(R)- and (S)-5,6,7,8-Tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten-8-ylamine. Stereoselective interactions with 5-HT1A-receptors in the brain

Abstract

The enantiomers of 5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten-8-++ +ylamine (3) have been synthesized and evaluated for central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor activity by use of behavioral and biochemical tests in rats. In addition, the ability of the compounds to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The absolute configuration of the enantiomers of 3 was determined indirectly by X-ray diffraction of (+)-(8R,alpha R)-5,6,7,8-tetrahydro-1-methoxy-N-(alpha-phenethyl)-9H- benzocyclohepten-8-ylamine hydrochloride (9.HCl), a resolved synthetic precursor. The stereoselectivity of the interaction of 3 with 5-HT1A receptors was more pronounced than that of 8-hydroxy-2-(dipropylamino)tetralin (1; 8-OH-DPAT); only (R)-3 displayed 5-HT activity. However, (R)-3 was of lower potency than any of the enantiomers of 1. The enantiomer (S)-3, which was found to be inactive as a 5-HT-receptor agonist, appeared to be a weakly potent DA-receptor agonist whereas (R)-3 seemed to be devoid of dopaminergic activity. The conformational preferences of 3 were studied by use of NMR spectroscopy and molecular mechanics calculations. Preferred conformations of (R)-3 are similar in shape to those of the stereoselective 5-HT1A-receptor agonist (2R,3S)-8-hydroxy-3-methyl-2-(dipropylamino)tetralin.

Derivatives as 5HT1A Receptor Ligands-Past and Present

“…Modification of the non-aromatic ring of the 2-aminotetralins, such as ring contraction (indamines) [44], or ring expansion (benzocycloheptamines) [45] decreases 5-HT 1A affinity (Fig. 2).…”

Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK)

“…Our lead inhibitor 1, as well as other known 26−28 ALK inhibitors, contains a diaminopyrimidine core motif. The synthetic strategy employed a highly convergent approach with fragment disconnections centered around the 5-chloro- The intermediate aniline 8 (Scheme 1) was derived from the known ketone 5 29 through reductive amination with morpho- procedures outlined in Scheme 4 to 27a,b. The absolute stereochemistry was determined using X-ray (anomalous dispersion) of a single crystal of the bis-p-bromobenzoyl derivative 31, which was available via reaction of the first eluting isomer with p-bromobenzoyl chloride.…”

“…The intermediate aniline 8 (Scheme ) was derived from the known ketone 5 through reductive amination with morpholine to provide 6 in near quantitative yield. Nitration provided a mixture of 2-nitro ( 7 ) and 4-nitro isomers (approximately 1:1) which were separable by silica gel chromatography.…”

“…Following the general procedure for S N Ar displacement on 2,5-dichloro- N -arylpyrimidin-4-amines, 12d (92 mg, 0.3 mmol) and 21e (0.1 g, 0.3 mmol) gave 26 (76 mg, 24% yield) as a tan solid. Mp 196–197 °C; LC/MS (ESI + ) m / z 630.18 (M + H) + ; 1 H NMR (400 MHz, CDCl 3 ) δ 9.42 (s, 1H), 8.57 (d, J = 8.3 Hz, 1H), 8.16 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.31–7.25 (m, 2H), 6.92–6.87 (m, 1H), 3.74 (s, 3H), 3.69 (br t, J = 5.2 Hz, 2H), 3.26 (br dd, J = 14.1, 6.8 Hz, 1H), 2.95–2.82 (br s, 4H), 2.76 (s, 6H), 2.75–2.61 (m, 8H), 2.54–2.37 (m, 2H), 2.20–2.10 (m, 2H), 1.82 (br s, 1H), 1.45–1.30 (m, 1H).…”

Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440

“… Unlike CEP-28122, the A-ring of 2 did not contain symmetry around the 7-membered ring, so a ring expansion approach was pursued. This key transformation to 5 was accomplished through the use of stoichiometric amounts of thallium. , The ring expansion was followed by a nonselective nitration, resulting in mixture of nitration products (ortho, para, and overnitration on both positions). This mixture required difficult chromatography and only afforded the desired product, 6 , in low yield (<30%).…”