Synthesis and antimuscarinic properties of some N-substituted 5-(aminomethyl)-3,3-diphenyl-2(3H)-furanones

Abstract

In a study aimed toward developing new, selective antimuscarinic drugs with potential utility in the treatment of urinary incontinence associated with bladder muscle instability, a series of N-substituted 5-(aminomethyl)-3,3-diphenyl-2(3H)-furanones, conformationally-constrained lactone relatives of benactyzine, was prepared. The compounds were examined in several paradigms that measure muscarinic (M1, M2, and M3) receptor antagonist activity. Selected members of the series that displayed potency and/or selectivity in these tests were studied for their effects on urinary bladder contraction, mydriasis, and salivation in guinea pigs. These studies revealed that incorporation of the amino functionality into an imidazole or pyrazole ring resulted in some novel, potent, and selective antimuscarinic agents. Appropriate alkyl substitution of position 2 of the imidazole strikingly affected muscarinic, particularly M3, receptor activity and may reflect a complementary site of interaction. Some of the compounds selectively reduced bladder pressure in a cystometrogram (CMG) model without producing concomitant mydriatic and salivary effects. The separate and distinct action of several compounds of this series in these in vivo protocols suggests the possibility of subtypes of muscarinic receptors that may correspond to previously characterized molecular cloned subpopulations. In this article, structure-activity relationships for the series of substituted lactones are discussed. These studies led to the identification of (R)-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4,5-dihydro-3,3-diphenyl-2(3H )- furanone (23) as a clinical candidate for treating urinary bladder dysfunction.

Product Class 5: Azaindolizines with Two Nitrogen Atoms in the Five-Membered Ring

“…Also, the very first synthesis of the basic ring system 1 (previously known as ªpyrimidazoleº) published by Tschitschibabin [1] applied this route, as shown in Scheme 3. [21±26] Thus, reaction of 11 with chloroacetaldehyde yields (depending on the R 1 substituent) 12 (R 1 = Me) [21] or 8-hydroxyimidazo[1,2-a]pyridine (13) (R 1 = OH), [22] whereas a similar transformation with phenacyl bromide gives the 2-phenyl-substituted product 14 [23] in high yield. Later studies on this transformation (an important milestone in this respect was the activity of Kröhnkes school [20] ) allowed this ring closure to 1 to be performed in almost quantitative yield.…”

“…á-Chlorocyclohexanone can also be used for this ring closure; its reaction with 11 (R 1 = H) gives the tricyclic compound 15 [23] in moderate yield. [21] ± Me H H chloropropan-2-one 197±199 b 23 [27] ± M e C O 2 Et H ethyl 2-chloroacetoacetate 69±70 66 [27] 13 H H OH chloroacetaldehyde 186 82 [22] ± H H C H 2 OMe chloroacetaldehyde oil 89 [28] 16 CH 2 Cl H H 1,3-dichloroacetone ± c 66 [24] 17 CHCl 2 H H 1,1,3-trichloroacetone 127±129 90 [25] 14 Thus, reaction of 11 (R 1 = H) with 1,3-dichloroacetone yields the 2-monochloromethyl derivative 16; [24] transformation of the same starting compound with 1,1,3-trichloroacetone gives the corresponding 2-dichloromethyl analogue 17 (a very useful intermediate for the synthesis of imidazo[1,2-a]pyridine-2-carbaldehyde).…”

“…Thus, 2-phenylimidazo[2,1-a]isoquinoline (20) has been obtained from isoquinolin-1-amine (19) in 59% yield (Scheme 5). [29] Although the related synthesis of 2-phenylimidazo[1,2-a]quinoline (21) can also be accomplished by this procedure, a more convenient way (i.e., synthesis starting with the quaternization of quinoline by phenacyl bromide and a subsequent reaction path involving 1,5-dipolar cyclization) will be discussed in Section 12.5.1.1.3.1.…”

“…Ph [21,70,71] The influence of some substituents has also been studied; [70] among the alkyl substituents, the 7-methyl group was found to exert the strongest activating effect. These experimental findings have also been supported by theoretical calculations.…”

A modified Prins reaction for the facile synthesis of structurally diverse substituted 5-(2-hydroxyethyl)-3,3-dihydrofurane-2(3H)-ones

“…1). Although a number of methods for the synthesis of similar furanones have been reported, 3,6 high yield, and facile routes to the structurally diverse target intermediates are lacking.…”