4,5,6,7-tetrahydroindazole derivatives as antitumor agents

Details 4,5,6,7-tetrahydroindazole derivatives as antitumor agents 4,5,6,7-tetrahydroindazole derivatives as antitumor agents

2001-11-09

2004-04-06

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S339000, C546S276700, C546S277100, C546S277400

Reexamination Certificate

active

06716856

ABSTRACT:

The present invention relates to 4,5,6,7-tetrahydroindazole derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use as antitumor agents. Several cytotoxic drugs such as, e.g. fluorouracil (5-FU), doxorubicin and camptothecins result to damage DNA or to affect cellular methabolic pathways and thus cause, in many cases, an indirect block of the cell cycle.
Therefore, by producing an irreversible damage to both normal and tumor cells, these agents result in a significant toxicity and side-effects.
In this respect, compounds capable of being highly specific antitumor agents by selectively leading to tumor cell arrest and apoptosis, with comparable efficacy but reduced toxicity than the currently available drugs, are desirable.
It is well known in the art that progression through the cell cycle is governed by a series of checkpoint controls which are regulated by a family of enzymes known as the cyclin-dependent kinases (cdk).
The cdks themselves are regulated at many levels such as, for instance, binding to cyclins.
For a general reference to cyclins and cyclin-dependent kinases see, for instance, Kevin R. Webster et al. in Exp. Opin. Invest. Drugs, 1998, Vol. 7(6), 865-887.
Checkpoint controls are defective in tumor cells due, in part, to disregulation of cdk activity. For example, altered expression of cyclin E and cdk's has been observed in tumor cells, and deletion of the cdk inhibitor p27 KIP gene in mice has been shown to result in a higher incidence of cancer.
Increasing evidence supports the idea that the cdks are rate-limiting enzymes in cell cycle progression and, as such, represent molecular targets for therapeutic intervention. In particular, the direct inhibition of cdk/cyclin kinase activity should be helpful in restricting the unregulated proliferation of a tumor cell.
It has now been found that the compounds of the invention, hereinafter referred to as 4,5,6,7-tetrahydroindazoles, are endowed with cdk/cyclin kinase inhibitory activity and are thus useful in therapy as antitumor agents whilst lacking, in terms of both toxicity and side effects, the aforementioned drawbacks known for currently available antitumor drugs.
In addition, besides of being useful in the treatment of cancer, these 4,5,6,7-tetrahydroindazoles are also useful in the treatment of a variety of other cell proliferative disorders such as, for instance, psoriasis, vascular smooth cell proliferation associated with atherosclerosis and post-surgical stenosis and restenosis, and in the treatment of Alzheimer's disease.
The compounds of the invention are also useful in the treatment and/or prevention of chemotherapy-induced or radiotherapy-induced alopecia.
Some 4,5,6,7-tetrahydroindazole derivatives, in particular 4-oxo-4,5,6,7-tetrahydroindazoles, are known in the art.
As an example, the compounds 1-phenyl-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole, 1-phenyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazole, 1-phenyl-3-methyl-4-oxo-4,5,6,7-tetrahydroindazole and 1-(2-pyridyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole, as well as their corresponding 7-brominated derivatives, are all reported by Strakova I. et al., as useful synthetic intermediates [see, for a reference, Chemical Abstracts 124(1996):145892; 82(1975):4173z; 80(1974):133332h; 79(1973):92097u].
Likewise, 7-amino-1-phenyl-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole has also been reported, as chemical intermediate by Strakova I. et al., in Latv. PSR Zinat. Akad. Vestis, Kim. Ser. 1974, (1), 113-14 [see, for a reference Chemical Abstracts 80(1974):133334k].
To the extent of our knowledge, however, none of these known compounds has been reported as possessing pharmaceutical activity, for instance antitumor activity and, even more particularly, cell cycle inhibitory activity.
Accordingly, the present invention provides a compound which is a 4,5,6,7-tetrahydroindazole derivative of formula (I)
wherein:
the dotted line (x) represents a single or double bond;
n is 0 or 1;
R
1
is hydrogen or a group selected from straight or branched C
1
-C
6
alkyl, aminocarbonyl, mono- or di-alkylaminocarbonyl with from 1 to 6 carbon atoms in the alkyl chains, aryl or arylalkyl with from 1 to 6 carbon atoms within the alkyl chain, each of which being optionally further substituted by one or more groups selected from halogen atoms, amino, nitro, cyano, hydroxy, C
1
-C
6
alkyl or C
1
-C
6
alkoxy groups;
R
2
is hydrogen or a group selected from straight or branched C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl or cycloalkylalkyl with from 1 to 6 carbon atoms within the alkyl chain, aryl or arylalkyl with from 1 to 6 carbon atoms within the alkyl chain, each of which being optionally further substituted by one or more groups selected from halogens, cyano, straight or branched C
1
-C
6
alkyl, straight or branched C
1
-C
6
alkoxy, aryl, aryloxy, amino, alkylamino, dialkylamino with from 1 to 6 carbon atoms within the alkyl chain;
R
3
is hydroxy or a straight or branched C
1
-C
6
alkoxy, amino, mono- or di-alkylamino with from 1 to 6 carbon atoms in the alkyl chains or, when (x) represents a double bond, R
3
is an oxygen atom (═O), a sulphur atom (═S) or an imino group (═N—R
4
) wherein R
4
is hydrogen, hydroxy or a C
1
-C
6
alkoxy group;
Ra and R′a are, each independently, hydrogen or straight or branched C
1
-C
6
alkyl;
Rb and R′b are, each independently, hydrogen, halogen, atom or a group selected from straight or branched C
1
-C
6
alkyl, straight or branched C
1
-C
6
alkoxy, straight or branched C
1
-C
6
alkylthio, cyano, hydroxy, amino, mono- or di-alkylamino with from 1 to 6 carbon atoms in the alkyl chains, arylthio, arylsulfinyl, arylsulfonyl, wherein each of the above aryl and alkyl moieties are optionally further substituted by one or more groups selected from halogen atoms, amino, nitro, hydroxy, C
1
-C
6
alkyl or C
1
-C
6
alkoxy groups;
Rc and R′c, present when n is 1, each independently represent hydrogen, straight or branched C
1
-C
6
alkyl or cyano; or,
Ra and Rb together and/or Ra and Rc together form a N-alkyl-piperydinyl ring with 1 to 6 carbon atoms in the alkyl chain or a phenyl ring;
or a pharmaceutically acceptable salt thereof; for use as a medicament.
The present invention further provides a compound which is a 4,5,6,7-tetrahydroindazole derivative of the above formula (I) in the manufacture of a medicament for treating cell proliferative disorders or Alzheimer's disease.
More in particular, the present invention provides a compound which is a 4,5,6,7-tetrahydroindazole derivative of the above formula (I) in the manufacture of a medicament for treating tumors.
In the present description, unless otherwise specified, with the term halogen atom we intend a fluorine, chlorine, bromine or iodine atom; chlorine, bromine and fluorine being preferred.
With the term straight or branched C
1
-C
6
alkyl, alkylthio or alkoxy we intend a group selected from, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or the like.
With the term C
3
-C
6
cycloalkyl we intend a carbocyclic ring comprised from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term aryl stands herewith for phenyl or for an optionally benzocondensed 5 or 6 membered aromatic heterocycle having one or more, preferably 1 or 2, heteroatoms selected from nitrogen, oxygen and sulphur such as, for instance, pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine or the like.
Pharmaceutically acceptable salts of the compounds of formula (I) are the acid addition salts with inorganic or organic acids, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulphonic, isethionic

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