Synthesis of halogenated trimetoquinol derivatives and evaluation of their .beta.-agonist and thromboxane A2 (TXA2) antagonist activities

Abstract

The 5,8-difluoro (4), 5-iodo (5), 8-iodo (6), and 5-trifluoromethyl (7) derivatives of trimetoquinol (TMQ, 1) have been synthesized and evaluated for their ability to stimulate beta 1 (guinea pig atria) and beta 2 (guinea pig trachea) adrenoceptors as well as for their inhibitory activity against U46619 [a thromboxane A2 (TXA2) mimetic]-mediated contraction of rat thoracic aorta and human platelet aggregation. Both 5 and 6 were considerably less active than TMQ on both beta-adrenergic systems and gave a rank order of stimulatory potency of 1 much greater than 6 greater than or equal to 5. Similarly, iodine substitution at either position also caused a reduction in TXA2 antagonist activity with a rank order potency of 1 greater than 6 much greater than 5. Compared to 1, however, 5-iodo-TMQ (5) showed a marked selectivity for blockade of U46619 responses in rat aorta over human platelets. On beta-systems, 4 had reduced potency compared to TMQ and was similarly nonselective. Introduction of a trifluoromethyl group at the 5-position of TMQ completely abolished both beta 1- and beta 2-adrenergic agonist activities while imparting weak antagonist activity on beta 1 receptors. On TXA2 systems, both 4 and 7 possessed significantly decreased inhibitory activity compared to TMQ. The synthetic approaches to the synthesis of 8-(trifluoromethyl)-TMQ (8) are also described. The enantiomers of the 8-fluoro derivative (3) of TMQ were separated on a preparative Chiralcel OD column and evaluated on beta-adrenergic systems and TXA2 systems. On beta-adrenergic systems, (S)-(+)-8-fluoro-TMQ was at least 10-fold more potent than (R)-(-)-8-fluoro-TMQ. Conversely, (R)-(-)-8-fluoro-TMQ was approximately 14-fold more potent as an antagonist of TXA2-mediated aggregation in human platelets than (S)-(+)-8-fluoro-TMQ. In contrast to platelets, (S)-(+)-8-fluoro-TMQ was an agonist in rat aorta whereas (R)-(-)-8-fluoro-TMQ was an antagonist.

Trifluoromethylation of aryl and heteroaryl halides

“…70 However, Ammann reported only a 25% yield for the same reaction in their asymmetric synthesis of (R)-and (S)-2-trifluoromethylepinephrine. 71 As in previous cases of trifluoromethylations, it was noted that rigorously anhydrous conditions are needed to prevent the undesired formation of veratraldehyde, the dehalogenated/reduced starting material.…”

“…71 As in previous cases of trifluoromethylations, it was noted that rigorously anhydrous conditions are needed to prevent the undesired formation of veratraldehyde, the dehalogenated/reduced starting material. 70 Toyota and co-workers also exploited this methodology by converting 9-iodoanthracene to its trifluoromethyl derivative (entry 5). 72 Notably, Matsui reported a 78% yield for the similar trifluoromethylation of 1-iodonaphthalene.…”

Total Synthesis of (−)‐Morphine

“…Phenol 8 , the coupling partner for the key Mitsunobu reaction, was prepared from isovanillin ( 17 ; Scheme ). After iodination of 17 according to the known procedure,9 protection of the hydroxy group with a MOM group and subsequent Wittig olefination gave enol ether 19 . Treatment of 19 with methanolic HCl furnished phenol 8 .…”

Iodination of phenols in water using easy to handle amine-iodine complexes

“…Using the complexes 1a or 1b, vanillin 5b and isovanillin 5c (entries 18-21), having activating and deactivating groups at the aromatic ring, also led to the corresponding ortho-iodophenol derivatives 14b 27 and 14c, 28 although the para position in 2h is not substituted. A mixture of non-identified products was obtained when the m-hydroxy-benzaldehyde (5d) was treated with the complex 1a (entry 22).…”

“…[19][20][21][22][23] A broad range of procedures are described in the literature for the iodination of phenols, involving the use of NIS, ICl, I 2 and iodides salts in the presence of an oxidant, in acid or basic conditions. [24][25][26][27][28][29][30][31][32][33][34] Recently, Esteves and Mattos 35 described the scope of the triiodoisocyanuric (TICA) acid as iodinating agent. The reaction of TICA with activated arenes in acetonitrile led to an efficient and highly regioselective formation of the corresponding iodoarenes.…”