- USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS
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The present invention relates to the use of a substituted 2-phenylbenzimidazole of formula I wherein R1, R2, R3, R 4, R5 and m have the meanings given in the claims, for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors, as well as new compounds of formula I wherein R1 is a group of formula
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- General and practical catalytic enantioselective Strecker reaction of ketoimines: Significant improvement through catalyst tuning by protic additives
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Significant improvement in enantioselectivity and catalyst activity was achieved for the catalytic enantioselective Strecker reaction. Using a catalyst (1-2.5mol%) prepared from Gd(OiPr)3 and D-glucose derived ligand 1, and in the pr
- Kato, Nobuki,Suzuki, Masato,Kanai, Motomu,Shibasaki, Masakatsu
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p. 3147 - 3151
(2007/10/03)
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- Lipase-catalyzed resolution of 5,5-disubstituted hydantoins
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Chiral non-racemic 5,5-disubstituted hydantoins were prepared by lipase-catalyzed enantioselective hydrolyses of their N-acyloxymethyl groups or esterification of their N-hydroxymethyl groups.
- Mizuguchi,Achiwa,Wakamatsu,Terao
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p. 1407 - 1410
(2007/10/02)
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- Novel resolution process for racemic spiro-hydantoins
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A novel three-step process for resolving a racemic spiro-hydantoin compound into its optical antipodes is disclosed, which involves (1) reacting said racemic compound with an optically-active asymmetric isocyanate of the formula RNCO, wherein R is (S)- or (R)-1-phenylethyl or (S) or (R)-1-(1-naphthyl)ethyl, to form the corresponding diastereomeric uredio compound; (2) separating the resulting diastereomeric mixture into its component parts, and (3) thereafter converting the separated ureido diastereomers obtained in step (b) to the corresponding asymmetric hydantoin compounds by treatment with an alkali metal lower alkoxide (C1 -C4), followed by acidification, whereupon the desired optical isomer is obtained. The final products so obtained, such as (4S)-(+)-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2', 5'-dione (sorbinil) and (5'S)-3'-chloro-5', 6', 7', 8'-tetra-hydro-spiro[imidazolidine-4,5'-quinoline]-2,5-dione, are known to be useful in preventing or alleviating certain chronic diabetic complications. The aforementioned diastereomeric uredio intermediates are novel compounds.
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- Process for the production of asymmetric hydantoins
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An improved process for preparing (4S)-6-fluorospiro-[chroman-4,4''-imidazolidine]-2'',5''-dione (sorbinil) or its (2R)-methyl derivative (2-methylsorbinil) is disclosed herein, starting from p-fluorophenol in each instance. The final products obtained ha
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- Spiro hydantoin aldose reductase inhibitors
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Sorbitol formation from glucose, catalyzed by the enzyme aldose reductase, is believed to play a role in the development of certain chronic complications of diabetes mellitus. Spiro hydantoin derived from five- and six-membered ketones fused to an aromatic ring or ring system inhibit aldose reductase isolated from calf lens. In vivo these compounds are potent inhibitors of sorbitol formation in sciatic nerves of streptozotocinized rats. Optimum in vivo activity is reached in spiro hydantoins derived from 6-halogenated 2,3-dihydro-4H-1-benzopyran-4-ones (4-chromanones). In 2,4-dihydro-6-fluorospirol[4H-1-benzopyran-4,4'-imidazolidine]-2',5'- ione, the activity resides exclusively in the 4S isomer, compound 115 (CP-45,634, USAN: sorbinil). This compound is currently being used to test, in humans, the value of aldose reductase inhibitors in the therapy of diabetic complications.
- Sarges,Schnur,Belletire,Peterson
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p. 230 - 243
(2007/10/02)
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- Substituted spiro-2',4'-diones as aldose reductase inhibitors
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Aldose reductase (EC 1.1.1.21) is believed to be involved in the pathogenesis of diabetic complications.Inhibitors of this enzyme could be useful for the treatment of diabetic cataracts and neuropathies.A series of spiro-2',4'-d
- Hasler, Heinz,Kaufmann, Franz,Pirson, Wolfgang,Schneider, Fernand
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p. 559 - 568
(2007/10/02)
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- S-6-fluoro-4-aminochroman-4-carboxylic acid derivatives useful as intermediates for sorbinil
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Chiral sorbinil intermediates of the formula STR1 wherein R is hydrogen or benzyloxycarbonyl and Y is hydroxy or amino, processes therefor, and processes for the conversion thereof to sorbinil.
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- Regeneration of 6-fluoro-4-chromanone from 6-fluoro-4-ureidochroman-4-carboxylic acid
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6-Fluoro-4-chromanone can be regenerated from (R)-6-fluoro-4-ureidochroman-4-carboxylic acid, or from mixtures of (R)-6-fluoro-4-ureidochroman-4-carboxylic acid and its racemic modification, by oxidation with a permanganate, especially potassium permanganate. 6-Fluoro-4-chromanone is a chemical intermediate useful for preparing sorbinil, an aldose reductase inhibitor which can be used in clinical medicine for the control of the chronic complications of diabetes. (R)-6-Fluoro-4-ureidochroman-4-carboxylic acid and its racemic modification are by-products from the production of sorbinil from 6-fluoro-4-chromanone.
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- Regeneration of 6-fluoro-4-chromanone from by-products in the synthesis of sorbinil
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6-Fluoro-4-chromanone, a sorbinil intermediate, is regenerated from enantiomeric and mixtures of enantiomeric and racemic compounds obtained as major by-products in the synthesis of sorbinil. The regenerated intermediate is useful in the synthesis of additional sorbinil.
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- Sorbinil by optical resolution of precursor 6-fluoro-4-ureidochroman-4-carboxylic acid
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Sorbinil is obtained by cyclization of S-6-fluoro-4-ureidochromane-4-carboxylic acid, which is in turn obtained by resolution of racemic 6-fluoro-4-ureidochroman-4-carboxylic acid via diasteromeric salts with either D-(+)-(1-phenethyl)amine or L-(-)-ephedrine.
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- Treatment of diabetic complications with hydantoins
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6-Methythio and 6-methylsulfinyl spiro-chroman-imidazolidine diones useful in the treatment of complications arising from diabetes mellitus.
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- Intermediates in the preparation of chiral hydantoins
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A novel process for the synthesis of chiral hydantoins of the structure STR1 wherein X is fluoro or chloro, from the corresponding 6-halo-4-chromanone of the structure STR2 is described. The compounds I are valuable in the treatment of certain chronic com
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- Synthesis of Optically Active Spirohydantoins by Asymmetric Induction. Hydantoin Formation from Amino Nitriles and Chlorosulfonyl Isocyanate
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Conversion of 6-chloro- or 6-fluoro-2,3-dihydro-4H-1-benzopyran-4-one with optically active (S)-α-methylbenzylamine in the presence of TiCl4 to the ketimine followed by treatment in EtOH with HCN gas gives excellent yields of crystalline, enantiomerically pure (4S)-4-cyano-2,3-dihydro-6-chloro(or 6-fluoro)-4--4H-1-benzopyran.These sterically hindered amino nitriles react smoothly with chlorosulfonyl isocyanate to give, after hydrolysis, the hydantoins (4S)-2,3-dihydro-6-chloro(or 6-fluoro)-3'-spiro-2',5'-dione.The α-methylbenzyl groups can be removed by aqueous HBr/acetic acid to give the unprotected spirohydantoins.
- Sarges, Reinhard,Howard, Harry R.,Kelbaugh, Paul R.
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p. 4081 - 4085
(2007/10/02)
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- Process for the preparation of chiral hydantoins
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A novel process for the synthesis of chiral hydantoins of the structure STR1 wherein X is fluoro or chloro, from the corresponding 6-halo-4-chromanone of the structure STR2 is described. The compounds I are valuable in the treatment of certain chronic com
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- Hydantoin derivatives as therapeutic agents
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A series of spiro-hydantoin compounds has been prepared by condensing the appropriate carbonyl ring compound, such as the corresponding 1-indanone, 1-tetralone, 4-chromanone, thiochroman-4-one, 7,8-dihydroquinolin-5(6H)-one, 6,7-dihydropyrindin-5(5H)-one, thiondane-3-one-1,1-dioxide and 4-oxoisothiochroman-2,2-dioxide, respectively, with potassium cyanide and ammonium carbonate. The resulting hydantoin derivatives are found to be useful in preventing or alleviating chronic diabetic complications. Preferred member compounds include spiro-[imidazolidine-4,1'-indan]-2,5-dione, 6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, 6-chloro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, 6,7-dichloro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, 6,8-dichloro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, 6'-fluoro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione and 6',7'-dichloro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione.
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- Hydantoin therapeutic agents
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Several novel dextrotatory spiro-hydantoin compounds have been obtained by resolving the corresponding dl-compounds which are initially synthesized by first condensing the appropriate carbonyl ring compound, such as the corresponding 4-chromanone or thiochroman-4-one, as the case may be, with potassium cyanide and ammonium carbonate. The resulting optically-active hydantoin derivatives, such as d-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione and d-6'-fluoro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione, are particularly useful in preventing or alleviating chronic diabetic complications.
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