Intramolecular Nonbonded S···O Interaction Recognized in (Acylimino)thiadiazoline Derivatives as Angiotensin II Receptor Antagonists and Related Compounds

IkB kinase (IKK) has been identified as a serine-threonine kinase complex, which phosphorylates the inhibitor of NFkB (IkB). [1][2][3] This complex is composed of three subunits, i.e. the catalytic subunits IKKa and IKKb, and the regulatory subunit IKKg, also called IKK-1, IKK-2, and NEMO, respectively. The complex plays a critical role in a signaling pathway leading to NF-kB (nuclear factor-kB) activation. 4) The activation of IKK by cytokine signals (tumor necrosis factor (TNF)-a, interleukin (IL)-1 etc.), lipopolysaccharide (LPS), and stress leads to phosphorylation of IkB, which triggers poly-ubiquitinylation and proteasome-dependent degradation of IkB, resulting in transcriptional activation of NF-kB. It has been recognized that the kinase IKKb plays a major role in activation of NF-kB via classical (canonical) pathway, and activation of the classical pathway promotes the production of TNF-a, IL-1, intercellular adhesion molecule (ICAM)-1, and cyclooxygenase (COX)-2, which indicates that this pathway is important for inflammation and the innate immune system. Therefore, IKKb inhibitors are expected to be useful for the treatment of acute and chronic inflammatory diseases and autoimmune disorders, such as rheumatoid arthritis (RA). 5) Alternatively, IKKb inhibitors are also thought to be useful for the treatment of type 2 diabetes because activation or overexpression of the IKKb attenuated insulin signaling.6) In addition, IKKb inhibitors may also have application for the treatment of asthma, chronic obstructive pulmonary disease (COPD), 7) and cancer. 8) Because of the key role played by the IKK complex in the NF-kB mediated transcription, and of the druggability of kinases as a target class, numerous companies have been pursuing discovery programs aimed at identifying small molecule inhibitors of this enzyme. 9,10) As part of our program to discover new IKK inhibitors, we identified 1 (MAYBRIDGE) as a potent hit compound. However, AstraZeneca has previously reported that the structurally-analogous urea derivative 2, 11) which could be derived from the compound 1, exhibited excellent inhibitory activity. The introduction of a urea group resulted in the improvement of activity by as much as 100-fold compared with the amino derivative 1 (Fig. 1). Because the benzene ring of 2 was considered to be coplanar to the thiophene ring in it's active conformation, 11) it seemed that the relative orientation of the urea, carbamoyl, and benzene was important for IKKb inhibition. Thus, it was also thought that constraining the terminal benzene to be in the active conformation could improve activity. From this point of view and taking into consideration of patentability issues, we designed tricyclic fused furan derivatives for the development of novel IKK inhibitors. In this manuscript, we describe the synthesis and the SAR of the series of tricyclic furan derivatives. ChemistryThe synthesis of benzothieno[3,2-b]furans 13a-i and 16a-o having a 2-carbamoyl and 3-urea group, is outlined in Chart 1. The substituted thiopheno...

Section: Resultsmentioning

confidence: 99%

Synthesis and Structure Activity Relationship Studies of Benzothieno[3,2-b]furan Derivatives as a Novel Class of IKK.BETA. Inhibitors

Sugiyama

Yoshida

Mori

et al. 2007

“…interactions have been observed in a large number of organosulfur compounds controlling the conformation of small and large molecules. [1][2][3][4][5][6][7][8][9][10][11][12] Some of these compounds showed the strong bioactivity, and we suggested that the intramolecular nonbonded S · · · X interactions play an important role on the mechanism of several biological effects.1,2,6-12) For example, the clear S · · · O close contact in the complex crystalline structure of carbonic anhydrase I and acetazolamide was recognized.12) The same nonbonded interaction was observed in the crystalline structure of acyliminothiadiazoline, which has potent angiotensin II receptor antagonistic activity. 6,11) It is estimated that the ring structure consisted of the intramolecular nonbonded S · · · X interactions was more flexible than that of covalent bonding, and this flexibility increased the binding affinity of the active compound to the flexible pocket of the enzyme or the receptor.…”

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confidence: 99%

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confidence: 99%

Intramolecular Nonbonded S...N Interaction in Rabeprazole

Hayashi

Ogawa

Sano

et al. 2008

Self Cite

Intramolecular nonbonded S · · · X (XϭS, O, N, etc.) interactions have been observed in a large number of organosulfur compounds controlling the conformation of small and large molecules. [1][2][3][4][5][6][7][8][9][10][11][12] Some of these compounds showed the strong bioactivity, and we suggested that the intramolecular nonbonded S · · · X interactions play an important role on the mechanism of several biological effects.1,2,6-12) For example, the clear S · · · O close contact in the complex crystalline structure of carbonic anhydrase I and acetazolamide was recognized.12) The same nonbonded interaction was observed in the crystalline structure of acyliminothiadiazoline, which has potent angiotensin II receptor antagonistic activity. 6,11) It is estimated that the ring structure consisted of the intramolecular nonbonded S · · · X interactions was more flexible than that of covalent bonding, and this flexibility increased the binding affinity of the active compound to the flexible pocket of the enzyme or the receptor. These results prompted us to disclose the new roles of intramolecular nonbonded S · · · X interactions in other drugs. Herein, we focus on rabeprazole, [13][14][15][16] and discuss the intramolecular nonbonded S · · · N interaction in rabeprazole and its role.Sodium rabeprazole (1) is one of the inhibitors of the gas-13,14) As a result of the investigations on the mechanism of action of these inhibitors, it has been expected that 1 will be activated by protonation in the parietal cell (intermediate 2), converted into the sulfenamide 5 via the spiro sulfoxide 3 and sulfenic acid 4, and the active principle 5 can react with the accessible cysteines of the gastric (H ϩ -K ϩ )-ATPase followed by the inhibition of the enzyme (compound 6), as shown in Chart 1. 14,[17][18][19][20] In this reaction cascade, the key step is the formation of the putative spiro sulfoxide 3 arising from nucleophilic attack of the pyridine nitrogen on the activated 2-position of the benzimidazole moiety.18) The fact that the nucleophilic attack of the pyridine nitrogen smoothly proceeds despite the week nucleophilicity is very interest, and made us guess that the intramoleculer nonbonded S · · · N interaction influenced this step. Because, if such intramoleculer nonbonded S · · · N interaction is possible in rabeplazole, the 4-membered quasiring in 2 containing the rabeplazole structure would be formed and bring the nitrogen atom of pyridine close to the electrophilic position of benzimidazole moiety, as shown in Fig. 1. Therefore, in order to make clear the presence of the intramoleculer nonbonded S · · · N interaction in 1, we characterized the crystal structures of derivatives of 1 at first, since 1 itself could hardly be crystallized. 21)The reactions of 1 with various electrophiles in the presence of amines gave the corresponding derivatives of 1 in 36-92% yields, as shown in Chart 2. The resultant derivatives 7a-d were recrystallized from suitable solvents to obtain the corresponding crystals available for X-ray crystal...

“…In a similar manner, with arylcopper reagents (e.g., Ar 2 Cu · MgBr · MgBrI), the salt MgBrI should coordinate with the sulfinyl oxygen in monodentate form. Alternatively, transition state B, which would arise due to such an intramolecular nonbonded S-O interaction, 15) is also possible; however, the observed diastereoselectivities were not consistent. When the de values obtained for (di)alkylcopper reagents were compared to those observed for (di)arylcopper reagents, a sterically bulky substituent has no significant influence on the asymmetric induction.…”

Section: )mentioning

confidence: 88%

1,6-Asymmetric Induction during the Conjugate Addition of Arylcopper Reagents to a Chiral Sulfinyl-Substituted Pyrrolyl .ALPHA., .BETA.-Unsaturated Amide.

Arai

Ueda

Xie

et al. 2001

Organocopper conjugate addition to a,b-unsaturated carbonyl systems represents an important area for organic synthesis.2) To overcome difficulties encountered with 1,4-addition to unsaturated aldehydes and esters due to competing 1,2-addition and to unsaturated amides owing to low reactivity of the C-C double bond in their carbonyl compounds, Lewis acid-and trimethylsilyl halide-mediated organocopper reagents have been devised. Moreover, to enhance the reactivity of the organocopper reagents, various types of reagents including the higher-order cuprates have also been developed.Asymmetric organocopper-conjugate addition reactions have been carried out by the use of 1) chiral auxiliaries in either the copper reagent or the a,b-unsaturated carbonyl compound, 2) chiral ligands, 3) a chiral catalyst, or 4) a chiral solvent. Compared with other asymmetric additions of cuprates, methods employing a conjugate acceptor with a chiral auxiliary are most reliable and promising in view of high performance because selectivities in the reactions by other methods are dependent on a large number of factors, including substrate and cuprate structure, solvent, 3) and the presence of added salts. Asymmetric conjugate addition of organometallic species to a,b-unsaturated enone with a chirally sulfinylated auxiliary has been developed by Posner et al.4) who reported highly stereoselective 1,4-additions of Grignard reagents with or without a Lewis acid, and organocuprates. On the other hand, studies of asymmetric organocopper-conjugate additions using a,b-unsaturated amides are not common since the amides are essentially inert toward organometallic reagents 5) unless another activating group is introduced in these molecules. To circumvent the low reactivity of the C-C double bond in these amides, activated amides (X*ϭchiral auxiliary, XϭC, N, O) such as the N-enoyl lactams 6) (A, B) and the N-enoyl sultams 7) (C), or the use of trimethylsilyl chloride (TMSCl) as an additive for the amide (D) 8) have been devised to date. In the course of our studies on asymmetric reactions using chiral sulfoxides, we recently reported the highly diastereoselective Diels-Alder reaction of a,b-unsaturated amides 1 and 2, which are obtained, respectively, from a chiral sulfinyl auxiliary 3 and (E)-cinnamoyl-and crotonoyl chloride. 9) Encouraged by the excellent results with both the reactivity and the diastereoselectivity of 1 in the cycloaddition, we were intrigued by the conjugate addition of an organocopper reagent to these amides. To evaluate the reactivity and selectivity in organocopper-conjugate addition, we planned the reaction using the a,b-unsaturated amides. Here we describe the diastereoselective conjugate addition of organocopper reagents to 1 and 2 with a remote chiral auxiliary 3. 10)First, we undertook the conjugate addition of methylcopper and dimethyl cuprate derived from methyllithium and copper(I) iodide to cinnamide 1 (Chart 1). The results are December 2001 Chem. Pharm. Bull. 49(12) 1609-1614 (2001) 1609 * To whom correspondenc...