The benzodiazepine story.

For 10 years Valium® (2) has been the most frequently prescribed drug. It is a safe, potent anxiolytic with pronounced muscle relaxant properties, and is the best known tranquilizer of its kind. It contains, as active ingredient, diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one).

[1]  K. Auwers,et al.  Ueber eine neue Synthese von Derivaten des Isindazols , 1891 .

[2]  K. Auwers.  Zur Konstitution der Acyl‐indazole , 1924 .

[3]  J. Meisenheimer,et al.  Über die isomeren Acyl‐indazole von K. v. Auwers , 1924 .

[4]  W. Ried,et al.  Über heterocyclische Siebenringsysteme, IV. Mitteil.): Synthesen und Eigenschaften von 4.5‐Benzo‐[hept‐1.2.6‐oxdiazinen] , 1954 .

[5]  L. Sternbach,et al.  Quinazoline 3-Oxide Structure of Compounds Previously Described in the Literature as 3.1.4-Benzoxadiazepines1 , 1960 .

[6]  L. O. Randall.  Pharmacology of methaminodiazepoxide. , 1960, Diseases of the nervous system.

[7]  L. Sternbach,et al.  Quinazolines and 1,4-Benzodiazepines. III.1 Substituted 2-Amino-5-phenyl-3H-1,4-benzodiazepine 4-Oxides , 1961 .

[8]  L. Sternbach,et al.  Quinazolines and 1,4-Benzodiazepines. IV.1,2 Transformations of 7-Chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-Oxide3 , 1961 .

[9]  L. Sternbach,et al.  Quinazolines and 1,4-Benzodiazepines. II.1 The Rearrangement of 6-Chloro-2-chloromethyl-4-phenylquinazoline 3-Oxide into 2-Amino Derivatives of 7-Chloro-5-phenyl-3H-1,4-benzodiazepine 4-Oxide , 1961 .

[10]  G. A. Heise,et al.  Pharmacological and clinical studies on Valium (T.M.) a new psychotherapeutic agent of the benzodiazepine class. , 1961, Current therapeutic research, clinical and experimental.

[11]  R. Lo.  Pharmacology of chlordiazepoxide (Librium). , 1961 .

[12]  L. Sternbach,et al.  Quinazolines and 1,4-Benzodiazepines. VI.1a Halo-, Methyl-, and Methoxy-substituted 1,3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones1b,c , 1962 .

[13]  A. Stempel,et al.  Quinazolines and 1,4-Benzodiazepines. IX. 2-Carbobenzoxyglycylamidobenzophenones and Their Conversion to 1,4-Benzodiazepinones , 1962 .

[14]  S. Bell,et al.  A Rearrangement of 5-Aryl-1,3-dihydro-2H-1,4-benzodiazepine-2-one 4-Oxides1 , 1962 .

[15]  G. Saucy,et al.  Chinazoline und 1,4‐Benzodiazepine. VII. Mitteilung. Trifluormethyl‐substituierte Verbindungen , 1962 .

[16]  C. Gochman,et al.  1,3-Dihydro-2H-1,4-benzodiazepine-2-ones and Their 4-Oxides , 1962 .

[17]  L. Sternbach,et al.  QUINAZOLINES AND 1,4-BENZODIAZEPINES. X. NITRO-SUBSTITUTED 5-PHENYL-1,4-BENZODIAZEPINE DERIVATIVES. , 1963, Journal of medicinal chemistry.

[18]  L. Sternbach,et al.  QUINAZOLINES AND 1,4-BENZODIAZEPINES. XVII. SYNTHESIS OF 1,3-DIHYDRO-5-PYRIDYL-2H-1,4-BENZODIAZEPINE DERIVATIVES. , 1964, Journal of pharmaceutical sciences.

[19]  M. I. Gluckman,et al.  1,4-BENZODIAZEPINES. , 1964, Journal of pharmaceutical sciences.

[20]  L. Sternbach,et al.  Quinazolines and 1,4-Benzodiazepines. XVI.1 Synthesis and Transformations of 5-Phenyl-1,4-benzodiazepine-2-thiones , 1964 .

[21]  L. Sternbach,et al.  Quinazolines and 1,4-benzodiazepines. XXVII. Mechanism of ring enlargement of quinazoline 3-oxides with alkali to 1,4-benzodiazepin-2-one 4-oxides. , 1965, Journal of Organic Chemistry.

[22]  Chinazoline und Benzodiazepine XXX Die Synthese von Tetrahydro-isochino[2,1-d] [1,4]-benzodiazepin-6(7H)-onen† , 1966 .

[23]  J. Harmatz,et al.  An evaluation of isoquinazepon (SAH-1123). , 1967, Current Therapeutic Research.

[24]  C. Gochman,et al.  3-substituted 1,4-benzodiazepin-2-ones. , 1968, Journal of Medicinal Chemistry.

[25]  H. Kaegi.  Synthesis of 7-Chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-5-14C hydrochloride (1) , 1968 .

[26]  P F Juby,et al.  Preparation and antininflammatory properties of some 5-(2-anilinophenyl)tetrazoles. , 1968, Journal of medicinal chemistry.

[27]  T. Hirohashi,et al.  Benzodiazepine, 2. Notiz über ein neues Verfahren zur Herstellung von 1.4‐Benzodiazepin‐Derivaten aus 2‐Aminomethyl‐indol‐Derivaten , 1968 .

[28]  G. Hardtmann,et al.  Tetrahydroisoquino[2,1-d][1,4]benzodiazepines. Synthesis and neuropharmacological activity. , 1968, Journal of Medicinal Chemistry.

[29]  L. Sternbach,et al.  Chemistry of benzodiazepines , 1968 .

[30]  J. Porath,et al.  7-Chlor-5-phenyl-1,9-trimethylen-1,4-benzodiazepin-2-on. , 1968 .

[31]  Peter Jb,et al.  New methods for the preparation of 1,4-benzodiazepinones, carbostyrils and indolo(2,3-c)quinolones. , 1969 .

[32]  W. Veldkamp,et al.  Pyrrolo[3,2,1-jk][1,4]benzodiazepines and pyrrolo[1,2,3-ef][1,5]benzodiazepines which have central nervous system activity. , 1970, Journal of Medicinal Chemistry.

[33]  S. Andronati,et al.  The Present State of the Chemistry of 1,4-Benzodiazepines , 1970 .

[34]  F. Kajfez,et al.  A new ring closure of 1,4‐benzodiazepine , 1970 .

[35]  Y. Take,et al.  Pharmacological studies on new potent central depressants, 8-chloro-6-phenyl-4H-s-triazolo [4,3a][1,4] benzodiazepine (D-40tA) and its 1-methyl analogue (D-65MT). , 1971, Japanese journal of pharmacology.

[36]  L. Sternbach,et al.  The reaction of epoxides with 1,4-benzodiazepines, mechanism and structural assignments , 1971 .

[37]  L. Sternbach.  1,4‐Benzodiazepine. Chemie und Betrachtungen zur Beziehung zwischen Struktur und Wirkung , 1971 .

[38]  H. Murata,et al.  Studies on the metabolism of oxazolam. II. Isolation and identification of the metabolites of oxazolam in rats. , 1971, Chemical & pharmaceutical bulletin.

[39]  C. Chidester,et al.  Synthesis and proof of structure of a novel 1,4-benzodiazepine , 1971 .

[40]  C. Tamura,et al.  Anxiolytic sedatives. 1. Synthesis and pharmacology of benzo[6,7]-1,4-diazepino[5,4-b]oxazole derivatives and analogs. , 1971, Journal of medicinal chemistry.

[41]  R. Nakajima,et al.  Structure-activity relationship of s-triazolo-1,4-benzodiazepines in central nervous depressant action. , 1971, Japanese journal of pharmacology.

[42]  T. L. Lemke,et al.  The synthesis of oxazolo- and oxazino[3,2-d] [1,4]benzodiazepinones , 1971 .

[43]  L. Sternbach,et al.  Quinazolines and 1,4-benzodiazepines. LI. The synthesis of the t-butyl analog of diazepam† , 1971 .

[44]  J. Hester,et al.  6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines which have central nervous system depressant activity. , 1971, Journal of medicinal chemistry.

[45]  K. Weber,et al.  Benzodiazepine mit psychotroper Wirkung, III. N-Aryl- und N-Heteroaryl-1H-1.5-benzodiazepin-2.4-[3H.5H]-dione , 1972 .

[46]  J. Topliss,et al.  1-Polyfluoroalkylbenzodiazepines; 1. , 1973, Journal of Medicinal Chemistry.

[47]  L. Sternbach,et al.  Quinazolines and 1,4-benzodiazepines. 58. The azido group, a novel pharmacophoric substitutent. 7-Azido-5-phenyl-1,4-benzodiazepines. , 1973, Journal of Medicinal Chemistry.

[48]  I. Nordin,et al.  Pyrazolodiazepines. 1,3-(And 2,3-) dialkyl-4,6-dihydro-8-arylpyrazolo(4,3-e)(1,4)diazepin-5-ones as antianxiety agents. , 1973, Journal of Medicinal Chemistry.

[49]  K. Meguro,et al.  Heterocycles. VII. Novel and Facile Syntheses of s-Triazolo-[4, 3-a] [1, 4] benzodiazepine Derivatives , 1973 .

[50]  Pharmacologic studies with triflubazam (ORF 8063): a new psychotherapeutic agent. , 1974 .

[51]  L. Sternbach,et al.  Quinazolines and 1,4-benzodiazepines. 64. Comparison of the stereochemistry of diazepam with that of close analogs with marginal biological activity. , 1974, Journal of Medicinal Chemistry.

[52]  Y. Kanai.  The biotransformation of 8-chloro-6-phenyl-4H-s-triazolo(4,3-a) (1,4) benzodiazepine (D-40TA), a new central depressant, in man, dog and rat. , 1974, Xenobiotica; the fate of foreign compounds in biological systems.

[53]  R. I. Fryer,et al.  Quinazolines and 1,4-benzodiazepines. LXX. v-Triazolo[1,5-a][1,4]benzodiazepines , 1975 .

[54]  U. Golik.  The synthesis of some 2,4-benzodiazepin-l-ones, potent c.n.s. agents , 1975 .

[55]  T. Okamoto,et al.  Benzodiazepines. XII. Synthesis of 5-(2-pyridyl)- and 3-methyl-1,4-benzodiazepin-2-ones. , 1975 .

[56]  A N Nicholson,et al.  Effect of a metabolite of diazepam, 3-hydroxydiazepam (temazepam), on sleep in man. , 1976, British journal of clinical pharmacology.

[57]  R. Priest,et al.  Nitrazepam and Temazepam: A Comparative Trial of Two Hypnotics , 1976, Journal of International Medical Research.

[58]  L. Borgen,et al.  Ripazepam (CI‐683): Double‐Blind Comparison with Placebo in Anxious Patients , 1976, Journal of clinical pharmacology.

[59]  F. S. Eberts.  Disposition of triazolam, 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a]benzodiazepine, in the dog. , 1977, Drug metabolism and disposition: the biological fate of chemicals.

[60]  L. Fabre,et al.  Pilot Open-Label Study of Alprazolam (U-31,889) in Anxious Alcoholic Out-Patients , 1977, Journal of International Medical Research.

[61]  Johnson Wl,et al.  Triazolam: an effective hypnotic in general practice. , 1977, Current Therapeutic Research.

[62]  S. Lobbestael,et al.  Pyrazolodiazepines. 2. 4-Aryl-1,3-dialkyl-6,8-dihydropyrazolo[3,4-e] [1,4]diazepin-7(1H)-ones as antianxiety and anticonvulsant agents. , 1977, Journal of Medicinal Chemistry.