Synthesis and Pharmacology of Benzoxazines as Highly Selective Antagonists at M₄Muscarinic Receptors

Abstract

Previously, we reported on PD 102807 (41) as being the most selective synthetic M(4) muscarinic antagonist identified to date. Synthesized analogues of 41 showed no improvement in affinity and selectivity at that time. However, several newly synthesized compounds exhibit a 7-fold higher affinity at M(4) receptors and demonstrate a selectivity of at least 100-fold over all other muscarinic receptor subtypes. For example, compound 28 showed an affinity of pK(i) = 9.00 at M(4) receptors and a selectivity of M(1)/M(4) = 13 183-fold, M(2)/M(4) = 339-fold, M(3)/M(4) = 151-fold, and M(5)/M(4) = 11 220-fold. This high selectivity along with high affinity has not been reported for any synthetic muscarinic antagonist, nor for natural occurring M(4) antagonists such as the M(4) selective Eastern Green Mamba venom MT3 (M(4) pK(b) = 8.7, M(1)/M(4) = 40-fold, M(2)/M(4) > or = 500-fold, M(3)/M(4) > or = 500-fold, and M(5)/M(4) > or = 500-fold). Derivative 24, a compound with a high selectivity pattern as well, has been tested for in vivo efficacy. It was able to block the L-3,4-dihydroxyphenylalanine accumulation produced by CI-1017, an M(1)/M(4) selective muscarinic agonist, in the mesolimbic region and striatum, which suggests that 24 is capable of crossing the blood-brain barrier and confirms the pharmacokinetic data obtained on this compound. This is evidence that suggests that agonist-induced increase in catecholamine synthesis observed in these regions is mediated by M(4) receptors.

Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole

“…The two small runs gave 70 and 80% yield (Table 2, entries 1, 2), respectively, which were close to that of the literature [41]. For the three large runs, the yields were 50, 37.7 and 55.7% (Table 2 entries 3, 4, 5), respectively, which were significantly lower that those of the small runs.…”

“…The second step from 2 to 1 was based on acid catalyzed hydrolysis and decarboxylation using 20% HCl (Table 2) by following the reference procedure [41]. Though base hydrolysis should work as well [40], the reaction was complicated and resulted in low yield (data not shown).…”

Methods for the Synthesis of Isogramines and Their Chemical Properties. (Review)

“…The ease of substitution of the dimethylamino group in unquaternized 1,2,3-trisubstituted 5-hydroxy-4-isogramines by an S-nucleophile (thiophenol) [69] can be explained by the realization for such structures of an elimination-addition mechanism [70] similar to that proposed earlier for gramine [71,72]. The reaction of substituted 5-hydroxy-4-isogramines with 3,4-dihydroisoquinolines, which leads to the complex conjugated 3,11,12,14-tetrahydroindolo [4',5:5,6][1,3]oxazino[2,3-a]isoquinoline system, may take place by a similar mechanism [73]. Another example of an S-nucleophile is sodium bisulfite, the reaction of which with 2-isogramine hydrochloride or methiodide leads to the double alkylation product bis(2-indolylmethyl) sulfone [74].…”

Lewis acid catalyzed nenitzescu indole synthesis

“…The Nenitzescu reaction followed by functional group interconversions has proved to be the simplest synthetic entry into 5-hydroxyindole-based key intermediates of pharmacologically active molecules and drugs [11,12], including those cited above. For example, the facile synthesis of an advanced E 09 intermediate comprises five steps including the Nenitzescu indolization, in contrast to the 15-step synthesis starting from 3-chlorophenol [13].…”

“…Moreover, under such conditions the reaction goes slowly (16 -48 hr) and fails altogether with enaminoanilides as enamino components in CH 2 Cl 2 [19]. Even as lately as 2002, ethyl 5-hydroxy-2-propyl-indole-3-carboxylate was reported to be obtained by the Nenitzescu reaction in acetic acid, in 6% yield only [12]. Thus, large-scale production of the Nenitzescu indoles should be expensive.…”