Tricyclic Pyridine Derivatives with High Affinity to the Central Benzodiazepine Receptor

Novel tricyclic heterocycles were prepared and evaluated for their affinity to the central benzodiazepine receptor. The most potent compounds with IC50's in the nanomolar range were; found among thienoquinolizines and benzo[a]quinolizines (cf. Tables 2–5). The central ring of the tricyclic ring system may be partially unsaturated (cf. Tables 2 and 4) or fully unsaturated (cf. Tables 3 and 5) without loss of the high affinity to the receptor. The position of the ester group in the pyridinone ring is crucial for good binding (cf. Tables 1 and 2). It may be replaced by a broad variety of functional groups, e.g. amides, alkyl carbamates, alkyl groups, and hydroxyalkyl groups (cf. Tables 2–5). In the benzo[a]quinolizines, shifting the halogen atom from C(10) to C(9) leads to complete loss of affinity to the benzodiazepine receptor (cf. Table 4).

[1]  K. T. Potts,et al.  Carbon-carbon bond formation via intramolecular cycloadditions: use of the thiocarbonyl ylide dipole in anhydro-4-hydroxythiazolium hydroxides , 1989 .

[2]  H. Fischer,et al.  Heterocyclische Siebenring‐Verbindungen, XXXIII. Synthese und Eigenschaften von 5‐Methoxy‐1,4‐benzothiazepin und von 5‐Methoxy‐1‐methyl‐1,4‐benzothiazepinium‐tetrafluoroborat , 1988 .

[3]  H. Fischer,et al.  Notiz über Synthese, Eigenschaften und Reaktionen des 4‐Methoxy‐2‐phenyl‐1,5‐benzothiazepins1) , 1987 .

[4]  L. Fodor,et al.  Sulfur extrusion from 1,4-benzothiazepines: formation of 3-aryl-4-carbomethoxyisoquinolines , 1987 .

[5]  K. T. Potts,et al.  Annulation to the quinazoline ring utilizing mesoionic ring systems , 1985 .

[6]  J. Rokach,et al.  Synthesis, chemistry, and photochemical substitutions of 6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-ones , 1983 .

[7]  K. T. Potts,et al.  Mesoionic compounds. 49. Ring annulation with heterocyclic ylides. Annulation of pyridones to the imidazole and 1,2,4-triazole systems , 1980 .

[8]  A. Foucaud,et al.  Reaction of N-substituted thioamides with gem-dicyano epoxides: a new synthetic route to anhydro-4-hydroxythiazolium hydroxides , 1978 .

[9]  H. Mohler,et al.  Benzodiazepine receptor: demonstration in the central nervous system , 1977, Science.

[10]  C. Braestrup,et al.  Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[11]  H. Suschitzky,et al.  Intramolecular cyclisation of arylalkyl isothiocyanates. Part I. Synthesis of 1-substituted 3,4-dihydroisoquinolines , 1976 .

[12]  K. Saigo,et al.  A facile synthesis of carboxamides by using 1-methyl-2-halopyridinium iodides as coupling reagents. , 1975 .

[13]  D. Johnston,et al.  Some novel heterocycles from deoxygenation of indole o-nitrophenyl sulphides , 1975 .

[14]  U. Singh,et al.  Mesoionic compounds. XXXI. Preparation and cycloaddition reactions of the anhydro-4-hydroxythiazolium hydroxide system with acetylenic dipolarophiles , 1974 .

[15]  W. Ried,et al.  Reaktionen von Acetylenketonen mit nucleophilen Agenzien vom Typ des o-Phenylendiamins, o-Amino-thiophenols und N1-disubstituierten Hydrazins , 1972 .

[16]  A. Robert,et al.  Epoxydes α,α-disubstitues par des groupements electroattracteurs—VI , 1971 .

[17]  P. Schmidt,et al.  Über die Umlagerung von Benzo[b]-1, 4-thiazepinen und 1, 4-Thiazepinen , 1970 .

[18]  F. Eloy,et al.  Synthèse d'isocarbostyriles et de chloro‐1‐isoquinoléines , 1969 .

[19]  W. Herz,et al.  Sulfur Analogs of Isoquinolines and β-Carbolines. III. The Pomeranz—Fritsch Reaction , 1953 .