Conformationally restricted benzothienoazepine respiratory syncytial virus inhibitors: their synthesis, structural analysis and biological activities

Abstract

Atropisomeric drug substances are known to have different biological properties. Compounds containing the N-benzoylbenzazepine motif have been shown to exhibit energetically restricted rotation around the Ar(CO)N axis. Herein we report, for the first time, the synthesis, physical characterisation and anti-viral profiles of a series of C-4 and C-5 methylated thieno-benzazepines. NMR analysis reveals that incorporation of a single additional substituent at either of these loci influences the conformational dynamics of the azepine ring system. In the case of the C-5 alkyl analogues, the influence of the new stereocentre is so pronounced that its absolute configuration determines which unique atropisomer is obtained following the generation of the benzazepine nucleus. Screening of the alkylated derivatives for their anti-respiratory syncytial virus (RSV) activity indicates that the desired viral pathogenicity is strongly associated with the conformation adopted by the modified tricyclic scaffolds. This is particularly evident in the case of the C-5 homologues in which one atropisomer was found to be potently active and the other essentially inert. These results provide compelling evidence that we have determined the bioactive conformation shared by RSV inhibitors that employ the thienobenazapine nucleus as their core molecular architecture. Furthermore, the understanding obtained from these studies may make it possible to design improved agents against RSV infection in the future.

Fig. 1. Biologically active compounds that exist as atropisomers.

Fig. 2. Structures of vasopressin receptor ligands: tolvaptan 4; N-benzoyl-1,5-benzodiazepine derivatives 5 and 6.

Fig. 3. Structures of benzothienoazepine based RSV polymerase inhibitors.

Fig. 4. Conformations of the seven membered ring in benzothienoazepines.

Scheme 1. Synthetic route for the preparation of 4-methylazepine derivative 14^a. ^aReagents and conditions: (a) LiAlH₄, THF, 0 °C to RT, 88%; (b) NBS, DCM, AcOH. RT, 63%; (c) TBSCl, ImH, DMF, RT, 70%; (d) ClCO₂Et, LDA, THF, –78 to –40 °C, 39%; (e) ArB(pin), Pd(PPh₃)₄, Na₂CO₃, 1,4-dioxane : H₂O (1 : 1), 95 °C, 76%; (f) TBAF, THF, RT, 90%; (g) PPh₃, DIAD, PhMe, 0 °C to reflux then TFA, RT, 54% + 19% of 12b; (h) ArCOCl, py, RT to 50 °C, 90%; (i) LiOH, THF : MeOH : H₂O (1 : 1 : 1), RT, 97%.

Scheme 2. Synthetic route for the preparation of 5-methylazepine derivative 20^a. ^aReagents and conditions: (a) DMP, DCM, RT then MeMgI, Et₂O, 0 °C to RT, 69%; (b) NBS, DCM, AcOH. RT, 78%; (c) TBSCl, ImH, DMF, RT, 90%; (d) ClCO₂Et, LDA, THF, –78 °C, 39%; (e) ArB(pin), Pd(PPh₃)₄, Na₂CO₃, 1,4-dioxane : H₂O (1 : 1), 95 °C, 83%; (f) TBAF, THF, 0 °C to RT, 87%; (g) PPh₃, DIAD, PhMe, 0 °C to reflux then TFA, RT, 40%; (h) ArCOCl, py, RT to 50 °C, 92%; (i) LiOH, THF : MeOH : H₂O (1 : 1 : 1), RT, 92%.

Scheme 3. Enantiospecific synthesis of (R)-20^a. ^aReagents and conditions: (a) (S)-2-methyloxirane, nBuLi, BF₃.Et₂O, THF, –78 to 0 °C, 74%.

Fig. 5. ¹H NMR spectrum of compound 13 (A) and 1D NOE experiment by selective irradiation of signal H5a (B).

Fig. 6. Chemical shifts and coupling constants for the key protons in the azepine ring of 19.