Analgesic agents. 3. New bridged aminotetralins

Abstract

A number of new bridged aminotetralins have been synthesized. Several modifications not previously examined have been tested for their effect on the analgesic properties. A number of the compounds prepared demonstrated analgesic activity on the order of morphine.In previous reports we described the synthesis and analgesic properties of a series of 1,3-bridged aminotetralins 1.2,s It was suggested that for optimum activity R k I I1 I11 of these compounds the amine function should be unsubstituted and oriented equatorially relative to the tetralin ring (@-epimer) and that the aromatic substituent (R3 = CH3 < H) should be located meta to the quaternary carbon. Steric crowding about the amine function, which is dependent on the sue of the alkyl group at the 5 position (Me < Et) and on bridge size ( n = 3 < 4 < 5), is an important feature of the molecular geometry.The goal of the present investigation was to develop analgesics having superior pharmacologic properties and to better defme the required features for analgesic activity.This led to the synthesis of molecular modifications in which the polarity of the compounds was altered by introduction of ester groups a t the 3 position or by conversion of the tertiary amine to its N-oxide. The conformational flexibility of the 1,3 bridge was restricted by unsaturation (11) and by increasing the bulk (Le., increasing the steric crowding about the amine function) by including an aromatic moiety (111). Compounds which exemplified each of these new structural variations were synthesized and pharmacologically evaluated. Although these modifications did not produce compounds with significantly enhanced analgesic properties, a number had potency in the range of morphine.Chemistry. The synthetic routes utilized for the preparation of the required compounds are described in Schemes 1-111.Treatment of a l-alkyl-7-methoxy-2-tetralone (I) with excess cis-1,4-dichlorobutene in the presence of potassium tert-butoxide yielded 2 (X = 0) (Scheme I). The oxime 2 (X = NOH) was obtained by refluxing 2 (X = 0) with methanolic NH20H-AcOH. Reduction of this oxime with lithium aluminum hydride (LiAlHd), a reagent which generally does not attack the isolated double bond, led to a somewhat surprising ring closure4 with formation of a tetracyclic amine (3 or 4). The absence of absorption in the area of 5 p in the ir of the hydrochloride indicated that the product was not a primary amine. In the NMR the base showed no vinylic protons and only one exchangeable proton. Mass spectral analysis was carried out and showed m/e a t 243 (mol wt for CitiH2iN0, 243). Addition of the amine function to the bridge double bond occurred a t the 7 or 8 position, but not both. This conclusion is supported by the fact that the product was obtained in 98% purity by GLC (hence is either 3 or 4). The structure of the tetracyclic system was not established unequivocally since from the available data we were unable to distinguish between these two isomers.Under Bouveault-Blanc conditions5 (Na-EtOH) the oxime 2 (X = NOH) w...

Pharmaceuticals that contain polycyclic hydrocarbon scaffolds

“…It was identified, through SAR studies, as a compound having analgesic properties comparable with morphine (74), 213,214 but also shares broad structural similarities with a number of other mixed agonist-antagonist pharmaceutical compounds, including butorphanol (75) and pentazocine (76) (Fig. 6).…”

“…221 Furthermore, whereas tolerance and toxicity upon extended administration of other agonist-antagonists, such as butorphanol, led to discontinuation of treatment, extended dezocine administration did not cause similar tolerance or toxicity. 216 Dezocine ( 73) is synthesised from 1-methyl-7-methoxy-2tetralone (79), 213,214 via alkylation with 1,5-dibromopentane in the presence of potassium t-butoxide (i.e. 80).…”

Quenching of *UF6 (A state) by alkanes

“…We have found very similar behavior for gases which must be inert quenchers (such as NZ and Ar, [9]), and the rates measured for the perfluoroalkanes are consistent with an inefficient physical quenching process. High-pressure saturation of quenching rates has been predicted theoretically by Freed [14] for physical quenching of small to intermediate type molecules, and has recently been observed for glyoxal (lA,) [15] and SO2 (3B1) [16-181 molecules. Excited-state coupling schemes have also been proposed to explain this behavior [19].…”

Sedimentation Equilibrium of Highly Nonideal Solutions of Polydisperse Polymers

“…The condition for equilibrium in an ultracentrifuge for each polymer component reads M¡( 1 -vp)u2r = ( µ;/dck)PT(dC)¡/dr) (12) k where is the angular velocity of the rotor and r is the distance from the rotor axis. Substitution of eq 10 into eq 12 yields Mj(lvp)w2r/RT = (l/c,)(dc¿/dr) + (ViV/VJU 1 -V./V* -2F08](dc"/dr) (13) Substitution of eq 3 into eq 13 and slight rearrangement leads to c,M,B(r) = dci/dr (14) B(r) = (1 -op)w2r/RT -(v2/Vs)E[l -Vt/Vk -2F0s](dc*/dr) (15) h Obviously, the function B(r), while dependent on the local composition of the solution, is common for all components of the solute. Summation of both sides of eq During the derivation of eq 16 and 17 the usual definitions of the weight-average molecular weight Mw and of the Z-average molecular weight Mz were employed.…”