Alicyclic Groups Research Articles

In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity on CYP-450 (Part 2)

Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency on the P-glycoprotein (P-gp) transporter. Previous studies showed that the replacement of the aromatic spacer group between nitrogen atoms (N 1 and N 2) in the P-gp inhibitor XR9576 with ethyl or propyl chain is optimal for P-gp inhibition potency. To confirm that observation, the ethyl or the propyl linker arm was replaced with a pyrrolidine or an alicyclic group such as cyclohexyl. In addition, an arylpiperazinyl group and two methoxyl groups onto the anthranilic part were introduced to assess their effect on the anti P-gp activity. Five molecules were prepared and evaluated on CEM/VLB500. All new anthranilamides were more potent than verapamil, most of them exhibited a lower cytotoxicity than XR9576. Compound 5 was the most potent and its inhibition activity was similar to XR9576. Interestingly, in vitro biotransformation studies of compounds 4 and 5 using human CYP-450 isoforms revealed, that conversely to XR9576, compounds 4 and 5 inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of numerous drugs, notably paclitaxel. In that context, 5 might be suitable for further drug development.

4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties

A systematic examination of the central aromatic portion of the lead (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(1′H-spiro[indene-1,4′-piperidin]-1′-yl)butanamide (9) led to the discovery of a novel class of CCR2 receptor antagonists, which carry small alicyclic groups such as cyclopropyl, cylobutyl, or cyclopropylmethyl attached at C2 of the carbon backbone. The most potent compound discovered, namely (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-[(1R,3′R)-3′-methyl-1′H-spiro[indene-1,4′-piperidin]-1′-yl]butanamide (29), showed very high binding affinity (IC50=4nM, human monocyte) and excellent selectivity toward other related chemokine receptors. The excellent pharmacokinetic profile of this new lead compound allows for extensive in vivo evaluation.

INFLUENCE OF ROASTING CONDITIONS ON VOLATILE FLAVOR OF ROASTED MALAYSIAN COCOA BEANS

In this study, commercial Malaysian cocoa beans (SMC1A) were roasted in a forced airflow-drying oven for 20, 30, 40 and 50 min at 120, 130, 140, 150, 160 and 170C. The products were evaluated for flavor compounds and sensory evaluation (as dark chocolate). The volatile fraction was isolated using the combined steam distillation–extraction procedure and was identified by gas chromatography–mass spectrometry. A quantitative descriptive analysis was used to evaluate the flavor intensity of the chocolates using a 9-point rating scale for selected flavor attributes, namely astringency, bitter taste, sour taste, cocoa and burnt. Panelists were asked to smell and taste the sample against a standard chocolate. It was found that there were significant differences in flavor compounds between the different conditions of roasting. The main flavoring compounds identified composed of aliphatic and alicyclic groups such as alcohol and ester, and heterocyclic groups such as pyrazine and aldehyde. A total of 19 volatile major components were identified: nine pyrazines (2,5-dimethyl-, 2,3-dimethyl-, 2-ethyl-6-methyl-, trimethyl-, 3-ethyl-2,5-dimethyl-, tetramethyl-, 2-ethenyl-6-methyl- and 3,5-dimethyl-2-methylpyrazine); five aldehydes (5-methyl-2-phenyl-2-hexenal, benzaldehyde, benzalacetaldehyde and α-ethyliden-benzenacetaldehyde); one methyl ketone (2-nonanone); two alcohols (linalool and 2-heptanol); and two esters (4-ethylphenyl acetate and 2-phenylethyl acetate). Based on the flavor profile of the compounds identified, an optimum production of the major flavoring compounds such as pyrazine, aldehyde, ketone, alcohol and ester occurred at 160C for 30 min of roasting. Trimethylpyrazine and tetramethylpyrazine compounds together with 5-methyl-2-phenyl-2-hexanal were found to be good indicators for the evaluation of the roasting process. However, based on chocolate evaluation, the best roasting temperature was 150C for 30 min, which gave the lowest astringency and at the same time gave the lowest bitter taste and low level of sour and burnt tastes. At 150C roasting temperature, the desirable cocoa flavor was at its optimum. Correlation coefficients among certain volatile flavor and sensory characteristics of cocoa beans and dark chocolate were significant (P < 0.05).

Kinetic and computational studies on aminolysis of bicyclic carbonates bearing alicyclic structure giving alicyclic hydroxyurethanes

Aminolysis of bicyclic carbonates, which consist of five-membered cyclic carbonate and five- or six-membered alicyclic groups, was examined. Kinetic studies revealed that the aminolysis of the bicyclic carbonate with cyclohexane ring proceeded more smoothly than that of the bicyclic carbonate with cyclopentane ring. Computational calculation suggested that the different reaction rates originate from the distinct ring-strain of the cyclic carbonate groups affected by the conformation of the alicyclic groups.

Isolation and characterization of tautomeric forms of 2,4-diacetyl-3-(o-R-aryl)-5-hydroxy-5-methylcyclohexanones

Keto-enol prototropic tautomerism of 2,4-diacetyl-3-(o-R-aryl)-5-hydroxy-5-methylcyclohexanones in the β-diketone fragment was studied. Individual tautomeric forms of β-diketones, viz., keto and enol forms, were isolated and characterized. The latter are generated through enolization of the alicyclic carbonyl group. Enolization is facilitated by the presence of an ortho substituent in the benzene ring.

Copolyimides containing alicyclic and fluorinated groups: Characterization of the film microstructure

AbstractThe microstructures of a series of copolyimide films were characterized with different experimental methods such as density measurements, X‐ray diffraction, ultraviolet‐visible spectrophotometry, positron annihilation spectroscopy, and dynamic mechanical analysis. The experimental data were linked to the chemical structures of the polymers and especially the alicyclic and fluorinated monomers. Some analysis responses were directly dependent on the fluorine atoms and, therefore, did not provide clear information about the microstructures. The chain organization in the amorphous films appeared to be significantly dependent on the effect of the casting solvent. The influence of the alicyclic group content was quite significant for a nonsubstituted diamine but was strongly attenuated with a fluorinated diamine. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 2998–3010, 2003

Synthesis and characterization of novel copolymers with acid‐labile ketal moieties derived from camphor

AbstractNovel diastereomeric acrylic ketal monomers derived from (+)‐camphor and (±)‐camphor were synthesized. To investigate the applications of the camphor derivatives on positive‐tone photoresists, the acrylic ketal monomers were copolymerized with methyl methacrylate, methacrylic acid, and n‐butyl methacrylate. The optical activities of the chiral monomers and polymers were all evaluated. After UV irradiation and postexposure baking, the optical activity of the polymers decreased because of the decomposition of the acid‐labile pendant chiral groups. The existence of alicyclic camphyl groups increased the etching resistance of the photoresists. The thermogravimetric properties of the copolymers, the exposure curves, the lithographic evaluation of the positive‐tone photoresists, and the effects of alicyclic groups on the plasma etching resistance of the copolymers were all investigated. A resolution of a line‐and‐space pattern of 0.3 μm was achieved. Acid‐catalyzed dehydration crosslinking was also found in this system. Sufficient UV irradiation and heat treatment could cause the acid‐catalyzed dehydration crosslinking of pendant carboxyl groups and thereby increase the efficiency of the thermal resistance of the polymers. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 2969–2978, 2003

Photocurable positive photoresist-comprising copolymers having pendant alkoxy ethyl moieties

A series of copolymers based on methacrylic acid (MAA), methyl methacrylate (MMA), n-butyl methacrylate (BM), and bornyl methacrylate (BMA) with various feed molar ratios were synthesized. To introduce the protecting alkoxy ethyl moieties onto copolymers, the pendant carboxyl groups were further reacted with alkyl vinyl ether. The pendant alkoxy ethyl groups on copolymers could be deprotected by acid catalyst. Characterization of positive-tone photoresist-comprising copolymers having pendant alkoxy ethyl groups was carried out. Effects of alicyclic bornyl groups on the sensitivity and thermal properties of copolymers were investigated. It was found that the existence of bornyl groups in polymer might interfere with the hydrogen bonding produced by pendant carboxyl groups, leading to the decrease of thermal resistance. Acid-catalyzed dehydration crosslinking of pendant carboxyl groups of copolymers was also investigated. The exposure characteristic curves and the lithographic evaluation of the positive-tone photoresist were all investigated. Effects of alicyclic bornyl groups on the plasma etching resist of copolymers were also evaluated. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 83: 889–897, 2002

Preparation and Characterization of Novel Polymers Having Pendant Ketal Moieties for Positive Photoresists

This investigation relates to the syntheses of two new monomers of the methacrylate type and the introduction of the new monomers to a series of polymers for photoresists. In order to investigate the applications of pendant ketal and carboxyl groups on the positive tone photoresist, a series of copolymers have been synthesized deriving from methacrylic acid (MAA), methyl methacrylate (MMA), n-butyl methacrylate (BMA), 1,3-dioxane-4-methyl methacrylate (DDMA), and 1,4-dioxaspiro-[4,5]-decane-2-methyl methacrylate (DSDMA) with various feed molar ratios. We investigated the deprotection of pendant ketal groups, and the dehydration crosslinking of pendant carboxyl groups of the copolymers. The following were also investigated: thermogravimetric properties of copolymers, exposure characteristic curves, lithographic evaluation of the positive tone photoresist, and the effects of alicyclic groups on the plasma etching resistance of copolymers. It was found that polymers synthesized in this investigation can be used as a positive tone photoresist. A resolution of line and space pattern of 0.3 μm was also achieved. Sufficient UV irradiation and heat treatment may cause the acid catalyzed dehydration crosslinking of pendant carboxyl groups to increase the efficiency of thermal resistance of polymers.

Preparation and lithographic performance of novel copolymers having acid labile pendant alicyclic ether moieties

A series of methacrylic copolymers derived from methacrylic acid (MAA), methyl methacrylate (MMA), n-butyl methacrylate (BM), and bornyl methacrylate (BMA) with various feed molar ratios was synthesized. In order to introduce acid labile alicyclic ether groups, the pendant carboxyl groups of copolymers were further functionalized with unsaturated alicyclic ethers of 2,3-dihydrofuran (DHF), 3,4-dihydro-2H-pyran (DHP), and 3,4-dihydro-2-methoxy-2H-pyran (DHMP). The existence of alicyclic bornyl groups was found to increase the thermal and plasma etching resistance of polymers but to decrease the sensitivity and contrast. Copolymers having pendant carboxyl groups can be crosslinked in the presence of photoacid after sufficient heat treatment. Acid catalyzed dehydration of pendant carboxylic acids may also cause the crosslinking of polymers. The thermogravimetric properties of copolymers, exposure characteristic curves and lithographic evaluation of the positive tone photoresist were all investigated. A line and space pattern resolution of 0.3 μm was also achieved.

Novel Crosslinking Method for Negative Tone Photoresist having Pendant Carboxyl Moieties

We have developed a novel photo-crosslinking method for the negative tone photoresist comprising binder resins with pendant carboxyl groups. A series of copolymers have been synthesized deriving from methacrylic acid, methyl methacrylate, n-butyl methacrylate, and α-methacryloxy-γ-butyrolactone with various feed molar ratios. The existence of lactonic methacrylate units in copolymers was found to increase the sensitivity of the photoresist. Increasing photosensitivity was investigated by using a model compound of α-acetoxy-γ butyrolactone (ACBL). Heat treatment of ACBL compounds in the presence of acid was found to cause the formation of dimers. The following were also investigated: thermogravimetric properties of binder resins, the exposure characteristic curves, and the lithographic evaluation of the negative tone photoresist of copolymers. The existence of alicyclic γ-butyrolactone groups was found to increase the etching resistance of the resists.

Advanced Materials for 193-nm Resists.

Acrylate monomers were synthesized using a novel aerobic oxidation reaction employing N-hydroxyphtalimide (NHPI) as a catalyst, and then polymerized. These reactions were confirmed to be applicable for the mass production of those compounds. We have synthesized series of reported 193-nm resist materials, and found that they are subject to certain problems. That is, acrylates having hydrophilic acid leaving groups, such as pyranyl or acid-leaving lactones usually have poor etching resistance. Moreover, t-butyl acid-leaving groups or acid-leaving alicyclic groups are too hydrophobic to achieve high performance of the resist. From this point of view, we have designed and synthesized advanced monomers having hybrid structure of alicyclic ring and polar moiety, using aerobic oxidation reaction Finally, patterns with a resolution of 0.13-micron, based on the 1G bit DRAM design rule, were successfully fabricated by optimizing the resist composition containing newly synthesized monomers.

Properties and mutual interactions of various acrylate monomers used in 193 nm resists

Both the physical and chemical properties of various acrylate monomers, typically used in polymer matrices for 193 nm lithography, are investigated. The influence of each monomer on the glass transition temperature (Tg) of the final polymer is determined. The high Tg values measured for the different polymers lead to the conclusion that most acrylate based formulations tend to be non-annealing type resists. Mutual chemical interactions between monomers are also demonstrated. These phenomena underline the limits of the introduction of alicyclic ester groups in acrylic polymers and the complexity of the mechanisms involved in these resists.

New ArF Single-Layer Resist for 193-nm Lithography.

A new class of photoresist matrix polymer based on alicyclic cyclopolymer was developed for use in ArF single-layer lithography. A novel polymer was synthesized by terpolymerization reaction between tert-butyl methacrylate and alicyclic-malefic anhydride alternating copolymer, which has a hydroxy substituent on the alicyclic group. The polymer showed good adhesion property to Si- substrate and adequate dissolution behavior in a 2.38wt% TMAH aqueous solution, high thermal stability up to 180°C, and a good dry-etch resistance against CF4 mixture gas (1.14 times the etching rate of novolak resist). Using an ArF excimer laser exposure system, a 140nm line and space patterns have been resolved.

Synthesis, electrochemistry and ab initio molecular orbital calculations on some norbornane- and bicyclo[2.2.2]octane-fused 5,12-bis(dicyanomethylidene)naphthalene systems

A series of norbornane- and bicyclo[2.2.2]octane-fused tetracyanonaphthoquinodimethane (benzoTCNQ) derivatives, 4,6,8,10 and 12 has been synthesized. Cyclic voltammetry measurements revealed two one-electron reduction waves for the benzo-TCNQ systems 4, 8 and 10 which possess either a cyclobutane or a norbornane moiety fused to the quinonoid ring, but a single (presumably two-electron) reduction wave for 6 and 12 which possess a bicyclo[2.2.2]octane group fused to the gmnonoid ring. The benzo-TCNQ systems were found to be potent electron acceptors. The results of (U)HF/3-21G calculations carried out on representative benzo-TCNQ derivatives suggest that steric interactions between the quinonoid ring and its adjacent fused alicyclic group are largely responsible for the observed decrease in the electron affinities along the series: 8 > 4 > 6. The MO calculations further suggest that LUMO energies of neutral TCNQ derivatives are qualitatively reliable predictors of electron affinities. The calculated (gas phase) internal reorganization energies, λi, for the benzo-TCNQ systems are ca. 54 kJ mol–1 and are comparable to that calculated for the dicyanovinyl (DCV) system, 27. The similarity between the λi values for the benzo-TCNQ systems and 27, together with the experimental finding that benzo-TCNQ systems are reduced at ca. 1.7 V less negative potentials than 27, should make the norbornane- and bicyclo [2.2.2] octane-benzo-TCNQ systems superior to the DCV moiety as acceptor chromophores in giant multichromophoric systems.

Mapping the melatonin receptor. 3. Design and synthesis of melatonin agonists and antagonists derived from 2-phenyltryptamines.

Three series of 2-phenyltryptamides were prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor in chicken brain and in Xenopus laevis melanophore cells. The 5-methoxy-2-phenyltryptamides (6a-j) have high binding affinities for the chicken brain receptor, in some cases (6a-d) greater than that for melatonin, confirming and extending the work of Spadoni et al., and act as agonists in the Xenopus melanophore assay. Analogues lacking the 5-methoxyl group (2a-n) had a considerably lower affinity for the chicken brain receptor. In the Xenopus melanophore assay the compounds acylated on nitrogen by an alkyl group (2a-d) were agonists whereas the compounds acylated on nitrogen by an alicyclic group (2f-i) were antagonists. Introducing a methyl group at N1 (7) led to an increase in binding affinity in the chicken brain assay, whereas introducing an ethyl group (13) led to a decrease in binding affinity. A methyl substituent at the beta-position of the 3-amidoethane side chain (8, 11) also led to an increase in the binding affinity. The only analogue acylated on nitrogen with an alkyl group (acetyl) which showed antagonist activity was 9, which has a beta-methoxymethyl side chain. In the absence of the 5-methoxyl group the methoxymethyl function may cause the molecule to bind in a different configuration so that it is no longer able to activate the receptor. All of these observations are in agreement with a model of melatonin at the receptor site in which the 3-amidoethane side chain is in a conformation close to the 5-methoxyl group.

Inhibitors of purine nucleoside phosphorylase

Disclosed is a compound containing a 2-amino-7-(R)-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one wherein R is cyclohexenyl, cyclohexyl, or -CH2-R1, and wherein R1 is an optionally substituted heteroalicyclic, pyridinyl or alicyclic group. Also disclosed is a compound of formula (I), wherein R1 is H, NH?2?, or OCH3, R?2? is an optionally substituted cyclic group of 5-7 carbon atoms optionally containing one or more heteroatoms, R?3 and R4? are independently H or C?1?-4 alkyl, m is 0-4, n is 0-6, p is 0-1, X is CN, CSNH2, PO(OH)2, COOH, SO2NH2, NH2, OH CNHNH2, tetrazole, or triazole, COR?5? where R5 is C1-4 alkyl, CF3, NH2, or OC1-4 alkyl, and Y is O or NH.

Preclinical toxicology and tissue platinum distribution of novel oral antitumour platinum complexes: ammine/amine platinum(IV) dicarboxylates.

The preclinical toxicology and tissue platinum distribution of a series of six orally given antitumour platinum complexes [ammine/amine platinum(IV) dicarboxylates] with structural variations of their alicyclic amine (c-C5, c-C6 or c-C7), axial dicarboxylate (CH3, C3H7 or NHC2H5) or leaving substituents (Cl2 or OCOOCO) was studied in the mouse. Platinum tissue levels measured at 48 h after a single oral dose at 0.5 of the MTD were highest in the liver (6.0-19 micrograms/g) and second highest in the kidney (2.8-12 micrograms/g), and these levels were up to 5 times higher than those reported with equi-toxic doses of i.v. cisplatin and i.v. carboplatin. Platinum levels in the lung, heart, spleen, skin, skeletal muscle and brain were all < or = 3.1 micrograms/g at this dose level. Liver platinum levels measured at 2 h, 2 days, 6 days and 10 days after a single oral dose at the MTD ranged widely (from 15 to 109 micrograms platinum/g), were related to the number of carbon atoms in the axial dicarboxylate and alicyclic amine groups (r = 0.9389) and showed a diversity of time-course profiles. Elevations of plasma ALT activity were recorded with single oral doses of JM225 and JM256 at the MTD. Accumulation of platinum in the liver with repeated oral dosing weekly for 4 consecutive weeks at 0.5 of the MTD occurred with JM269 (3.3-fold increase, P < 0.05) and JM225 (2.4-fold increase, P < 0.05), and elevated plasma ALT activity (44 +/- 33 IU/l) was recorded with repeated oral doses of JM269. JM216 was selected from this series of analogues for further study on the basis of the elevated plasma ALT activity (JM225, JM256 and JM269), liver platinum accumulation (JM269 and JM225), poor activity against human ovarian carcinoma xenografts (JM291) or severe emetogenesis (JM221) of other examples. Following a single oral dose of JM216 at the MTD, transient reductions in the WBC (nadir, 1.6 x 10(9)/l, 2 days, 74% reduction), platelet count (nadir, 613 x 10(9)/l, 10 days, 33% reduction) and bone marrow cellularity (nadir, 0.5 x 10(7) nucleated cells/femur, 4 days, 75% reduction) were found, and these had recovered by 21 days after treatment. Jejunal mucosal disaccharidase activity following single MTDs indicated that small-intestinal mucosal damage was less severe for oral JM216 (nadir maltase activity, 68% +/- 16% of control, NS) than for i.v. cisplatin (nadir maltase activity).(ABSTRACT TRUNCATED AT 400 WORDS)

Antifeedant activity of Piper guineense Schum &amp; Thonn. Amides against larvae of the sorghum stem borer Chilo partellus (Swinhoe)

Six amide alkaloids of Piper guineense were tested for antifeedant activity against fifth instar larvae of Chilo partellus in choice assays. These amides include piperine, Δα, β-dihydropiperine, wisanine, Δα, β-dihydrowisanine, trichostachine and N-isobutyl-trans-2-trans-4-eicosadienamide. Piperine and its dihydrosaturated derivative exhibited the most potentantifeedant activity. Δα, β-dihydrowisanine and trichostachine were intermediate in activity followed by wisanine. The N-isobutyl derivative was the least active. These results suggest that the presence of a methylenedioxybenzene and an alicyclic amide group in the compound may be crucial for high antifeedant activity.

Some principles in the deformation of homo- and copolyimide fibres containing alicyclic groups in the repeating unit

-- On the basis of dilatometric studies, it has been found that the appearance of a high-temperature peak on the δl/l0 = f(t°) dependences is connected with spontaneous elongation of specimens in the temperature region above the glass point (ascending branch) and an effect of quasielasticity (descending branch).