Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-26
2002-10-01
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S254000
Reexamination Certificate
active
06458796
ABSTRACT:
The present invention relates to novel dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one, to processes for their preparation and to their use as medicaments, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.
The synthesis of triazolopyrimidines has been described in J. Chem. Soc., C, 1971, 706. Fungicidal properties of dihydrotriazolopyrimidinones and their synthesis have been described in Liebigs Ann. 1984, 1848, by Nielsen et. al.
The synthesis of dihydrotriazolpyrimidinones by cyclization of an ester with an aminotriazolocarbonamide in the presence of a base has been described in J. Het. Chem. 1985, 22, 1607 by Biagi et al. and in Het. 1996, 42, 691 by Miyashita et al.; the analogous synthesis starting from amidines can be found in J. Chem. Soc., Perkin Trans. 1, 1979, 922.
Antiallergic properties of 1-unsubstituted dihydrotriazolopyrimidinones have been described in Eur. J. Med. Chem. 1975, 447, in J. Med. Chem. 1975, 1117 and in J. Am. Chem. Soc. 1978, 100, 6474. The synthesis of 5-amino-dihydrotriazolopyrimidinones has been described in J. Chem. Soc. 1961, 4433, and their antiviral activity has been reported in J. Med. Chem. 1987, 30, 1091 and J. Med. Chem. 1984, 27, 1416.
Anticytokine properties of 8-azaadenines are reported by Karanov et al. in Plant Growth Regul. 1993, 13, 7.
A synthesis method for azahypoxanthines and azaadenines is described by Biagi et al in J. Het. Chem. 1991, 28, 1351 and J. Het. Chem. 1989, 26, 39.
Anticonvulsive properties of 5-amino-dihydrotriazolopyrimidinones have been described in EP-288 431. Furthermore, the synthesis of 5-amino-dihydrotriazolopyrimidinones is described in J. Het. Chem. 1996, 33, 1605. Adenosine A1 receptor affinity of azaadenines and binding to adenosine deaminase has been reported in Farmaco 1996, 51, 395, Farmaco 1995, 50, 659 and Farmaco 1994, 49, 187.
Purine-nucleoside phosphorylase-inhibitory properties of azaguanines are described in J. Med. Chem. 1996, 39, 949.
Syntheses of dihydrotriazolopyrimidinones are furthermore found in Farmaco 1995, 50, 13, Farmaco 1994, 49, 183, Farmaco 1992, 47, 1457, Farmaco 1992, 47, 525 and in Chem. Ztg. 1990, 114, 246.
The synthesis of intermediates of the type II has been described in EP 0 229 011 and in J. Chem. Soc. 78, 1956, 5832.
Triazolopyrimidinones of the general formula (I) having the stated substitution pattern R
1
, A, D and L are novel.
The compounds according to the invention are potent inhibitors of either one or more of the phosphodiesterases which metabolize cyclic guanosine 3′,5′-monophophate (cGMP PDE's). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990), these are the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.
An increase in the cGMP concentration can lead to beneficial antiaggregatory, antithrombotic, antiprolific, antivasospastic, vasodilative, natriuretic and diuretic effects. It can influence the short- or long-term modulation of vascular and cardiac inotropy, the pulse and cardiac conduction (J. C. Stoclet, T. Keravis, N. Komas and C. Kugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100).
The present invention relates to dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-ones of the general formula (I)
in which
R
1
represents cycloalkyl having 3 to 8 carbon atoms, or represents a radical of the formula
in which
R
2
represents straight-chain or branched alkyl having up to 10 carbon atoms which is optionally substituted by hydroxyl,
E represents a radical of the formula —CH
2
—T,
in which
T represents a straight-chain or branched alkylene chain having up to 10 carbon atoms,
R
3
represents hydrogen or aryl having 6 to 10 carbon atoms which is optionally substituted up to 3 times by identical or different substitutents from the group consisting of halogen, hydroxyl, nitro, trifluoromethyl and straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,
A and D represent hydrogen,
or
A represents hydrogen
and
D represents hydroxyl,
or
A and D together represent a radical of the formula ═O,
L represents a radical of the formula
represents aryl having 6 to 10 carbon atoms or represents a 5- to 7-membered aromatic, optionally benzo-fused heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, where the ring systems listed above under L are substituted up to 3 times by one or more identical or different of the following substituents: halogen, hydroxyl, nitro, trifluoromethyl, carboxyl, straight-chain or branched alkyl, alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms, a radical of the formula —(V)
a
—NR
4
R
5
,
in which
a represents a number 0 or 1,
V represents a radical of the formula —CO or —SO
2
,
R
4
and R
5
are identical or different and represent hydrogen or straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, or
represent straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, amino or by straight-chain or branched alkyl- or dialkylamino having in each case up to 6 carbon atoms, or
R
4
and R
5
together with the nitrogen atom form a 5- or 6-membered saturated heterocycle which may optionally contain a further heteroatom from the group consisting of S and O or a radical of the formula —NR
6
and which is optionally substituted by straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms,
in which
R
6
represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and/or the ring systems listed under L are optionally substituted by aryl having 6 to 10 carbon atoms and a 5- to 7-membered aromatic, optionally benzo-fused heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, where these ring systems for their part are optionally substituted up to 2 times by identical or different substituents from the group consisting of halogen, hydroxyl, nitro, carboxyl, trifluoromethyl and straight-chain or branched alkyl, alkoxy, or alkoxycarbonyl having in each case up to 5 carbon atoms, or by a group of the formula —(V′)
b
—NR
7
R
8
,
in which
b has the meaning of a given above and is identical to or different from this meaning,
R
7
and R
8
have the meanings of R
4
and R
5
given above and are identical to or different from these meanings,
V′ has the meaning of V given above and is identical to or different from this meaning,
and their tautomers and salts.
The substances according to the invention can also be present as salts. In the context of the invention, preference is given to physiologically acceptable salts.
Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to s alts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid, or naphthalenedisulphonic acid.
Physiologically acceptable salts can also 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 organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The compounds of the general formula (I) according to the invention can be present in various stereochemical forms which are either like image and mirror image (enantiomers) or which are not like image and mirror image (diastereomers). The invention relates both to the different stereoisomers and to the racemic forms and the diastereomer
Bischoff Erwin
Haning Helmut
Niewöhner Ulrich
Rosentreter Ulrich
Schenke Thomas
Balasubramanian Venkataraman
Bayer Aktiengesellschaft
Chiu Jerrie L.
Shah Mukund J.
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