- Identification, characterization, synthesis and strategy for minimization of potential impurities observed in the synthesis of brivaracetam
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A first systematic impurity profile research concerning nine observed and potential process related impurities of antiepileptic drug brivaracetam is reported. Among which three (impurity G/H/I) have not been discovered or reported before, these nine impurities were monitored by HPLC, and their structures were identified on the basis of MS and NMR spectroscopy. In addition to the formation, synthesis, and characterization, strategies for minimizing these impurities to the levels accepted by ICH are also described in this report.
- Liao, Shouzhu,Chen, Hongjun,Wang, Guifei,Wu, Shuming,Yang, Zaiyou,Luo, Weihe,Liu, Zhuanfeng,Gao, Xun,Qin, Junhai,Li, Chuan-hua,Wang, Zhongqing
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- Oxazolidin-2-one-Pyrimidine Derivatives
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The present invention relates to oxazolidin-2-one substituted pyrimidine compounds that act as PI3K (phosphatidylinositol-3-kinase) inhibitors, as well as pharmaceutical compositions thereof, methods for their manufacture and uses for the treatment of conditions, diseases and disorders dependent on PI3K.
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Paragraph 0230
(2014/05/20)
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- Assay and inhibition of diacylglycerol lipase activity
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A series of N-formyl-α-amino acid esters of β-lactone derivatives structurally related to tetrahydrolipstatin (THL) and O-3841 were synthesized that inhibit human and murine diacylglycerol lipase (DAGL) activities. New ether lipid reporter compounds were developed for an in vitro assay to efficiently screen inhibitors of 1,2-diacyl-sn-glycerol hydrolysis and related lipase activities using fluorescence resonance energy transfer (FRET). A standardized thin layer chromatography (TLC) radioassay of diacylglycerol lipase activity utilizing the labeled endogenous substrate [1″- 14C]1-stearoyl-2-arachidonoyl-sn-glycerol with phosphorimaging detection was used to quantify inhibition by following formation of the initial product [1″-14C]2-arachidonoylglycerol and further hydrolysis under the assay conditions to [1-14C]arachidonic acid.
- Johnston, Meghan,Bhatt, Shachi R.,Sikka, Surina,Mercier, Richard W.,West, Jay M.,Makriyannis, Alexandros,Gatley, S. John,Duclos Jr., Richard I.
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scheme or table
p. 4585 - 4592
(2012/08/08)
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- Tripeptidylpeptidase inhibitors
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A compound of formula wherein the substituents are defined as in the specification and salts or hydrates thereof is disclosed as well as a method of treating disorders associated with the inactivation or excessive degradation of cholecystokinin.
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- THIAZOLIDINE DERIVATIVES
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An object of the present invention is to provide novel thiazolidine derivatives which are useful as drugs. The thiazolidine derivatives according to the present invention are compounds represented by the following general formula [I] and salts thereof, wherein R 1is alkyl, hydroxy, alkoxy, alkoxyalkyl, phenyl, phenylalkyl, phenylalkoxy, phenoxy, phenoxyalkyl, amino, alkylamino or a nonaromatic heterocycle; R 2is H or alkyl; R 3is H, alkyl or phenyl; R 4is H or alkyl; R 5is alkyl, halogenoalkyl, hydroxy, alkoxy, phenyl, phenylalkoxy, phenoxy, carboxyl, alkoxycarbonyl, phenylalkoxycarbonyl or an aromatic heterocycle; A 1is alkylene; and A 2is alkylene.
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- Syntheses of optically active, protected and unprotected vinylglycines
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Vinylglycine (2) has been shown to undergo racemization under acidic conditions. Optically pure 2 was obtained from 2 · HCl by enzymatic hydrolysis through N-acetylvinylglycine (5), followed by recrystallization. (S)N-(Methoxycarbonyl)vinylglycine (6) was configurationally so unstable under acidic conditions that 6 could not be obtained from 2 in an optically pure form. On the other hand, configurationally stable (S)-N-(9-phenylfluoren-9-yl)vinylglycine methyl ester (9) was synthesized from (S)-homoserine; 9 was hydrolyzed with sodium hydroxide to afford the carboxylic acid 10 of more than 99% ee.
- Itaya,Shimizu,Nakagawa,Morisue
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p. 1927 - 1930
(2007/10/02)
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- Structure-Activity Study of 5-Substituted 1-Carbobenzoxy-2-iminohydantoins as Potential Anticonvulsant Agents
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On the basis of our previous findings, a series of 5-substituted 2-iminohydantoins has been synthesized and tested for anticonvulsant activity to better understand the SAR of 2-iminohydantoins.Among the compounds tested, (S)-(+)-1-carbobenzoxy-2-iminohydantoin analogs with ethyl (6)-, n-propyl (7a)-, isopropyl (8)-, allyl (9)-, and sec-butyl (11)-substituted groups at the C5 of the iminohydanotin ring provided the best activities against the MES test with ED50 values in the range of 52-74 mg/kg.All of the above compounds except 8 also showed activity against the scMET test with ED50 values in the range of 141-223 mg/kg.All significantly active compounds (1, 6, 7a, 8, 9, and 11) possesed aliphatic hydrocarbon side chains of two- to three-carbon lengths at the C5 position.All of the compounds with no or minimal activity had either shorter or longer side chains.The compounds substituted at the C5 position by aryl groups, arylalkyl groups, or alkyl and arylalkyl groups containing heteroatoms also showed no activity against the MES and scMET tests.The results suggested that the C5 side chain with the correct stereochemistry in 2-iminohydantoins provides optimal anticonvulsant activity when the side chains are aliphatic hydrocarbons with a lenght, ignoring branchingg, of two to three carbons.
- Sun, Zhong-Yue,Kwon, Chul-Hoon,Wurpel, John N. D.
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p. 2841 - 2845
(2007/10/02)
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- Isoindoline derivatives
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Optically active 8-methoxyquinolonecarboxylic acids represented by the formula (I) wherein R1 is lower alkyl have been found to possess potent antibacterial activity against both Gram-negative and Gram-positive bacteria. The compounds may be synthesized from novel optically active intermediates.
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- Regioselective functionalization of chiral nickelacycles derived from N-protected aspartic and glutamic anhydrides
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The electrophilic cleavage of the nickelacycles resulting from oxidative addition of Ni(o) complexes to N-protected aspartic and glutamic anhydrides, followed by decarbonylation, gives rise regioselectively to derivatives of α- and β-alanine or α- and γ-aminobutyric acid, respectively.
- Castano,Echavarren
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p. 4783 - 4786
(2007/10/02)
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- Porcine Pancreatic Lipase Catalyzed Enantioselective Hydrolysis of Esters of N-Protected Unusual Amino Acids
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Porcine pancreatic lipase catalyzed the highly enantioselective hydrolysis of a kind of α-substituted carboxylic esters, i.e., the 2,2,2-trifluoroethyl esters of the N-benzyloxycarbonyl derivatives of unusual amino acids.
- Miyazawa, Toshifumi,Iwanaga, Hitoshi,Ueji, Shinichi,Yamada,Takashi,Kuwata, Shigeru
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p. 2219 - 2222
(2007/10/02)
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- Optical Resolution of Unusual Amino-Acids by Lipase-catalysed Hydrolysis
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The 2-chloroethyl esters of the N-benzyloxycarbonyl (Z) derivatives of several unusual amino-acids are converted by Aspergillus niger lipase into enantiomerically enriched Z-amino-acids with fairly high optical purities, the L-enantiomers being preferentially hydrolysed.
- Miyazawa, Toshifumi,Takitani, Tadanori,Ueji, Shinichi,Yamada, Takashi,Kuwata, Shigeru
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p. 1214 - 1216
(2007/10/02)
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- Conversion of Serine β-Lactones to Chiral α-Amino Acids by Copper-Containing Organolithium and Organomagnesium Reagents
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A method for the synthesis of optically pure α-amino acids has been developed.Mono- and di-N-protected α-amino-β-lactones 3a (L, R1=H, R2=COOCH2Ph (Z)), 3b (D, R1=H, R2=Z), 3c (L, R1=CH2Ph, R2=Z), and 3d (D, R1=CH2Ph, R2=Z) are readily produced by cyclization of the corresponding serine derivatives 2 under modified Mitsunobu conditions without loss of optical purity.Stereochemical integrity was demonstrated by conversion of 3 to 2-methoxy-2-(trifluoromethyl)phenylacetate esters 6 and analysis by HPLC, (19)F NMR, and (1)H NMR.Reaction of 3 with organolithium-derived cuprate reagents (R2CuLi or R2Cu(CN)Li2) at low temperature produces N-protected α-amino acids by attack at the β-methylene group.Yields of di-N-protected amino acids are generally higher (ca. 50-75percent), but some decrease in enantiomeric excess (ee) can occur (0-27percent).In contrast, the mono-N-protected β-lactones 3a and 3b give slightly lower yields (ca. 44-62percent) but negligible decrease in ee (0-1.7percent) with the exception of Ph2Cu(CN)Li2 (67percent loss of ee).However, the use of Cu(I)-catalyzed Grignard (RMgCl) additions gives better yields (44-83percent), complete retention of optical purity ( 99.4percent), and fewer side products.Reductive removal of the protecting groups in a single step (H2/Pd-C or Na/NH3) affords the free α-amino acids in 91-99percent yield.Their stereochemical purity was determined by conversion to the corresponding N-(-)-camphanoyl methyl esters and analysis by gas chromatography and (1)H NMR spectroscopy.
- Arnold, Lee D.,Drover, John C. G.,Vederas, John C.
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p. 4649 - 4659
(2007/10/02)
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