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Intranasal administration is an attractive route for systemic delivery of small, lipophilic drugs because they are rapidly absorbed through the nasal mucosa into systemic circulation. However, the low solubility of lipophilic drugs often precludes aqueous nasal spray formulations. A unique approach to circumvent solubility issues involves coadministration of a hydrophilic prodrug with an exogenous converting enzyme. This strategy not only addresses poor solubility but also leads to an increase in the chemical activity gradient driving drug absorption. Herein, we report plasma and brain concentrations in rats following coadministration of a hydrophilic diazepam prodrug, avizafone, with the converting enzyme human aminopeptidase B. Single doses of avizafone equivalent to diazepam at 0.500, 1.00, and 1.50 mg/kg were administered intranasally, resulting in 77.8% 6 6.0%, 112% 6 10%, and 114% 6 7% bioavailability; maximum plasma concentrations 71.5 6 9.3, 388 6 31, and 355 6 187 ng/ml; and times to peak plasma concentration 5, 8, and 5 minutes for each dose level, respectively. Both diazepam and a transient intermediate were absorbed. Enzyme kinetics incorporated into a physiologically based pharmacokinetic model enabled estimation of the first-order absorption rate constants: 0.0689 6 0.0080 minutes21 for diazepam and 0.122 6 0.022 minutes21 for the intermediate. Our results demonstrate that diazepam, which is practically insoluble, can be delivered intranasally with rapid and complete absorption by coadministering avizafone with aminopeptidase B. Furthermore, even faster rates of absorption might be attained simply by increasing the enzyme concentration, potentially supplanting intravenous diazepam or lorazepam or intramuscular midazolam in the treatment of seizure emergencies.

The present invention provides novel peripherally-restricted benzodiazepines with reduced blood brain barrier permeability and methods of use thereof for reducing tactile dysfunction, social impairment, and anxiety in a subject diagnosed with Autism Spectrum Disorder, Rett syndrome, Phelan McDermid syndrome, or Fragile X syndrome.

As the inhibitory γ-aminobutyric acid–ergic (GABAergic) transmission has a pivotal role in the central nervous system (CNS) and defective forms of its synapses are associated with serious neurological disorders, numerous versions of caged GABA and, more recently, photoswitchable ligands have been developed to investigate such transmission. While the complementary nature of these probes is evident, the mechanisms by which the GABA receptors can be pho-tocontrolled have not been fully exploited. In fact, the ultimate need for specificity is critical for the proper synaptic exploration. No caged allosteric modulators of the GABAA receptor have been reported so far; to introduce such an investigational approach, we exploited the structural motifs of the benzodiazepinic scaffold to develop a pho-tocaged version of diazepam (CD) that was tested on basolateral amygdala (BLa) pyramidal cells in mouse brain slices. CD is devoid of any intrinsic activity toward the GABAA receptor before irradiation. Importantly, CD is a photoreleasable GABAA receptor-positive allosteric modulator that offers a different probing mechanism compared to caged GABA and photoswitchable ligands. CD potenti-ates the inhibitory signaling by prolonging the decay time of postsynaptic GABAergic currents upon photoactivation. Additionally, no effect on presynaptic GABA release was recorded. We developed a photochemical technology to individually study the GABAA receptor, which specifically expands the toolbox available to study GABAergic synapses.

Unprecedented palladium-catalyzed denitrogenative Suzuki and carbonylative Suzuki coupling reactions of benzotriazoles with boronic acids have been realized, which afforded structurally diverse ortho-amino-substituted biaryl and biaryl ketone derivatives. The key to this success is due to the development of a rationally designed strategy to achieve the ring opening of benzotriazoles with a synergistic activating-stabilizing effect, which enables the in situ generation of the corresponding ortho-amino-arenediazonium species. The present work opens up a new avenue to utilize benzotriazoles as synthetic equivalents of ortho-amino-arenediazoniums, which otherwise could not be directly accessed by existing synthetic methods.

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.

Electrospray and Leidenfrost droplet accelerated reactions were used as a predictive tool for estimating the outcome of microfluidic synthesis as demonstrated by Wleklinski et al. Rapid analysis by electrospray-mass spectrometry (ESI-MS) also provided immediate feedback on reaction outcomes in flow reactions. Significant reaction acceleration was observed in electrospray relative to the corresponding bulk reaction. This rapid reaction screening and analysis method has allowed for the detection of previously unreported outcomes in the reaction between 5-chloro-2-(methylamino)benzophenone and haloacetyl chloride (halo = Cl or Br) in the continuous synthesis of diazepam. In our current study, a more detailed extension of the previous work, we report acceleration factors that are solvent dependent; additional byproducts that were observed on the microfluidic scale that were absent in the droplet reactions. Gaining insight from this combined droplet and microfluidic screening/rapid ESI-MS analysis approach, we have helped guide the synthesis of diazepam and showcased the potential of this method as a reaction optimization and discovery tool. Informed by these new insights, diazepam was synthesized in a high-yield two-step continuous flow process.

Aniline-derived diaryliodonium salts were synthesized and functionalized in good to excellent yields by judicious utilization of electron-withdrawing protecting groups. This simple approach opens another route to radiolabeling amino arenes in relatively complex molecules, such as flutemetamol.

A new method for the synthesis of 8-chloro-1-methyl-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (alprazolam) and 7-chloro-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (diazepam) from 2-amino-5-chloro benzophenone was described under mild conditions. Most of the synthetic steps were carried out under solvent-free conditions, and the products were obtained in high yield and purity. The products were characterized by comparison of physical properties with authentic samples and also by IR, 1H NMR and 13C NMR. Three-dimensional (3D) model of GABAA was constructed using X-ray crystal structure of homopentameric caenorhabditis elegans glutamate-gated chloride channel (GluCl) (3RHW) at 3.3?? as the template based on sequence comparison and homology modeling method. The homology modeling and MD simulation studies predicted the 3D structure of receptor in a water environment. The resulted conformation of the receptor was used for docking of the alprazolam and diazepam. Docking studies indicated many important interactions of the drugs with the receptor. Furthermore, the complex of GABA with drugs was used in MD simulation to realize the conformation changes of the complex.

Certain embodiments of the invention provide a formulation suitable for nasal administration comprising water, a prodrug of a therapeutic agent, and an enzyme that is suitable for intranasal conversion of the prodrug to the therapeutic agent, as well as methods of use thereof.

A palladium-catalyzed oxidative C-H bond decarboxylative acylation of N-nitrosoanilines using α-oxocarboxylic acid as the acyl source is described. The catalyst Pd(OAc)2 and oxidant (NH4)2S2O8 enabled ortho-acylation of N-nitrosoanilines at room temperature, affording an array of N-nitroso-2-aminobenzophenones in moderate to excellent yields.

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

The aldol reaction of the C(3) carbanion of 7-chloro-1,3-dihydro-1- methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (2) with a series of aromatic and aliphatic aldehydes at -78°afforded threo/erythro diastereoisomers 3-16 of 7-chloro-1,3-dihydro-3-(hydroxymethyl)-1-methyl-5-phenyl-2H-1,4- benzodiazepinones, substituted at the C(3) side chain, in a ratio from 55:45 to 94:6 (Scheme 1). Lewis acids exhibited limited effect on the syn/anti diastereoselectivity of this reaction, and kinetic control of the reaction was confirmed. 1H-NMR Data suggested the assignment of the threo relative configuration to the first-eluted diastereoisomers 3, 5 7, and 9 on reversed- phase HPLC, and the erythro configuration to the second-eluted counterparts 4, 6, 8, and 10, respectively. The structures and relative configurations threo and erythro of the diastereoisomers 5 and 6, respectively, were established by single-crystal X-ray analysis, confirming the assignment based on the 1H-NMR data. A tentative mechanistic explanation of the diastereoselectivity invokes the enolate anion of 1,3-dihydro-2H-1,4- benzodiazepin-2-one as the reactive species (Scheme 2). Acid-catalyzed hydrolytic ring opening of 3 afforded threo-β-hydroxy-phenylalanine 17, whereas from 4, the N-(benzyloxy)carbonyl derivative 18 of erythro-β- hydroxy-phenylalanine was obtained (Scheme 3); in both cases, neither elimination of H2O from the C(3)-CHOH moiety nor epimerization at C(3) were observed. This result opens a new pathway to various configurationally uniform α-amino-β-hydroxy carboxylic acids and their congeners of biological importance.

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The use of a preformed desmethyldiazepam sodium salt/ benzo-15-crown-5 complex in aprotic media allows for rapid and clean [11C]methylation without contamination and loss of activity due to alkylation of solvent residues and other dissolved basic-nucleophilic material.

Diazepam (1) is a frequently prescribed hypnotic/anxiolytic drug worldwide. 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2,2-dioxide (2) is an initial alkaline hydrolysis product of 1. The mechanisms in the conversion of 2 to 2-methylamino-5-chloro-α-(phenylbenzylidene)glycinate (3), 2-methylamino-5-chlorobenzophenone (4), and 1 in aqueous solutions with pH ranging from 0 to 12.2 is the subject of this report. Results of temperature-dependent hydrolysis kinetics and product identification indicated that: (1) in solutions with pH between 7 and 12.2, 2 underwent a ring-opening reaction to form 3; the rate decreased with increasing pH. (2) In solutions with pH between 2 and 7, 2 was rapidly converted to 3, followed by a pH-dependent conversion to 4; the rate increased with decreasing pH and became less sentitive to pH at pH ≤ 4.5. (3) In solutions with pH between 0 and 2, 2 was rapidly converted to 4 and 1; the percentage of 1 increased with decreasing pH. (4) A 2 containing one oxygen-18 atom lost 50% of its oxygen-18 following conversion to 1 in 1 M HCl. In addition to understanding the mechanism in the transformations of 2 in various pH solutions, this study established a simple and efficient method in the quantitative conversion of 1 to 4 and in the preparation of an oxygen-18-containing 1 at C2 position.

The rate of absorption of drugs across skin and other body membranes such as mucous membranes and the blood brain barrier is enhanced by adding to the drug composition a compound which enhances the rate. This compound may be a macrocyclic ester, diester, amide, diamide, amidine, diamidine, thioester, dithioester, thioamide, ketone or lactone. The macrocyclic ketone contains at least 12 carbon atoms.

The preparation consists of millispheres, microspheres, nanospheres or array-type particles consisting of a nucleus of a gellable hydrocolloid onto which has been deposited a film of a cationic polysaccharide, and incorporating inside a pharmacologically useful drug. The procedure consists of dissolving, suspending or emulsifying the drug in a solution of the gellable hydrocolloid; adding the resulting mixture to a gelling solution; and suspending the resulting millispheres, microspheres, nanospheres or array-type particles in a solution of the cationic polysaccharide.

A water-dispersible condensate of water-insoluble ultrafine particles of medicine or hormones having a particle size of at largest 4 μm prepared by the steps of heating the medicine or hormone in a vacuum vessel at a temperature of 30° C. higher than the boiling point and at a pressure between 0.01 Torr and 10 Torr to evaporate the medicine or hormone and condensing the medicine or hormone on a recovery plate to obtain the condensate.

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A method of inhibiting the proliferation of tumor cells is disclosed which comprises the treatment of such tumor cells with a benzodiazepine having a selective affinity to bind peripheral binding sites on the tumor cell in order to induce non-proliferation of said tumor cells.

An efficient preparation of 7-chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione from 5-chloro-N-methylisatoic anhydride and glycine has been devised, and from it, by the action of phenylmagnesium chloride on its N-acetyl-derivative followed by treatment with hydroxylamine and cleavage of the resulting desacetyl oxime with sodium bisulfite, diazepam has been synthesized.The overall yield is about 50percent from 5-chloroisatoic anhydride.

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This invention relates to an improved process for the preparation of 1,3-dihydro-2H-1,4-benzodiazepin-2-ones and 2,3-dihydro-1H-1,4-benzodiazepines by the condensation of a 2-(2-haloacylamido)-benzophenone or a 2-(2-haloethylamino)-benzophenone, respectively, in the presence of hexamethylenetetramine, a water miscible alcohol containing 5 to 50 volume percent water, and an ammonium salt.

A process for alleviating proliferative skin diseases such as psoriasis, atopic dermatitis, etc. comprising administering to humans, or domesticated animals, topically and/or systemically a composition comprising a pharmaceutical carrier and at least one active compound selected from the groups, substituted alkyl zanthines, tricyclic antidepressants, organic nitrates, antihypertensives, anti-asthma agents and central nervous system depressants and combinations of certain compounds from specifically named groups of compounds.

Intermediates for preparing novel benzodiazepines having the formula SPC1 In which R1 is a hydrogen or halogen atom or a trifluoromethyl, loweralkyl, loweralkoxy, nitro or amino group; R2 is a furyl, a thienyl, cyclohexyl, a loweralkyl group or a phenyl group which may be substituted by a halogen atom or by a trifluoromethyl, nitro, loweralkoxy or loweralkyl group; and R3 is a hydrogen atom or a loweralkyl group; and R4 is lowercarbalkoxy, carbamoyl, N-loweralkylcarbamoyl, N,N-diloweralkylcarbamoyl, N-(diloweralkylaminoalkyl)carbamoyl, a group having the formula --COOCat in which Cat is a cation of an alkali metal or a semication of an alkaline earth metal or COOCat.CatOH, said intermediates being ortho-aminoaryl ketimines having the formula SPC2 Wherein R is hydrogen or EQU1 R1, R2, and R3 are as defined above, R4 is a hydrogen atom, a lowercarbalkoxy, carbamoyl, N-loweralkylcarbamoyl, N,N-diloweralkylcarbamoyl, N-(diloweralkylaminoalkyl)-carbamoyl, alkyl or substituted alkyl group; and R5 is a loweralkyl group.

A 1,4-benzodiazepine derivative, or a pharmaceutically acceptable acid salt thereof, of the formula, SPC1 Wherein R1 is hydrogen, halogen, nitro or trifluoromethyl; R2 and R3 are independently hydrogen, halogen, lower alkyl or trifluoromethyl; R4 is lower alkyl, alkenyl, trihaloalkyl, alkoxyalkyl, alkenyloxyalkyl, alkoxyalkoxyalkyl, alkanoyloxyalkyl, cycloalkylalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or a group of the formula EQU1 in which R6 and R7 are independently lower alkyl, and n is an integer of 1 to 4; and R5 is hydrogen or lower alkyl, is obtained by reacting a benzophenone derivative of the formula, SPC2 Wherein R1, R2, R3 and R4 are as defined above, with a 2-isocyanatoacetyl chloride derivative of the formula EQU2 wherein R5 is as defined above.

1,4-Benzodiazepin-2-ones are prepared via the reaction of a haloacetamidophenyl ketone with hexamethylenetetramine in the presence of ammonia. The 1,4-benzodiazepin-2-ones so prepared are known compounds useful as muscle relaxant and anti-convulsant agents.

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