- CYCLOPROPYLAMINE COMPOUND AS LSD1 INHIBITOR AND USE THEREOF
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Provided is a cyclopropylamine compound as lysine-specific demethylase 1 (LSD1) inhibitor, and a use thereof in preparation of drug for treating diseases associated with LSD1. The cyclopropylamine compound is a compound represented by formula (I), an isomer thereof, and a pharmaceutically acceptable salt thereof.
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Paragraph 0062-0064
(2021/07/24)
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- SALT OF LSD1 INHIBITOR AND A POLYMORPH THEREOF
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Provided are a compound III serving as an LSD1 inhibitor and a crystal form thereof, as well as use of the compound and the crystal form thereof in preparation of a medicament for treating an LSD1 related disease.
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Paragraph 0038-0040
(2021/10/15)
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- Synthetic method for arylcyclopropylamine compound
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The invention relates to a synthetic method for an arylcyclopropylamine compound. The method comprises the following steps: with a cinnamaldehyde compound as a raw material, reacting the cinnamaldehyde compound with bis(pinacolato)diboron to obtain a boroalkylated product; and then subjecting the boroalkylated product and an aminated compound to a ring-closure reaction so as to obtain the arylcyclopropylamine compound. Compared with the prior art, the invention has the following advantages: the synthetic method of the invention is simple to operate and short in reaction time; reagents used inthe invention are cheap and easily available; the target arylcyclopropylamine compound can be prepared from most substrates at a high overall yield and is mainly in the form of transconfiguration; anda route of the method is obviously improved, more economical, safer and easy for industrial production.
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- Gram-Scale Synthesis of Chiral Cyclopropane-Containing Drugs and Drug Precursors with Engineered Myoglobin Catalysts Featuring Complementary Stereoselectivity
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Engineered hemoproteins have recently emerged as promising systems for promoting asymmetric cyclopropanations, but variants featuring predictable, complementary stereoselectivity in these reactions have remained elusive. In this study, a rationally driven strategy was implemented and applied to engineer myoglobin variants capable of providing access to 1-carboxy-2-aryl-cyclopropanes with high trans-(1R,2R) selectivity and catalytic activity. The stereoselectivity of these cyclopropanation biocatalysts complements that of trans-(1S,2S)-selective variants developed here and previously. In combination with whole-cell biotransformations, these stereocomplementary biocatalysts enabled the multigram synthesis of the chiral cyclopropane core of four drugs (Tranylcypromine, Tasimelteon, Ticagrelor, and a TRPV1 inhibitor) in high yield and with excellent diastereo- and enantioselectivity (98–99.9% de; 96–99.9% ee). These biocatalytic strategies outperform currently available methods to produce these drugs.
- Bajaj, Priyanka,Sreenilayam, Gopeekrishnan,Tyagi, Vikas,Fasan, Rudi
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p. 16110 - 16114
(2016/12/26)
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- Targeting Cancer with PCPA-Drug Conjugates: LSD1 Inhibition-Triggered Release of 4-Hydroxytamoxifen
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Targeting cancer with small molecule prodrugs should help overcome problems associated with conventional cancer-targeting methods. Herein, we focused on lysine-specific demethylase 1 (LSD1) to trigger the controlled release of anticancer drugs in cancer cells, where LSD1 is highly expressed. Conjugates of the LSD1 inhibitor trans-2-phenylcyclopropylamine (PCPA) were used as novel prodrugs to selectively release anticancer drugs by LSD1 inhibition. As PCPA-drug conjugate (PDC) prototypes, we designed PCPA-tamoxifen conjugates 1 a and 1 b, which released 4-hydroxytamoxifen in the presence of LSD1 in vitro. Furthermore, 1 a and 1 b inhibited the growth of breast cancer cells by the simultaneous inhibition of LSD1 and the estrogen receptor without exhibiting cytotoxicity toward normal cells. These results demonstrate that PDCs provide a useful prodrug method that may facilitate the selective release of drugs in cancer cells.
- Ota, Yosuke,Itoh, Yukihiro,Kaise, Asako,Ohta, Kiminori,Endo, Yasuyuki,Masuda, Mitsuharu,Sowa, Yoshihiro,Sakai, Toshiyuki,Suzuki, Takayoshi
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supporting information
p. 16115 - 16118
(2016/12/26)
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- KDM1A INHIBITORS FOR THE TREATMENT OF DISEASE
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Disclosed herein are new compounds and compositions and their application as pharmaceuticals for the treatment of diseases. Methods of inhibition of KDMIA, and methods of increasing gamma globin gene expression in a human or animal subject are also provided for the treatment diseases such as sickle cell disease.
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- COMPLEMENT PATHWAY MODULATORS AND USES THEREOF
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The present invention provides a compound of formula I: (I) a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
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Page/Page column 67; 68
(2014/01/17)
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- (HETERO)ARYL CYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS
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The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula I as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection.
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Page/Page column 150
(2013/05/09)
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- (HETERO)ARYL CYCLOPROPYLAMINE COMPOUNDS AS LSD1 INHIBITORS
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The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection.
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Page/Page column 7156
(2013/05/09)
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- Asymmetric syntheses of pharmaceuticals containing a cyclopropane moiety using catalytic asymmetric Simmons-Smith reactions of allylalcohols: Syntheses of optically active tranylcypromine and milnacipran
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Asymmetric synthesis of tranylcypromine was achieved using an enantioselective Simmons-Smith cyclopropanation catalyzed by a simple disulfonamide derived from an -amino acid. The optically active milnacipran was also synthesized by porcine pancreas lipase-catalyzed selective monoacylation of the C4-hydroxy group in (Z)-2-phenylbut-2-ene-1,4-diol and the enantioselective Simmons-Smith cyclopropanation as the key steps.
- Ishizuka, Yuki,Fujimori, Hirohisa,Noguchi, Takuya,Kawasaki, Masashi,Kishida, Mari,Nagai, Takuya,Imai, Nobuyuki,Kirihara, Masayuki
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p. 1311 - 1313
(2013/10/22)
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- Catalytic asymmetric synthesis of nitrocyclopropane carboxylates
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A Cu(I)-catalyzed asymmetric cyclopropanation of alkenes with an iodonium ylide has been developed. The copper source, hypervalent iodine source, solvent, and additives all have a significant effect on the yields and enantioselectivities. High enantioselectivity (up to 99:1 er) and diastereoselectivity (95:5 dr trans/cis) were achieved for a wide range of alkenes. Conditions were developed to convert the trans products to the cis isomers. In addition, 1-nitrocyclopropyl carboxylates were transformed into the corresponding substituted cyclopropane amino acids and aminocyclopropanes. Moreover, a comparative study between Zn- and In-mediated reduction reactions of the nitro group in these compounds with regards to the er erosion in the process is also documented.
- Moreau, Benoit,Alberico, Dino,Lindsay, Vincent N.G.,Charette, Andre B.
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experimental part
p. 3487 - 3496
(2012/06/04)
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- Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2- phenylcyclo- propyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydro-imidazo[1,5-a] pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, Part 2
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The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development.
- Kinzel, Olaf,Alfieri, Anna,Altamura, Sergio,Brunetti, Mirko,Bufali, Simone,Colaceci, Fabrizio,Ferrigno, Federica,Filocamo, Gessica,Fonsi, Massimiliano,Gallinari, Paola,Malancona, Savina,Hernando, Jose Ignacio Martin,Monteagudo, Edith,Orsale, Maria Vittoria,Palumbi, Maria Cecilia,Pucci, Vincenzo,Rowley, Michael,Sasso, Romina,Scarpelli, Rita,Steinkuehler, Christian,Jones, Philip
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scheme or table
p. 4429 - 4435
(2011/09/12)
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- Enantioselective synthesis of tranylcypromine analogues as lysine demethylase (LSD1) inhibitors
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Asymmetric cyclopropanation of styrenes by tert-butyl diazoacetate followed by ester hydrolysis and Curtius rearrangement gave a series of tranylcypromine analogues as single enantiomers. The o,- m- and p-bromo analogues were all more active than tranylcypromine in a LSD1 enzyme assay. The m- and p-bromo analogues were micromolar growth inhibitors of the LNCaP prostate cancer cell line as were the corresponding biphenyl analogues prepared from the bromide by Suzuki crosscoupling.
- Benelkebir, Hanae,Hodgkinson, Christopher,Duriez, Patrick J.,Hayden, Annette L.,Bulleid, Rosemary A.,Crabb, Simon J.,Packham, Graham,Ganesan
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scheme or table
p. 3709 - 3716
(2011/08/02)
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- Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2
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LSD1 and LSD2 histone demethylases are implicated in a number of physiological and pathological processes, ranging from tumorigenesis to herpes virus infection. A comprehensive structural, biochemical, and cellular study is presented here to probe the potential of these enzymes for epigenetic therapies. This approach employs tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. This drug is a clinically validated antidepressant known to target monoamine oxidases A and B. These two flavoenzymes are structurally related to LSD1 and LSD2. Mechanistic and crystallographic studies of tranylcypromine inhibition reveal a lack of selectivity and differing covalent modifications of the FAD cofactor depending on the enantiomeric form. These findings are pharmacologically relevant, since tranylcypromine is currently administered as a racemic mixture. A large set of tranylcypromine analogues were synthesized and screened for inhibitory activities. We found that the common evolutionary origin of LSD and MAO enzymes, despite their unrelated functions and substrate specificities, is reflected in related ligand-binding properties. A few compounds with partial enzyme selectivity were identified. The biological activity of one of these new inhibitors was evaluated with a cellular model of acute promyelocytic leukemia chosen since its pathogenesis includes aberrant activities of several chromatin modifiers. Marked effects on cell differentiation and an unprecedented synergistic activity with antileukemia drugs were observed. These data demonstrate that these LSD1/2 inhibitors are of potential relevance for the treatment of promyelocytic leukemia and, more generally, as tools to alter chromatin state with promise of a block of tumor progression.
- Binda, Claudia,Valente, Sergio,Romanenghi, Mauro,Pilotto, Simona,Cirilli, Roberto,Karytinos, Aristotele,Ciossani, Giuseppe,Botrugno, Oronza A.,Forneris, Federico,Tardugno, Maria,Edmondson, Dale E.,Minucci, Saverio,Mattevi, Andrea,Mai, Antonello
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supporting information; experimental part
p. 6827 - 6833
(2010/07/03)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 61
(2010/12/31)
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- The first synthesis of nitro-substituted cyclopropanes and spiropentanes via oxidation of the corresponding amino derivatives
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A novel approach to nitro-substituted cyclopropanes and spiropentanes via oxidation of the corresponding amines with dimethyldioxirane is reported. The method is used successfully for the preparation of a series of nitrocyclopropanes as well as for the first synthesis of 1,4-dinitrospiro[2.2]pentane.
- Volkova, Yuliya A.,Ivanova, Olga A.,Budynina, Ekaterina M.,Revunov, Eugene V.,Averina, Elena B.
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experimental part
p. 2793 - 2796
(2009/09/28)
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- Enantiomerically pure cyclopropylamines via C-B to C-N conversion
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For the first time cyclopropyltrifluoroborates have been utilized to form cyclopropylamines in a one-pot procedure. The scope was not only demonstrated by successfully reacting various racemic cis- and trans-2-substituted cyclopropanes as well as azides, but also by applying the sequence to enantiomerically pure building blocks. An approach to tranylcypromine as well as belactosin A is outlined. Georg Thieme Verlag Stuttgart.
- Pietruszka, J?rg,Solduga, Gemma
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scheme or table
p. 1349 - 1352
(2009/04/06)
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- The kulinkovich reaction in the synthesis of constrained N,N-dialkyl neurotransmitter analogues
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An intermolecular Ti(IV)-mediated cyclopropanation reaction has been used to synthesize substituted 2-phenylcyclopropylamines and constrained analogues of the neurotransmitters histamine and tryptamine. Many hydroxy- and methoxy-substituted phenylcyclopropylamines are known to inhibit monoamine oxidase and have been shown to mimic hallucinogens. These compounds were made in 1 to 5 steps from readily available starting materials.
- Faler, Catherine A.,Joullie, Madeleine M.
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p. 1987 - 1990
(2008/02/02)
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- Expedient synthesis of cyclopropane α-amino acids by the catalytic asymmetric cyclopropanation of alkenes using iodonium ylides derived from methyl nitroacetate
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A highly enantioselective (up to 97.5% ee) and diastereoselective (95:5 dr trans/cis) Cu(I)-catalyzed cyclopropanation of alkenes using phenyliodonium ylide generated in situ from iodosobenzene and methyl nitroacetate is reported. The cyclopropanation took place with high enantioselectivity for a wide range of alkenes, and the reaction was performed at room temperature. 1-Nitrocyclopropyl esters are versatile building blocks to access the corresponding cyclopropane amino esters and aminocyclopropanes in two and three steps, respectively, from commercially available products. Copyright
- Moreau, Benoit,Charette, Andre B.
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p. 18014 - 18015
(2007/10/03)
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- Enantioselective acylation of rac-2-phenylcycloalkanamines catalyzed by lipases
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The kinetic resolution of some 2-phenylcycloalkanamines was performed by means of aminolysis reactions catalyzed by lipases, with Kazlauskas' rule being obeyed in all cases. The size of the ring and the stereochemistry of the stereogenic centers of the amines had a strong influence on both the enantiomeric ratio and the reaction rate of these aminolysis processes. Lipase B from Candida antarctica (CAL-B) showed excellent enantioselectivities toward trans-2-phenylcyclohexanamine in a variety of reaction conditions (E >150), whereas lipase A from C. antarctica (CAL-A) was the best catalyst for the acylation of cis-2-phenylcyclohexanamine (E = 34) and trans-2- phenylcyclopropanamine (E = 9).
- Gonzalez-Sabin, Javier,Gotor, Vicente,Rebolledo, Francisca
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p. 3070 - 3076
(2007/10/03)
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- An exploratory study of ring closures of aryl radicals onto cyclopropyl- and oxiranyl-isocyanate acceptors
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The idea that ring closures of C-centred radicals onto isocyanates could be made permanent by designing the cyclised radical to undergo a rapid onward β-scission, was investigated for the 2-(2-isocyanato)cyclopropylphenyl and 2-(2-isocyanato)oxiranylphenyl radicals. The radical precursors, trans- and cis-l-bromo-(2-isocyanatocyclopropyl)benzene and (2-bromophenyl)-3- isocyanatooxirane, were prepared from the corresponding bromophenylcyclopropane and bromophenyloxirane carboxylic acids via Curtius rearrangements of the derived azides. The structure of the trans-2-(2-isocyanato)cyclopropylphenyl radical prevents cyclization, however, it was shown that isomerisation to the analogous cis-radical occurred, probably by scission of the disubstituted cyclopropane bond followed by internal rotation of the resulting resonance stabilised diradical. It was found, however, that the main product from homolytic reactions of both trans- and cis-isocyanatocyclopropyl compounds, with tributyltin hydride and tris(trimethylsilyl)silane, was the direct reduction product, trans-(2-isocyanatocyclopropyl)benzene. Only traces of cyclised products, that were probably 4,5-dihydrobenzo[c]azepin-1-one from the cyclopropane precursor and 5H-6-oxa-8-azabenzocyclohepten-9-one from the oxirane precursor, were detected. We conclude, therefore, that the rate of cyclization onto isocyanate acceptor groups must be slower in these systems than hex-5-enyl cyclization or that the reverse ring-opening process must be faster than for analogous radicals.
- Minin, Patricia L.,Walton, John C.
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p. 2471 - 2475
(2007/10/03)
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- Catalytic cyclopropanation of alkenes using diazo compounds generated in situ. A novel route to 2-arylcyclopropylamines
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(Equation presented) A user-friendly, one-pot process for catalytic cyclopropanation of alkenes from tosylhydrazones is described. The cyclopropanation of N-vinylphthalimide provides a new route to 2-arylcyclopropylamines, and this is exemplified in the efficient synthesis of the HIV-1 reverse transcriptase inhibitor 6.
- Aggarwal, Varinder K.,De Vicente, Javier,Bonnert, Roger V.
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p. 2785 - 2788
(2007/10/03)
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- Pyrimido?5,4-D!pyrimidines, medicaments comprising these compounds, their use and processes for their preparation
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The present invention relates to pyrimido?5,4-d!pyrimidines of the general formula STR1 in which Ra to Rc are as defined herein, their tautomers, their stereoisomers and their salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases which have valuable pharmacological properties, in particular an inhibiting action on signal transduction mediated by tyrosine kinases, their use for the treatment of diseases, in particular tumor diseases.
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- Method for inhibition of HIV related viruses
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Treatment of AIDS, inhibition of the replication of HIV and related viruses thereof, and formulations using thiourea derivative compounds or salts thereof is disclosed. Also disclosed are novel thiourea derivative compounds.
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- Synthesis of the enantiomer of the antidepressant tranylcypromine
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Both enantiomers of the antidepressant tranylcypromine, trans 2-phenyl-cyclopropylamine 1, were prepared in enantiomerically pure form by a chemoenzymatic approach starting from racemic (±)-(1RS, 2RS)-trans ethyl 2-phenyl-cyclopropane carboxylate (±)-3.
- Csuk, Rene,Schabel, Magda J.,Von Scholz, Yvonne
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p. 3505 - 3512
(2007/10/03)
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- Brain-specific analogues of centrally acting amines
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The subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are compounds of the formula STR1 and the non-toxic pharmaceutically acceptable salts thereof, wherein D is the residue of a centrally acting primary, secondary or tertiary amine and STR2 is an unsubstituted or substituted dihydropyridyl, dihydroquinolyl or dihydroisoquinolyl radical. The corresponding ionic pyridinium, quinolinium and isoquinolinium salts STR3 X-, wherein X- is the anion of a non-toxic pharmaceutically acceptable acid, are also disclosed.
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