- HETEROCYCLIC COMPOUNDS WITH WORKING MEMORY ENHANCING ACTIVITY
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The present invention relates to a chemical compound having the general formula (I): wherein R1 and R2 are, equal or independently, aryl, heteroaryl; wherein RTA is a 2-1,3-, or 4- 1,3- or 5-1,3-thiazole ring and its use in for improving; the short term memory and/or the working memory.
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Page/Page column 34
(2016/02/29)
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- A kind of central nervous system drugs intermediate arab League Qu Feini the synthetic method of the compound of
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The invention relates to a synthesis method of a central nervous system drug adrafinil intermediate compound, namely the synthesis method of a compound expressed by a formula (I) as shown in the specification. According to the synthesis method, a compound expressed by a formula (II) as shown in the specification reacts with a compound expressed by a formula (III) as shown in the specification in an acidic organic solvent in the presence of a catalyst, an organic ligand and an activator to obtain the compound expressed by the formula (I), wherein X is a halogen. Besides, the invention also provides a purification method of the compound expressed by the formula (I); according to the purification method, the target product with extremely high purity can be obtained by virtue of appropriate selection of a recrystallization solvent, a temperature rise rate and a cooling rate.
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Paragraph 0054-0056
(2017/03/17)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROLOGICAL DEGENERATIVE DISORDERS AND NEUROLOGICAL DISEASES
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The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of neurological degenerative disorders and neurological diseases may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of narcolepsy, shift work sleep disorder, and as an adjunct treatment for obstructive sleep apnea/hypopnea, hypersomnias, like idiopathic hypersomnia, Psychiatric/neurodegenerative disorders, ADHD, Psychiatric/neurodegenerative disorders, Depersonalization disorder, Cognitive enhancement, Fatigue, Post-chemotherapy cognitive impairment and weight loss.
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Paragraph 0106; 0107
(2015/05/26)
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- Elucidation of structural elements for selectivity across monoamine transporters: Novel 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues
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2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, (±)-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of (±)-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of (±)-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT.
- Okunola-Bakare, Oluyomi M.,Cao, Jianjing,Kopajtic, Theresa,Katz, Jonathan L.,Loland, Claus J.,Shi, Lei,Newman, Amy Hauck
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p. 1000 - 1013
(2014/03/21)
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- POTENT AND SELECTIVE INHIBITORS OF MONOAMINE TRANSPORTERS; METHOD OF MAKING; AND USE THEREOF
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Disclosed herein are bisarylmethylthioacetamides and bisarylmethylthioethylamines useful as inhibitors of monoamine transporters. The compounds are potent and/or selective inhibitors of dopamine (DA), serotonin (5-HT), and/or norepinephrine (NE) reuptake via their respective transporters, DAT, SERT and NET. Also disclosed are methods for eliciting a wake-promoting or cognitive or attention enhancing effect and for treating substance use disorders, attention deficit (hyperactivity) disorder, depressive disorders, bipolar disorder or other neuropsychiatric disorders sleep disorders or cognitive impairment using the compounds.
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Paragraph 0074; 0086
(2014/09/29)
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- Electron transfer in the peroxytrifluoroacetic acid-assisted sulfoxidation and oxidative destruction of benzhydryl sulfides
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The reactions of benzhydryl sulfides Ph2CHSCH2R (R = H, CONH2, COOH, CN) with peroxytrifluoroacetic acid in CF 3COOH were studied experimentally and by the quantum chemical density functional theory (DFT) method and exhibited an unusual dependence on the substituent R. When R≠H, a complicated oxidative destruction of the substrates occurs to form 2,4,6-tribenzhydrylphenol as one of the products, while in the case of R = H, the starting benzhydryl sulfide is smoothly sulfoxidated. This fact is due to the common electron transfer from the substrate to reagent at the initial step and the difference in subsequent transformations of the species formed.
- Akopova,Morkovnik,Khrustalev,Bicherov
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p. 1164 - 1175
(2014/03/21)
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- COMPOSITIONS AND METHODS FOR TREATMENT OF NEUROLOGICAL DEGENERATIVE DISORDERS AND NEUROLOGICAL DISEASES
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Disclosed are compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. Provided are also pharmaceutical compositions comprising an effective amount of the above compounds for treating neurological degenerative disorders and neurological diseases, which may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used for the treatment of narcolepsy, shift work sleep disorder, and as an adjunct treatment for obstructive sleep apnea/hypopnea, hypersomnias, like idiopathic hypersomnia, psychiatric/neurodegenerative disorders, ADHD, psychiatric/neurodegenerative disorders, depersonalization disorder, cognitive enhancement, fatigue, post-chemotherapy cognitive impairment and weight loss.
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Paragraph 0095-0097
(2014/01/07)
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- Simple synthesis of modafinil derivatives and their anti-inflammatory activity
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Simple synthesis of modafinil derivatives and their biological activity are described. The key synthetic strategies involve substitution and coupling reactions. We determined the anti-inflammatory effects of modafinil derivatives in cultured BV2 cells by measuring the inhibition of nitrite production and expression of iNOS and COX-2 after LPS stimulation. It was found that for sulfide analogues introduction of aliphatic groups on the amide part (compounds 11a-d) resulted in lower anti-inflammatory activity compared with cyclic or aromatic moieties (compounds 11e-k). However, for the sulfoxide analogues, introduction of aliphatic moieties (compounds 12a-d) showed higher anti-inflammatory activity than cyclic or aromatic fragments (compounds 12e-k) in BV-2 microglia cells.
- Jung, Jae-Chul,Lee, Yeonju,Son, Jee-Young,Lim, Eunyoung,Jung, Mankil,Oh, Seikwan
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p. 10446 - 10458
(2012/11/07)
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- SARs at the monoamine transporters for a novel series of modafinil analogues
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A series of modafinil (1) analogues were synthesized wherein (1) para-halo-substitutents were added to the aryl rings, (2) the sulfoxide function was removed, and (3) the primary amide group was replaced with secondary and tertiary amides and amines to investigate the effects of these chemical modifications on dopamine transporter, serotonin transporter, and norepinephrine transporter binding. In addition, the locomotor-stimulant effects in mice of (±)-modafinil (1), its R-and S-enantiomers, and its para-chloro sulfinylacetamide analogue (5c) were compared to those of cocaine.
- Cao, Jianjing,Prisinzano, Thomas E.,Okunola, Oluyomi M.,Kopajtic, Theresa,Shook, Matthew,Katz, Jonathan L.,Newman, Amy Hauck
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supporting information; experimental part
p. 48 - 52
(2011/04/22)
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- Microbial sulfoxidation and amidation of benzhdrylsulfanyl carboxylic acids and uses thereof
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The present invention provides novel methods for the synthesis of racemic and enantiomers of modafinil via microbial oxidation-amidation transformation. The methods include the successive oxidation-amidation of benzhydrylsulfanyl carboxylic acid to produce racemic and enantiomers of modafinil using at least one microorganism of yeast, bacteria, or fungus. Also disclosed are pharmaceutical compositions of racemic and enantiomers of modafinil along with their use in the treatment of diseases, including attention deficit hyperactivity disorder and drug addiction.
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- NOVEL CRYSTALLINE POLYMORPH OF ARMODAFINIL AND AN IMPROVED PROCESS FOR PREPARATION THEREOF
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The present invention relates to a novel crystalline polymorph of armodafinil. In another aspect the invention relates to an improved process for preparation of the novel polymorph of armodafinil.
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Page/Page column 8
(2009/08/16)
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- Towards a robust and reliable method for the reduction of functionalized sulfoxides
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Several functionalized sulfoxides in the modafinil series, which bear another reducible function, were chemoselectively reduced to thioethers using the KI/AcCl system.
- Ternois, James,Guillen, Frederic,Piacenza, Guy,Rose, Sebastien,Plaquevent, Jean-Christophe,Coquerel, Gerard
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p. 614 - 617
(2013/01/03)
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- HETEROCYCLIC AMIDE DERIVATIVES AS CALCIUM CHANNEL BLOCKERS
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Methods and compounds effective in ameliorating conditions characterized by unwanted calcium channel activity, particularly unwanted N-type or T-type calcium channel activity are disclosed. Specifically, a series of heterocyclic amides are disclosed of the general formula (I) where Z is N or CHNR2 and X is NR2, O, S, S=O or SO2. Among other definitions for R, R1, W and Y, the compounds of formula (1) are further characterized by at least one of W or Y being CR3Ar2 where Ar is an aromatic or heteroaromatic ring (for example, where W or Y is a benzhydryl moiety).
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Page/Page column 24
(2008/06/13)
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- ISOXAZOLE DERIVATIVES AS CALCIUM CHANNEL BLOCKERS
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Methods and compounds effective in ameliorating conditions characterized by unwanted calcium channel activity, particularly unwanted N-type or T-type calcium channel activity are disclosed. Specifically, a series of isoxazole containing compounds are disclosed of the general formula (1) where Z is N or CHNR3 and (Ar1)2CR4 is optionally substituted benzhydryl.
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Page/Page column 31
(2008/06/13)
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- Microbial oxidation/amidation of benzhydrylsulfanyl acetic acid. Synthesis of (+)-modafinil
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A highly enantioselective oxidation of benzhydrylsulfanyl acetic acid to the corresponding (S)-sulfinyl carboxylic acid was achieved employing the fungus Beauveria bassiana in very good yield. This product was amidated using the bacteria Bacillus subtilis to afford (S)-modafinil in good yield.
- Olivo, Horacio F.,Osorio-Lozada, Antonio,Peeples, Tonya L.
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p. 3507 - 3511
(2007/10/03)
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- Synthesis and determination of the absolute configuration of the enantiomers of modafinil
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The asymmetric synthesis of both enantiomers of modafinil, a unique CNS stimulant with a reduced abuse liability, is described. This approach effectively prepares modafinil on a multigram scale in several steps from benzhydrol. The described synthetic route has also been used to produce the more water soluble analogue, adrafinil. X-ray crystallographic analysis on (-)-(diphenylmethanesulfinyl)acetic acid has determined the absolute configuration to be R.
- Prisinzano, Thomas,Podobinski, John,Tidgewell, Kevin,Luo, Min,Swenson, Dale
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p. 1053 - 1058
(2007/10/03)
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- Comparison of the labelling characteristics of mercaptoacetyltriglycine (MAG3) with different S-protective groups
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A number of different thiol protective groups have been synthesized and attached to mercaptoacetyltriglycine (MAG3) ligand. The newly made MAG3 analogues were labelled with 99mTc by direct labelling under alkaline condition and by stannous tartrate exchange labelling method. In the latter method, the amount of the ligand, reaction temperature and pH varied and their effects on the labelling efficiencies were studied. Radiochemical purities of 51% to 70%, 58% to 75% and 46% to 81% respectively, were obtained by radio-HPLC analysis for the studied MAG3 precursors when, 0.1 mg, 0.4 mg and 1.6 mg of the ligand was used and labelling was performed at both low temperature (70°C) and pH (pH 3). All the studied ligands were efficiently labelled with 99mTc (up to 99%) when heated for 10 min at pH 9 and 100°C. The labelling efficiency obtained by the direct labelling method for MAG3 analogues varied from 32% to 94% and was in all cases lower than after the exchange labelling at pH 9 and at 100°C. It was observed that the radiochemical purities can be improved significantly by heating the 'direct labelling mixture' at elevated temperature.
- Okarvi, Subhani M.,Adriaens, Paul,Verbruggen
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p. 853 - 874
(2007/10/03)
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- Ferrocene compounds XXII. Synthesis and reactions of some ferrocenylthiaaliphatic acids
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Condensation of several ferrocenylcarbinols (1) with thioglycolic acid, β-mercaptopropionic acid or ss-mercaptoisobutyric acid in the presence of trifluoroacetic acid have given the corresponding ferrocenylthiaaliphatic acids (2-4) with 65-99% yields. Instead of the expected intramolecularly cyclized products, reactions of the acids 2-4 with trifluoroacetic anhydride give 23-30% of the 1,2-disubstituted 1,2-diferrocenylethanes (8), 15-26% of trimeric species (9), and about 30% of oligomeric species (10). The mechanism of the reactions is discussed.
- Lisac,Rapic
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p. 215 - 220
(2007/10/03)
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- Synthesis and Structure-Activity Relationships of 1-Acyl-4-(2-methyl-3-pyridyl)cyanomethyl)piperazines as PAF Antagonists
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A second generation of (cyanomethyl)piperazines, 1-acyl-4-((2-methyl-3-pyridyl)cyanomethyl)piperazines, with increased oral activity was prepared and evaluated in vitro in PAF-induced platelet aggregation assay (PAG) and in vivo in a PAF-induced hypotension test in normotensive rats (HYP).Oral activity was ascertained through a PAF-induced mortality test in mice (MOR).Attachment of a methyl group at position 2 of our earlier pyridine derivatives resulted in an improvement of 1 order of magnitude or greater in the ID50 of the oral test.Three different types of acylsubstituents of similar potency emerge from this work: N-(diphenylmethylamino)acetyl, 3-substituted 3-hydroxy-3-phenylpropionyl, and N-substituted 3-amino-3-phenylpropionyl groups.The most interesting compounds, 26 (UR-12460, PAG IC50 = 0.040 μM, HYP, ID50 = 0.021 mg/kg iv, MOR, ID50 = 0.30 mg/kg po) and 58 (UR-12519, PAG IC50 = 0.041 μM, HYP, ID50 = 0.015 mg/kg iv, MOR, ID50 = 0.044 mg/kg po), compare favorably with WEB-2086.Compounds 26 and 58 were also tested in active anaphylactic shock (AAS) and endotoxin-induced mortality (EIM) tests.On the basis of these data, compounds 26 and 58 have been selected for further pharmacological development.
- Carceller, Elena,Merlos, Manuel,Giral, Marta,Almansa, Carmen,Bartroli, Javier,et al.
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p. 2984 - 2997
(2007/10/02)
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