- 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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- The synergistic effect of copper chromite spinel nanoparticles (CuCr2O4) and basic ionic liquid on the synthesis of cyclopropanecarboxylic acids
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Abstract: An efficient synthesis of cyclopropanecarboxylic acids using copper chromite spinel nanoparticles and basic ionic liquid is described. In this study, a relatively simple method starting with trans-cinnamic acid for the synthesis of (±)-trans-2-phenylcyclopropanecarboxylic acid, a key intermediate in the synthesis of tranylcypromine sulfate as an active pharmaceutical ingredient, was employed. Using a combination of basic ionic liquid [Bmim]OH and copper chromite spinel nanoparticles as a catalytic system, the best results were obtained in THF as a polar solvent. This method is a useful alternative to other approaches described in the literature. The use of commercially available chemicals, decreased environmental hazards, with no need for the separation of stereoisomers, and consequently a reduced number of overall steps, are the advantages of this approach that make it an appropriate choice at an increased scale. Graphical Abstract: [Figure not available: see fulltext.]
- Ghasemi, Mohammad Hadi,Kowsari, Elaheh
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p. 7963 - 7975
(2016/11/25)
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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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supporting information
p. 16110 - 16114
(2016/12/26)
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- Reversible C-C bond activation enables stereocontrol in Rh-catalyzed carbonylative cycloadditions of aminocyclopropanes
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Upon exposure to neutral or cationic Rh(I)-catalyst systems, amino-substituted cyclopropanes undergo carbonylative cycloaddition with tethered alkenes to provide stereochemically complex N-heterocyclic scaffolds. These processes rely upon the generation and trapping of rhodacyclopentanone intermediates, which arise by regioselective, Cbz-directed insertion of Rh and CO into one of the two proximal aminocyclopropane C-C bonds. For cyclizations using cationic Rh(I)-systems, synthetic and mechanistic studies indicate that rhodacyclopentanone formation is reversible and that the alkene insertion step determines product diastereoselectivity. This regime facilitates high levels of stereocontrol with respect to substituents on the alkene tether. The option of generating rhodacyclopentanones dynamically provides a new facet to a growing area of catalysis and may find use as a (stereo)control strategy in other processes.
- Shaw, Megan H.,McCreanor, Niall G.,Whittingham, William G.,Bower, John F.
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supporting information
p. 463 - 468
(2015/01/30)
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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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- 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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- 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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- 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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- 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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- 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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- 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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- 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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- Flavin chemical models for monoamine oxidase inactivation by cyclopropylamines, α-silylamines, and hydrazines
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Models for the inactivation of the monoamine oxidase A and B, two closely related flavoenzymes, by cyclopropylamines, α-silylamines, and hydrazines have been investigated in order to gain insight into the possible chemical mechanisms for these processes. The activated (i.e. high reduction potential and electrophilicity) flavin, 3-methyl-5-ethyllumiflavinium perchlorate (5), was employed in this effort along with trans-2-phenylcyclopropylamine (1), a host of monosubstituted hydrazines (13-16), and α-(trimethylsilyl)benzylamine (9). Admixture of 5 with 1 (25°C, MeCN) results in instantaneous formation of the stable and completely characterized flavin-amine adducts 6 (K(e) = 2 x 104) derived by addition of the amine function in 1 to the 4a-position of 5. Reaction of the 4a-adduct 6 with cyclopropylamine 1 (85°C, MeCN) cleanly (80%) produces the aldimine 7 formed by condensation of the initial product, trans-cinnamaldehyde and amine 5. These results demonstrate that 4a-adducts related to 6 are capable of undergoing cyclopropane ring opening reactions by polar pathways to produce electrophilic α,β-unsaturated carbonyl products. Consequently, ring opening reactions proposed for monoamne oxidase inactivation by primary and perhaps secondary cyclopropylamines can occur by polar routes and, thus, are not uniquely attributable to radical mechanistic pathways. In a similar manner, the flavinium salt 5 undergoes rapid reaction with the α-silylamine 9 to produce a stable 4a-adduct 10 (K(e) = 7 x 104). Reaction of this adduct with 9 (45°C, MeCN) leads to initial production of N-[(α-trimethylsilyl)benzyl]benzaldimine (12) which undergoes desilylation to produce N-benzylbenzaldimine (11) under these conditions. Also, 4a-adduct 10 is rapidly converted to aldilne 11 by reaction with TBAF at 25°C in MeCN. These results show that 4a-adducts, generated from activated flavins and α-silylamines, participate in fragmentation processes leading to silylation of nucleophiles and production of carbonyl products. This polar mechanistic pathway models the known inactivation reactions of the MAOs by α-silylamines previously attributed to SET (radical) routes. Reaction of flavinium salt 5 with phenyl- or benzylhydrazine results in formation of 4a-phenyl or -benzyl flavin adducts. For example, admixture of 5 and PhNHNH2 in CH3CN at 25°C provides the characterizable 4a-phenyl and 4a-cyanomethyl flavins, 21 (28%) and 22 (55%), and benzene. Benzylhydrazine reacts similarly with 5 to produce only the 4a-benzyl adduct 23 (89%). Information about the mechanism for adduct formation in these reactions has come from studies with the hydrazine analogs, NH2NHCO2CH2Ph (15) and NH2OCH2Ph (16). These substances react rapidly with 5 in MeCN at 25°C to cleanly produce stable 4a-hydrazine adducts, 17. The results suggest that 4a-alkylation or -arylation reactions of the activated flavin 5 with hydrazines probably occur via the intermediacy of 4a-hydrazine flavin adducts related to 17. Thus, a polar mechanistic model is also consistent with the known inactivation reactions of the MAOs with hydrazines which are also reported to generate 4a-flavin alkylated and arylated MAO derivatives.
- Kim, Jong-Man,Hoegy, Susan E.,Mariano, Patrick S.
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p. 100 - 105
(2007/10/02)
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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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