Barbiturates And Minor Tranquilizers
S.J. Mulé, Henry Brill in Chemical and Biological Aspects of Drug Dependence, 2019
The major route of synthesis of chlordiazepoxide and other derivatives, as shown in Figure 8, is via a ring enlargement of quinazoline 3-oxides with either a primary aliphatic amine or hydrazine.49,54 “ 56 Several 2-amino-l, 4-benzodiazepine derivatives may also be fabricated from this type of chemical reation by utilizing substituted quinazoline 3-oxides, in which R may be a phenyl or a substituted phenyl,54-56 2- or 4-pyridyl,5.7 2-thienyl,56 hydrogen,49 alkyl,49 or cyclohexyl56 group. In addition, X at the number 6 carbon may be a alkylthio,58 chlorine,54–56 bromine,55 hydrogen,55,56 methyl,55,56 methoxycarbonyl,49 nitro,59 or a trifluoromethyl substituted group.49 Although quinazoline 3-oxide derivatives are primarily reacted with primary amines to cause the enlargement of a ring from a 6 to a 7 membered structure, a similar reaction may occur with some secondary amines.51 The two weak basic amines that have been utilized are dimethylamine60 and pyrrolidine,49 thereby resulting in a compound with a tertiary amine in the number 2 position. The leaving group at the number 2 position of quinazoline is usually chlorine.54-56
Asymmetric Reduction of C=N Bonds by Imine Reductases and Reductive Aminases
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Reductive amination is the most atom-efficient synthesis to prepare a desired secondary amine (Fig. 14.5, green path). The elegance of the enzymatic reductive amination lies in its atom economy: It is a one-step reaction, compared to the established multi-step procedures of chemical synthesis (Fig. 14.5, red path). Other established enzymatic routes (Fig. 14.5, blue paths) are restricted to the synthesis of primary amines only. Only monoamine oxidases (MAO) were evolved to access a comparable product scope (Batista et al., 2018): They require the amine racemate as substrates and arrive at the enantiopure amine via deracemization. IREDs allow a one-step synthesis of secondary and tertiary amines (green path), compared to multi-step approaches of chemical or alternative enzymatic routes (shown in red or blue, respectively).
Pharmacokinetics of Amphetamines: In Vivo and in Vitro Studies of Factors Governing Their Elimination
John Caldwell, S. Joseph Mulé in Amphetamines and Related Stimulants: Chemical, Biological, Clinical, and Sociological Aspects, 2019
Measuring the difference spectra of microsomes in the presence of a wide range of concentrations of D-(+)-N-methylamphetamine and cytochrome P-450 (a type I binding spectrum)74 reveals a complex Lineweaver Burke plot,75 which can be explained by the presence of distinctly binding sites, each with its own affinity (Ks value). D-(+)-N-dimethylamphetamine on the contrary shows a linear Lineweaver Burke plot, indicating one binding site. These data are confirmed by the results of measurements of metabolic rates at different substrate concentrations. For the N-dimethylamphetamines normal Lineweaver Burke plots were found, while N-methylamphetamines show a complex Lineweaver Burke plot (Figures 9A and 9B). The N-demethylation of the secondary amine, N-methylamphetamine, shows a manifest stereoselectivity, in contrast to the tertiary amine, N-dimethylamphetamine (Figure 9). The complex Lineweaver Burke plots seen for the secondary amines may be the result of (1) a negative cooperativity which means that at higher substrate concentrations the conversion is facilitated, (2) two different binding sites, or (3) binding sites on two different enzymes. Studies of the in vitro metabolism of these compounds in subcellular preparations have revealed that amphetamines are metabolized by different enzyme identities.
Pharmacokinetic evaluation of quetiapine fumarate controlled release hybrid hydrogel: a healthier treatment of schizophrenia
Published in Drug Delivery, 2018
Muhammad Akhlaq, Faiza Maryam, Abdelhamid Elaissari, Hashmat Ullah, Muhammad Adeel, Abid Hussain, Muhammad Ramzan, Obaid Ullah, Muhammad Zeeshan Danish, Shehla Iftikhar, Nighat Aziz
Swelling increases as the quantity of Gel increases. The functional groups of Gel responsible for swelling of hydrogels are amine (–NH2) and carboxylic acid group (–COOH) (Raafat, 2010). Amine contains basic nitrogen and is basically a derivative of ammonia with one or more hydrogen atom(s) replaced by alkyl or aryl group. At pH below pKb of basic components (acidic pH), ionization (protonation) occurs that results in formation of –NH3+ ions and due to the presence of similar cations, electrostatic repulsion takes place within them resulting in swelling of hydrogel in acidic medium (Gil et al., 2005). Gel also contains -COOH group which is an acidic component and at pH above pKa (basic medium) loses H + ion thus becomes COO−, ionization of COOH group at pH 7.4 causes the repulsion of anions due to electrostatic repulsion and thus swelling of the hydrogel occurs in basic medium. Because of the presence of these functional groups, Gel/HPMC hydrogel showed swelling at both acidic and basic pH (Lou & Chirila, 1999).
PDE1 inhibitors: a review of the recent patent literature (2008-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Mei-Ling Le, Mei-Yan Jiang, Chuan Han, Yi-Yi Yang, Yinuo Wu
In 2015, Kehler and coworkers disclosed a series of PDE1 inhibitors with quinazoline scaffold (Figure 27). The X group on the quinazoline was a halogen atom in the first patent. The IC50 values of these compounds against PDE1 ranged from 7 nM to 2800 nM. Most compounds in this patent had two or more stereoisomers and one showed better inhibitory activities than others [79]. For the representative compound 86, stereoisomer 1 gave the IC50 value of 9.9 nM, while stereoisomer 2 gave the IC50 value of 65 nM against PDE1B. However, no configuration was provided for each stereoisomer. In another patent by Kehler, the X group on the quinazoline was instead by the methoxy group. The amine can be primary amine, secondary amine, or cyclic aliphatic amine [80]. The configuration had a significant impact on the inhibitory activities. For example, the (S)-87 was 30-fold more potent against PDE1B than (R)-87 [81].
Challenging inflammatory process at molecular, cellular and in vivo levels via some new pyrazolyl thiazolones
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Perihan A. Elzahhar, Rana A. Alaaeddine, Rasha Nassra, Azza Ismail, Hala F. Labib, Mohamed G. Temraz, Ahmed S. F. Belal, Ahmed F. El-Yazbi
The synthetic strategy adopted for the preparation of the target compounds is outlined in Scheme 1. The starting aldehydes were prepared as previously reported47–51. The target compounds 1–10 were attained by a one-pot reaction of the aldehydes a-e with rhodanine and cyclic secondary amines (namely; piperidine and morpholine) in refluxing ethanol using catalytic amount of acetic acid, similar to previously reported procedure52,53. The reaction proceeded via Knoevenagel condensation of the appropriate aldehyde and rhodanine with subsequent replacement of the sulphur of the thiocarbonyl functionality with secondary amine in the same reaction mixture. The secondary amine has a dual role by acting as the catalyst for the Knoevenagel condensation and behaving as the nucleophile in the next step. It is necessary to point out that compounds 3 and 4 were previously reported by different synthetic route instead of the one-pot reaction32.