N-alkyl Carbamates Research Articles

Recent Advances in Approved, Withdrawn, Experimental and Investigational Drugs in Clinical Trials for Alzheimer’s disease

Alzheimer’s disease (AD) is an irreversible, chronic degenerative disease that slowly destroys memory and thinking skills, and eventually destroys the ability to carry out the simplest of day-to-day routine tasks. This disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. Presence of beta-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) in brains of the affected patients are the distinguishable characteristics of this disease. Currently, no treatment is available to stop or reverse progression of AD, though it may temporarily improve symptoms. There are four USFDA approved drugs which are helpful for symptomatic treatment in AD namely Donepezil, Rivastigmine, Galantamine and Memantine. Memantine functions as an NMDA receptor antagonist, whereas the other three drugs act by inhibiting the acetylcholinesterase enzyme (AChE) resulting in an increase in the levels of acetylcholine (ACh) in the body. In the past decades, many advancements in the current drugs as well as the experimental drugs for AD have been made and these involve structural modifications and mechanistic improvements to increase the capacity of the molecules to cross the blood brain barrier (BBB). Synthesis of 2-acetylphenol-donepezil hybrids is an example of an approach which was adopted based on MultiTarget Directed Ligand (MTDL) strategy. Recently, synthesis of salicylanilide N-alkyl carbamates was carried out and these were observed to possess higher AChE inhibiting capacity than Rivastigmine. Memogain is an inactive prodrug of galantamine which has shown improved effectiveness, fewer side effects and due to its lipophilic nature is said to penetrate the BBB where it gets cleaved into active galantamine. Huperzine A is another highly selective AChE inhibitor and is approved for use only in China though not by USFDA. Tacrine and Huperazine A were combined together to form a hybrid molecule Huprine X, which is said to possess not only potency but also higher selectivity for AChE inhibition alongside anti-Aβ properties.

N-Aryl and N-Alkyl Carbamates from 1 Atmosphere of CO2.

We have successfully isolated and characterized the zinc carbamate complex (phen)Zn(OAc)(OC(=O)NHPh) (1; phen=1,10-phenanthroline), formed as an intermediate during the Zn(OAc)2 /phen-catalyzed synthesis of organic carbamates from CO2 , amines, and the reusable reactant Si(OMe)4 . Density functional theory calculations revealed that the direct reaction of 1 with Si(OMe)4 proceeds via a five-coordinate silicon intermediate, forming organic carbamates. Based on these results, the catalytic system was improved by using Si(OMe)4 as the reaction solvent and additives like KOMe and KF, which promote the formation of the five-coordinated silicon species. This sustainable and effective method can be used to synthesize various N-aryl and N-alkyl carbamates, including industrially important polyurethane raw materials, starting from CO2 under atmospheric pressure.

N-[3,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide Analogues: Novel Acetyl- and Butyrylcholinesterase Inhibitors.

Development of acetyl- (AChE) and butyrylcholinesterase (BuChE) inhibitors belongs to viable strategies for the treatment of dementia and other diseases related to decrease in cholinergic neurotransmission. That is why we designed twenty-two analogues of a dual AChEBuChE salicylanilide inhibitor, N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide 1, to improve its potency. We prepared N,N-disubstituted (thio)carbamates via direct acylation with (thio)carbamoyl chloride, N-n-alkyl monosubstituted carbamates using isocyanates as well as its salicylanilide core analogues. The derivatives were evaluated in vitro against AChE from electric eel and BuChE from equine serum using spectrophotometric Ellman's method. The compounds showed moderate inhibition of both AChE and BuChE with IC50 from 18.2 to 196.6 μmol.L-1 and 9.2 to 196.2 μmol.L-1, respectively. Importantly, based on the substitution pattern, it is possible to modulate selectivity against AChE or BuChE and some derivatives also produced a balanced inhibition. In general, the most promising analogues were N-alkyl (C2-C6) carbamates and isomers with a changed position of phenolic hydroxyl. N-[3,5-Bis(trifluoromethyl)phenyl]-3-bromo-5- hydroxybenzamide 4a was the best inhibitor of both cholinesterases. A wide range of the derivatives improved the activity of the hit 1, they were superior to carbamate drug rivastigmine against AChE and some of them also against BuChE. The most promising derivatives also fit physicochemical space and structural features for CNS drugs together with an escalated lipophilicity.

Organocatalytic Regioselective Synthesis of Sulfur-Containing N-Alkyl Carbamates from Alkyne-Derived Cyclic Carbonates

Organocatalytic Regioselective Synthesis of Sulfur-Containing N-Alkyl Carbamates from Alkyne-Derived Cyclic Carbonates

Amidation through carbamates

N-Alkyl carbamates of primary amines are easily converted into amides under treatment with Grignard reagents. Consequently, primary amines can be converted into amides in a one-pot reaction through carbamate protection and Grignard addition.

N to C Aryl Migration in Lithiated Carbamates: α-Arylation of Benzylic Alcohols

We report a new mode of reactivity displayed by lithiated O-benzyl carbamates carrying an N-aryl substituent: upon lithiation, the N-aryl group is transferred cleanly from N to C. An arylation of the carbamate results, providing a route to alpha,alpha-arylated secondary or tertiary alcohols. We also report density functional theory calculations supporting the proposal that arylation proceeds through a dearomatizing attack on the aromatic ring, a significantly lower energy pathway than the 1,2-acyl transfer observed with related N-alkyl carbamates.

The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors

A series of para-substituted phenolic N-alkyl carbamates were evaluated for their FAAH and MGL inhibitory activities. The compounds were generally selective for FAAH, with IC 50 values in the nM range, whereas inhibition of MGL required concentrations three orders of magnitude higher. The most potent compounds, dodecylcarbamic acid 4-(4,5-dihydrothiazol-2-yl)phenyl ( 12) and 4-(1,2,3-thiadiazol-4-yl)phenyl ( 26) esters, inhibited FAAH and MGL with IC 50 values at the low-nanomolar (IC 50s; 0.0063 and 0.012 μM) and the low-micromolar ranges (IC 50s; 2.1 and 1.0 μM), respectively. Compound 26 also inhibited both FAAH-dependent AEA uptake and AEA hydrolysis (IC 50; 0.082 μM) by intact RBL2H3 cells, and could also reduce 2-AG hydrolysis by these cells at concentrations ≥0.030 μM.

The Kinetics of Inhibition of Human Acetylcholinesterase and Butyrylcholinesterase by Two Series of Novel Carbamates

Controlled inhibition of brain acetyl- and butyrylcholinesterases (AChE and BChE, respectively) and of monoamine oxidase-B (MAO-B) may slow neurodegeneration in Alzheimer's and Parkinson's diseases. It was postulated that certain carbamate esters would inhibit AChE and BChE with the concomitant release in the brain of the OH-derivatives of rasagiline or selegiline that can serve as inhibitors of MAO-B and as antioxidants. We conducted a detailed in vitro kinetic study on two series of novel N-methyl, N-alkyl carbamates and compared them with rivastigmine, a known anti-Alzheimer drug. The rates of carbamylation (k(i)) and decarbamylation (k(r)) of recombinant human AChE were mainly determined by the size of the N-alkyl substituent and to a lesser extent by the nature of the leaving group. k(i) was highest when the alkyl was methyl, hexyl, cyclohexyl, or an aromatic substituent and lowest when it was ethyl. This suggested that k(i) depends on a delicate balance between the length of the residue and its degree of freedom of rotation. By contrast, presumably because of its wider gorge, inhibition of human BChE was less influenced by the size of the alkyl group and more dependent on the structure of the leaving group. The data show how the degree of enzyme inhibition can be manipulated by structural changes in the N-methyl, N-alkyl carbamates and the corresponding leaving group to achieve therapeutic levels of brain AChE, BChE, and MAO-B inhibition.

Dextran carbamates—materials for microencapsulation

Hydrophobic dextran- N-alkyl carbamates were synthesised as wall materials for microparticles with core/shell structure, using the hydrophilic indicator phenolphthalein as core material. The performance of the carbamates was possible by adding alkylisocyanates to the hydroxy-groups of the dextrans. The synthesises were carried out by using homogeneous reaction conditions with dimethyl sulfoxide (DMSO) as solvent. Two different average molecular weights of the dextrans (9900 and 505,000 g/mol), a theoretical degree of substitution (DS) of the carbamates, DS=2 and different alkyl chains with 7, 11 and 18 carbon atoms were chosen as structural features of the dextran carbamates. Both intrinsic viscosities and the solubility of the dextran derivatives in selected organic solvents were investigated. Additionally, the average molecular weights were analysed by gel permeation chromatography. The preparation of microparticles with core/shell structures was performed by a solvent evaporation technique. The release of phenolphthalein was analysed by suspending the particles in alkaline solution. The dependence of the described structural features on the releasing properties of the manufactured microparticles was discussed.

Efficient and Clean Synthesis of N‐Alkyl Carbamates by Transcarboxylation and O‐Alkylation Coupled Reactions Using a DBU—CO2 Zwitterionic Carbamic Complex in Aprotic Polar Media.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficient and clean synthesis of N-alkyl carbamates by transcarboxylation and O-alkylation coupled reactions using a DBU–CO 2 zwitterionic carbamic complex in aprotic polar media

N-Alkyl carbamates were obtained with good to excellent yields by clean and mild transcarboxylation of several amines with the previously synthesized DBU–CO 2 complex and subsequent O-alkylation. Transcarboxylation was found to be selective, as only carbamate was formed from 1-hydroxy-2-aminobutanol.

Catalytic synthesis of N-alkyl carbamates by methoxycarbonylation of alkylamines with dimethyl carbonate using Pb(NO 3) 2

Lead compounds such as Pb(NO 3) 2 are efficient catalysts for the methoxycarbonylation of aliphatic amines (RNH 2: R=C 3H 7, C 4H 9, and C 6H 13) with dimethyl carbonate. Butylamine and hexylamine were almost quantitatively converted into methyl N-butyl carbamate and methyl N-hexyl carbamate, respectively, at 393 K in 2 h, while 98% of propylamine was converted into methyl N-propyl carbamate with a 93% yield at 373 K in 2 h. By reduction of reaction temperature, butylamine was converted into methyl N-butyl carbamate with a 99% yield and a 98% selectivity at 313 K in 18 h. The effects of reaction variables were examined in the reaction of hexylamine with dimethyl carbonate.

Interfacial Energy and Adhesion between Acrylic Pressure Sensitive Adhesives and Release Coatings

The interfacial adhesive behavior between acrylic pressure sensitive adhesive-like networks (PSA-LNs) and poly(vinyl N-alkyl carbamate) release coatings was studied using a contact mechanical method and peel tests. Surface energy and interfacial energy were directly measured in JKR tests using a novel sample construction. The surface energy of the poly(vinyl N-alkyl carbamates) was found to be around 20 mJ/m2. Interfacial energies between PSA-LNs and the release coatings were found to be quite high – between 7 and 24 mJ/m2. Changes in adhesion dynamics were governed by acid-base interactions between the carbamate in the release coating and the acid groups in the PSA-LN. The length of the alkyl chain in the release coating moderated this effect. We also found a correlation between fundamental adhesion energy and peel strength. Examination of this phenomenon provides a basis for understanding the poor storage stability of PSA tapes made using alkyl carbamates and acid-containing PSAs.

An efficient one-pot synthesis of N-alkyl carbamates from primary amines using Cs 2CO 3

A facile one-pot synthesis of N-alkyl carbamates is described. A primary amine, CO 2, and an alkyl halide underwent a three-component coupling using cesium carbonate and tetrabutylammonium iodide (TBAI) giving rise to the resultant carbamate. In the presence of Cs 2CO 3, subsequent N-alkylation of the in situ generated carbamate with a different alkyl halide afforded various aliphatic N-alkyl carbamates, respectively.

Synthesis and in vitro/in vivo evaluation of novel oral N-alkyl- and N,N-dialkyl-carbamate esters of entacapone

Entacapone has a relatively low oral bioavailability which may, in part, be due to its low aqueous solubility at low pH and/or its hydrophilic character at neutral pH. Various novel N-alkyl and N,N-dialkyl carbamate esters of entacapone were synthesized as possible prodrugs of entacapone in order to increase its aqueous solubility at an acidic pH and to increase its lipophilicity at neutral pH. Oral bioavailability of entacapone and selected carbamate esters were investigated in rats. Both N-alkyl and N,N-dialkyl carbamate esters were relatively stable against chemical hydrolysis at pH 7.4 (t 1/2 = 14.9–20.7 h), but hydrolyzed rapidly (t 1/2 = 0.8–2.7 h) in human serum. However, in contrast to N-alkyl carbamates, N,N-dialkyl carbamates did not release entacapone in in vitro enzymatic hydrolysis (human serum) studies. N-Alkyl carbamates, 2a-c, showed increased aqueous solubility at pH 7.4, of which 2a and 2c also show increased aqueous solubility at pH 5.0, compared to entacapone. In addition to increased aqueous solubility, 2c showed increased lipophilicity at pH 7.4. However, two N-alkyl carbamates of entacapone did not increase the oral bioavailability of the parent drug in rats. Thus, it can be concluded that the relatively low lipophilicity of entacapone is not the cause of its low bioavailability.

Surface and Interfacial Structure of Release Coatings for Pressure Sensitive Adhesives I. Polyvinyl N-Alkyl Carbamates

Polyvinyl N-alkyl carbamates belong to the general class of long alkyl side chain polymers. Such polymers are commonly used as release coatings for pressure sensitive adhesive tapes. In this paper the bulk, surface, and interfacial structures of polyvinyl N-alkyl carbamates having either decyl or octadecyl side chains are examined. The bulk structures and thermal transitions were characterized using X-ray scattering and differential scanning calorimetry. Dynamic mechanical thermal analysis was used to investigate thermal transitions and rheology (i.e., segmental mobility) of the polyvinyl N-alkyl carbamates. The surface energies of polyvinyl N-alkyl carbamate coatings were determined using contact angle methods, while X-ray photoelectron spectroscopy and static secondary ion mass spectrometry were employed to characterize the near-surface compositional profiles of the coatings. The peel force provided by the polyvinyl N-alkyl carbamate coatings, as a function of aging time and temperature, was measured for a tape having an acrylic acid containing alkyl acrylate based pressure sensitive adhesive. The changes in peel force with aging time and temperature were related to the ability to maintain a stable interfacial structure between the PSA and polyvinyl N-alkyl carbamate coatings. Changes in the interfacial composition upon aging were characterized by comparing the surface compositions of the PSA and polyvinyl N-alkyl carbamate coatings initially, prior to contact, as well as after aging and peeling them apart. The increase in peel force upon aging can be attributed, in large part, to a restructuring at the PSA/polyvinyl alkyl carbamate interface. Energetically favorable acid-base interactions between the basic urethane and acetate groups in the polyvinyl alkyl carbamates and the acrylic acid groups in the PSA provide a driving force for the restructuring. If the segmental mobility within the polyvinyl alkyl carbamate is sufficient, restructuring can occur, leading to increased concentrations of these groups at the PSA/polyvinyl alkyl carbamate interface, resulting in higher attractive forces and greater adhesion. The propensity for the polyvinyl N-alkyl carbamate coatings to restructure upon contact with a polar medium was also characterized by monitoring the receding contact angle of water, as a function of water contact time and temperature. A good correlation is seen between the ability of the polyvinyl alkyl carbamate coatings to provide a low peel force for the acrylate PSA tape and the ability of the coatings to maintain a high water receding contact angle.

N-Pentafluorosulfanyl-N-nitro carbamates

Unlike N-alkyl carbamates, N-pentafluorosulfanyl carbamates (SF 5NHCO 2R) did not readily undergo nitration to provide the N-NO 2 derivatives. Although trifluoroacetyl nitrate did provide nitration, work-up yielded a mixture of SF 5N(NO 2)CO 2R and starting material. The ratio of nitration product to starting material was not changed after prolonged reaction times and the N-NO 2 product was stable to the work-up conditions. A rationale for these results as well as the effect of varying R is discussed.

The relationship between chemical structure and the in vivo metabolism of an homologous series of n-alkyl carbamates.

The metabolism and pharmacokinetics of carbonyl [14C] labelled ethyl, n-butyl, n-hexyl and n-octyl carbamates has been examined in rats after oral and intravenous administration. Hydrolysis of the carbamate group was a major metabolic fate, particularly of the more water soluble carbamates. Conversely, with increasing lipophilicity increasing amounts of omega-1 oxidation products were found both in plasma and urine. The plasma pharmacokinetic data could not be explained by a simple bi-exponential model, ethyl carbamate in particular showing unexpectedly persistent blood levels. A model has been proposed to explain the pharmacokinetic data for ethyl, n-butyl, n-hexyl and n-octyl carbamates. The essential features of this model are that carbamate is thought not to be in equilibrium between the peripheral and central compartment and that hydrolytic metabolism takes place in the peripheral compartment while oxidative metabolism to urinary metabolites occurs in the central compartment.

The relationship between binding to cytochrome P-450 and metabolism of n-alkyl carbamates in isolated rat hepatocytes

The binding constants of an homologous series of n-alkyl (C 2-C 10) carbamates ▪ to the cytochrome P-450 of suspensions of isolated, viable rat hepatocytes have been measured. All the carbamates except ethyl and propyl carbamate produced type I difference spectra and their binding affinities (1/ K s ) were found to be directly dependent upon their lipophilicity. These binding affinities were similar to those determined in rat liver microsomes. Maximum development of the binding spectrum in hepatocytes was always within one second of the addition of each carbamate, indicating that for these carbamates membrane permeability was not rate limiting for access to, and metabolism by, cytochrome P-450 and that much of the cells' cytochrome P-450 was unoccupied by endogenous substrates. The major metabolites of C 4-C 8 carbamates were unconjugated ω-1 oxidation products. Below hexyl carbamate only the ω-1 hydroxylated metabolite was observed but for the more lipophilic carbamates the keto metabolite was also a major product. The same products were found in blood after i.p. dosing of rats with hexyl carbamate. A direct relationship was observed between the affinity constant of the carbamate for cytochrome P-450 and the total rate of oxidative metabolism in the ω-1 position. Hydrolysis of the carbamate group was a minor metabolic pathway in contrast to the in vivo situation.

Rapid absorption from the urinary bladder of a series of n-alkyl carbamates: a route for the recirculation of drugs.

1 The rate of loss of a series of n-alkyl carbamates from the lumen of the urinary bladders of female rats has been studied. 2 The rate of loss obeys first order kinetics and was not affected by water flux across the bladder wall nor by binding of the carbamates to it. 3 The rate of loss of octyl carbamate was reduced by about 76% by the presence of 5% Tween 80. Histological evidence indicates that this may be due to the formation of a thin luminal lining which may be adsorbed Tween 80 or mucopolysaccharide material. 4 The absorption rate of the carbamates was limited by their hydrophilicity but reached a plateau for the more lipophilic homologues with a half life for loss of approximately 10 min. 5 The implications of these results with regard to the recirculation of unmetabolized drugs and hydrolysed conjugates of drugs, the systemic absorption of intravesically applied cancer chemotherapeutic agents and bladder wall permeability to carcinogens are discussed.