Indanylidenes. 1. Design and synthesis of (E)-2-(4,6-difluoro-1-indanylidene)acetamide, a potent, centrally acting muscle relaxant with antiinflammatory and analgesic activity.
The design of rigid cyclic analogues derived from cinnamamide 1, (E)-N-cyclopropyl-3-(3-fluorophenyl)prop-2-enamide, and beta-methylcinnamamide 2, (E)-N-cyclopropyl-3-(3-fluorophenyl)but-2-enamide, has led to the discovery of the potent, centrally acting muscle relaxant (E)-2-(4,6-difluoro-1-indanylidene)acetamide, 17. Compound 17 also possesses potent antiinflammatory and analgesic activity. This paper describes the synthesis and the muscle relaxant, antiinflammatory, and analgesic structure-activity relationships of 17 and 67 of its analogues. Compound 17 has been taken into phase I clinical trials.
Musso
David L
DL
GlaxoSmithKline Research and Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. dm12907@gsk.com
Cochran
Felicia R
FR
Kelley
James L
JL
McLean
Ed W
EW
Selph
Jeffrey L
JL
Rigdon
Greg C
GC
Orr
G Faye
GF
Davis
Ronda G
RG
Cooper
Barrett R
BR
Styles
Virgil L
VL
Thompson
James B
JB
Hall
William R
WR
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009125:Muscle Relaxants, Central / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C471168:2-(4,6-difluoro-1-indanylidene)acetamide; D000081:Acetamides; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D006993:Hypnotics and Sedatives; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D009125:Muscle Relaxants, Central; D008995:Monoamine Oxidase