Trisubstituted Urea Research Articles

One pot, three component synthesis of fluoro and trifluoromethyl substituted unsymmetrical dihydropyrazine fused acridine-3-carboxamide using renewable 2-MeTHF solvent and their DFT studies

Six novel unsymmetrical trisubstituted urea derivatives were synthesized, characterised and their DFT studies were reported in this present work. 1,1′-carbonyldiimidazole (CDI) was used to generate carbonyl functional group of unsymmetrical urea by employing non-hazardous, renewable 2-MeTHF solvent. Excellent yields of unsymmetrical urea (90-95%) and higher purities of the products (>97%) were achieved under slow addition of a solution of 1.5 equivalent of CDI in 2-MeTHF to a pre-dissolved solution of 1.0 equivalent of fluoro or trifluoromethyl substituents containing aniline and 1.0 equivalent of dihydropyrazine fused acridine in 2-MeTHF at room temperature. Column chromatographic purification is not required in this methodology. DFT studies were carried for all six novel products.

Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity.

Strontium ranelate, a drug approved and until recently used for the treatment of osteoporosis, mediates its effects on bone at least in part via the calcium-sensing (CaS) receptor. However, it is not known whether bone-targeted CaS receptor positive allosteric modulators (PAMs; calcimimetics) represent an alternative (or adjunctive) therapy to strontium (Sr2+ o ). We assessed three structurally distinct calcimimetics [cinacalcet, AC-265347 and a benzothiazole tri-substituted urea (BTU-compound 13)], alone and in combination with extracellular calcium (Ca2+ o ) or Sr2+ o , in G protein-dependent signalling assays and trafficking experiments in HEK293 cells and their effects on cell differentiation, tartrate-resistant acid phosphatase (TRAP) activity and hydroxyapatite resorption assays in human blood-derived osteoclasts. Sr2+ o activated CaS receptor-dependent signalling in HEK293 cells in a similar manner to Ca2+ o , and inhibited the maturation, TRAP expression and hydroxyapatite resorption capacity of human osteoclasts. Calcimimetics potentiated Ca2+ o - and Sr2+ o -mediated CaS receptor signalling in HEK293 cells with distinct biased profiles, and only cinacalcet chaperoned an endoplasmic reticulum-retained CaS mutant receptor to the cell surface in HEK293 cells, indicative of a conformational state different from that engendered by AC-265347 and BTU-compound 13. Intriguingly, only cinacalcet modulated human osteoclast function, reducing TRAP activity and profoundly inhibiting resorption. Although AC-265347 and BTU-compound 13 potentiated Ca2+ o - and Sr2+ o -induced CaS receptor activation, they neither replicated nor potentiated the ability of Sr2+ o to inhibit human osteoclast function. In contrast, the FDA-approved calcimimetic, cinacalcet, inhibited osteoclast TRAP activity and hydroxyapatite resorption, which may contribute to its clinical effects on bone mineral density LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.

The role of non-covalent interactions in the self-healing mechanism of disulfide-based polymers.

In this work, a theoretical protocol based on classical molecular dynamics has been defined, in order to study weak non-covalent interactions in diphenyl disulfide based compounds. This protocol is then used to study the influence of hydrogen bonds and π-π stacking in four selected cases, namely, monosubstituted and amine ortho trisubstituted urea and urethane-based diphenyl disulfides. In all cases, it has been observed that hydrogen bonds are much more relevant than π-π stacking, which has little influence. In addition, hydrogen bonds are the responsible to maintain the polymeric chains close, so that the disulfides may reach the reacting region, even in urethane-based materials, where the lower amount of hydrogen bonds formed make the chains more flexible and mobile. Combining the results obtained by classical molecular dynamics with those obtained earlier by means of quantum mechanics, we conclude that there are two main factors that are relevant to the self-healing properties of disulfide-based materials: firstly, the capacity to generate sulfenyl radicals by breaking the disulfide S-S bond and, secondly, the ability of these radicals to attack neighboring disulfides. The former is dominated by the bond dissociation energy of the S-S bond, while the latter is strongly influenced by two other factors. On the one hand, the hydrogen bonding interactions established between chains, and on the other, the energy barriers for the attack of sulfur radicals to neighbor disulfides. We have defined three new parameters to estimate the influence of these features, with the aim of predicting the self-healing capacity of disulfides and related materials, which will help experimentalists in the development of improved materials.

Discovery of 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase inhibitors and orally active drug candidates for treating of chronic kidney diseases

We identified 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted ureas as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating chronic kidney diseases. Compound 19 exhibited excellent sEH inhibitory activity and bioavailability. When administered orally at 30mg/kg, 19 lowered serum creatinine in a rat model of anti-glomerular basement membrane glomerulonephritis but 2,8-diazaspiro[4.5]decane-based trisubstituted ureas did not. These results suggest that 19 is an orally active drug candidate for treating chronic kidney diseases.

Discovery of 2,8-diazaspiro[4.5]decane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase inhibitors and orally active drug candidates for treating hypertension

We identified 2,8-diazaspiro[4.5]decane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating hypertension. Docking studies using human and murine sEH X-ray crystal structures revealed steric hindrance around the side chain of Phe406 of murine sEH. The trifluoromethyl moiety (11) was replaced with a trifluoromethoxy moiety (12) to prevent steric clash, and improved murine sEH inhibitory activity was observed. The oral administration of 12, 20, and 37 at a dose of 30mg/kg reduced blood pressure in spontaneously hypertensive rat, but had little effect on blood pressure in normotensive rat.

New potent calcimimetics: I. Discovery of a series of novel trisubstituted ureas

Starting from Fendiline and R-568, we identified a novel series of urea compounds as positive allosteric modulators of the calcium sensing receptor (CaSR), as part of a program to identify novel therapeutics for secondary hyperparathyroidism. Initially identified disubstituted ureas were converted to trisubstituted urea lead 20e, which was further modified to increase in vivo potency. Replacing a carbomethoxy substituent by various bioisosteres led to compound 46 which exhibited potent in vitro and in vivo activity after oral administration.

Hindered Ureas as Masked Isocyanates: Facile Carbamoylation of Nucleophiles under Neutral Conditions

Hindered Ureas as Masked Isocyanates: Facile Carbamoylation of Nucleophiles under Neutral Conditions

Discovery of 3,3-disubstituted piperidine-derived trisubstituted ureas as highly potent soluble epoxide hydrolase inhibitors

3,3-Disubstituted piperidine-derived trisubstituted urea ent A-2b was discovered as a highly potent and selective soluble epoxide hydrolase (sEH) inhibitor. Despite the good compound oral exposure, excellent sEH inhibition in whole blood, and remarkable selectivity, compound ent A-2b failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This observation further challenges the premise that sEH inhibition can provide a viable approach to the treatment of hypertensive patients.

Three-component condensation of α-nitroacetophenone, aromatic aldehydes, and methylurea

The three-component condensation of aromatic aldehydes, methylurea, and α-nitroacetophenone affords both N(1)-and N(3)-methyl-substituted 4,6-diaryl-5-nitro-3,4-dihydropyrimidin-2(1H)-ones depending on the structure of aldehyde. Intermediate 4,6-diaryl-4-hydroxy-3-methyl-5-nitrohexahydropyrimidin-2-ones and trisubstituted urea, which is the transformation product of the 4-hydroxy-3-methyl derivative in an acidic medium (retro-Henry reaction), were identified in the reaction mixtures.

Hydroxymethylation and polycondensation reactions in urea–formaldehyde resin synthesis

AbstractFormaldehyde–urea (F/U) reaction products with molar ratios of 1.8, 2.1, and 2.4 were synthesized at pH 8.3, and the last one also at pH 4.5 using 45% formaldehyde aqueous solution. For obtaining the resin, the synthesis of F/U 2.1 was continued by acid‐catalyzed condensation at pH 4.5 and posttreatment with second part of U (F/U 1.05/1) at 70°C and pH 8.3. The products were analyzed using 13C‐NMR spectrometry. Higher excess of F increases the dihydroxymethyl content on account of smaller dimethylene ether content. Certain 13C chemical shifts in carbonyl and methylene region of spectra were assigned to trishydroxymethylurea, being the main trisubstituted urea compound in hydroxymethylated product. Acid catalyst promotes the formation of methylene groups by polycondensation of hydroxymethyl groups, against the background of similar content of dimethylene ethers in both catalytic conditions. The ratio of linear/branched chains is emphasized in characterizing the resin structure. Higher hydroxymethyl content in acid‐catalyzed polycondensation is an advantage of three‐step synthesis technology. The amount of binding methylene and dimethylene ether groups linked only to secondary amino groups can be increased by transhydroxymethylation with subsequent polycondensation in posttreatment with U in suitable reaction conditions. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 1673–1680, 2006

Development of an efficient strategy for the synthesis of the ET B receptor antagonist BQ-788 and some related analogues

BQ-788 [ N- cis-2,6-dimethylpiperidine-1-carbonyl- l-γ-methylleucyl- d-1-methoxycarbonyltryptophanyl- d-norleucine sodium salt] is a very potent and selective ET B receptor antagonist. The formation of the highly hindered trisubstituted urea functionality in the peptide chain and the carbamination on the indole nitrogen of the tryptophan side chain are major challenges in the synthesis of this particular antagonist. Furthermore, the high cost of the unnatural amino acids in the sequence of BQ-788 and its reported synthesis render this pseudopeptide very expensive to produce. In order to improve the yield and to reduce the number of steps compared to previous reported syntheses, we developed an efficient strategy involving a novel one-pot procedure for the synthesis of a highly hindered trisubstituted urea. Under very mild conditions, the urea was obtained by using triphosgene and sodium iodide. This strategy allowed us to synthesize BQ-788 in seven steps with an overall yield of 53%. We also generalized the use of this powerful methodology by creating some new structural analogues of the cis-2,6-dimethylpiperidine moiety by replacing it with other bulky secondary amines. We evaluated the antagonist properties of those three new analogues of BQ-788 in two bioassays in vitro. These new antagonists were less potent than BQ-788 in an ET B rich preparation and inactive in an ET A rich preparation.

Synthesis and characterization of new polyureas based on 4‐(4′‐aminophenyl)urazole and various diisocyanates

Abstract4‐(4′‐Aminophenyl)urazole (AmPU) was prepared from 4‐nitrobenzoic acid in six steps. The reaction of monomer AmPU with n‐isopropylisocyanate was performed in N,N‐dimethylacetamide solutions at different ratios, and the resulting disubstituted and trisubstituted urea derivatives were obtained in high yields and were finally used as models for polymerization reactions. The step‐growth polymerization reactions of AmPU with hexamethylene diisocyanate, isophorone diisocyanate, and toluene‐2,4‐diisocyanate were performed in N‐methylpyrrolidone solutions in the presence of pyridine as a catalyst. The resulting novel polyureas had inherent viscosities of 0.11–0.18 dL/g in dimethylformamide at 25°C. These polyureas were characterized with IR, 1H‐NMR, elemental analysis, and thermogravimetric analysis. Some physical properties and structural characterization of these novel polyureas are reported. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 2692–2700, 2003

Inhibitors of acyl-CoA:cholesterol acyltransferase: novel trisubstituted ureas as hypocholesterolemic agents

Our continued interest in developing novel, potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, and our discovery of several active series of disubstituted urea ACAT inhibitors, have led us to investigate a series of trisubstituted ureas that are structural hybrids of our disubstituted series and of a trisubstituted urea ACAT inhibitor series disclosed by scientists at Lederle. This investigation has led to the discovery of novel trisubstituted ureas, several of which inhibit ACAT in the nanomolar range and effectively lower total plasma cholesterol when administered as a diet admixture in an acute model of hypercholesterolemia in rats. One analogue ( 35) also lowered total cholesterol as efficaciously as CL 277,082 in our chronic hypercholesterolemic rat model. The most notable finding of this study is that the SAR of the trisubstituted ureas diverges from that seen in our previously disclosed disubstituted urea series. This series showed optimal activity with 2,4-difluoro and 2,4,6-trifluoro substitution on the urea N-phenyl, whereas the disubstituted series showed optimal activity with bulky 2,6-disubstitution on the phenyl ring.

Reaction of trisubstituted ureas with amino-containing compounds

Trisubstituted urea derivatives efficiently carbamoylate amino compounds in neutral and alkaline media.

Reactions of Amines with Urea and its Derivatives. V

Unsymmetrical di-substitution products of urea do not give N, N, N'-ri-substitution produts by the reaction with primary amines from its reaction mechanism. However, a mono- or di-substituted urea with the primary amines was formed by the exchange reaction of a secondary amine liberated on the thermal dissociation of unsymmetrical disubstitution product of urea, with primary amines. In the most cases the reaction of unsymmetrical di-substitution products of urea with amines gives a mono or di-substituted urea with the primary amines. Further reaction of the mono or di-substituted urea with the secondary amine gave N, N, N'-tri-substituted urea in some cases.

Chemical Relaxation of Stress in Polyurethan Elastomers

Abstract The chemical stress-behavior of polyester urethan elastomers and a polyether elastomer have been determined through a temperature range of 90° to 130° C. Since both the polyether and poylester had approximately the same rates of stress decay, it was necessary to exclude ester-ester interchange as a reaction mechanism, and to regard the known thermal lability of the urea and urethan groups as indicative of possible sites of network scission. A likely possibility for the weak link is the trisubstituted urea (biuret) cross-linkage.

Chemical relaxation of stress in polyurethane elastomers

Chemical stress relaxation behavior of polyester urethane elastomers and a polyether elastomer have been determined over a temperature range of 90° to 130° C. Since both polyether and polyester samples have approximately the same rate of stress decay, it has been necessary to exclude ester-ester interchange as a reaction mechanism, and regard the known thermal lability of the urea and urethane groups as indicative of possible sites of network scission. A likely possibility for the weak link is the tri-substituted urea (biuret) cross-linkage.

Chemical relaxation of stress in polyurethane elastomers

Chemical stress relaxation behavior of polyester urethane elastomers and a polyether elastomer have been determined over a temperature range of 90° to 130° C. Since both polyether and polyester samples have approximately the same rate of stress decay, it has been necessary to exclude ester-ester interchange as a reaction mechanism, and regard the known thermal lability of the urea and urethane groups as indicative of possible sites of network scission. A likely possibility for the weak link is the tri-substituted urea (biuret) cross-linkage.