Struktur‐Wirkungs‐Beziehungen bei Nefopamhydrochlorid

Abstract

Die an (+)-Nefopamhydrochlorid (1) durchgefiihrte Rontgenstrukturanalyse (P2,/c, a = 1176,1, b = 773,9, c = 1689,7pm, fi= 97,43", Z = 4) zeigt, da8 der Heterocyclus aus zwei einfachen Strukturelementen zusammengesetzt ist. Fiinf Atome (2,3,4,5 und 6) haben die Anordnung eines Cyclohexan-Fragmentes; zugleich liegen fiinf Atome (2, 1, 10a, 6a und 6) in der Ebene des anellierten Benzolringes. Die beiden Benzolringe stehen, anders als bei den strukturell verwandten Benzodiazepinen, nahezu senkrecht aufeinander. Die fjbereinstimmung der Strukturen von 1 und (-)-Nefopamhydrochlorid-monohydrat wird im Hinblick auf die Starrheit der Konformation diskutiert. Nefopam kann danach als Modellsubstanz f i r Serotonin-Agonisten und -Antagonisten dienen. Als strukturelle Gemeinsamkeit dieser Verbindungen tritt eine aliphatische Aminogruppe auf, die ca. 600 pm vom Zentrum eines Aromaten entfernt etwa in dessen Ringebene liegt oder leicht in diese Position uberfiihrt werden kann. Structure-Activity Relationships of Nefopam HydrochlorideAn X-ray study of (+)-nefopam hydrochloride (1) (P2,/c, a = 1176.1, b = 773.9, c = 1689.7~1~1, = 97.43", Z = 4) shows that the heterocyclic ring has two structurally simple features: Five atoms (2-6) form the C, fragment of a cyclohexane ring, while another five atoms (2, 1,10a, 6a and 6) lie within the plane of the fused benzene ring. The two benzene rings are almost perpendicular to each other, which is remarkably different from the structurally related benzodiazepines. The structure of 1 is practically identical with that found for (-)-nefopam hydrochloride monohydrate, a fact which is discussed under the aspect of conformational rigidity. Nefopam can be taken as a model substance for serotonin agonists and antagonists. As a common structural feature these compounds have an aliphatic amino group which lies (or can be easily placed) at a distance of about 600pm from the center of the aromatic system and nearly within the plane of the system.

Eight-Membered-Ring Solid-State Conformational Interconversion via the Atom-Flip Mechanism, a CPMAS13C NMR and Crystallographic Stereochemical Study

“…Nefopam hydrochloride [5-methyl-1-phenyl-3,4,5,6-tetrahydro-1 H -2,5-benzoxazocine, ( 1 )] is a benzannelated eight-membered heterocyclic non-narcotic analgesic drug with antidepressant properties . X-ray crystallographic determination of the structures of (+)- , and (−) chiral crystals and of the racemic modification ,, of nefopam hydrochloride ( 1 ) showed the 2,5-benzoxazocine ring to be bent into the boat-boat conformation (BB). This is illustrated in the 2D-iconic projection ( 2 ) of the actual 3D X-ray determined structure of (±)- 1 .…”

1H and 13C NMR conformational studies on quaternary nitrogen derivatives of the analgesic drug nefopam

“…Whereas 3J(3a, 4e) and 3J(3e, 4a) were also readily ascertained, the small 3J(3e, 4e) coupling constant between the two equatorial protons could not be measured owing to line broadening at ambient temperature. All the proton resonances of 6 [and for the diastereomeric N-CD, labelled isotopomers 8 and 9 (see below)] are considerably broadened. For example, both N-methyl proton singlets are ca.…”

The stereochemistry of a nine-membered ring analogue of nefopam, a nonnarcotic analgesic drug

“…The order of the transitions is 1,2,3,4, [5,9], [6,10], [7,11], [8,12,17], 18,19,20,13,14,15,[ 16,21,25], [22,26], [23,27], [24,28] …”

“…The solid-state and solution-state conformations of heterocyclic eight-membered rings related to nefopam hydrochloride (1) have been the subject of a series of investigations [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. X-ray crystallography [3][4][5]7] showed a conformation for crystalline 1 which may be described as a boat-boat (BB-le) in which the two close C--Hendo... Hendo--C BB-cyclooctane transannular nonbonding interactions have been converted into longer-distance C--He,do" 9 9 Z interactions (where Z is a nonpro~Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel. 21~partement de Chimie, Universit6 de Sherbrooke, Sherbrooke, Qu6bec, Canada.…”