Ethylamine Derivatives Research Articles

Application of thin-layer chromatographic data in quantitative structure–activity relationship assay of thiazole and benzothiazole derivatives with H 1-antihistamine activity. I

A quantitative structure–activity relationship analysis of H 1-antihistamine activity and chromatographic data of 2-[2-(phenylamino)thiazol-4-yl]ethanamine; 2-(2-benzyl-4-thiazolyl)ethanamine; 2-(2-benzhydrylthiazol-4-yl)ethylamine derivative; 2-(1-piperazinyl- and 2-(hexahydro-1 H-1,4-diazepin-1-yl)benzothiazole derivatives was made. The RP2 thin-layer chromatography (TLC) plates (silica gel RP2 60F 254 silanised precoated), impregnated with solutions of selected amino acid mixtures ( l-Asp, l-Asn, l-Thr and l-Lys), were used in two developing solvents as hH1R antagonistic interaction models. Using regression analysis, the relationships between chromatographic and biological activity data were found. The correlations obtained in regression analysis for the examined thiazole and benzothiazole derivatives with H 1-antihistamine activity [pA 2(H 1)] represent their interaction with all the proposed biochromatographic models (S1–S7). Some of the calculated equations can be applied to predict the pharmacological activity of new drug candidates. The best multivariate relationships useful in predicting the pharmacological activity of thiazole and benzothiazole derivatives were obtained under the condition of experiment with RP2 TLC plates using the developing solvent acetonitrile–methanol–buffer (40:40:20, v/v). The log P values of particular compounds are extremely important for this kind of activity.

Analysis of benzene ethylamine derivatives in urine using the programmable dynamic liquid-phase microextraction (LPME) device.

An automated LPME device for a dynamic LPME method was manufactured and its extraction efficiency was tested using spiked urine samples. The developed home-made LPME device was a programmable automated syringe dispenser to overcome deteriorating precision and difficulties in manually manipulating the plunger repeatedly. To establish the optimum parameters for benzene ethylamines, the effects of sampling volume, solvent volume, pH, salt-effect, choice of solvents, plunger speed, and number of samplings were investigated. Good repeatabilities for the extraction of mephentermine, ephedrine, methoxyphenamine, selegiline, and bupropion were obtained and the RSD values were 2.4, 1.9, 1.3, 1.6 and 1.5% at a concentration of 3 microg mL(-1) in spiked urine samples, respectively. The limit of detection was below 0.05 microg mL(-1) for the investigated drugs. This developed device for LPME analysis gave good validation results and improved convenience.

Radical polyaddition reaction of bis(α-trifluoromethyl-β,β-difluorovinyl) terephthalate with ethylamine compounds

In order to develop the radical polyaddition of bis(α-trifluoromethyl-β,β-difluorovinyl) terephthalate [CF 2C(CF 3)OCOC 6H 4COOC(CF 3)CF 2] (BFP) with 1,4-dioxane, the polyaddition of BFP with ethylamine derivatives was investigated. Prior to preparation of polymers, the model reactions, 2-benzoxypentafluoropropene [CF 2C(CF 3)OCOC 6H 5] (BPFP) with several ethylamine compounds, were examined to discover the proper polyaddition reaction condition. A 3:1 addition product was yielded by the reaction of BPFP with triethylamine in the presence of benzoyl peroxide or 2,2′-azobisisobutyronitrile at 60 °C for 24 h. The reaction of BPFP with diethylaniline afforded no addition products. Polyaddition of BFP with triethylamine was investigated to afford soluble polymers possessing triethylamine moiety in main chain. The highest molecular weight obtained was M n=6.3×10 3. The reaction turned out to take place mainly at methylene groups of triethylamine.

Oxo-transfer reaction from a bis(mu-oxo)dicopper(III) complex to sulfides.

Oxygenation of sulfides to the corresponding sulfoxides by a distinct bis(mu-oxo)dicopper(III) complex has been accomplished for the first time using 2-(2-pyridyl)ethylamine derivative L(Py1Bz) (N-ethyl-N-[2-(2-pyridyl)ethyl]-alpha,alpha-dideuteriobenzylamine) as the supporting ligand. Detailed kinetic analysis has indicated that the reaction consists of two distinct steps, where the first quick process is association of the substrate to the bis(mu-oxo)dicopper(III) complex (k(1)) and the second slow process is intramolecular oxygen atom transfer from the copper-oxo species to the substrate in the associated complex (k(2)). The rate constant k(2) of the second process is rather insensitive to the oxidation potential of the substrates, suggesting that the oxo-transfer reaction proceeds via a mechanism involving direct oxygen atom transfer rather than a mechanism involving electron transfer.

New Chiral Kemp's Acid Diamides for Chiral Amine Recognition by 1 H NMR

Two Kemp's acid diamides were synthesized and applied to chiral amine recognition using 1H NMR analysis. One derivative based on 1-(1-naphthyl)ethylamine had good chiral recognition of six amines and was useful to determine the optical purity for three amines, i.e., methylbenzylamine, 1-(1-naphthyl)ethylamine and 1- henylpropylamine,however, the cyclohexylethylamine derivative showed little discrimination for the amines studied. Together with the results for alkylamines, it was shown that aromatic structure was important for aromatic shielding anisotropy and π––π interactions between host and guest. The structure of the 1-(1-naphthyl)ethylamine derivative in solution was also considered based on 1H NMR data and computer simulation.

Preparation and crystal structures of trans-bis(imidato)bis(1,2-diphenylethylamine)copper(II) complexes (imidato=5,5-diphenylhydantoinato and succinimidato). Particular boundary cases of coordination geometry and monodentate ligand conformation.

Two new copper(II) complexes, trans-[Cu(phent) 2( R-diphenea)( S-diphenea)]·2CHCl 3 ( 1) and trans-[Cu(succim) 2( R-diphenea)( S-diphenea)] ( 2) (phent=5,5-diphenylhydantoinate, succim=succinimidate, and diphenea=1,2-diphenylethylamine) were prepared and crystal structures were determined. Nevertheless both complexes have the same diphenea ligands, 1 affords a distorted square planar [CuN 4] coordination with imidate and amine trans-NCuN bond angles 156.6(2) and 161.4(2)°, while 2 affords a square planar [CuN 4] coordination with both trans-NCuN bond angle 180.0°. Complex 2 was the first example of square planar [CuN 4] complexes with 1-phenyl substituted ethylamine derivatives. Structural features are compared among 1, 2, and previously reported distorted square planar trans-[Cu(phent) 2( R-phenea)( S-phenea)] ( 3) and trans-[Cu(succim) 2( R-phenea)( S-phenea)] ( 4) (phenea=1-phenylethylamine) complexes. The structural features suggest that the [CuN 4] coordination environment of 1 is distorted by particular edge-to-face arrangement of phenyl groups of amines and imidates which reasonably corresponds to the most and the second stable conformation of diphenea ligands with respect to rotation of two phenyl groups.

Synthesis and cytotoxicity of gossypol related compounds

Gossypol, gossypolone, reduced gossypol and new Schiff’s bases of racemic gossypol and gossypolone were extracted or synthesized. Their cytotoxic activities on KB human cancer cells were determined. Gossypolone and the ethylamine derivative of gossypolone were the most active compounds (IC 50 in the micromolar range in both cases). The cytotoxicity of gossypol and gossypolone was increased when the tests were performed in the absence of serum and decreased when catalase as well as mannitol were added to the culture medium.

Synthesis of 1,2-benzisothiazole derivatives and investigation of their putative histaminergic activity

Some new 2-(1,2-benzisothiazol-3-yl)ethylamine derivatives were synthesised and their putative histaminergic activity was investigated in in vitro gastrointestinal and cardiac preparations. In the isolated guinea pig duodenum, all the compounds induced a tetrodotoxin- and atropine-sensitive contractile activity, which was minimally affected by mepyramine in the case of the compound 2-(1,2-benzisothiazol-3-yl)ethylamine. In the same tissue, all the compounds were devoid of any H 3 receptor agonistic or antagonistic activity, but caused a nicotinic and/or 5-HT 3 receptor activation. None of these compounds induced any histamine H 2 agonistic or antagonistic activity in the isolated guinea pig gastric mucosa or in the isolated papillary muscle. On this latter substrate, the compound N, N, N-trimethyl-2-(1,2-benzisothiazol-3-yl)ethylammonium iodide induced a positive inotropic activity, apparently due to a release of catecholamines. These results demonstrate the substantial inability of 1,2-benzisothiazole derivatives to interact with histamine receptors in functional tests. These compounds, however, possess gangliomimetic properties, related to the activation of 5HT 3 and/or nicotinic receptors.

Synthesis and SAR of 1-alkyl-2-phenylethylamine derivatives designed from N,N-dipropyl-4-methoxy-3-(2-phenylethoxy)phenylethylamine to discover sigma(1) ligands.

The synthesis and structure-activity relationships (SAR) of 1-alkyl-2-phenylethylamine derivatives 5-8 designed from N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride (1, NE-100) are presented. The SAR between compound 1 and 1-alkyl-2-phenylethylamine derivatives suggested that the alkyl group on the 1-position carbon of 2-[4-methoxy-3-(2-phenylethyl)phenyl]ethylamine derivatives played the role of one of the propyl groups on the aminic nitrogen of compound 1. (-)-N-Propyl-1-butyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylam ine hydrochloride ((-)-6d, NE-537) and (-)-N-propyl-1-(3-methybutyl)-2-[4-methoxy-3-(2-phenylethoxy )phenyl]e thylamine hydrochloride ((-)-6i, NE-535), typical compounds in this series, have potent and selective sigma(1) affinity.

Identification of amino acid residues contributing to the pore of a P2X receptor.

P2X receptors are ion channels opened by extracellular ATP. The seven subunits currently known are encoded by different genes. It is thought that each subunit has two transmembrane domains, a large extracellular loop, and intracellular N- and C-termini, a topology which is fundamentally different from that of other ligand-gated channels such as nicotinic acetylcholine or glutamate receptors. We used the substituted cysteine accessibility method to identify parts of the molecule that form the ionic pore of the P2X2 receptor. Amino acids preceding and throughout the second hydrophobic domain (316-354) were mutated individually to cysteine, and the DNAs were expressed in HEK293 cells. For three of the 38 residues (I328C, N333C, T336C), currents evoked by ATP were inhibited by extracellular application of methanethiosulfonates of either charge (ethyltrimethylammonium, ethylsulfonate) suggesting that they lie in the outer vestibule of the pore. For two further substitutions (L338C, D349C) only the smaller ethylamine derivative inhibited the current. L338C was accessible to cysteine modification whether or not the channel was opened by ATP, but D349C was inhibited only when ATP was concurrently applied. The results indicate that part of the pore of the P2X receptor is formed by the second hydrophobic domain, and that L338 and D349 are on either side of the channel 'gate'.

Enantioselective Hydrogenation of Ethyl Pyruvate over Pt/Alumina Modified by (R)-1-(1-Naphthyl)ethylamine Derivatives

A new chiral modifier, (R)-1-(1-naphthyl)ethylamine, has been tested in the enantioselective hydrogenation of ethyl pyruvate to ethyl lactate over 5 wt% Pt/Al2O3. The influence of catalyst (2–28 g liter−1) and modifier concentration (0–20 mM), temperature (282–333 K), pressure (1–75 bar), and solvents was studied in a slurry reactor. The 82% enantiomeric excess (ee) at full conversion was achieved in acetic acid after optimizing the reaction parameters. Under mild conditions the new modifier affords ee's better than that achieved with cinchona alkaloids. A drop in ee at pressures higher than 10 bar and temperatures above 288 K is attributed to partial hydrogenation of the naphthalene ring, which hinders the adsorption of the modifier parallel to a flat Pt surface. Maximum rate acceleration by a factor of 12, compared to the racemic reaction, was observed after thermal treatment of the catalyst in flowing hydrogen at 673 K, followed by aerobic treatment at 273–298 K in acetic acid. It is shown that naphthylethylamine is only a precursor of the actual modifier, which is a secondary amine formedin situfrom naphthylethylamine and ethyl pyruvate by condensation to the corresponding imine and subsequent reduction of the C=N bond. Several other derivatives of naphthylethylamine were prepared by reductive alkylation and tested as modifiers. The results indicate that the presence of an oxygen function such as a hydroxy or methoxy group, as in previously used modifiers, is not an indispensable requirement for obtaining high ee in the hydrogenation of α-ketoesters.

Effects of 2-(3,4-dimethoxyphenyl)ethylamine derivative (ecabapide, DQ-2511) and its metabolites on water-immersion restraint stress-induced gastric ulcers in rats

Ecabapide (DQ-2511) has been demonstrated to be effective in preventing water-immersion restraint stress ulceration of rats. In the present study, we aimed to define the active molecular features of ecabapide. Seven of 9 degraded materials identified as ecabapide metabolites were synthesized and their antiulcer activities were compared with that of the parent compound. Ecabapide was potent to prevent gastric ulcer formation at the doses of 30-300 mg/kg i.p. Three metabolites (V, VIII and IX) were also active to inhibit ulceration induced by the stress. The antiulcer activity of IX was similar to that of ecabapide, whereas V and VIII had less activities. After the oral administration of ecabapide, the plasma levels of IX reached to less than 15% of that of ecabapide and also IX was largely excreted into the feces. Therefore, the potential implication of the metabolite (IX) as the active component in the antiulcer effect of ecabapide could be excluded. Furthermore, it is also unlikely that the high polar metabolites (IV and VII) are implicated in significant contribution for antiulcer action. In conclusion, we have shown that ecabapide prevents water-immersion restraint stress-induced gastric ulcers, and that this activity is probably mediated by the action of the parent compound.

Preliminary Preformulation Studies of a 2-(3,4-Dimethoxyphenyl)ethylamine Derivative for Oral Administration at an Exploratory Stage of New Drug Development.

Preliminary preformulation studies of a 2-(3,4-dimethoxyphenyl)ethylamine derivative were investigated. The hydrochloride form showed incompatibility with the excipients used for oral dosage forms. There were several crystal forms of the free base, namely, alpha-anhydrate, beta-anhydrate, monohydrate, and trihydrate. The trihydrate form was unstable. The degree of crystallinity of the beta-anhydrate form was difficult to control. The monohydrate form was difficult to manufacture with constant quality. The serum levels of the compounds in rats were almost related to the dissolution rates in the JP 1st disintegration medium from the discs. The serum level of alpha-anhydrate was the lowest. However, the dissolution rates from the formulations of alpha-anhydrate were improved. After oral administration of the improved formulation, the serum level of alpha-anhydrate in beagle dogs was almost triple that after the oral administration of the capsule of the hydrochloride form.

Preparation and Utilization of Some lon‐Exchange Starches

AbstractFive types of cationic starches were prepared via reacting methylolated poly (acrylamide)‐starch graft copolymer with different aminating agents. These aminating agents include ammonia, ethylamine, diethylamine, triethylamine and ethylene diamine. The different factors affecting these reactions were investigated. These factors include liquor ratio, amine / methylol molar ratio, type of aminating agent, reaction duration and temperature. The amination extent and amination reaction efficiency % were traced by estimating the nitrogen content of the aminated starches. Characterization of the prepared cationic starches such as solubility, anion‐exchange capacity, heavy metal anion removal, and metal ions sorption were studied. Heavy metal anion removal efficiency % depends on the cationic starch used as well as the removed anion. The removal efficiency % of dichromate anion > removal efficiency % of ferricyanide anion irrespective the cationic starch used. The removal efficiency % of both anions follow the order: ammonia derivative > triethylamine derivative > ethyl amine derivative > ethylene diamine derivative > diethyl amine derivative.The metal ion sorption behaviour of the cationic starches follow the order: Pb++ > Cd++ > Zn++ > Cu++ > Co++The sorption efficiency % of any metal ion depends on the used cationic starch. The sorption efficiency % of all metal ions on different cationic starches follow the order: ammonia derivative > triethylamine derivative > ethylamine derivative > ethylene diamine derivative > diethylamine derivative. The prepared cationic starch bearing primary amino group acquires the highest metal ion sorption efficiency % irrespective the sorbed metal ion.

Synthesis and cholinergic properties of N-aryl-2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamino analogs of ranitidine.

A series of N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamino analogs of the H2-antagonist, ranitidine, was synthesized and the abilities of the compounds to alleviate the cholinergic deficit characteristic of Alzheimer's disease evaluated. The compounds were initially tested for their ability to inhibit human erythrocyte acetylcholinesterase activity in vitro. Selected compounds were further evaluated for butyrylcholinesterase inhibition, M1 and M2 cholinergic receptor binding, potentiation of ileal contractions, and the ability to elevate brain acetylcholine levels in mice. The analogs were compared to tetrahydroaminoacridine and to a recently reported series of bis-[[(dimethylamino)methyl]furans]. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamine derivatives were generally comparable to tetrahydroaminoacridine and the bis[[(dimethylamino)methyl]furans] in acetylcholinesterase inhibition, M1/M2 receptor binding, and the potentiation of ileal contractions, while being more potent inhibitors of acetylcholinesterase than butyrylcholinesterase. The 4-nitro-3-pyridazinyl analog, 26, was notable in demonstrating a potent and selective binding to the M2 receptor, with an M2 IC50/M1 IC50 of 0.060. Compounds in which the substituents on the dinitro-N-aryl moiety were relatively small were the best at inhibiting acetylcholinesterase in vitro. The N-aryl-2-[[[5-[(dimethylamino)methyl]-2- furanyl]methyl]thio]ethylamines in general, and those with small N-aryl substituents in particular, were superior to the bis[[(dimethylamino)methyl]furans] in elevating brain ACh levels in mice, probably due to enhanced distribution into the CNS. The 1,5-difluoro-2,4-dinitrophenyl analog, 8, resulted in the largest elevation in brain acetylcholine levels, affording a 53% increase at 88 mg/kg.

Syntheses of 2-(3,4-dimethoxyphenyl)ethylamine derivatives and their antiulcer activities.

A series of acyl derivatives of 2-(3,4-dimethoxyphenyl)ethylamine (4) were synthesized and evaluated for their effectiveness to prevent water-immersion stress-induced gastric ulceration when given intraperitoneally to rats. Among them N-[2-(3,4-dimethoxyphenyl)ethyl]-2-phenylaminoacetamide hydrochloride (15) had significant antiulcer activity. Further modification of the four parts of 15 revealed that only the introduction of a carbamoyl group into 2- or 3-position of the phenylamino part gave compounds (49-51, 54 and 55) which retained antiulcer activity comparable to the lead compound. However, the compounds (49-51 and 54) did not exert a prophylactic effect when administered orally except for the 3-substituted bezamide derivative 55. Alkyl substitution on the nitrogen of benzamide gave 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl] amino-N-methylbenzamide (66, DQ-2511) and the related compounds (67, 70, 74 and 77) which all had potent antiulcer activities at oral doses of 50-400 mg/kg.

Preparation and Characterization of Anion‐Exchange Starches

AbstractTreatment of poly (glycidyl methacrylate (GMA))‐starch graft copolymer containing 270 m.eq.epoxy groups/100 g sample with ethylenediamine was carried out under different conditions. Results indicated that three reactions are likely to occur during this treatment, namely amination, crosslinking and hydrolysis. The highest amine content could be achieved upon using amine/epoxy molar ration of 2.5 and material to liquor ratio 1:3, at 90°C for 180 min. The dependence of the amination percent on the type and nature of the amine was also studied. The values of amination percent for the different types of amine follows the order: O‐phenylene‐diamine > m‐phenylenediamine > p‐phenylenediamine > ethylenediamine; whereas studying the nature of the amine brings about the order: diethylamine derivative > ethylamine derivative > ethanolamine derivative > triethylamine derivative. Evaluation of the different reaction products (aminated copolymers) for their anion exchange properties was made. The capacity of the anion exchangers relied on the inital epoxy content of the copolymer and type and nature of the amine used. On the other hand, heavy metal anions and dye removal efficiency followed the order: diethylamine derivative > ethylenediamine derivative > triethylamine derivative > p‐phenylenediamine > derivative > ethylamine derivative. The pH‐metric titration curves revealed that triethylamine derivative behaves as a strong base while the other exchangers as weak bases. Other properties such as pKb value, durability, solubility, etc. indicated that the synthesized products can be regarded as anion exchangers with acceptable properties.

2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity

A series of 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives was examined for the ability to inhibit both rat brain imipramine receptor binding and the synaptosomal uptake of norepinephrine (NE) and serotonin (5-HT). Neurotransmitter uptake inhibition was highest for a subset of 2-phenyl-2-(1-hydroxycyclohexyl)dimethylethylamines in which the aryl ring has a halogen or methoxy substituent at the 3- and/or 4-positions. Potential antidepressant activity in this subset was assayed in three rodent models--the antagonism of reserpine-induced hypothermia, the antagonism of histamine-induced ACTH release, and the ability to reduce noradrenergic responsiveness in the rat pineal gland. An acute effect seen in the rat pineal gland with several analogues, including 1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol (23) and 1-[2-(dimethylamino)-1)-(4-methoxyphenyl)ethyl]cyclohexanol (4), was taken as a possible correlate of a rapid onset of antidepressant activity. Compound 4 (venlafaxine) is presently undergoing clinical evaluation.

ChemInform Abstract: trans‐1‐(4‐Phenylcyclohexyl)ethylamine Derivatives with Antidepressant Activity. Part 2.

AbstractStarting with the acetylphenylcyclohexane (I), the p‐substituted arylcyclohexylamines (II) are synthesized by known methods.

ChemInform Abstract: Synthesis and Oxidation of 2‐(2,5‐Dihydroxyphenyl)‐ethylamine Derivatives. Part 2.

AbstractCatalytic oxidation of the title ethylamine derivatives (IV), (VIII) and (X) yields the indole (V) and the indolines (IX) and (XI), respectively.