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The described synthesis starts from the commercially available furan-3-one derivative (I) which undergoes a reductive dehydration and conversion to a triflate derivative.

Le nouveau mode de liaison propose est corrobore par des comparaisons de charges atomiques partielles, par une modelisation moleculaire, et une nouvelle synthese des xanthines, permettant l'introduction d'une unite de reconnaisance chirale en position 8

A series of benzo [1,2-c:3,4-c']dipyrazoles was prepared from cyclohexane-1,3-dione. Several related systems with different central rings were also prepared. In addition, benzo[1,2-c:4,3-c']dipyrazoles were synthesized from 1,4-cyclohexanedione monoethylene ketal

The diastereoselectivity in the intramolecular 1,3-dipolar cycloaddition reactions of 4 and 5 (RBn, 4-MeOBn) was examined.

Brief treatment of 2-aminobenzoylhydrazine (2) with diethyl acetonedicarboxylate in ethanol gave 3-(benzoylhydrazono)-pentanedioic acid diethyl ester (3). However, with extended reaction times the product of this condensation was 3-amino-3,4-dihydro-4-oxo-2,2(1H)-quinazolinediacetate (5). In the latter transformation, diethyl 1,3,4,5-tetrahydro-5-oxo-2H-1,3,4-benzotriazepine-2,2-diacetate (6) is an obligatory intermediate. Cyclization of 5 with sodium carbonate in ethanol gave ethyl 2,3,4,9-tetrahydro-2,9-dioxopyrazolo[5,1-b]quinazoline-3a(1H)-acetate (8), and methylation of 8 afforded its 1-methyl derivative (9)

2,5-Bis-(3,4,5-trimethoxyphenyl)-2-oxazoline (5, MDL 100,270) was desi- gned as a potential plateletactivating factor (PAF) antagonist on the basis of computer modeling comparison studies with known PAF antagonis- ts. An efficient, four-step synthesis of oxazoline (5) was developed, starting from 3,4,5-trimethoxybenzaldehyde (6). Oxazoline (5) was found to inhibit the PAF-induced aggregation of human platelets with an IC 50 value of 708 μM

Treatment of the amido esters (9) and (17) with PPSE (polyphosphoric acid trimethylsilyl ester) followed by NaBH 4 in ethanol gave the qui- nolizidinones (11-14) and (19) via a vinylogous Bischler-Napieralski nitrilium ion cyclization-reductive lactamization two-step process. Subsequent ozonolysis and reduction afforded chiral hydroxylated quino- lizidines in moderate to good yield. In contrast to five-membered-ring formation, six-membered-ring formation via nitrilium-ion cyclization requires a p-methoxy-substituted styryl terminator. The effect para-su- bstituted styryl terminators have on the energy of activation and ΔH for the cyclization process has been calculated by semiemprical and ab initio methods

The reactions of ninhydrin (1) with β-ketoesters and β-diketones were studied. Two kinds of products were observed, which were either simple adducts of the dicarbonyl compounds to the center carbonyl group of ninhydrin, or tricyclic indeno[1,2-b]furans. Treatment of methyl 3-aminocrotonate (2) with ninhydrin led in analogous fashion to an indeno[1,2-b]pyrrole (3) which was reduced to a complex tetracyclic dihydropyridine 12. A mechanism for the production of 12 is presented. Structures for the novel heterocycles are supported by high resolution nmr studies and X-ray crystallography.

Androstenes bearing a cyclopropyl group attached to the C-17β position with a heteroatom linker, designed as mechanism-based inhibitors of steroid C 17(20) lyase, were found to be potent, time-dependent inhibitors of this enzyme.

The preparation and reactions of optically and chemically stable (S)-4-hydroxy-1,3-dioxolane 3 as a 2-hydroxy aldehyde equivalent were explored. Hydroxydioxolane 3 was prepared by reduction of ketodioxolane 2 which was obtained from (S)-2-hydroxycarboxylic acid 1. The reactions of 3 with triethyl phosphonoacetate and organometallic reagents were carried out. These and other conversions gave synthetically and biologically useful products in moderate to good chemical and moderate stereochemical yields.

Acylation of hydroxy aromatic compounds with 2-bromo-2-methylpropionamide followed by Smiles rearrangement of the resulting 2-aryloxypropionamide in a one-pot procedure produced the corresponding 2-hydroxy-2-methyl-N-arylpropionamides which can be converted to arylamines by hydrolysis. Particularly important applications of this new process were the conversions of estrone (6) and estradiol (14) to the corresponding 3-aminoestratriene derivatives 8 and 15, respectively. In addition, an improved Semmler-Wolff procedure is described for the conversion of 19-nortestosterone (22) to 3-aminoestra-1,3,5(10)-trien-17β-ol hydrochloride (26).

8-Hydroxyquinoline (9) was converted to 8-aminequinoline (10) in a one-pot procedure involving alleviation with 2-bromo-2-methylpropionamide (2) followed by Smiles rearrangement and hydrolysis, in 41% yield. The scope and limitations of this new procedure were explored with additional hydroxyquinolines.

The ketomethylene phenylalanal and alanal analogues of Cbz-Val-Phe-H and Cbz-Val-Ala-H have been prepared and the K i values versus chicken gizzard smooth muscle calpain were determined. The ketomethylene isosteres were significantly less potent than the corresponding dipeptide aldehydes, and this loss in activity is attributed to the absence of a critical interaction between the P1–P2 amide bond and the peptide binding region of calpain.

The structurally related neuropeptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB), which belong to a family of molecules termed tachykinins and are widely distributed in the central and peripheral nervous systems, influence the function of many tissues. SP and NKA have links to the following chronic diseases: asthma, inflammatory bowel disorders, rheumatoid arthritis, pain and psychiatric disorders. These peptides exert their effects through three G-protein coupled receptor subtypes, namely, the NK1, NK2, and NK3 receptors. Non-peptide antagonists of these receptors may provide opportunities for disease treatments. In this review, the very recent advances in nonpeptide neurokinin receptor antagonists will be described with an emphasis on structure-activity relationships which have been developed.

Three novel nucleosides 1, 2, and 3 were prepared that contained side chains at the 2-position of adenosine. Compound 1 was shown to be the most selective A2a receptor agonist reported to date having an A1/A2 ratio of 2400. In addition, compound 1 was shown to reduce blood pressure in rats and dogs with only minimal effects on heart rate.

An efficient and reliable three-step synthesis of 7-amino-3-hydroxyindan-1-one (7) is described. Compound 7 is a versatile, three-dimensional, three-point scaffold that is useful for the construction of focused compound libraries.

A new method for the synthesis of peptidyl α-keto esters is described, which is particularly useful for the construction of proteinase inhibitors with a lysine side chain.

Opening of the epoxide of (E)-4-phenyl-2-buten-1-ol with trimethylaluminum gave two phenonium ion-mediated products, whose ratio was dependent on reaction conditions.

Treatment of 5-chloro-2-aminobenzophenone (1) with o-phenylenediamine, sodium acetate, and acetic acid gave 2-(acetyl)amino-5-chlorobenzophenone (5) rather than N-[(2-amino-5-chlorophenyl)phenylmethylene]-1,2-benzenediamine (3), as reported by Kulkarni et al, [1]. Authentic 3 was prepared and treated with chloroacetic acid and polyphosphoric acid (PPA) to give 1, recovered 3, 2,8-dichloro-6,12-diphenyldibenzo[b,f][1,5]diazocine (9) and 2-chloro-6-(chloromethyl)-13-phenyl-5H-dibenzo[d,h][1,3,6]triazonine (10). Treatment of 5 with PPA, with or without chloroacetic acid, gave [5-chloro-2-[(6-chloro-4-phenyl-2-quinolinyl)amino]phenyl]phenylmethanone (11) as the sole product in 90% yield. Treatment of other benzophenones, acetophenones, and anilines with sodium acetate and acetic acid provided acetanilides in 78-96% yield, with the exception of 2′-aminoacetophenone (20), which gave a quantitative yield of 2-[((2-acetyl)phenyl)amino]-4-methylquinoline (21). The mechanism of acetanilide formation with sodium acetate and acetic acid is discussed. The structure of 21 was established using high resolution 1H nmr techniques. Attempts to prepare an authentic sample of 21 from 2-chlorolepidine (26) and (20) gave 4-methyl-N-[2-(4-methyl-2-quinolinyl)phenyl]-2-quinolinamine (29) as the major product.

Dealkylations of N-alkyl 6- and 7-methoxy quinolinium and isoquinolinium iodides in the mass spectrometer proceeded to give predominantly O-demethylation when resonance stabilized ions were produced. When O-demethylation did not provide a resonance stabilized ion, N-dealkylation predominated.

Recently reported [1] syntheses of 6-methyl-1,2,4,5-tetrahydro-1,4-dioxo-3H[1,2]diazepino[5,6-b]indole (5) and 4-hydroxy-6-methyl-3H[1,2]diazepino[5,6-b]indole (12) were reinvestigated and shown to be in error. The correct assignments for these respective structures are 3-amino-1,9-dihydro-9-methyl-2H-pyrido[4,3-b]indol-2,4(3H)-dione (6) and 3-amino-3,9-dihydro-9-methyl-2H-pyrido[4,3-b]indol-2-one (13). Condensation of 6 and 13 with p-nitrobenzaldehyde produced benzylidene derivatives, which confirmed the presence of the amino groups.

Treatment of 2-isocyanatobenzoyl chloride (4) with 5-aminotetrazole (5-AT) gave 3-(5-tetrazolyl)quinazoline-2,4(1H,3H)-dione (1) directly. Treatment of 2-carbomethoxyphenyl isocyanate (5) with 5-AT gave 2-[((5-amino-1H-tetrazol-1-yl)carbonyl)amino]benzoic acid methyl ester (6) as a kinetic product, which was thermally isomerized to 2-[((1H-tetrazol-5-ylamino)carbonyl)amino]benzoic acid methyl ester (7), the thermodynamically more stable urea. Cyclization of 7 with polyphosphoric acid gave 2-(1H-tetrazol-5-ylamino)-4H-3,1-benzoxazin-4-one (2). Urea 6 was quite labile in solution, as shown by nmr, and readily reacted with methanol to give 2-[(methoxycarbonyl)amino]benzoic acid methyl ester (10).

A new synthesis of the recently reported 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone, sodium salt (1, MDL-427), an experimental mediator release inhibitor, was developed from: (1) reaction of 5-aminotetrazole 3 and triethyl orthoformate 6 to give ethyl N-(1H-tetrazol-5-yl)formimidate 8, (2) reaction of methyl anthranilate and imidate 8 to give amidine 11, and (3) treatment of 11 with base to give 1. Investigation of each of these steps independently led to a significantly more efficient, facile and higher-yielding 1-pot process. A brief examination of anthranilic acid 13 and its salts and derivatives 14 to 17 in this process found them to have dissimilar reactivities. The formation of amidine 11 as an isolable intermediate was unusual, as was its failure to cyclize under standard neutral or acidic conditions. The absolute requirement for base to effect cyclization of 11 appears to be unprecedented.

The reaction of 2-hydrazinobenzothiazole (1) with ethyl acetoacetate has twice been reported to yield a fused triazepinobenzothiazolone, namely, 3-methyl[1,2,4]triazepino[3,4-b]benzothiazol-5(4H)-one (4). We have repeated this work and reassigned the reaction product as 2-(2-benzothiazolyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (5) on the basis of X-ray crystallography.

New methodology is described for the construction of tricyclic heterocycles. Thus, a double displacement reaction of l-(2-fluorobenzoyl)-2-methylthio-2-imidazoline (8a) with 1,1-dialkylhydrazines gave 10-substituted 2,10-dihydroimidazo[2,1-b]quinazolin-5(3H)-ones in good yield. The corresponding 1-(2-nitrobenzoyl)-2-meth-ylthio-2-imidazolines also underwent double displacement reactions with hydrazines. Other tricyclics made using double displacement reactions were pyrimido[2,1-b]quinazolines, imidazo[1,2-a]pyrido[2,3-d]pyrimidines, and imidazo[1,2-a]pyrazolo[3,4-d]pyrimidines. Treatment of 8a with hydrazine hydrate or methylhydrazine gave products resulting from displacement, but did not afford fused benzotriazepinones.

Syntheses for 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone sodium salt monohydrate (9; MDL 427) and the related formamido compound, 2-(formylamino)-N-1H-tetrazol-5-ylbenzamide (10), are described. Both compounds are active in the rat passive cutaneous anaphylaxis and passive peritoneal anaphylaxis tests. A 94:6 equilibrium mixture of 9 and ionized 10, respectively, forms in aqueous buffer systems at a pH-dependent rate. In addition, analogues of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone (8) bearing substituents on the benzene ring, substituents at the 2-position, and heteroaryl groups at the 3-position other than tetrazole were prepared. These analogue sets demonstrated that an accessible electrophilic center and an acidic functionality were requirements for good antiallergic activity.

The oxidation of α-hydroxy esters, including peptidyl α-hydroxy esters, with the Dess-Martin periodinane reagent is a useful and general method for the preparation of α-keto esters.

Treatment of o-nitrobenzenesulfonyl chloride (3) with 5-aminotetrazole (5-AT) gave [(2-nitrophenyl)-sulfonyl]carbamimidic azide (6), a ring-opened isomer of the expected N-(1H-tetrazol-5-yl)-2-nitrobenzenesulfonamide (4). Sulfonylcarbamimidic azide 6 was converted to 2-amino-N-(aminoiminomethyl)benzene-sulfonamide (7) with ethanolic stannous chloride, and to 3-amino-1,2,4-thiadiazine 1,1-dioxide (8) with sodium dithionite. Methanesulfonyl chloride (9) and 5-AT gave 2-(methylsulfonyl)carbamimidic azide (10), which isomerized to 5-[(methylsulfonyl)amino]-1H-tetrazole (11) in warm ethanol. Attempted cycloaddition of 2-(phenylsulfonyl)carbamimidic azide (13) and ethyl vinyl ether led only to alkylated tetrazole products. In addition, other tetrazole-alkylating reactions are described. Isomers produced from these alkylations were differentiated with 13C nmr spectroscopy.

3,5-Dimethylbenzo[1,2-c:5,4-c']dipyrazoles, optionally substituted in the 1-, 7-, and 8-positions, were synthesized from resorcinols. These compounds display affinity for adenosine A1 (rat brain) and A2 (human platelet) receptors. In addition, these compounds reverse contractions of guinea pig tracheal cylindrical segments induced by potassium chloride, histamine, acetylcholine, and 5-hydroxytryptamine, as well as reverse bronchospasm induced by aerosolized histamine in the conscious guinea pig.

A synthetic route to 5-substituted 3-(1H-tetrazol-5-yl)pyrazolo[1, 5-a]quinazolines is described. An unexpected displacement of a 4-morpholinyl group from the 5-position of this system occurred during tetrazole formation by the ammonia produced by in situ generation of hydrazoic acid from ammonium chloride and sodium azide.

Metalated veratraldehyde and veratrole were quenched with perchloryl fluoride to provide one-step syntheses of 2-fluoroveratraldehyde and 2-fluoroveratrole, respectively. Previous syntheses of these precursors to 2-fluorodopamine and 5-fluoronorepinephrine are multi-step processess which involve introduction of fluorine at an early stage. Perchloryl fluoride is a potentially hazardous reagent, and should be used only on an appropriate (millimolar) scale with precautions.