Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-05-05
2001-01-30
Tsang, Cecilia (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S259500, C514S254090, C514S365000, C514S405000, C546S275700, C546S153000, C544S235000, C544S144000, C544S284000, C544S298000, C544S333000, C544S371000, C548S131000, C548S159000, C548S181000, C548S240000, C548S305100, C548S306700, C548S361500
Reexamination Certificate
active
06180637
ABSTRACT:
New 1,2,5-trisubstituted 1,2-dihydroindazol-3-ones having anti-asthmatic, anti-allergic, anti-inflammatory, immunomodulating and neuroprotective action, process for their preparation and their use as medicaments.
TECHNICAL FIELD
The invention relates to the preparation and use of novel derivatives of indazol-3-one as medicaments having anti-asthmatic, anti-allergic, anti-inflammatory, immunomodulating and neuroprotective properties.
PRIOR ART
Cyclosporin A (CsA) and FK 506 are immunosuppressant natural substances originating from fungi, which inhibit the Ca
2+
-dependent signal transmission pathway in some cell types. In T cells, both compounds inhibit the transcription of a number of genes. CsA and FK-506 both bind with high affinity to soluble receptor proteins such as, for example, cyclophilin (Cyp) or FK-506 binding protein (FKBP) (G. Fischer et al., Nature 337 (1989), 476-478; M. W. Harding et al., Nature 341 (1989), 755-760).
The complex of CsA-Cyp or FK 506-FKBP binds calcineurin (CN) and inhibits its phosphatase activity. The cytosolic, phosphorylating component of the transcription factor NF-AT was recognized as a cellular target molecule of CN, so that in the absence of CN activity the active transcription complex on the IL 2 promoter cannot be switched on (M. K. Rosen, S. L. Schreiber, Angew. Chem. 104 (1992), 413-430; G. Fischer, Angew. Chem. 106 (1994), 1479-1501).
The allergic, asthmatic diseases are based on an inflammatory reaction which is controlled by T cells and their mediators. Corticosteroids are still the agent of choice in the treatment of many allergic diseases. CsA and FK 506 also proved to be a favourable therapeutic in bronchial asthma and underlying inflammations both in animal experiments and in clinical studies.
Despite the large number of attempts at the identification of new active immunophilin inhibitors, until now it was not possible to prepare or isolate any more active structures than CsA, FK 506, rapamycin or derivatives of these natural substances. The high inhibitory potential of CsA, FK 506 and rapamycin, however, is very considerably reduced by the various side effects, in particular the nephrotoxicity (N. H. Sigal et al., J. Exp. Med. 173 (1991), 619-6128). What is behind this fact is the non-specificity of the interaction between immunophilin ligands and the cell-specific binding proteins. As a result, the known medicinal-therapeutic action of these immuno-suppressants is considerably restricted. Furthermore, the lacking selectivity of the compounds proves to be problematic especially in long-term therapy.
Substances which inhibit the activity of peptidylprolyl isomerases (PPIases) such as Cyp or FKBP, have neuroprotective properties, stimulate neuronal growth and are suitable for the treatment of neurodegenerative diseases (WO 96/40140, U.S. Pat. No. 5,696,135, WO 97/18828).
Substituted indazole derivatives are known which, however, differ from the claimed compounds with respect to the substituents X, Y, Z, R
1
, R
2
and R
3
and their pharmacodynamic action.
Baiocchi et al. [Synthesis 1978 (9), 633-648] give a general survey of syntheses and properties of the 1,2-dihydro-3H-indazol-3-ones.
Schindler et al. [WO 97/34874] describe 1,3,5-trisubstituted indazoles having anti-asthmatic, anti-allergic, anti-inflammatory and immunomodulating action.
EP 0 199 543 includes 1,6-disubstituted 1,2-dihydroindazol-3-ones and their use for pharmaceutical purposes.
WO 94/24109 includes indazole derivatives which are suitable for the treatment of HIV infections.
Ketami et al. [J. Heterocycl. Chem. 7 (4), 807-813 (1970)] describe 1,5-disubstituted 1,2-dihydroindazol-3-ones.
U.S. Pat. No. 3,470,194 mentions the formation of disubstituted (1,2-dihydro-3-oxyindazol-2-yl)alkanoic acids when using polar solvents.
K. v. Auwers [Ber. Dtsch. Chem. Ges. 58, 2081-2088 (1925)] and K. v. Auwers et al. [Justus Liebigs Ann. Chem. 451, 281-307 (1927)] describe the constitution of acylindazoles and their migration.
Zoni et al. [Il Farmaco Ed. Sci. 23 (5), 490-501 (1968)] and Zoni et al. [Boll. Chim. Farm. 107, 598-605 (1968)] describe the alkylation of 1-substituted 1H-indazol-3-ols.
Evans et al. [Tetrahedron 21, 3351-3361 (1965)] describe the synthesis of 1,3-substituted acyl- and tosylindazoles.
Tse et al. [Arch. Pharm. 329 (1), 35-40 (1996)] report on anti-inflammatory properties of N-substituted indazoles.
Anderson et al. [J. Chem. Soc. C, 3313-3314 (1971)] describe 1,3-substituted tosylindazoles.
Palazzo et al. [J. Med. Chem 9, 38-41 (1996)] and Gyula et al. [Acta pharm. Hung. 44, 49-57 (1974)] describe the synthesis of 2-dimethylaminoalkyl-1-phenylindazol-3-ones.
Klicnar [Coll. Czech. Chem. Comm. 42, 327-337 (1977)] describes acetylindazoles.
Tserng et al. [J. Org. Chem. 38, 3498-3502 (1973)] describe the synthesis of 1,2-disubstituted 1,2-dihydroindazol-3-ones.
Aran et. al. [Heterocycles 45, 129-136 (1997)] describe the selective synthesis of 2-substituted indazol-3-ones without N-1 substitution.
Aran et al. [Liebigs Ann. 1996, 683-691], Aran et al. [Liebigs Ann. 1995, 817-824] and Aran et al. [J. Chem. Soc. Perkin Trans. I, 1119-1127 (1993)] describe 1,2-substituted 5-nitroindazol-3-ones and their -cytostatic activity.
Bruneau et al. [J. Med. Chem. 34, 1028-1036 (1991)] describe 1- and 2-substituted indazol-3-ones as 5-lipoxygenase inhibitors.
Wyrick et al. [J. Med. Chem. 27, 768-772 (1984)] describe 1,2-disubstituted indazol-3-ones having cholesterol-lowering action.
Schmutz et al. [Helv. Chim. Acta 47, 1986-1996 (1964)] describe the alkylation of indazolones.
Yamaguchi et al. [Chem. Pharm. Bull. 43 (2), 332-334 (1995)] describe 2-substituted (1-pyridin-3-yl)indazol-3-ones and their anti-asthmatic action.
On account of numerous side effects of the preparations introduced, lack of curative effects and the hitherto too non-specific therapy, a great need for compounds having a high effectiveness and safety furthermore exists for the treatment of asthmatic diseases.
The invention is based on the object of finding new compounds having rotamase-inhibiting and/or pulmonary eosinophil infiltration-inhibiting properties and making them available by targeted synthesis.
A completely novel class of substance, which surprisingly binds immunophilins specifically, is represented by the compounds of the formula I according to the invention. This class of compounds has a high affinity for immunophilins such as CypB.
DESCRIPTION OF THE INVENTION
Surprisingly, it has now been found that the new indazole derivatives are able to inhibit the action of PPIase. Accordingly, these compounds are of great importance for the production of medicaments where the inhibition of PPIase is of benefit. Such illnesses are, for example: peripheral neuropathies, neurodegeneration, stroke, Parkinson's and Alzheimer's diseases, traumatic brain diseases, multiple sclerosis.
It has furthermore been demonstrated that the compounds according to the invention are able to inhibit the infiltration of eosinophilic granulocytes into the tissue, which is characteristic of the asthmatic late-phase reaction.
The invention relates to new 1,2,5-trisubstituted 1,2-dihydroindazol-3-ones of the general formula I
in which X, Y, Z, R
1
, R
2
and R
3
have the following meaning:
X can be —SO
2
—, —SO—, —(CH
2
)
p
—, —(CH
2
)
p
—O—, —(CH
2
)
p
—(C═O)—, —(CH
2
)
p
—(C═O)—NH—, (CH
2
)
p
—CHOH—; —CHOH—(CH
2
)
p
—, —(CH
2
)
p
—CH═CH—, —CH═CH—(CH
2
)
p
— where p=1 . . . 4,
Y can be —(C═O)—, —(C═O)—NH—, —(C═O)—NH—(CH
2
)
p
—, —(C═O)—(CH
2
)
p
—, —(CH
2
)
p
—, —(CH
2
)
p
—O—, —(CH
2
)
p
—(C═O)—, —(CH
2
)
p
—(C═O)—NH—, —(CH
2
)
p
—(C═O)—NH—(CH
2
)
p
—, —(CH
2
)
p
—CHOH—, —CHOH—(CH
2
)
p
—, —(CH
2
)
p
—CH═CH—, —CH═CH—(CH
2
)
p
—where p=1 . . . 4,
Z can be —O—, —O—(CH
2
)
p
— where p=1 . . . 4, —NH—, —NH—(C
Brune Kay
Hofgen Norbert
Poppe Hildegard
Schindler Rudolf
Arzneimittelwerk Dresden GmbH
Gabriel P. Katona L.L.P.
Tsang Cecilia
Wright Sonya N
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