Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-22
2004-08-17
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252020, C514S260100, C544S238000, C544S255000
Reexamination Certificate
active
06777416
ABSTRACT:
The present invention relates to novel isoxazolopyrimidinones, to processes for preparing them and to their use as medicaments, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.
The publication Bull. Soc. Chim. Belg. (1994), 103 (5-6), 181-4 describes the synthesis of isoxazolo[4,5-d]pyrimidinones which are unsubstituted in the 5 position. Compounds possessing a phenyl radical or substituted phenyl radical in the 5 position are not described. There is no report of the described substances having a biological effect, in particular being able to inhibit phosphodiesterases.
The compounds according to the invention are potent inhibitors of cyclic guanosine 3′,5′-monophophate-metabolizing phosphodiesterases (cGMP-PDEs). In accordance with the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990), these phosphodiesterases are the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.
An increase in the concentration of cGMP can lead to therapeutic, antiaggregatory, antithrombotic, antiproliferative, antivasospastic, vasodilatory, natriuretic and diuretic effects. It can exert an effect on the short-term or long-term modulation of vascular and cardiac inotropy, cardiac rhythm and stimulus conduction in the heart (J. C. Stoclet, T. Keravis, N. Komas and C. Kugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100). Inhibition of the cGMP-PDEs can also strengthen erection. These compounds are therefore suitable for treating erectile dysfunction.
The present invention now relates to novel isoxazolidinones of the general formula (I)
in which
R
1
represents (C
3
-C
8
)-cycloalkyl or represents straight-chain or branched alkyl having up to 4 carbon atoms,
A represents radicals of the formulae
in which
R
2
and R
7
are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R
3
, R
4
, R
5
and R
6
are identical or different and denote hydrogen, a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, N and/or O or aryl having from 6 to 10 carbon atoms, where the ring systems are optionally substituted, up to three times, identically or differently, by hydroxyl, halogen, (C
1
-C
5
)-alkyl or (C
1
-C
6
)-alkoxy, or
R
3
, R
4
, R
5
and R
6
are identical or different and denote (C
1
-C
6
)-alkyl which is optionally substituted by aryl having from 6 to 10 carbon atoms and can, for its part, be substituted, up to 3 times, identically or differently, by (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, hydroxyl or halogen, or
R
3
and R
4
and/or R
5
and R
6
, together with the nitrogen atom to which they are bonded, form radicals of the formulae
where
R
8
denotes hydrogen or (C
1
-C
6
)-alkyl, which is optionally substituted by hydroxyl, and
R
9
denotes hydrogen or hydroxyl,
and the salts, N-oxides and isomeric forms thereof.
The compounds according to the invention can exist in stereoisomeric forms which either relate to each other as image and mirror image (enantiomers) or which do not relate to each other as image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers or their respective mixtures. The racemic forms, as well as the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.
The substances according to the invention can also be present as salts. Within the context of the invention, preference is given to physiologically harmless salts.
Physiologically harmless salts can be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid or benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
Physiologically harmless salts can equally well be metal or ammonium salts of the compounds according to the invention. Particular preference is given, for example, to sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia, or to organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
(C
3
-C
8
)-Cycloalkyl represents cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Those which may be mentioned as being preferred are: cyclopropyl, cyclopentyl and cyclohexyl.
(C
6
-C
10
)-Aryl represents an aromatic radical having from 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
(C
1
-C
6
)-Alkyl represents a straight-chain or branched alkyl radical having from 1 to 6 carbon atoms. Those which may be mentioned by way of example are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Preference is given to a straight-chain or branched alkyl radical having from 1 to 4 carbon atoms. Particular preference is given to a straight-chain or branched alkyl radical having from 1 to 3 carbon atoms.
(C
1
-C
6
)-Alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Those which may be mentioned by way of example are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy. Preference is given to a straight-chain or branched alkoxy radical having from 1 to 4 carbon atoms. Particular preference is given to a straight-chain or branched alkoxy radical having from 1 to 3 carbon atoms.
Halogen generally represents fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine and bromine. Particular preference is given to fluorine and chlorine.
A 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, O and/or N represents, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Preference is given to pyridyl, pyrimidyl, pyridazinyl, furyl and thienyl.
Preference is given to compounds according to the invention of the general formula (I),
in which
R
1
represents (C
3
-C
6
)-cycloalkyl or represents n-propyl,
A represents radicals of the formulae
in which
R
2
and R
7
are identical or different and denote hydrogen, methyl or ethyl,
R
3
, R
4
, R
5
and R
6
are identical or different and denote hydrogen, pyridyl, pyrimidyl, pyridazinyl, furyl, imidazolyl, thienyl, pyrryl or phenyl, where the ring systems are optionally substituted, up to 2 times, identically or differently, by hydroxyl, fluorine, chlorine, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-alkoxy, or
R
3
, R
4
, R
5
and R
6
are identical or different and denote (C
1
-C
4
)-alkyl which is optionally substituted by phenyl which, for its part, can be substituted, up to 2 times, identically or differently, by (C
1
-C
4
)-alkoxy, fluorine or chlorine, or
R
3
and R
4
and/or R
5
and R
6
, together with the nitrogen atom to which they are bonded, form radicals of the formulae
where
R
8
denotes hydrogen or (C
1
-C
6
)-alkyl which is optionally substituted by hydroxyl, and
R
9
denotes hydroxyl,
and the salts, N-oxides and isomeric forms thereof.
Particular preference is given to compounds according to the invention of the general formula (I),
in which
R
1
represents cyclopentyl or n-propyl,
A represents radicals of the formulae
in which
R
2
and R
7
are identical or different and denote methyl or ethyl,
R
3
, R
4
, R
5
and R
6
are identical or different and denote hydrogen, pyridyl or phenyl, where the ring systems are optionally substituted, up to 2 times, identically or differently, by fluorine, methoxy or ethoxy, or
R
3
, R
4
, R
5
and R
6
are identical or different and denote (C
1
-C
3
)-alkyl which is optionally substituted by phenyl which, for its part, is substituted, up to 2 times, ident
Bischoff Erwin
Dembowsky Klaus
Es-Sayed Mazen
Haning Helmut
Lampe Thomas
Bayer Aktiengesellschaft
Pellegrino Susan M.
Raymond Richard L.
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