P-Dimethoxy-substituted trans-octahydrobenzo[f]- and -[g]quinolines: synthesis and assessment of dopaminergic agonist effects

Abstract

The N-n-propyl homologues of the title compounds were prepared for further assessment of the ability of the "p-dimethoxy" moiety to confer dopaminergic agonism upon a variety of ring systems. Both the angularly and the linearly annulated trans-benzoquinoline ring derivatives displayed prominent DA2 dopaminergic effects on the peripheral sympathetic nerve terminal and displayed postjunctional dopamine receptor agonist properties in the striatum. It is speculated that the angular octahydrobenzo[f]quinoline derivative (but not the linear octahydrobenzo[g]quinoline derivative) may owe its dopamine-like effects to metabolic activation phenomena. In contrast, the cis-fused isomer of the angularly annulated benzoquinoline was inactive, as was the simple benzene derivative N,N-di-n-propyl-beta-(2,6-dimethoxyphenyl)ethylamine.

cis-1,2,3a,4,5,9b-Hexahydro-3H-benz[e] indoles: Synthesis and In Vitro Binding Affinity at Dopamine D1 and D2 Receptors

“…16 The sodium borohydride or sodium cyanoborohydride gave equal mixtures of cis and trans or mixtures with mostly trans stereochemistry.gJ9 Higher percentages of the trans isomers were produced with platinum oxide in acetic acid. 19 Based on the I3C NMR spectra, catalytic and metal hydride reduction (methods C-G) of the tricyclic enamines 10-14 consistently gave only one isomer. The stereochemistry of the hexahydro-3H-benz[e]indoles [15][16][17][18][19][20] could not be established by examination of the bridgehead protons (3a,9b).…”

“…19 Based on the I3C NMR spectra, catalytic and metal hydride reduction (methods C-G) of the tricyclic enamines 10-14 consistently gave only one isomer. The stereochemistry of the hexahydro-3H-benz[e]indoles [15][16][17][18][19][20] could not be established by examination of the bridgehead protons (3a,9b). In the octahydrobenzo[flquinolines, the 'H NMR of the N-benzyl derivatives produced spectra that were consistent with spectra obtained with octahydrobenzo[g]quinolines.~~7~~ The methylene protons of the N-benzyl substituent gave an AB quartet with a large chemical shift difference in the trans isomers (48-60 Hz).…”

“…The combined organic phase was washed with H,O (2 x 10 mL), dried (Na,SO,), and evaporated to give 6.8 g (100%) of 10 as a dark oil; IR (neat): 1638 (C=C-N) cm-'; 'H NMR (CDCl,): 6 0.93 (t, 3 H, CH,), 1.54 (m, 2 H, CH,CH,), 2.21-3.39 (m, 10 H, ring CH, and NCH,), 3.79 (s,3 H, OCH,), 6.79 (m, 3 H, ArH). Due to the extreme air sensitivity of 10-14, elemental analyses were not obtained (with the exception of 12) and the compounds were used directly in the synthesis of 15-20. -3-(n-propyl)-1,2,4,5-tetrahydro-3H-be~e7indole (13)-The enamine 8 (3.7 g, 17 mmol), 2 M i-propylmagnesium chloride (16.0 Butyl)-&methoxy-1,2,4,5-tetrahydro-3H-ben~e7~ndole (14)-Compound9 (13.3 g, 57.7 mmol), 2 M i-propylmagnesiumchloride (54 mL, 109 mmol), and BrCH,CH,Cl ( Method C: Synthesis of cis-6- Methoxy-3-(n-propyl)-1,2,3a,4,5,9bhexahydro-3H-benz[elindole (15) with Platinum Oxide in Ethanol-The enamine 10 (6.8 g, 28 3 H, OCH,), 6.68 (m, 3 H, ArH); "C NMR (CDCl,, 300 MHz): 6 12.2 (NCH&H,CH3), 19.1 (C-5), 22.0 (NCH,CH,CH,), 25.5 (C-4), 33.6 (C-l), 41.0 (C-gb), 52.9 (C-2), 56.7 (NCH,), 62.1 (C-3a), 106.8 (C-7), 120.9 (C-9), 126.2 (C-B), 126.3 (C-5a), 142 (C-ga), and 156.4 (C-6); MS: mlt 245 (M+).…”

“…Method F: Reduction of 10 with Platinum Oxide in Acetic Acid-Compound 10 (3.0 g, 12 mmol) in HOAc (50 mL) was shaken overnight on a Parr hydrogenator at 50 psi in the presence of PtOz (120 mg1. 19 The catalyst was filtered, and the reaction mixture was treated with saturated NaHCO, and then with 40% NaOH solution to adjust the pH to 9-10, The solution was extracted with CH,C1, (3 x 50 mL), and the combined CH,Cl, extracts were washed with H,O (1 x 100 mL), dried (Na,SO,), filtered, and evaporated. Vacuum distillation of the residue gave 1.3 g (44%) of 15, bp 150-155 "C (1 mmHg).…”

A new synthesis method for benzo[f]quinolin‐3‐carbonyl urea and thiourea derivatives in aqueous media catalyzed by TEBAC

“…Benzoquinoline and its derivatives are well known compounds exhibiting a wide spectrum of pharmacological activities, such as antibacterial activity [1], vibronic activity [2], antimicrobial activity [3], antimalarial activity [4], pesticidal and growth-regulating activity [5], dopanminergic activity [6], and stimulating activity [7], or displaying postjunctional dopamine receptor against properties in the stiatum [8]. An increasing interest in this class of compounds has led to the development of new synthetic strategies.…”