- Synthesis and photocleavage of a new polymerizable [2+2] hetero dimer for phototriggered drug delivery
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7-Hydroxy-1,1-dimethylnaphtalenone is introduced as a versatile photocleavable linker system for drug attachment to polymer materials with significantly improved two-photon-absorption efficiency. The synthesis of TBDMS-protected 7-hydroxy-1,1-dimethylnaphtalenone monomer is described, which is the release group attached to the polymer moiety. The cytotoxic 5-fluoro-1-heptanoyluracil was photochemically attached via [2+2] cycloaddition to this release group. The linker-drug conjugate was photochemically polymerized into a HEMA/MMA copolymer. Photo-triggered drug release from the polymer via single-photon-absorption as well as two-photon-absorption in solution were carried out. The detachment of 5-FU from the polymer and its release from the polymer were monitored in the polymer as well as in the aqueous medium and multidose drug release was successfully demonstrated.
- Liese, Julia,Hampp, Norbert A.
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Read Online
- IMPROVED PROCESS FOR THE PREPARATION OF 9-ETHYL-6,6-DIMETHYL-8-[4-(MORPHOLIN-4-YL) PIPERIDIN-1-YL]-11-OXO-6,11-DIHYDRO-5H-BENZO[B]CARBAZOLE-3-CARBONITRILE HYDROCHLORIDE
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The present invention relates to novel process for the preparation of 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride compound of formula-1a, represented by the following structural formula: The present invention also provides an improved process for the preparation of tert-butyl-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate having the following structural formula which is useful in the preparation of Alectinib and its pharmaceutical acceptable salts.
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Page/Page column 19
(2019/11/19)
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- 4-(2-AMINO-TETRAHYDRONAPHTHALENYL)PYRIMIDINE DERIVATIVE, PREPARATION METHOD THEREFOR, AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING CANCER, CONTAINING SAME AS ACTIVE INGREDIENT
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The present invention relates to a 4-(2-amino-tetrahydronaphthaleneyl)pyrimidine derivative, a preparation method thereof, and a pharmaceutical composition for the prevention or treatment of cancer comprising the same as an active ingredient. The 4-(2-amino-tetrahydronaphthaleneyl)pyrimidine derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention is very effective in suppressing anaplastic lymphoma kinase (ALK) activity and as a result it can improve the effectiveness of treatment on cancer cells having anaplastic lymphoma kinase (ALK) fusion proteins such as EML4-ALK and NPM-ALK, so that it can be effectively used as a pharmaceutical composition for preventing or treating cancer.
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Paragraph 0170; 0171; 0172
(2018/04/26)
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- Four and circular Anaplastic lymphoma kinase inhibitors
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The invention belongs to the technical field of medicines, and particularly relates to a four-ring anaplastic lymphoma kinase inhibitor as shown in a general formula (I), or stereisomers, or pharmaceutically acceptable salts, esters or solvates of the inhibitor, wherein A1, A2, A3, M, X, Y, Q, R4, R5, R6, R7 and n are defined in the specification. The invention also relates to a preparation method of these compounds, pharmaceutical preparations and pharmaceutical compositions containing these compounds, and application of the compound or the stereisomers, or the pharmaceutically acceptable salts, esters or solvates of the compound in preparation of medicines for treating and/or preventing ALK-mediated cancer related diseases.
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Paragraph 0443; 0444; 0445
(2017/08/25)
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- Novel 2,4-diaminopyrimidines bearing tetrahydronaphthalenyl moiety against anaplastic lymphoma kinase (ALK): Synthesis, in vitro, ex vivo, and in vivo efficacy studies
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A series of novel 2,4-diaminopyrimidines bearing tetrahydronaphthalenyl moiety were synthesized and evaluated for their anti-anaplastic lymphoma kinase (ALK) activities using enzymatic and cell-based assays. Among the compounds synthesized, compound 17b showed promising pharmacological results in in vitro, ex vivo, and pharmacokinetic studies. An in vivo efficacy study with compound 17b demonstrated highly potent inhibitory activity in H3122 tumor xenograft model mice. A series of kinase assays showed that compound 17b inhibited various kinases including FAK, ACK1, FGFR, RSK1, IGF-1R, among others, thus demonstrating its potential for synergistic anti-tumor activity and development as a multi-targeted non-small cell lung cancer (NSCLC) therapy.
- Song, Dawn,Lee, Minji,Park, Chi Hoon,Ahn, Sunjoo,Yun, Chang Soo,Lee, Chong Ock,Kim, Hyoung Rae,Hwang, Jong Yeon
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supporting information
p. 1720 - 1725
(2016/07/27)
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- COMPOSITION COMPRISING TETRACYCLIC COMPOUND
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A composition which comprises substance represented by Formula (I), [Meanings of the symbols that are included in the formula are given in the specification as definitions] a pharmaceutically acceptable carrier, and a dissolution aid. is useful for improving solubility, oral absorbability and/or absorbability in blood of a poorly water-soluble or water insoluble tetracyclic compounds having an ALK inhibitory activity that are useful as a prophylactic and/or therapeutic agent for cancer, depression, and cognitive function disorder.
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Paragraph 0524; 0525; 0526; 0527; 0492; 0493; 0494; 0495
(2013/06/26)
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- TETRACYCLIC COMPOUND
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A compound represented by the general Formula (I) below, or a salt or solvate thereof, which is useful as an ALK inhibitor, and is useful for prophylaxis or treatment of a disease accompanied by abnormality in ALK, for example, cancer, cancer metastasis,
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Page/Page column 39-40
(2012/04/11)
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- Thermal [2 + 2] cycloreversion of a cyclobutane moiety via a biradical reaction
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The nature of the Woodward-Hoffmann-forbidden, thermal activated cycloreversion mechanism of cyclobutane has long been the subject of speculation and intense research. We were now able to prove the theoretically postulated biradicalic mechanism directly from radical scavenging reactions and electron paramagnetic resonance (EPR) experiments on [2 + 2] heterodimers of 5-fluoro-1-heptanoyluracil and 7-methoxy-1,1-dimethylnaphthalenon. The dimers show both the "allowed" photochemically as well as the "forbidden" thermally triggered [2 + 2] cycloreversion of the cyclobutane ring. The quantum efficiency of the photochemical cleavage is about 1%. The thermal cycloreversion reaction is independent from solvent and occurs at low activation energies of about 13 kcal/mol, even in the solid state. The radical scavenger and EPR results are further supported by the finding, that the reaction products are solely the educts for the anti-head-to-tail heterodimer. But for the syn-head-to-head heterodimer two additional products are observed, which require a sufficiently stable biradical intermediate to facilitate the required intramolecular rearrangements. Because of the surprisingly high lifetime of the radical species of these heterodimers it was possible to prove the long-discussed biradical mechanism experimentally.
- Liese,Hampp
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body text
p. 2927 - 2932
(2011/06/20)
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- 1,1-Dimethylnaphthalenon-dimers as photocleavable linkers with improved two-photon-absorption efficiency and hydrolytic stability
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Coumarins are well known for reversible dimer formation with wavelengths greater than 300. nm and dimer cleavage below 300. nm. In a photochemical [2+2]-cycloaddition a cyclobutane ring is formed. Formation as well as cleavage of the cyclobutane ring may be accomplished by a single-photon-absorption as well as by a two-photon-absorption triggered reaction. The coumarin system is of interest for various kinds of applications, ranging from drug delivery for ophthalmic implants to optical data storage. However, the two-photon-absorption coefficient of coumarin dimers is rather low falling in the range of 1. GM in the visible range. We present here a substitute for the coumarin dimer system which not only has an about one order of magnitude higher two-photon-absorption coefficient, but also overcomes several other problems of the coumarin dimer system. Coumarines and in particular coumarine dimers have a very limited solubility in common solvents and are susceptible to hydrolysis of the lactone ring, which leads to an undesired complexity in the photochemical cleavage reaction. The 1,1-dimethylnaphtalenone dimers introduced here show excellent stability, lead only to a single cleavage product, and have a two-photon-absorption coefficient of about 10. GM at 532. nm. These properties make the 1,1-dimethylnaphtalenone dimers a superior substitute over the well-known coumarin dimers in particular in applications where two-photon-absorption induced photocleavage is required.
- Liese, Julia,Hampp, Norbert A.
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experimental part
p. 128 - 134
(2010/10/19)
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- AMINOTETRALIN COMPOUNDS AS MU OPIOID RECEPTOR ANTAGONISTS
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The invention provides aminotetralin compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, n, and m are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are antagonists at the mu opioid receptor. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat conditions associated with mu opioid receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 16
(2009/06/27)
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- AMINO- AND AMIDO-AMINOTETRALIN DERIVATIVES AND RELATED COMPOUNDS AS MU OPIOID RECEPTOR ANTAGONISTS
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The invention provides amino- and amido-aminotetralin compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, and n are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are antagonists at the mu opioid receptor. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat conditions associated with mu opioid receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 16
(2009/10/06)
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- 3-CARBOXYPROPYL-AMINOTETRALIN DERIVATIVES AND RELATED COMPOUNDS AS MU OPIOID RECEPTOR ANTAGONISTS
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The invention provides 3-carboxypropyl-aminotetralin compounds of formula (I): wherein R1, R2, R3, R4, R5, and R6 are defined in the specification, or a pharmaceutically-acceptable salt the
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Page/Page column 15
(2009/06/27)
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