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A stereoselective asymmetric route to novel potent NK 1 antagonists based on a 1,2,4-trisubstituted cyclohexane core is discussed.

The development of a novel series of 4-aryl, 4-phenylsulfonyl cyclohexananone-derived γ-secretase inhibitors for the potential treatment of Alzheimer’s disease is described.

Octahydropyrrolo[2,3-b]pyrroles were synthesised by treatment of azidolactams successively with tri-n-butylphosphine and LiAlH 4 .

The in vivo properties of a series of 2-arylindole NK(1) antagonists have been improved, by modification of the amide substituent. The 1-(2-methoxyphenyl)piperazine amide was identified as a major area of metabolism in the lead compound 1. Replacement of this amine moiety by a 4-benzyl-4-hydroxypiperidine resulted in a compound 18 with reduced clearance and improved central duration of action.

Novel 2-aryl indole hNK1 receptor ligands were prepared utilising palladium cross-coupling chemistry of a late intermediate as a key step. Compounds with high hNK1 receptor binding affinity and good brain penetration (e.g., 9d) were synthesised.

A general method for the synthesis of cyclopropyl ethers from phenols is described. Alkylation of a phenol using 1-iodo-1-(phenylthio)cyclopropane followed by removal of the phenylthio group furnishes the cyclopropyl ethers in modest to excellent yields. The procedure tolerates a wide range of functional groups.

Protected phenylalanines 23 (seven examples), homophenylalanines 7 (eight examples), and bishomophenylalanines 8 (seven examples) have been prepared by palladium-catalyzed coupling of the amino acid-derived organozinc reagents 13, 5, and 6, respectively, with aryl iodides. While the reactions of the zinc reagent 13 may be conducted in both THF and DMF as solvent, the results obtained in DMF are generally superior. In the case of the reagents 5 and 6 the results are far superior in DMF. NMR investigations on the structure of the zinc reagents 13 in THF suggest that there is strong intramolecular coordination of the urethane carbonyl group, whereas in DMF this interaction is completely suppressed.

Modifications to the spirocyclic aryl sulfonamide portion of serine derived NK1 antagonists allow a partial pharmacophore model to be developed.

The regioselective, scaleable synthesis of three 4-(2-alkyl-5-methyl-2 H -pyrazol-3-yl)-piperidines is discussed.

The competitive area of neurokinin (NK) receptor antagonists has recently seen the publication of early clinical results which provide strong support for their use in the treatment of pain, emesis and asthma. Preclinical models support their use in a number of additional disorders including anxiety, arthritis, migraine, cancer and schizophrenia. New indications, such as glaucoma and ocular hypotension, neuronal injury and stroke, cardiac disorders and topical applications have recently been claimed. Published patent applications from most of the major pharmaceutical companies claim a wide variety of structural classes as antagonists at all three neurokinin receptors. This review discusses the significance of new clinical data for ongoing drug discovery efforts, and patent claims for new indications and new structural classes for the period since the last review in early 1996.

Protected phenylalanines 23 (seven examples), homophenylalanines 7 (eight examples), and bishomophenylalanines 8 (seven examples) have been prepared by palladium-catalyzed coupling of the amino acid-derived organozinc reagents 13, 5, and 6, respectively, with aryl iodides. While the reactions of the zinc reagent 13 may be conducted in both THF and DMF as solvent, the results obtained in DMF are generally superior. In the case of the reagents 5 and 6 the results are far superior in DMF. NMR investigations on the structure of the zinc reagents 13 in THF suggest that there is strong intramolecular coordination of the urethane carbonyl group, whereas in DMF this interaction is completely suppressed.

A general method for the synthesis of cyclopropyl ethers from phenols is described. Alkylation of a phenol using 1-iodo-1-(phenylthio)cyclopropane followed by removal of the phenylthio group furnishes the cyclopropyl ethers in modest to excellent yields. The procedure tolerates a wide range of functional groups.

A new class of potent NK3R antagonists based on the N',2-diphenylquinoline-4-carbohydrazide core is described. In an ex vivo assay in gerbil, the lead compound 2g occupies receptors within the CNS following oral dosing (Occ(90) 30 mg/kg po; plasma Occ(90) 0.95 microM) and has good selectivity and promising PK properties.

A new class of high affinity hNK 1 R antagonists based on seven-membered ring cores has been identified. This series, with relatively simple, compact structures, includes compounds with high affinity, good selectivity, and promising in vivo properties.

Previously, chemistry effort on the gem-cyclohexane series of gamma-secretase inhibitors has focused on the 4-position of the cyclohexane ring. Recently chemistry has been directed towards the 3-position and substitution here has also provided compounds with high gamma-secretase activity.

Treatment of tertiary formamides with a silylated diazoester in the presence of a rhodium(II) catalyst leads to the formation of 3-amino-2-silyloxyacrylates in good yield. No olefination is observed if a nonsilylated diazo compound is employed. [reaction: see text]

A series of 4,4-disubstituted cyclohexylamine NK 1 antagonists containing a lactam ring is described. The compounds are brain penetrant and activity is demonstrated in a ferret emesis model.

[3R,5R,6S]-3-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)- 6-phenyl- 1-oxa-7-azaspiro[4.5]decane is a substance P (Neurokinin 1 receptor) antagonist. Substance P antagonists are proven in concept to have excellent potential for the treatment of major depression, and they allow superior and sustained protection from acute and delayed chemotherapy-induced emesis. The metabolism of this compound was investigated in rat hepatocytes, and circulating rat plasma metabolites were identified following oral and intravenous dosing. The turnover in rat hepatocytes within 4 h was about 30%, and the major metabolites were identified as two nitrones and a lactam associated with the piperidine ring. Although these metabolites were also observed in rat plasma, the major circulating metabolite was a keto acid following oxidative de-amination of the piperidine ring. Liquid chromatography/tandem mass spectrometry and nuclear magnetic resonance were used to confirm the structure of the latter metabolite. A mechanism leading to the formation of the keto acid metabolite has been suggested, and most intermediates were observed in rat plasma.

The synthesis and biological evaluation of a series of 2-aryl indoles with high affinity for the human neurokinin-1 (hNK1) receptor are reported, concentrating on optimisation of the indole substitution.

The decomposition of beta-amidozinc reagent 4 by beta-elimination has been shown to be a unimolecular process in both THF and DMF as solvent, with relative rates of 4:1 at room temperature, and activation parameters have been determined. These results indicate the beta-elimination is a syn-process. NMR experiments reveal that as little as 2 equiv of DMF can have a significant stabilizing influence on reagent 4. Use of a mixture of DMA and toluene as the bulk solvent, in place of DMF, has allowed successful palladium-catalyzed cross-coupling reactions of both 4 and the homologous reagent 5 with acid chlorides to yield unsymmetrical ketones (nine examples).

A series of novel serine derived NK1 antagonists is described. The effect of variations in the N-benzyl, O-benzyl and serine groups are used to define the elements which are necessary for binding.

Aryl triflates may be cross-coupled with the amino acid derived zinc reagents 1 , 2 and 3 using palladium catalysis at room temperature, in the presence of anhydrous lithium chloride, conveniently yielding phenylalanine 4 , β-homophenylalanine 5 and γ-bishomophenylalanine 6 derivatives respectively (nine examples).