- Investigation of the chiral recognition ability of human carboxylesterase 1 using indomethacin esters
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Human carboxylesterase 1 (hCES1) is an enzyme that plays an important role in hydrolysis of pharmaceuticals in the human liver. In this study, elucidation of the chiral recognition ability of hCES1 was attempted using indomethacin esters in which various chiral alcohols were introduced. Indomethacin was condensed with various chiral alcohols to synthesize indomethacin esters. The synthesized esters were hydrolyzed with a human liver microsome (HLM) solution and a human intestine microsome (HIM) solution. High hydrolytic rate and high stereoselectivity were confirmed in the hydrolysis reaction in the HLM solution but not in the HIM solution, and these indomethacin esters were thought to be hydrolyzed by hCES1. Next, these indomethacin esters were hydrolyzed in recombinant hCES1 solution and the hydrolysis rates of the esters were calculated. The stereoselectivity confirmed in HLM solution was also confirmed in the hCES1 solution. In the hydrolysis reaction of esters in which a phenyl group is bonded next to the ester, the Vmax value of the (R) form was 10 times larger than that of the (S) form.
- Takahashi, Masato,Takani, Daisuke,Haba, Masami,Hosokawa, Masakiyo
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Read Online
- A fluorescent ESIPT-based benzimidazole platform for the ratiometric two-photon imaging of ONOO-: In vitro and ex vivo
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In this work, we have developed an ESIPT-based benzimidazole platform (MO-E1 and MO-E2) for the two-photon cell imaging of ONOO- and a potential ONOO-activated theranostic scaffold (MO-E3). Each benzimidazole platform, MO-E1-3, were shown to rapidly detect ONOO- at micromolar concentrations (LoD = 0.28 μM, 6.53 μM and 0.81 μM respectively). The potential theranostic MO-E3 was shown to release the parent fluorophore and drug indomethacin in the presence of ONOO- but unfortunately did not perform well in vitro due to low solubility. Despite this, the parent scaffold MO-E2 demonstrated its effectiveness as a two-photon imaging tool for the ratiometric detection of endogenous ONOO- in RAW264.7 macrophages and rat hippocampus tissue. These results demonstrate the utility of this ESIPT benzimidazole-based platform for theranostic development and bioimaging applications. This journal is
- Bull, Steven D.,Gardiner, Jordan E.,James, Tony D.,Kim, Hwan Myung,Odyniec, Maria L.,Park, Sang-Jun,Sedgwick, Adam C.,Webb, Emily C.,Yoon, Juyoung
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Read Online
- Direct 3-Acylation of Indolizines by Carboxylic Acids for the Practical Synthesis of Red Light-Releasable Caged Carboxylic Acids
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To enhance the practicality of photouncaging system using 3-acyl-2-methoxyindolizines, direct acylation of indolizines with carboxylic acids was developed using condensation reagents, generally used for peptide coupling. This method allowed for caging a broad range of carboxylic acids with indolizines. The method enabled a facile synthesis of water-soluble caged bioactive carboxylic acids having an intramolecular photosensitizer. The efficient release of carboxylic acids from the synthesized caged compounds upon red light irradiation was confirmed in neutral buffered solutions.
- Watanabe, Kenji,Terao, Nodoka,Niwa, Takashi,Hosoya, Takamitsu
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p. 11822 - 11834
(2021/07/31)
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- PHOTOLYTIC COMPOUNDS AND TRIPLET-TRIPLET ANNIHILATION MEDIATED PHOTOLYSIS
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The invention provides novel photolytic compounds and prodrugs, nanoparticles and compositions thereof, and methods of conducting photolysis mediated by triplet-triplet annihilation.
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Paragraph 0026
(2021/04/17)
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- Synthesis method of indometacin and analogues thereof
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The invention belongs to the technical field of indometacin synthesis, and discloses a synthesis method of indometacin and analogues thereof. The synthesis method of indometacin and analogues thereofcomprises the following steps: directly introducing alkyl, aromatic ring or heteroaromatic ring to the C2 position of indole through palladium catalyzed reaction; introducing a carboxylic acid fragment to the C3 position of the indole; and introducing an aroyl group to the N1 position of the indole. The method solves the problems that most of existing indometacin synthesis methods carry out modification by constructing an indole ring, simple structure change of indometacin molecules based on the synthesis strategy often needs de novo synthesis and synthesis steps for later modification and structure-activity relationship research of the indometacin molecules are tedious.
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Paragraph 0059-0060; 0062; 0068-0070
(2020/04/29)
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- Organocatalyzed Aerobic Oxidation of Aldehydes to Acids
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The first example organocatalyzed aerobic oxidation of aldehydes to carboxylic acids in both organic solvent and water under mild conditions is developed. As low as 5 mol % N-hydroxyphthalimide was used as the organocatalyst, and molecular O2 was used as the sole oxidant. No transition metals or hazardous oxidants or cocatalysts were involved. A wide range of carboxylic acids bearing diverse functional groups were obtained from aldehydes, even from alcohols, in high yields.
- Dai, Peng-Fei,Qu, Jian-Ping,Kang, Yan-Biao
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supporting information
p. 1393 - 1396
(2019/02/26)
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- Pd-tBuONO Cocatalyzed Aerobic Indole Synthesis
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A Pd-tBuONO co-catalyzed scalable and practical synthesis of indoles with molecular oxygen as terminal oxidant is developed. Either terminal or internal 2-vinylanilines could be smoothly converted to desired indoles under one general condition. This method has been evaluated in the large scale synthesis of indomethacin and a potential anti-breast cancer drug candidate 1. (Figure presented.).
- Ning, Xiao-Shan,Liang, Xin,Hu, Kang-Fei,Yao, Chuan-Zhi,Qu, Jian-Ping,Kang, Yan-Biao
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p. 1590 - 1594
(2018/04/30)
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- Synthesis of Functionalized Indoles via Palladium-Catalyzed Aerobic Cycloisomerization of o-Allylanilines Using Organic Redox Cocatalyst
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A scalable and practical synthesis of functionalized indoles via Pd-tBuONO cocatalyzed aerobic cycloisomerization of o-allylanilines is reported. Using molecular oxygen as a terminal oxidant, a series of substituted indoles were prepared in moderate to good yields. The avoidance of hazardous oxidants, heavy-metal cocatalysts, and high boiling point solvents such as DMF and DMSO enables this method to be applied in pharmaceutical synthesis. A practical gram-scale synthesis of indomethacin demonstrates its application potential.
- Ning, Xiao-Shan,Wang, Mei-Mei,Qu, Jian-Ping,Kang, Yan-Biao
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p. 13523 - 13529
(2018/10/25)
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- A aldehyde or mellow directly converted into the carboxylic acid (by machine translation)
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The invention discloses a aldehyde or mellow oxidation can be directly transformed into carboxylic acid, is characterized in that the pure oxygen environment, in N - hydroxy imide compound under the catalysis of the imide compound or N - hydroxy and nitrous acid ester compound common under the catalysis, the CH2 OH and CHO oxidation directly converted into the carboxylic acid compounds. The invention using oxygen as the oxidizing agent, does not add any metal catalyst, environment-friendly, high catalytic efficiency, simple and convenient operation. With the previous metal catalytic system complex and different catalytic system, has some metal catalytic system in the process, the use of transition metal will cause the transition metal of the residual, the invention adopts the non-metallic catalytic system, environmental protection, preventing the metal residue problem, this to the solution of the drug in the synthesis of transition metal residue problem and provides a new method of thinking. (by machine translation)
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Paragraph 0077-0079
(2018/08/03)
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- Water-Soluble Hypervalent Iodine(III) Having an I-N Bond. A Reagent for the Synthesis of Indoles
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A readily accessible and bench-stable water-soluble hypervalent iodine(III) reagent (phenyliodonio)sulfamate (PISA) with an I-N bond was synthesized, and its structure was characterized by X-ray crystallography. With PISA, various indoles were synthesized via C-H amination of 2-alkenylanilines involving an aryl migration/intramolecular cyclization cascade with excellent regioselectivity in aqueous CH3CN. Notably, using this new method as the key step, not only two drug molecules, indometacin and zidometacin, but also another bioactive molecule, pravadoline, were synthesized.
- Xia, Hai-Dong,Zhang, Yan-Dong,Wang, Yan-Hui,Zhang, Chi
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p. 4052 - 4056
(2018/07/15)
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- Application of hypervalent iodine reagent-mediated in preparation of indole derivatives
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The invention relates to application of hypervalent iodine reagent-mediated in preparation of indole derivatives, in particular to the application of organic trivalent iodine reagent iodoyl benzene aminosulfonate in preparing N-protected 2-substituted indole compounds and indomethacin, zidometacin, pravadoline. The invention relates to the application of organic trivalent iodine reagent iodoyl benzene aminosulfonate in preparing N-protected 2-substituted indole compounds, and the reaction undergoes functional group exchange of a substrate. In addition, iodoyl benzene aminosulfonate plays two important roles in this application, as an oxidant and as Bronsted acid. The application has the advantages of good regioselectivity, wide substrate range, mild conditions, simple operation and amplification of experimental steps. The application of the organic trivalent iodine reagent iodoyl benzene aminosulfonate in the preparation of indomethacin, zidomeprin and pravadoline provided by the invention has the advantages of high synthesis efficiency, simple operation and the like.
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- Chemoselective ester/ether C–O cleavage of methyl anisates by aluminum triiodide
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The aluminum triiodide mediated chemoselective ester/ether C–O cleavage of methyl anisates was investigated. o-Anisate undergoes ether cleavage at low temperatures in carbon disulfide, cyclohexane and acetonitrile. Further cleavage of the ester group occurs at elevated temperatures to afford salicylic acid. The cleavage of p-anisate is solvent-dependent. In cyclohexane, the ester and ether groups were cleaved non-selectively to give equimolar amounts of p-anisic acid and methyl p-hydroxybenzoate. The ester group was preferentially cleaved in acetonitrile, compared to ether group cleavage in carbon disulfide. The ester cleavage reaction was improved using pyridine as an acid scavenger additive. Reasons for the contrasting reactivity of anisates towards AlI3 were explored, and the methods were applied to cleavage of the tert-butyl ester of acemetacin which gave different products under these conditions.
- Sang, Dayong,Yi, Cuicui,He, Zhoujun,Wang, Jiahui,Tian, Juan,Yao, Ming,Shi, Hong
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supporting information
p. 1469 - 1472
(2018/03/13)
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- Myoglobin-Catalyzed C?H Functionalization of Unprotected Indoles
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Functionalized indoles are recurrent motifs in bioactive natural products and pharmaceuticals. While transition metal-catalyzed carbene transfer has provided an attractive route to afford C3-functionalized indoles, these protocols are viable only in the presence of N-protected indoles, owing to competition from the more facile N?H insertion reaction. Herein, a biocatalytic strategy for enabling the direct C?H functionalization of unprotected indoles is reported. Engineered variants of myoglobin provide efficient biocatalysts for this reaction, which has no precedents in the biological world, enabling the transformation of a broad range of indoles in the presence of ethyl α-diazoacetate to give the corresponding C3-functionalized derivatives in high conversion yields and excellent chemoselectivity. This strategy could be exploited to develop a concise chemoenzymatic route to afford the nonsteroidal anti-inflammatory drug indomethacin.
- Vargas, David A.,Tinoco, Antonio,Tyagi, Vikas,Fasan, Rudi
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supporting information
p. 9911 - 9915
(2018/07/31)
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- Tert-Butyl Iodide Mediated Reductive Fischer Indolization of Conjugated Hydrazones
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A novel reductive Fischer indolization of readily available N-aryl conjugated hydrazones with tert-butyl iodide has been developed. In this reaction, tert-butyl iodide is used as anhydrous HI source, and the generated HI acts as a Br?nsted acid and a reducing agent. This operationally simple method allows access to various indole derivatives. Furthermore, the procedure can be applied to the synthesis of biologically active compounds.
- Ito, Yuta,Ueda, Masafumi,Takeda, Norihiko,Miyata, Okiko
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p. 2616 - 2619
(2016/02/26)
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- Synthesis of indoles through Rh(III)-catalyzed C-H cross-coupling with allyl carbonates
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A practical Rh-catalyzed reaction was developed to achieve 2-alkyl-substituted indole synthesis. The reaction can tolerate a variety of synthetically important functional groups. The indole products can also be transformed into other important skeletons. Two bioactive compounds, that is indomethacin and pravadoline were prepared using the new method.
- Gong, Tian-Jun,Cheng, Wan-Min,Su, Wei,Xiao, Bin,Fu, Yao
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p. 1859 - 1862
(2014/03/21)
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- Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans
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Phospho-tyrosol-indomethacin (PTI; MPI 621), a novel anti-cancer agent, is more potent and safer than conventional indomethacin. Here, we show that PTI was extensively metabolized in vitro and in vivo. PTI was rapidly hydrolyzed by carboxylesterases to generate indomethacin as its major metabolite in the liver microsomes and rats. PTI additionally undergoes cytochromes P450 (CYP)-mediated hydroxylation at its tyrosol moiety and O-demethylation at its indomethacin moiety. Of the five major human CYPs, CYP3A4 and CYP2D6 catalyze the hydroxylation and O-demethylation reactions of PTI, respectively; whereas CYP1A2, 2C9 and 2C19 are inactive towards PTI. In contrast to PTI, indomethacin is primarily O-demethylated by CYP2C9, which prefers acidic substrates. The hydrolyzed and O-demethylated metabolites of PTI are further glucuronidated and sulfated, facilitating drug elimination and detoxification. We observed substantial inter-species differences in the metabolic rates of PTI. Among the liver microsomes from various species, PTI was the most rapidly hydrolyzed, hydroxylated and O-demethylated in mouse, human and rat liver microsomes, respectively. These results reflect the differential expression patterns of carboxylesterase and CYP isoforms among these species. Of the human microsomes from various tissues, PTI underwent more rapid carboxylesterase- and CYP-catalyzed reactions in liver and intestine microsomes than in kidney and lung microsomes. Together, our results establish the metabolic pathways of PTI, reveal significant inter-species differences in its metabolism, and provide insights into the underlying biochemical mechanisms.
- Xie, Gang,Zhou, Dingying,Cheng, Ka-Wing,Wong, Chi C.,Rigas, Basil
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p. 1195 - 1202
(2013/05/22)
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- Coupling and cyclization of O-iodoanilines and propargylic bromides via allenes: An efficient entry to indomethacin
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A sequential allene synthesis and cyclization has been realized in a one-pot manner. A Pd(0)-catalyzed one-pot reaction of N-Ts or -Ms 2-iodoanilines and propargylic bromides afforded indoles with pharmaceutical importance highly efficiently with diversity via sequential carbon-carbon bond coupling forming allenes and azapalladation. With this newly established methodology, an efficient approach to indomethacin, an anti-inflammatory drug (NSAID), has been accomplished.
- Zhu, Can,Ma, Shengming
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supporting information
p. 2782 - 2785
(2013/07/19)
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- Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer
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Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5α-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3·NADP +·2′-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC.
- Liedtke, Andy J.,Adeniji, Adegoke O.,Chen, Mo,Byrns, Michael C.,Jin, Yi,Christianson, David W.,Marnett, Lawrence J.,Penning, Trevor M.
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p. 2429 - 2446
(2013/05/09)
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- Design and synthesis of indomethacin analogues that inhibit P-glycoprotein and/or multidrug resistant protein without Cox inhibitory activity
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We designed and synthesized conformationally restricted analogues and regioisomers of the nonsteroidal anti-inflammatory drug indomethacin. Evaluation of the inhibitory effects of these compounds on COX, P-glycoprotein, and multidrug resistance indicated that NSAIDS modulation of multidrug-resistant P-glycoprotein and multidrug-resistant protein-1 is not associated with COX-1 and COX-2 inhibitory activities.
- Arisawa, Mitsuhiro,Kasaya, Yayoi,Obata, Tohru,Sasaki, Takuma,Nakamura, Tomonori,Araki, Takuya,Yamamoto, Koujirou,Sasaki, Akito,Yamano, Akihito,Ito, Mika,Abe, Hiroshi,Ito, Yoshihiro,Shuto, Satoshi
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p. 8152 - 8163
(2012/11/07)
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- Indomethacin analogues that enhance doxorubicin cytotoxicity in multidrug resistant cells without cox inhibitory activity
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Conformationally restricted indomethacin analogues were designed and prepared from the corresponding 2-substituted indoles, which were synthesized by a one-pot isomerization/enamide-ene metathesis as the key reaction. Conformational analysis by calculations, NMR studies, and X-ray crystallography suggested that these analogues were conformationally restricted in the s-cis or the s-trans form due to the 2-substituent as expected. Their biological activities on cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, and modulation of MRP-1-mediated multidrug resistance (MDR) are described. Some of these indomethacin analogues enhanced doxorubicin cytotoxicity, although they do not have any COX inhibitory activity, which suggests that the MDR-modulating effect of an NSAID can be unassociated with its COX-inhibitory activity. This may be an entry into the combination chemotherapy of doxorubicin with a MDR modulator.
- Arisawa, Mitsuhiro,Kasaya, Yayoi,Obata, Tohru,Sasaki, Takuma,Ito, Mika,Abe, Hiroshi,Ito, Yoshihiro,Yamano, Akihito,Shuto, Satoshi
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p. 353 - 357
(2011/07/09)
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- Fischer indole synthesis with organozinc reagents
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Updated classic: Primary and secondary alkylzinc reagents add to various aryldiazonium salts leading regioselectively to polyfunctional indoles by means of a [3,3]-sigmatropic shift and subsequent aromatization. This organometallic variation of the Fischer indole synthesis tolerates a wide range of functional groups and displays absolute regioselectivity. Copyright
- Haag, Benjamin A.,Zhang, Zhi-Guang,Li, Jin-Shan,Knochel, Paul
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supporting information; experimental part
p. 9513 - 9516
(2011/02/24)
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- UNIQUE DUAL-ACTION THERAPEUTICS
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A new family of therapeutics which provides a controlled-release delivery platform for non-steroidal anti-inflammatory agents on an ester or an ester-carbonate backbone is disclosed herein. These agents are reversible inhibitors of acetylcholinesterase and are thus useful for clinical conditions benefiting from inflammation suppression and cholinergic intervention. These compounds are of the general formula wherein n = 0, 1; X = C, Si, and N+ and NSAID = ibuprofen, naproxen, indomethacin and diclofenac. Other embodiments are also disclosed
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Page/Page column 46; 47; 49
(2010/05/14)
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- COMPOSITION FOR TREATING SULFUR MUSTARD TOXICITY AND METHODS OF USING SAME
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One embodiment of the present invention provides a composition, comprising, in amounts effective to treat sulfur mustard or half sulfur mustard induced toxicity or skin damage: an agent that inhibits alkylation of —SH and >NH protein groups; an agent that reduces —SS— to SH; a scavenger of reactive oxygen species; a substrate that maintains tissue reduction-oxidation status; an agent that protects against invading inflammatory cells and associated oxidative stress; an antagonist of prostaglandin synthesis; and an agent that induces tissue regeneration. Methods of using the composition are also provided.
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- Method for Distinguishing Mesenchymal Stem Cell Using Molecular Marker and Use Thereof
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Disclosed is a method for distinguishing a mesenchymal stem cell comprising, using at least one gene selected from the genes having the nucleotide sequences indicated by the accession numbers shown in Table 1 as a distinguish marker, detecting the difference in expression of the distinguish marker between a mesenchymal stem cell and a connective tissue cell to distinguish the mesenchymal stem cell from the connective tissue cell. This method enables to distinguish an undifferentiated mesenchymal stem cell from other connective tissue cell such as fibroblasts, osteoblasts, chondrocytes and adipose cells with good accuracy. A mesenchymal stem cell given by this method or a composition comprising the mesenchymal stem sell can be used as a therapeutic for use in the regenerative medicine.
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- Aromatic enamide/ene metathesis toward substituted indoles and its application to the synthesis of indomethacins
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A. steric and electronic effect: on enamide/ene metathesis, a novel preparation of 2-substituted indoles and 3-substituted indoles using enamide-ene metathesis as a key reaction, and its application to the synthesis of indoniethacin are described. Wiley-VCH Verlag GmbH & Co. KGaA.
- Kasaya, Yayoi,Hoshi, Kosuke,Terada, Yukiyoshi,Nishida, Atsushi,Shuto, Satoshi,Arisawa, Mitsuhiro
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experimental part
p. 4606 - 4613
(2009/12/27)
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- N-Alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of carboxylic acid containing drugs
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Synthesis and hydrolysis in aqueous buffers of novel N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) and N-aryl-N-alkyloxycarbonylaminomethyl (NArNAOCAM) derivatives of carboxylic acid containing drugs were carried out. The hydrolysis follows a SN1 type mechanism and is dependent on the nucleofugacity of the leaving group. Topical delivery of the NANAOCAM derivative of naproxen from IPM across hairless mice skin was examined in in vitro diffusion cell experiments. The prodrug was 4.5-fold less lipid soluble, 2.4-fold less water soluble and 3.6-fold less permeable than the parent drug.
- Majumdar, Susruta,Sloan, Kenneth B.
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p. 1447 - 1450
(2008/09/21)
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- Substituted aminoalcohol ester analogs of indomethacin with reduced toxic effects
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Synthesis and evaluation of five different N,N-disubstituted aminoethanol ester derivatives of indomethacin bearing structural resemblance to the aminoethanol ester class of anticholinergics are reported herein. The anticholinergic activity was incorporated into the intact esters to overcome the gastric toxicity of indomethacin, not only by blocking the acidic functionality but also by decreasing gastric secretions and motility. These derivatives exhibited in vitro stability in buffers of pH 2.0 and 7.4 for 6 h and were readily hydrolyzed by human plasma esterases to liberate the parent drug. All the derivatives were significantly less irritating to the gastric mucosa than the parent drug. Though only two esters showed antiinflammatory activity similar to that of the parent drug at equivalent dose levels, all the esters were equipotent to indomethacin in the mouse acetic acid-induced writhing assay for analgesic action. The present evaluation indicates that the combined pharmacological properties of these ester derivatives may prove useful for design and development of novel gastric sparing antiinflammatory molecules with potentially important therapeutic applications. Birkhaeuser 2007.
- Haien, Parmeshwari K.,Chagti, Kewal K.,Giridhar, Rajani,Yadav, Mange Ram
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p. 101 - 111
(2008/04/01)
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- α-(1H-Imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters as prodrugs of carboxylic acid containing drugs
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Synthesis of α-(1H-imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters have been reported in 2-3 simple steps. α-(1H-Imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters were found to be chemically labile and thus serve as novel prodrugs of carboxylic acids.
- Majumdar, Susruta,Spaeth, Maren Mueller,Sivendran, Sashikala,Juntunen, Juha,Thomas, Joshua D.,Sloan
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p. 4609 - 4611
(2008/02/06)
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- Vehicle for topical delivery of anti-inflammatory compounds
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A vehicle for topical application which contains a liquid eutectic mixture of hydrophobic compounds to improve solubility of pharmaceutically active component and enhance topical and transdermal delivery.
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- Treatment of genitourinary tract disorders
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Genitourinary system disorders are treated with therapeutic agents, and optionally further with radiation treatments.
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- A new entry to the synthesis of 2,3-disubstituted indoles
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(Chemical Equation Presented) The Stille coupling of N-acyl-2-iodoanilines with the 1-(tributylstannyl)-1-substituted allenes affected the successive one-step formation of the 2-methyl-3-substituted indoles. Alternatively, the other type of 2-alkyl-3-substituted indoles could be synthesized in a one-pot operation, which consists of the Stille coupling reaction with the 1-(tributylstannyl)-1,3-disubstituted allenes, followed by TBAF treatment. This procedure could be applied to the synthesis of indomethacin.
- Mukai, Chisato,Takahashi, Yukie
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p. 5793 - 5796
(2007/10/03)
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- New procedure for obtaining indomethacin
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A new procedure has been developed for the synthesis of indomethacin by the Fischer reaction, based on the acylation of sodium 2-(4-methoxyphenyl)-1- hydrazosulfonate with 4-chlorobenzoyl chloride and subsequent interaction with levulinic acid in the presence of formic acid. 2005 Springer Science+Business Media, Inc.
- Magedov,Maklakov,Smushkevich
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p. 449 - 451
(2007/10/03)
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- Modulation of MRP-1-mediated multidrug resistance by indomethacin analogues
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Multidrug resistance (MDR) is a major limiting factor in the development and application of drug candidates. MDR caused by MRP-1 is known to be modulated by the nonsteroidal antiinflammatory drug indomethacin. We have synthesized and biologically evaluated a library of indomethacin analogues. The indomethacin-derived compound library was synthesized employing the Fischer-indole synthesis as the key transformation and making use of a resin-capture-release strategy. Sixty representative members of the library were evaluated in a cell biological cytotoxicity assay employing the MRP-1 expressing human glioblastoma cell line T98G as a model system. Nine of the 60 tested derivatives increased the doxorubicin-mediated cytotoxicity at a comparable or higher level than indomethacin itself. Analysis of these derivatives revealed an interesting structure-function relationship. Most remarkably, two substances increased the toxicity, when doxorubicin was used at clinically relevant low concentrations, at a higher degree than indomethacin.
- Rosenbaum, Claudia,R?hrs, Sonja,Müller, Oliver,Waldmann, Herbert
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p. 1179 - 1187
(2007/10/03)
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- A General Synthesis of Substituted Indoles from Cyclic Enol Ethers and Enol Lactones
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(Equation presented) A general method was developed for the one-pot synthesis of highly functionalized indoles from simple, commercially available aryl hydrazines and cyclic enol ethers. Enol lactones were also used as substrates, affording substituted indole acetic acid or indole propionic acid derivatives. This procedure affords 2,3-disubstituted indoles as single regioisomers from the appropriately substituted enol ether or enol lactone. This method was highlighted in the efficient synthesis of the antimigraine drug sumitriptan and the antiinflammatory drug indomethacin.
- Campos, Kevin R.,Woo, Jacqueline C. S.,Lee, Sandra,Tillyer, Richard D.
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- Synthesis and Biological Evaluation of an Indomethacin Library Reveals a New Class of Angiogenesis-Related Kinase Inhibitors
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Capture and release: Indomethacin has served as a lead compound for the synthesis of a library that revealed a new class of kinase inhibitors. A synthetic approach termed "resin-capture-release" was developed (see scheme) that allowed a large library to be synthesized easily. Six of the library compounds were found to be inhibitors of angiogenesis-related receptor tyrosine kinases.
- Rosenbaum, Claudia,Baumhof, Patrick,Mazitschek, Ralf,Mueller, Oliver,Giannis, Athanassios,Waldmann, Herbert
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p. 224 - 228
(2007/10/03)
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- Synthesis method of nitroxymethylphenyl esters of aspirin derivatives
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The invention describes a method for the synthesis of nitroxymethylphenyl esters of aspirin derivatives.
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- Treatment of genitourinary tract disorders
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Genitourinary system disorders are treated with therapeutic agents, and optionally further with radiation treatments.
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- The self-association of the drug acemetacin and its interactions and stabilization with beta-cyclodextrin in aqueous solution as inferred from NMR spectroscopy and HPLC studies.
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Strongly concentration dependent, (1)H NMR chemical shifts of the non-steroidal anti-inflammatory drug acemetacin sodium salt (sodium [[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetoxy]acetate), were observed in aqueous solution. Self-titration and nOe experiments, point to a self-association model where stacking takes place via the indole portion of the drug. In addition, conformational isomerism (atropisomerism) of the anti to syn form was confirmed. Further increase of the concentration eventually led to stable chemical shifts and nearly simultaneous appearance of microcrystals. In the presence of betaCD, 1:1 inclusion complexation occurred through the p-chlorobenzoyl part of the drug, whereas with excess betaCD the indole part seemed to participate to a minor degree. The anti isomer is suggested to be involved in the inclusion process. In addition, aggregation of acemetacin was also evident, as competing with the conformational and inclusion equilibria. The present case demonstrates that many competitive processes are simultaneously active in a seemingly simple system. The measurements were strongly dependent upon the pH and use of buffered solutions was mandatory. Finally, for the quantitative analysis of acemetacin in the presence of betaCD, a special HPLC method was developed. The stability of the drug, studied by the identification of the degradation products and the pseudo-first order rate of hydrolysis, was found to be unaffected by the presence of betaCD.
- Zouvelekis, Dimitris,Yannakopoulou, Konstantina,Mavridis, Irene M,Antoniadou-Vyza, Ekaterini
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p. 1387 - 1395
(2007/10/03)
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- Palladium catalyzed indolization
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Indoles of structural formula (III): STR1 are synthesized by the palladium-catalyzed coupling/ring closure of a 2-halo or 2-trifluoromethylsulfonyloxy aniline and an alkyl ketone derivative. The process is particularly useful to form indoles containing acid-labile substituents such as triazole, acetyl, ketal, cyano, and carbamate, or indoles having a facile leaving group in the benzyl position. The advantages of the present process are that it does not require the use of triphenyl phosphine or tetrabutyl ammonium chloride or lithium chloride.
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- Cyclic amide derivatives as potential prodrugs II: N- hydroxymethylsuccinimide- / isatin esters of some NSAIDs as prodrugs with an improved therapeutic index
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Ester prodrugs of aspirin la, ibuprofen 1b, naproxen 1c and indomethacin 1d were synthesized using N-Hydroxymethylsuccinimide (HMSI) 3 and N- hydroxymethylisatin (HMIS) 4 as promoieties to reduce their gastrointestinal toxicity and improve bioavailability. Additionally, the kinetics of hydrolysis of the synthesized prodrugs 5a-d and 6a-d were studied at 37°C in non-enzymatic simulated gastric fluid (SGF; hydrochloric acid buffer pH = 1.2); 0.02 M phosphate buffer (pH = 7.4); 80% human plasma and 10% rat liver homogenate. The results indicate higher chemical stability of the ester prodrugs in non-enzymatic SGF (t(1/2) ? 6.5-18.6 h) and rapid conversion to the parent drugs in 80% human plasma (t(1/2) ? 11.4-235 min) as well as in 10% rat liver homogenates (t(1/2) ? 12.0-90.0 min). As a general pattern, the HMSI esters 5a-d revealed higher chemical stability than the corresponding HMIS analogues 6a-d. The pH-rate profile of 5c and 6a indicated maximum stability of the former at pH = 1.2-8.0 and of the latter at pH = 1.2-4.0. The distribution coefficient (D7.4) values of the prodrugs 5a-d, 6a-d and the parent drugs 1a-d in an n-octanol/phosphate buffer (pH =7.4) system indicated enhanced lipophilic properties of the prodrugs. Furthermore, the HMIS ester prodrugs 6a-d are more lipophilic than the corresponding HMSI derivatives 5a-d. In vivo ulcerogenicity studies using scanning electron microscopy on stomach specimens of rats treated with an oral dose for 4 d revealed that the synthesized ester prodrugs are significantly less irritating to gastric mucosa than the parent drugs. These results suggested HMSI and/or HMIS esters possess good potential as prodrugs with an improved therapeutic index for oral delivery of NSAIDs.
- Mahfouz, Nadia M.,Omar, Farghaly A.,Aboul-Fadl, Tarek
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p. 551 - 562
(2007/10/03)
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- Bioadhesive emulsion preparations for enhanced drug delivery
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The invention relates to an oil-in-water emulsion and related method for administration of a drug to a mucosal surface. The emulsion has an aqueous continuous phase and a plurality of submicron particles having an average particle diameter of from 10 nm to 600 nm, with the particles having a hydrophobic core of a fat or oil which is surrounded by a surfactant layer. The emulsion further includes a drug and a mucoadhesive polymer which is a polymer or copolymer of acrylic acid or methacrylic acid, a poly(methyl vinyl ether/maleic anhydride) copolymer, pectin, alginic acid, hyaluronic acid, chitosan, gum tragacanth, karaya gum or carboxymethylcellulose. The hydrophobic core has less than 1% (w/w) protein, relative to the weight of the hydrophobic core, and the emulsion contains less than 5% (w/w) surfactant, relative to the weight of the hydrophobic core.
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- Lactone compounds for treating patient with precancerous lesions
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Substituted lactone compounds are useful in the treatment of precancerous lesions and neoplasms.
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- Prodrugs: Part 3. 2-Formylphenyl esters of indomethacin, ketoprofen and ibuprofen and 6-substituted 2-formyl and 2-acylphenyl esters of aspirin
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The synthesis and study of a novel series of potential prodrugs of indomethacin, ketoprofen, ibuprofen and aspirin are reported. 2-Formylphenyl esters of the NSAIDs, together with two 6-substituted 2-formyl and two 2-acylphenyl aspirins and 4-formylphenyl indomethacin, have been prepared. A study of their alkaline and neutral hydrolysis shows that these compounds, with the exception of 2-acetylphenyl aspirin, act as true prodrugs of the NSAIDs, giving the NSAID and acylphenol. The rates of hydrolysis and activation parameters indicate that the 2-acylphenyl esters employ an intramolecular catalytic route. The 2-formylphenyl esters were more potent as anti-inflammatory agents than the parent compounds in the carragheenan-induced paw oedema test.
- Abordo, Evelyn A.,Bowden, Keith,Huntington, Anthony P.,Powell, Sarah L.
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- Cyclic amide derivatives as potential prodrugs. Synthesis and evaluation of N-hydroxymethylphthalimide esters of some non-steroidal anti-inflammatory carboxylic acid drugs
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N-Hydroxymethylphthalimide (HMPhI) esters 5a-d of some nonsteroidal anti-inflammatory drugs were synthesized and evaluated as potential prodrugs with the aim of depressing the gastrotoxicity of the parent drugs by temporarily masking the carboxylic acid function. The ester prodrugs were synthesized through condensation of N-hydroxymethylphthalimide and the mixed carboxylic-carbonic anhydride intermediate or the corresponding acid chloride of the parent acid. Their structures were confirmed by 1H-NMR spectra and the purity has been assessed by TLC and elemental analyses. An HPLC method has been developed for investigation of the hydrolysis kinetics in aqueous buffer solutions and in 80% rabbit plasma. The lipophilicity parameters log P and log k' were determined and showed that the prodrugs were found to be more lipophilic (log P > 2) than the parent drugs. A considerable chemical stability of all compounds (t( 1/4 ) = 4.7-21.9 h) has been observed in non-enzymatic simulated gastric fluid (hydrochloric acid buffer of pH 1.3), while at pH 7.4 only prodrugs 5b-d are sufficiently stable (t( 1/4 ) ~3-5 h). Meanwhile, rapid conversion to the parent drugs 3a-d was observed in 80% rabbit plasma (t( 1/4 ) ~1.0-11.5 min). Potential ulcerogenicity on rat stomach mucosa of the prodrugs and the parent drugs after oral administration for 4 days was studied using a scanning electron microscope. Gross observations and scanning electro-micrographs showed that the prodrugs are significantly less irritating to gastric mucosa than the parent NSAIDs. This result suggests that N-hydroxymethylphthalimide esters may be useful as nonulcerogenic prodrug forms for acidic NSAIDs.
- Omar, Farghaly A.
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p. 123 - 131
(2007/10/03)
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- Mucosal adhesive device for long-acting delivery of pharmaceutical combinations in oral cavity
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Mucosal adhesive devices are provided for use in the oral cavity for therapy against infections. The devices are dosage units which comprise a combination of antimicrobial agents such as antifungal agents and anti-inflammatory agents, optionally also a local anesthetic. The dosage units yield a gradual and relatively constant release of the pharmaceuticals over at least a 12-hour period.
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- New class of potent ligands for the human peripheral cannabinoid receptor
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A new class of potent ligand for the human peripheral cannabinoid (hCB2) receptor is described. Two indole analogs 13 and 17 exhibited nanomolar potencies (K(i)) with good selectivity for the hCB2 receptor over the human central cannabinoid (hCB1) receptor.
- Gallant, Michel,Dufresne, Claude,Gareau, Yves,Guay, Daniel,Leblanc, Yves,Prasit, Petpiboon,Rochette, Chantal,Sawyer, Nicole,Slipetz, Deborah M.,Tremblay, Nathalie,Metters, Kathleen M.,Labelle, Marc
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p. 2263 - 2268
(2007/10/03)
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- Pharmaceutical composition for ophthalmic use comprising a nonsteroidal anti-inflammatory and a decongestant drug
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A pharmaceutical aqueous solution for ophthalmic use comprising a nonsteroidal anti-inflammatory drug, having a carboxylic group, a decongestant drug and a mixture of a polysorbate and a poloxamer.
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- Water dispersion containing ultrafine particles of organic compounds
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A water-dispersible condensate of water-insoluble ultrafine particles of medicine or hormones having a particle size of at largest 4 μm prepared by the steps of heating the medicine or hormone in a vacuum vessel at a temperature of 30° C. higher than the boiling point and at a pressure between 0.01 Torr and 10 Torr to evaporate the medicine or hormone and condensing the medicine or hormone on a recovery plate to obtain the condensate.
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- Gastric preparation with sustained release
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A gastric preparation developed in order to solve the technical problems of conventional preparations, which is prepared by the bilayer packing technique and comprises 5 to 60%, desirably 10 to 40% of a rapid release portion which can establish the therapeutic level of a drug shortly after the administration and 95 to 40%, desirably 90 to 60% of a sustained release portion which has a specific gravity or 1 or less and can maintain a satisfactory release rate.
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- Synthesis and pharmacological evaluation of oligoethylene ester derivatives as indomethacin oral prodrugs
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Five indomethacin oligoethylene ester derivatives (3-7) were synthesized and evaluated for their anti-inflammatory, analgesic, and ulcerogenic activity after oral administration. The molecular weight of the oligoethylene glycols used for synthesizing esters 3-7 ranged from 106 to 282. The chemical and enzymatic stabilities of esters 3-7 were evaluated in pH 7.4 and 2.0 buffers and in human plasma, respectively. All the prodrugs showed a good stability both in pH 7.4 phosphate buffer and in pH 2.0 buffer, and they were readily hydrolyzed by human plasma. Esters 3-7 showed an anti-inflammatory activity, determined as the percent inhibition of carrageenan-induced edema, similar to that of indomethacin, although at higher doses. From writhing test results, we observed that all the prodrugs exhibited better or similar analgesic activity compared to indomethacin. Esters 3-7 were significantly less irritating to the gastric mucosa than indomethacin, after oral administration, and esters 3-5 did not show any ulcerogenic activity, although they were administered at higher doses than indomethacin.
- De Caprariis,Palagiano,Bonina,Montenegro,D'Amico,Rossi
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p. 1578 - 1581
(2007/10/02)
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