The cuprous iodide catalyzed reaction of 2-methyl-2-[1-(3-benzoyl-4-phenylpyridinium)]acetic acid methyl ester bromide (5), prepared by reaction of 3-benzoylpyridine (4) with racemic methyl 2-bromopropionate, with phenylmagnesium chloride at −23 °C afforded the 2-methyl-2-[1-(3-benzoyl-4-phenyl-1,4-dihydropyridyl)acetic acid methyl ester (6, 74%), which was a mixture of four diastereomers. Recrystallization of this diastereomeric mixture from diethyl ether afforded a solid product (6a-solid, 30%, 4R*,2R* and 4S*,2S*) and an oil product (6b-oil, 39%, 4R*,2S* and 4S*,2R*), each consisting of a mixture of two diastereomers that differ in relative configuration (R* or S*) at the 1,4-dihydropyridine C-4 position and the-CH(Me)CO2Me moiety. Addition of the Grignard reagent from either of the two diastereotopically different faces of the planar pyridinium salt (5) gives rise to two diastereomeric products 6a-solid and 6b-oil in which the C-4 phenyl substituent is pseudo-axial to the boat-shaped 1,4-dihydropyridine ring. Alkaline hydrolysis, or ammonolysis, of the acetic acid methyl ester (6) afforded the respective acetic acid (7), or acetamide (8), derivative. Keywords: 1,4-dihydropyridines, diastereomers.

A group of 2‐methyl‐2‐[1‐(3‐benzoyl‐4‐substituted‐1,4‐dihy‐dropyridyl)] acetic acid methyl esters (7), weak acetic acids (8), and acetamides (9) were designed for evaluation as less acidic non‐ulcerogenic non‐steroidal antiinflammatory drugs (NSAIDs). In this respect, the model compound 2‐methyl‐2‐[1‐(3‐benzoyl‐4‐phenyl‐1,4‐dihydropyridyl)]acetic acid (8a), unlike traditional arylacetic acid NSAIDs, was shown to be a weak acid with a pKa of 9.17. In contrast to arylacetic acid NSAIDs, the α‐methylacetic acid sodium salt of 8a, or the methyl α‐methylacetate ester (7a) did not inhibit cyclooxygenase‐1 (COX‐1) or ‐2 (COX‐2). In vitro stability studies showed that the methyl α‐methylacetate ester (7a) acts as a prodrug to the α‐methylacetic acid derivative (8a), undergoing rapid (> 10 minutes) and quantitative conversion upon incubation with rat plasma, or incubation with rat liver homogenate (t1/2 = 25 min). In contrast, the α‐methylacetamide (9a) underwent negligible (< 2%) conversion to the α‐methylacetic acid derivative (8a) upon incubation with either rat plasma, or rat liver homogenate, for incubation times up to 24 h. The effect of a C‐3 para‐substituted‐benzoyl substituent (R1 = H, Cl, Me), a C‐4 substituent (R2 = aryl, benzyl, cyclohexyl, alkyl), and the nature of the N1‐acetic acid moiety [methyl ester (R3 = OMe), acetic acid (R3 = OH), acetamide (R3 = NH2)] on analgesic activity was determined using the 4% NaCl‐induced abdominal constriction (writhing) assay. Compounds 7—9 inhibited writhing 27—95% relative to the reference drug aspirin (58% inhibition). The analgesic potency with respect to the para‐benzoyl substituent was H > Cl or Me. Although the effect of the C‐4 R2‐substituent on analgesic activity was variable within the ester, acid and amide sub‐groups of compounds, compounds having a R2‐cyclohexyl substituent generally provided superior analgesic activity relative to those having a lipophilic alkyl substituent. The nature of the R3‐substituent (OMe, OH, NH2) was a determinant of analgesic activity where the potency order was acetic acid methyl ester > acetic acid or acetamide, except when the C‐4 R2‐substituent was cyclohexyl or benzyl where the potency order was acetamide > acetic acid methyl ester or acetic acid. Reduction of the 5,6‐olefinic bond of the 1,4‐dihydropyridyl compound (9a, 94% inhibition) to the corresponding 1,2,3,4‐tetrahydropyidyl derivative (10, 69% inhibition) reduced analgesic activity.

Reaction of ethyl 2‐(3‐pyridyl)acetate 4a or ethyl 2‐methyl‐2‐(3‐pyridyl)acetate 4b, with phenyl chloroformate or methyl chloroform ate, afforded the intermediate pyridinium salt 5 which undergoes regioselective nucleophilic attack at C‐4 upon reaction with a Grignard reagent in the presence of a cuprous iodide catalyst at −23° to yield the corresponding ethyl 2‐[3‐(1‐phenoxy(methoxy)carbonyl‐4‐aryl(alkyl)‐1,4‐dihydropyridyl)]acetates 6a‐f in 64–96% chemical yield. No product arising from reaction of the ester substituent of the pyridinium salt 5 with the Grignard reagent was observed. The 1H nmr spectra of 6a‐f exhibited dual resonances for the 1,4‐dihydropyridyl H‐2, H‐5 and H‐6 protons at 25° in deuteriochloroform. These dual resonaces were attributed to two different rotameric configurations resulting from restricted rotation about the nitrogen‐to‐carbonyl carbamate bond due to its double bond character. Compound 6 generally exhibited superior analgesic and antiinflammatory activities, compared to the reference drugs aspirin and ibuprofen, respectively. These structure‐activity correlations indicate the 1,4‐dihydropyridyl ring system present in 6 is a suitable bioisostere for the aryl (heteroaryl) ring present in aryl(heteroaryl)acetic acid non‐steroidal antiinflammatory drugs.

A group of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates (10–15), and the related acetamide derivative (16), that possess a variety of C‐7 substituents (Br, Cl, F, H), were designed for evaluation as analgesic‐antiinflammatory agents. The effect of the C‐7 substituent(s) and the nature of the acetic acid ester (R1 = Ome) or acetamide (R1 = NH2) moiety on analgesic activity was determined using a 4% NaCl‐induced abdominal constriction assay. Compounds 10–16 inhibited writhing by 36–82%, relative to the reference drugs aspirin (58% inhibition) and celecoxib (62% inhibition). The nature of the C‐7 substituents was a determinant of analgesic activity in the 7,7‐dihalo group of compounds where the relative activity profile was 7‐Cl2 > 7‐Br2 > 7‐F2 > 7‐Cl,7‐F, and for 7‐monohalo compounds where the potency order was 7‐Br > 7‐Cl. Elaboration of the 7,7‐dibromo methyl acetate ester (10) to the corresponding acetamide derivative (16) enhanced analgesic activity. The nature of the 7‐halo substituent(s) in the 7,7‐dihalo group of compounds was a determinant of antiinflammatory activity, determined using the carrageenan‐induced rat paw edema assay, where the relative potency order was 7‐Br2 > 7‐Cl2 > 7‐F2 > 7‐Cl,7‐F. The most potent 7,7‐dibromo compound (10) inhibited inflammation by 62%, relative to the reference drug ibuprofen (44%), and 10 inhibited COX‐2 (IC50 = 26.4 μM) and COX‐1 (IC50 = 227 μM) for a COX‐2 selectivity index of 8.6. Docking 10 in the active site of human COX‐2 showed it binds in the center of the COX‐2 binding site with the C‐5 phenyl ring oriented toward the acetylation site (Ser530), and the phenyl group of the C‐4 benzoyl moiety oriented in the vicinity of the COX‐2 secondary binding pocket near Val523. Drug Dev. Res. 49:75–84, 2000. © 2000 Wiley‐Liss, Inc.

Synthesis and Analgesic Activity of 2-Methyl-2-[1-(3-benzoyl-4substituted-1,4-dihydropyridyl)]acetic Acid Methyl Esters (IV), Acetic Acids (V), and Acetamides (VI).--(AGUDOAWU, SAMMY A.; YIU, SAI-HAY; WALLACE, JOHN L.; KNAUS, EDWARD E.; Arch. Pharm. (Weinheim, Ger.) 332 (1999) 6, 213-218; Fac. Pharm. Pharm. Sci., Univ. Alberta, Edmonton, Alberta T6G 2N8, Can.; EN)