Tricyclic alkylhydroxamate derivatives

Details Tricyclic alkylhydroxamate derivatives Tricyclic alkylhydroxamate derivatives

2002-04-22

2003-01-28

Davis, Brian J. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S354000, C562S621000, C562S623000

Reexamination Certificate

active

06512123

ABSTRACT:

BACKGROUND OF THE INVENTION
Transcriptional regulation is a major event in cell differentiation, proliferation, and apoptosis. Transcriptional activation of a set of genes determines cell destination and for this reason transcription is tightly regulated by a variety of factors. One of its regulatory mechanisms involved in the process is an alteration in the tertiary structure of DNA, which affects transcription by modulating the accessibility of transcription factors to their target DNA segments. Nucleosomal integrity is regulated by the acetylation status of the core histones. In a hypoacetylated state, nucleosomes are tightly compacted and thus are nonpermissive for transcription. They are relaxed by acetylation of the core histones, with the result being permissiveness to transcription. The acetylation status of the histones is governed by the balance of the activities of histone acetyl transferase (HAT) and histone deacetylase (HDAC). Recently, HDAC inhibitors have been found to arrest growth and apoptosis in several types of cancer cells, including colon cancer, T-cell lymphoma, and erythroleukemic cells. Given that apoptosis is a crucial factor in detecting cancer progression, HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis (Koyama, Y., et al., Blood 96 (2000) 1490-1495).
Several structural classes of HDAC inhibitors have been identified and are reviewed in Marks, P. M., et al., Journal of the National Cancer Institute 92 (2000) 1210-1216. More specifically, WO 98/55449 (by The University of Queensland et al, “Hydroxamic Acid Compounds Having Anticancer And Anti-Parasitic Properties”), and U.S. Pat. No. 5,369,108 (by Breslow, R., et al., “Potent Inducers Of Terminal Differentiation And Methods Of Use Thereof”) report alkanoyl hydroxamates with HDAC inhibitory activity.
We have now found that certain tricyclic alkylhydroxamate derivatives possess anti-cell-proliferation properties which are more potent than those in the aforementioned references. These properties are due to HDAC inhibition.
DESCRIPTION OF THE INVENTION
According to the invention there is provided a tricyclic alkylhydroxamate derivative of the formula I
wherein
A denotes a bond, the groups —CH
2
—O—, —CH
2
—S—, —CH
2
—CH
2
-, or —NH—CO—;
X denotes the group —NR
3
—, ═CO, or —CH(OH,)—;
Y denotes an oxygen atom, a sulfur atom, or the group —NR
4
—;
Z denotes a straight chain alkylene group comprising 4, 5, 6, 7, or 8 carbon atoms, wherein one CH
2
group may be replaced by an oxygen or a sulfur atom, or wherein 2 carbon atoms form a C═C double bond, and which is either unsubstituted or substituted by one or two substituents selected from (1-4C)alkyl and halogen atoms;
R
1
and R
2
denote substituents independently selected from a hydrogen atom, halogen atoms, (1-4C)alkyl, trifluoromethyl, hydroxy, (1-4C)alkoxy, benzyloxy, (1-3C)alkylenedioxy, nitro, amino, (1-4C)alkylamino, di[(1-4C)alkyl]-amino, or (1-4C)alkanoylamino groups;
R
3
and R
4
independently denote hydrogen atoms or (1-4C)alkyl groups;
their enantiomers, diastereoisomers, racemates, salts and mixtures thereof.
A suitable value for a substituent when it is a halogen atom is, for example, fluoro, chloro, bromo and iodo; when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl; when it is (1-4C)alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy; when it is (1-4C)alkylamino is, for example, methylamino, ethylamino or propylamino; when it is di-[(1-4C)alkyl]amino is, for example, dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino or dipropylamino; when it is (1-4C)alkanoylamino is, for example, formylamido, acetamido, propionamido or butyramido; and when it is (1-3C)alkylenedioxy is, for example, methylenedioxy, ethylenedioxy or propylenedioxy.
Preferred tricycles of formula I are dibenzoxepine, dibenzazepine, fluorene or carbazol.
Y is preferred an oxygen atom. Z is a straight chain alkylene group with 4 to 8 carbon atoms, preferably 4 to 7. The chain can be substituted by one or two halogen atoms, preferably chlorine, or a C
1
-C
4
-alkyl group, preferably methyl. One —CH
2
-group of the chain can be replaced by an oxygen or sulfur atom, however, this group should not be the first or last member of the chain. A CH
2
—CH
2
-group of the chain can also form a —H═CH-group.
Preferred compounds of the invention include tricyclic alkylhydroxamate derivatives of the formula I
wherein
A denotes a bond, the groups —CH
2
—O—, or —NH—CO—;
X denotes the group —NR
3
—, ═CO, or —CH(OH)—;
Y denotes an oxygen atom, a sulfur atom, or the group —NR
4
—;
Z denotes a straight chain alkylene group comprising 4, 5, 6, 7, or 8 carbon atoms, wherein one CH
2
group may be replaced by an oxygen or a sulfur atom, or wherein 2 carbon atoms form a C═C double bond, and which is either unsubstituted or substituted by one or two substituents selected from (1-4C)alkyl and halogen atoms;
R
1
and R
2
denote substituents independently selected from halogen atoms, (1-4C)alkyl, trifluoromethyl, hydroxy, (1-4C)alkoxy, benzyloxy, (1-3C)alkylenedioxy, nitro, amino, (1-4C)alkylamino, di[(1-4C)alkyl]-amino, or (1-4C)alkanoylamino groups;
R
3
and R
4
independently denote hydrogen atoms or (1-4C)alkyl groups;
their enantiomers, diastereoisomers, racemates, salts and mixtures thereof.
Preparation of the Compounds of the Invention
A tricyclic alkylhydroxamate derivative of the formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a tricyclic alkylhydroxamate derivative of the formula I, or a pharmaceutically-acceptable salt thereof, are provided as a further feature of the invention and are illustrated by the following representative examples in which, unless otherwise stated, A, X, Y, Z, R
1
, R
2
, R
3
, and R
4
have any of the meanings defined hereinbefore. The starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting examples. Alternatively starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skills of an organic chemist.
a) One preferred method for the preparation of compounds of the formula I is the deprotection of compounds of the formula II
wherein R
5
is a suitable protecting group. Compounds of the formula II are new and included in the present invention.
Suitable protecting groups are the benzyl-, p-methoxybenzyl-, tert.butyloxy-ccarbonyl-, trityl-, or silyl groups such as the trimethylsilyl- or dimethyl-tert.butylsilyl-group. The reactions carried out depend on the type of the protecting group. When the protecting group is a benzyl- or p-methoxybenzyl group, the reaction carried out is a hydrogenolysis in an inert solvent such as an alcohol like methanol or ethanol, in the presence of a noble metal catalyst such as palladium on a suitable carrier such as carbon, barium sulfate, or barium carbonate, at ambient temperature and pressure. When the protecting group is the tert.butyloxycarbonyl-, trityl-, or a silyl group such as the trimethylsilyl- or dimethyl-tert.butylsilyl-group, the reaction is carried out in the presence of acids at a temperature between −20° C. and 60° C., preferably between 0° C., and ambient temperature. The acid may be a solution of hydrochloric acid in an inert solvent such as diethyl ether or dioxane, or trifluoro acetic acid in dichloromethane. Alternatively, when the protecting group is a silyl group such as the trimethylsilyl or dimethyl-tert.butylsilyl group, the reaction is carried out in the presence of a fluoride source such as sodium fluoride or tetrabutyl ammonium fluoride in an inert solvent such as dichloromethane.
Compounds of the formula II are obtained by the reaction of a tricyclic alkylhydroxamate of the formula III
with a compo

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