ABSTRACT
The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , HIV-1/drug effects , Piperazines/chemical synthesis , Piperidines/chemical synthesis , Potassium Channels, Voltage-Gated , Pyrimidines/chemical synthesis , Administration, Oral , Animals , Anti-HIV Agents/adverse effects , Anti-HIV Agents/pharmacology , Biological Availability , Brain/drug effects , Cation Transport Proteins/drug effects , Digestive System/drug effects , Ether-A-Go-Go Potassium Channels , HIV-1/isolation & purification , Humans , In Vitro Techniques , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Macaca fascicularis , Piperazines/adverse effects , Piperazines/chemistry , Piperazines/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Potassium Channels/drug effects , Pyrimidines/adverse effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Aryl carboxamides are useful structural units found in several biologically active compounds. Unlike their benzoic acid counterparts, fluorinated versions of naphthoic acids are relatively unknown. In connection with a recent project, we needed viable syntheses of several mono- and difluorinated naphthoic acids. Herein we describe the synthesis of 5-, 6-, 7-, and 8-fluoro-1-naphthalenecarboxylic acids and 5,7-, 5,8-, 6,7-, and 4,5-difluoro-1-naphthalenecarboxylic acids. The 5-fluoro derivative 1was obtained from the corresponding 5-bromo compound via electrophilic fluorination of the lithio-intermediate. The rest of the monofluoro (2, 3, and 4) and the difluoro acids (5, 6, and 7) were prepared by a new, general route which entailed the elaboration of commercial fluorinated phenylacetic acids to 2-(fluoroaryl)glutaric acids with differential ester groups; selective hydrolysis to a mono acid, intramolecular Friedel-Crafts cyclization, and aromatization furnished the target structures. An alternative process to assemble a naphthalene skeleton is also presented for the difluoro acids 5 and 6. Finally, 4,5-difluoro-1-naphthalenecarboxylic acid (8) was prepared expeditiously from 1,8-diaminonaphthalene by adapting classical reactions.
ABSTRACT
The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.
