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The inhibition of LTB(4) binding to and activation of G-protein-coupled receptors BLT1 and BLT2 is the premise of a treatment for several inflammatory diseases. In a lead optimization effort starting with the leukotriene B(4) (LTB(4)) receptor antagonist (2), members of a series of 3,5-diarylphenyl ethers were found to be highly potent inhibitors of LTB(4) binding to BLT1 and BLT2 receptors, with varying levels of selectivity depending on the substitution. In addition, compounds 33 and 38 from this series have good in vitro ADME properties, good oral bioavailability, and efficacy after oral delivery in guinea pig LTB(4) and nonhuman primate allergen challenge models. Further profiling in a rat non-GLP toxicity experiment provided the rationale for differentiation and selection of one compound (33) for clinical development.

The 25-hydroxy and 1α,25-dihydroxy vitamin D3 metabolites are obtained by solvolytic rearrangements of the 1-desoxy and 1α-hydroxy cyclopropyl vinylogous alcohols 31 and 29, respectively, with simultaneous formation of the vitamin D structural triene and the 3-hydroxy function. Two complementary methods have been employed to direct the stereoselectivity of the samarium induced olefin cyclopropanations which ultimately lead to key chiral ring A precursors. One protocol uses the two stereogenic centers of the (R,R)-2,3-butanediol ketal moiety of 8, while the other method uses the allylic hydroxyl group of (R)-16.

Leukotriene B4 (LTB4) is a potent proinflammatory lipid mediator derived from arachidonic acid via the 5-lipoxygenase pathway. It is a powerful chemoattractant and activator of neutrophils and exhibits effects on other cell types as well. This eicosanoid has been implicated in a variety of inflammatory diseases including asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, contact dermatitis, cystic fibrosis, inflammatory bowel disease, gout, myocardial ischaemia, NSAID-induced gastropathy, psoriasis and rheumatoid arthritis. Thus orally active and non-toxic antagonists of LTB4 could prove to be novel anti-inflammatory drugs with potential advantages over existing therapies. This article reviews recent developments regarding the discovery of second generation LTB4 antagonists with sufficient potency and oral activity in animal models to justify clinical examination in humans. It is hoped that such trials will lead to new treatment modalities for inflammatory disorders.

1,25-Dihydroxycholecalciferol (23) was synthesized from A-ring precursor 18 and Windaus-Grundmann ketone 19 via cyclovitamin D 21. Key reactions include highly stereoselective (5 to 6) and stereospecific (13 to 14) cyclopropanations.

The 25-hydroxy and 1α,25-dihydroxy vitamin D3 metabolites are obtained by solvolytic rearrangements of the 1-desoxy and 1α-hydroxy cyclopropyl vinylogous alcohols 31 and 29, respectively, with simultaneous formation of the vitamin D structural triene and the 3-hydroxy function. Two complementary methods have been employed to direct the stereoselectivity of the samarium induced olefin cyclopropanations which ultimately lead to key chiral ring A precursors. One protocol uses the two stereogenic centers of the (R,R)-2,3-butanediol ketal moiety of 8, while the other method uses the allylic hydroxyl group of (R)-16.

1,25-Dihydroxycholecalciferol (23) was synthesized from A-ring precursor 18 and Windaus-Grundmann ketone 19 via cyclovitamin D 21. Key reactions include highly stereoselective (5 to 6) and stereospecific (13 to 14) cyclopropanations.

Novel 6-hydroxychroman-2-carbonitrile compounds have been synthesized, and their anti-peroxidant activity against superoxide-dependent, iron-promoted mycocardial phospholipid peroxidation has been evaluated quantitatively. With few exceptions, these compounds afforded significant, concentration-dependent antiperoxidant protection to myocardial-membrane phospholipid at sub- to low-micromolar concentrations. Structure-activity correlation demonstrated that R 1 -, R 2 -, and R 3 -methyl groups in the aromatic ring enhanced antiperoxidant activity, whereas hydrophobic groups at either R 4 or R 5 of the pyran ring compromised antiperoxidant efficacy. The most efficacious anti-peroxidant synthesized contained a catechol moiety at R 4 and was some 10-fold more potent than α-tocopherol. None of the 6-hydroxychroman-2-carbonitrile antiperoxidants scavenged Superoxide or inhibited the enzymatic Superoxide generator, xanthine oxidase, at effective antiperoxidant concentrations. The ability of these compounds to interrupt the propagatory phase of an on-going peroxidation reaction indicated that they acted as antiperoxidants by trapping chain-carrying lipid peroxyl radicals. Since a number of the 6-hydroxychroman-2-carbonitriles were most potent antiperoxidants than a variety of known chain-breaking compounds, this new class of phenolic antioxidants may represent a novel approach to the design of therapeutics against diseases in which lipid peroxidation is a causative factor or in which lipid peroxidases serve as mediators.

2,3-O-isopropylidene-d-erythronolactone intermediate: d-erythronolactone product: 2,3-O-isopropylidene-d-erythronolactone Keywords: acetal (and thioacetal) formation; cleavage, oxidative; oxidation, miscellaneous

Les substitutions nucleophiles des chromannes du titre avec le [cyano trimethyl] silane sont etudiees. Le catalyseur, TiCl 4 ou SnCl 4 , a une influence sur la regioselectivite des reactions

Asymmetric induction in 19-norsteroid total synthesis is discussed. It should be noted that the (S)-(+)-enedione can be made available by cyclization of the triketone with (S)-proline and its derivatives (asymmetric synthesis). Also mention must be made of the elegant approaches to progesterone and 11-substituted progesterones using biomimetic polyolefin cyclizations in which substantial asymmetric induction at several chiral centers is observed (diastereoselective synthesis). It is concluded that the successful utilization of asymmetric transformations demonstrated in the steroid field defines the potential of such processes and bodes well for their equally successful application in other areas of natural product synthesis.

Several allylic isothiuronium salts 6 have been shown to yield 4-substituted 2-amino-5,6-dihydro-4H-1,3-thiazines (2; R3 = H) and the 2-phenylimino compound 10 on exposure to trifluoroacetic acid or trifluoroacetic acid-stannic chloride. The overall process constitutes a convenient transformation of readily available ketones or aldehydes 3 into the target hetero-cycles. The scope and limitations of this approach are discussed in terms of carbenium ion intermediates (7). Whereas this method successfully led to the imidazo[2,l-b][1,3]thiazine 13 (93% from 12), its application to the synthesis of 2-amino-2-thiazolines (eg. 14 15) or imidazo-[2,1-b]thiazoles (eg. 16 17) was unsuccessful. The 2-acetylimino derivatives 9 were found to be useful for purification of the 2-aminothiazines.

It has been established by an evaluation of 6 production samples ofall-rac-α-tocopheryl acetate that all 4 racemates (RRS/SSR, RRR/SSS, RSR/SRS and RSS/SRR) are consistently present in equimolar amounts (SD

As an extension of previous studies on the total synthesis of (2R,4′R,8′R)-α-tocopherol (1) [1] [2], (S)-(−)-2-(6-benzyloxy-2,5,7,8-tetramethylchroman)acetic acid (6), a pivotal intermediate, possessing the absolute configuration required for construction of 1 was prepared by optical resolution of the racemic modification 11. the latter substance was obtained by two routes, one emanating from the hydroxy acetal 7 [1] and the other based upon the Lewis acid mediated cycloaddition of trimethylhydroquinone to rac.-3-hydroxy-3-methylpent-4-en-l-yl acetate (16) giving rac. ethyl 2-(6-hydroxy-2,5,7,8-tetramethyl-chroman)acetate (12).

The syntheses and biological activity of (all Z )-7,7-dimethyl-5-8,- 11,14-eicosatetraenoic acid, (all Z )-7,7,-dimethyl-5,8,11-eicosatrienoic acid, ( Z , Z -7,7-dimethyl-5,8-eicosadienoic acid, (all Z )-10,10-dimetyl- 5,8,11,14-eicosatetraenoic acid, (all Z -10,10-dimethyl-5,8,11-eicosatrienoic acid, and rac .-( Z , Z -15-hydroxy-7,7-dimethyl-5,8-eicosadienoic acid are described. These arachidonic acid analogs are all inhibitors of ionophore-induced SRS-A biosynthesis in rat peritoneal cells. Their mode of action may involve inhibition of phospholipase A2 rather than Δ5-lipoxygenase. These compounds failed to exhibit significant activity in an in vivo model designed to detect inhibitors of antigen-induced, leukotriene-mediated bronchoconstriction is sensitized guinea pigs.

Les substitutions nucleophiles des chromannes du titre avec le [cyano trimethyl] silane sont etudiees. Le catalyseur, TiCl 4 ou SnCl 4 , a une influence sur la regioselectivite des reactions

All eight stereoisomers of α-tocopheryl acetate have been synthesized in a state of high chemical and stereoisomeric purity. Key chiral side-chain intermediates were prepared from (+)-(S)-3-hydroxy-2-methylpropanoic acid. New routes to (2R, 4′ RS, 8′ RS)-α-tocopheryl acetate, a mixture of four diastereoisomers, were also developed. A sensitive gas chromatographic method was developed to determine the diastereoisomeric and enantiomeric purity of α-tocopherol samples as the methyl ethers. It was established for the first time that naturally occurring α-tocopherol is essentially a single enantiomer (2 R, 4′ R, 8′ R), synthetic all-rac-α-tocopherol an equimolar mixture of four racemates, and that natural (E)-(7 R, 11 R)-phytol is diastereoisomerically and enantiomerically homogeneous.

In an approach to SRS-A and analogues thereof, the key (5 S , 6 S )-epoxy alcohol 9 and its 6-epimer 18 were prepared starting from D -araboascorbic acid and L -diethyl tartrate, respectively.

Evaluation of a series of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acids linked to the 2-hydroxyacetophenone pharmacophore present in the standard peptidoleukotriene antogonist FPL 55712 (1) has led to the discovery of Ro 23-3544 (7), an antagonist possessing greater potency and duration of action vs LTD4 than the standard (aerosol route of administration, guinea pig bronchoconstriction model). Interestingly, this compound also potently inhibited bronchoconstriction induced by LTB4 whereas 1 did not. Attempts to establish structure--activity relationships in this series involved modifications in the 2-hydroxyacetophenone moiety, the linking chain, and the chroman system. All variations produced analogues which were either inactive or possessed reduced potency relative to acid 7. Optical resolution of 7 was achieved by two methods. Absolute configurations of the enantiomers were determined via X-ray crystallographic analyses of an intermediate as well as a salt of the S enantiomer. Although the enantiomers exhibited similar potencies in in vitro assays and in vivo when administered intravenously, significant differences were observed in the guinea pig bronchoconstriction model vs LTC4 and LTD4 when administered by the aerosol route (S antipode 15-fold more potent). The properties of 7 have been compared with several recently reported leukotriene antagonists.

All eight stereoisomers of α-tocopheryl acetate have been synthesized in a state of high chemical and stereoisomeric purity. Key chiral side-chain intermediates were prepared from (+)-(S)-3-hydroxy-2-methylpropanoic acid. New routes to (2R, 4′ RS, 8′ RS)-α-tocopheryl acetate, a mixture of four diastereoisomers, were also developed. A sensitive gas chromatographic method was developed to determine the diastereoisomeric and enantiomeric purity of α-tocopherol samples as the methyl ethers. It was established for the first time that naturally occurring α-tocopherol is essentially a single enantiomer (2 R, 4′ R, 8′ R), synthetic all-rac-α-tocopherol an equimolar mixture of four racemates, and that natural (E)-(7 R, 11 R)-phytol is diastereoisomerically and enantiomerically homogeneous.

Asymmetric induction in 19-norsteroid total synthesis is discussed. It should be noted that the (S)-(+)-enedione can be made available by cyclization of the triketone with (S)-proline and its derivatives (asymmetric synthesis). Also mention must be made of the elegant approaches to progesterone and 11-substituted progesterones using biomimetic polyolefin cyclizations in which substantial asymmetric induction at several chiral centers is observed (diastereoselective synthesis). It is concluded that the successful utilization of asymmetric transformations demonstrated in the steroid field defines the potential of such processes and bodes well for their equally successful application in other areas of natural product synthesis.

(+/-)-2-Amino-7-oxa-3-thia-1-azaspiro[5,5]undec-1-ene (1a) and many of its derivatives exhibit significant activity in the phenylquinone writhing and yeast inflamed foot assays. In order to develop structure-activity relationships, the related spiroheterocycles, (+/-)-2-amino-7-oxa-3-thia-1-azaspiro[5,4]dec-1-ene (2), (+/-)-2-amino-3-thia-1-azaspiro[5,5]undec-1-ene (3), and (+/-)-2-amino-7-oxa-1-azaspiro[5,5]undec-1-ene (4), were examined. Of these, only 4 failed to show activity indicating that the analgetic properties displayed by compounds 1--3 are associated, mainly, with the 2-amino-1,3-thiazine ring system. In the 2-acylimino series, evidence is presented suggesting a contribution to the observed activity on the part of the spiroannulated ether ring as well. Both 1a and its p-fluorobenzoyl derivative 33 exhibit analgesic activity in the rat tail-flick assay.