease.

Wang X., Berger D.M., Salaski E.J., Torres N., Hu Y., Levin J.I., Powell D., Wojciechowicz D., Collins K., Frommer E.

A series of pyrazolo[1,5-alpha]pyrimidine analogs has been prepared and found to be potent and selective B-Raf inhibitors. Molecular modeling suggests they bind to the active conformation of the enzyme.

Zask A., Kaplan J., Verheijen J.C., Richard D.J., Curran K., Brooijmans N., Bennett E.M., Toral-Barza L., Hollander I., Ayral-Kaloustian S., Yu K.

Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC(50) values and up to 26000-fold selectivity versus PI3Kalpha were prepared. Chiral morpholines gave inhibitors whose enantiomers had different selectivity and potency profiles. Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.

Huang X., Chen D., Wu N., Zhang A., Jia Z., Li X.

A series of non-basic building blocks was synthesized and introduced to the C7 position of the quinolone nucleus 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid to afford the corresponding fluoroquinolones in 46-85% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. The sulfur-containing quinolone, 7-(2-thia-5-azabicyclo[2.2.1]heptan-5-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid exhibited a superior antibacterial activity against quinolone-susceptible and multidrug-resistant strains in comparison with the clinically used fluoroquinolones ciprofloxacin and vancomycin, especially to the Streptococcus pneumonia and multidrug-resistant S. pneumonia clinical isolates.

Nagelschmitz J., Voith B., Wensing G., Roemer A., Fugmann B., Haynes R.K., Kotecka B.M., Rieckmann K.H., Edstein M.D.

ABSTRACT In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10- to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t1/2) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t1/2, its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t1/2 is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria.

Chênevert R., Jacques F., Giguère P., Dasser M.

The enzymatic desymmetrization of various meso-N-Boc-2,5-cis-disubstituted pyrrolidines and pyrrolines compounds by ester hydrolysis or transesterification provided the corresponding monoesters in high enantiomeric excess.

Roecker A.J., Coleman P.J., Mercer S.P., Schreier J.D., Buser C.A., Walsh E.S., Hamilton K., Lobell R.B., Tao W., Diehl R.E., South V.J., Davide J.P., Kohl N.E., Yan Y., Kuo L.C., et. al.

Inspired by previous efforts in the pyrazolobenzoxazine class of KSP inhibitors, the design and synthesis of 1,4-diaryl-4,5-dihydropyrazole inhibitors of KSP are described. Crystallographic evidence of binding mode and in vivo potency data is also highlighted.

Biava M., Porretta G.C., Poce G., Supino S., Deidda D., Pompei R., Molicotti P., Manetti F., Botta M.

On the basis of suggestions derived either from a pharmacophoric model for antitubercular agents or from a structure-activity relationship analysis of many pyrroles previously described by us, we report here the design and synthesis of new analogues of 1,5-(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM212). Various substituents with different substitution patterns were added to both positions 1 and 5 of the pyrrole nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis (MTB) and atypical mycobacteria. Biological data showed that, although some nontuberculosis mycobacterial strains were found to be sensitive, MIC values were higher than those found toward MTB. The best compound (1-(4-fluorophenyl)-2-methyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole, 5) possessed a MIC of 0.4 microg/mL (better than BM212 and streptomycin) and a very high protection index (160), better than BM212, isoniazid, and streptomycin (6, 128, and 128, respectively). Finally, molecular modeling studies were performed to rationalize the activity of the new compounds in terms of both superposition onto a pharmacophoric model for antitubercular compounds and their hydrophobic character.

Haynes R.K., Fugmann B., Stetter J., Rieckmann K., Heilmann H., Chan H., Cheung M., Lam W., Wong H., Croft S.L., Vivas L., Rattray L., Stewart L., Peters W., Robinson B.L., et. al.

Artemisinin - the next generation: Efficacies of artemisone against the malaria parasite are substantially greater than those of the current artemisinin gold standard, artesunate. Also, in contrast to most current artemisinins it displays low lipophilicity and negligible neuro- and cytotoxicity in in vitro and in vivo assays. Thus, the drug offers promise for use in artemisinin-based combination therapy. (Chemical Equation Presented). © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

Levin J.I., Chen J.M., Laakso L.M., Du M., Schmid J., Xu W., Cummons T., Xu J., Jin G., Barone D., Skotnicki J.S.

A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.

Donohoe T.J., Sintim H.O., Hollinshead J.

[reaction: see text] A flexible route to polyhydroxylated pyrrolizidine alkaloids is described, starting from commercially available N-Boc pyrrole and using a partial reduction as the key step. Tactics for varying the stereochemistry around the ring by choice of partial reduction conditions are discussed and methods for constructing the bicyclic ring system of the pyrrolizidine targets are examined. Intramolecular S(N)2 type displacement reactions were found to be an efficient way of forming the requisite bicyclo ring systems while iodine-promoted cyclizations proved unsuitable. A first synthesis of hyacinthacine A1 is described that also confirmed the structure of the natural product, and a short stereoselective synthesis of 1-epiaustraline is also discussed in detail.

Donohoe T.J., Headley C.E., Cousins R.P., Cowley A.

[reaction: see text] The partial reduction of electron-deficient 2,5-disubstituted pyrroles has been developed into a flexible procedure that gives control of relative stereochemistry by variation of the reduction conditions. After the reaction, the pyrroline products were dihydroxylated at C-3,4 to give either the cis or trans isomers; this flexibility means that a variety of polyhydroxylated pyrrolidines can be prepared in a short sequence. Finally, this method was applied to a synthesis of the naturally occurring glycosidase inhibitor DMDP.

Zhang J., Zhang K., Wang K., Wang B., Zhu S., Qian H., Ma Y., Zhang M., Liu T., Chen P., Shen Y., Fu Y., Fang S., Zhang X., Zou P., et. al.

AbstractOrganic fluorophores are the keystone of advanced biological imaging. The vast chemical space of fluorophores has been extensively explored in seek of molecules with ideal properties. However, within the current molecular constraints, there appears to be a trade-off between high brightness, robust photostability, and tunable biochemical properties. Herein we report a general strategy to systematically boost the performance of donor-acceptor-type fluorophores by leveraging SO2and O-substituted azabicyclo[3.2.1] octane auxochromes. These bicyclic heterocycles give rise to a collection of ‘Bridged’ dyes (BD) spanning the UV and visible range with top-notch quantum efficiencies, enhanced water solubility, and tunable cell-permeability. Notably, these azabicyclic fluorophores showed remarkable photostability than its tetramethyl or azatidine analogue, at the same time completely resistant to oxidative photobluing rendered by the Bredt’s rule. Functionalized BD dyes are tailored for applications in single-molecule imaging, super-resolution imaging (STED and SIM) in fixed or live mammalian cells and plant cells, and live zebrafish imaging or chemigenetic voltage imaging. Synergizing with advanced imaging methods, the bridge bicycle dyes represent a versatile palette for biological researches.

Kubyshkin V., Rubini M.

Yamazaki S.

In this chapter, the monocyclic, benzo and dibenzo-fused ring systems, thiepine, thiepane, 1-benzothiepine, 2-benzothiepine, 3-benzothiepine, dibenzo[b,d]thiepine, dibenzo[b,e]thiepine, dibenzo[b,f]thiepine, dibenzo[c,e]thiepine and their carbocycle and heterocycle-fused systems are included. Further dihydro, and tetrahydro derivatives and their bridged bicyclic analogs are also described, as well as the corresponding sulfoxides and sulfones. The present chapter is intended to update the previous work on thiepines and thiepanes, and covers literature published since 2008. Theoretical studies on thiepine-benzene sulfide valence isomerization have been of continuous interest. In addition, the theoretical interest related to aromaticity and anti-aromaticity has been studied. Furthermore, fused systems, such as dibenzo[b,f]thiepines has become important structural motifs found in a diverse array of biologically active molecules. In the last decade, many reports on the synthesis and reactions of thiepines by transition-metal catalysts have appeared.

Lagoutte R., Lefebvre Q., Salome C., Fessard T.

The interest for 4-membered unsaturated nitrogen-containing bicyclic systems has been very limited owing to their difficult access that limits their use, and they therefore rather remain lab curiosities. In stark contrast, fused and spirocyclic azetidines have been more extensively investigated for they find applications in medicinal chemistry in the context of lead optimization. Because traditional syntheses are lengthy and low yielding, this has in addition triggered a resurge of interest from the synthetic community to develop novel and efficient strategies to access them. These will be overviewed in this chapter together with representative theoretical studies on these systems and key structural data.

Borst M.L., Ouairy C.M., Fokkema S.C., Cecchi A., Kerckhoffs J.M., de Boer V.L., van den Boogaard P.J., Bus R.F., Ebens R., van der Hulst R., Knol J., Libbers R., Lion Z.M., Settels B.W., de Wever E., et. al.

The design and synthesis of three novel polycyclic scaffolds containing sulfoximines are presented in this work, which exemplify that sulfoximines represent a real opportunity for the discovery of new drug candidates. Additionally, the structures present at least two points of diversification and contain a high level of sp3-character, hence being very interesting 3D scaffolds. The compounds synthesized were added to the compound collection of the European Lead Factory.

Walker D.P., Rogier D.J.

Thiomorpholine and thiomorpholine 1,1-dioxide are important building blocks in medicinal chemistry research, and some analogues containing these moieties have entered human clinical trials. Analogues containing bridged bicyclic thiomorpholines have also shown interesting biological profiles. 3-Thia-6-azabicyclo[3.1.1]heptane, 3-thia-8-azabicyclo[3.2.1]octane, and their corresponding 1,1-dioxide counterparts were prepared as novel bicyclic thiomorpholine building blocks. Each heterocycle was synthesized from an inexpensive starting material by straightforward chemistry.