Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-12-11
2000-01-04
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549323, A61K 3134
Patent
active
060110600
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new chiral phenyldihydrofuranone derivatives, the process for their production and their use as pharmaceutical agents.
It is known that selective inhibitors of the cAMP-specific phosphodiesterase IV (CAMP-PDE IV inhibitors) have pharmacological properties, on the basis of which they represent suitable active ingredients in pharmaceutical agent preparations. To improve the action, numerous modifications were carried out on the molecule without, however, achieving the desired increase of action.
It has now been found, surprisingly enough, that the compounds of formula I represent very potent selective cAMP-PDE IV inhibitors, which are metabolically very stable.
The invention relates to racemic and enantiomer-pure compounds of formula I, ##STR1## in which R.sup.1 means a hydrocarbon radical with up to 8 C atoms and
As hydrocarbon radical R.sup.1, alkyl, alkenyl, alkinyl, cycloalkyl and cycloalkylalkyl are suitable.
Alkyl radical R.sup.1 preferably has up to 6 carbon atoms and can be straight-chain or branched like alkyl radical R.sup.2, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-methyl-butyl, 2,2-dimethylpropyl and hexyl.
If the hydrocarbon radical means alkenyl or alkinyl, for example vinyl, 1-propenyl, 2-propenyl, 3-methyl-2-propenyl and 2-propinyl with up to 4 C atoms can thus be mentioned.
The cycloalkyl radical has 3-7 C atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
As cycloalkylalkyl radical R.sup.2, C.sub.3-7 cycloalkyl-C.sub.1-2 alkyl is suitable, in the same way as, for example, cyclopropyl methyl, cyclopropyl ethyl, cyclopentyl methyl, i.a., are suitable.
The compounds of formula I contain one or more chiral centers and comprise the racemic diastereomeric mixtures as well as the individual isomers.
The subject matter of the invention is also the process for the production of compounds of formula I and their isomers.
The production of the compounds of formula I is characterized in that a compound of formula II ##STR2## in which R.sup.1 and R.sup.2 have the above meaning, is reacted with an acrylic acid ester in the presence of samarium(II) iodide and a proton donor, and optionally then the isomers are separated.
The coupling of the acrylic acid ester and a compound of formula II that is induced by samarium(II) iodide is generally carried out at room temperature, by 2 molar equivalents of samarium(II) iodide and 1 molar equivalent of substrate being reacted in a solvent. As a solvent, especially tetrahydrofuran is suitable. Samarium(II) iodide in a 0.1 molar solution in THF, stabilized with samarium powder, can be ordered from the Aldrich Company. The addition of an alcohol as a proton donor, such as, for example, methanol, ethanol or tert-butanol, prevents the development of by-products and makes possible the production of the compounds according to the invention under mild conditions in very good yield. The reaction can be completed after a few minutes or else several hours.
By adding an additive such as tetramethylethylenediamine or hexamethylphosphorus amide, the reaction rate can be elevated, and the yield can be increased. As esters of acrylic acid, especially alkyl esters are suitable, but other esters can also be used.
The isomers can be separated into enantiomers according to commonly used methods, such as, for example, chromatography, crystallization or conversion into diastereomer mixtures with chiral adjuvants. The optically active phenyldihydrofuranones of formula I can be obtained from the corresponding racemates by chromatography on chiral columns.
The new compounds of formula I and their isomers are inhibitors of phosphodiesterase IV and, via the specific intervention in the cAMP metabolism, affect the signal function of this important intracellular transmitter, which represents the molecular substrate for information transfer in a large number of biochemical reactions. The various sub-aspects of the profile of action can be attributed to this pharmaco
REFERENCES:
Lienne, M. et al Optimization of Direct Chiral Separation of Potential Cytoloxic Alpha-Methylene-Gamma Butyrolactones and Alpha-Methylene-Gamma Butyrolactams by Liquid Chromatography. CA 110:127899, 1989.
Esperling Peter
Hamp Kurt
Laurent Henry
Schneider Herbert
Wachtel Helmut
Owens Amelia
Schering Aktiengesellschaft
LandOfFree
Chiral phenyldihydrofuranones as PDE-IV inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Chiral phenyldihydrofuranones as PDE-IV inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Chiral phenyldihydrofuranones as PDE-IV inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1073000