Tetralone derivatives

Details Tetralone derivatives Tetralone derivatives

2001-12-04

2003-03-11

Solola, Taofiq (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S319000, C514S427000, C514S617000, C544S107000, C546S206000, C548S560000, C564S172000

Reexamination Certificate

active

06531472

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 an 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. On the other hand, nucleosomes 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 for cancer progression, HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis.
Several structural classes of HDAC inhibitors are described in the state of the art and were reviewed by Marks, P. M., et al., J. Natl. Cancer Inst. 15 (2000) 1210-1216. Hydroxamic acid compounds having HDAC inhibitory activity are also described in WO 98/55449 and U.S. Pat. No. 5,369,108.
Suberoylanilide hydroxamine acid (SAHA) was shown to have HDAC inhibitory activity as indicated in U.S. Pat. No. 5,369,108.
SUMMARY OF THE INVENTION
The present invention relates to (1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-alkanoic acid hydroxamides. These compounds possess anti-cell proliferation activity such as anti-cancer activity.
The present invention provides a compound selected from compounds of formula I
wherein:
R1 is selected from hydrogen, (1-4C)alkyl, COOH, and COO(1-4C)alkyl;
R2, R3, R4, R5 are independently selected from hydrogen, a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, aryloxy-, arylalkyloxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]-amino-, piperidino, morpholino, pyrrolidino, (1-4C)alkanoylamino-, an aryl group, and a heteroaryl group, or R2 and R3 together or R3 and R4 together or R4 and R5 together, respectively, can form an (1-3C)alkylenedioxy ring, or R2 and R3 together or R3 and R4 together or R4 and R5 together, respectively, can form an (3-5C)alkylene chain;
Y is —CH2—CH2—;
X is an alkylene chain of 4 to 10 carbon atoms which can be saturated or unsaturated with one or two double bonds or one or two triple bonds or a one double and one triple bond, and which can be branched or unbranched or interrupted by a (3-7C) cycloalkyl ring;
and pharmaceutically acceptable salts thereof.
The present invention also provides a process for making a compound of formula I by reacting a compound of formula III
with a compound of formula IV
wherein
A is a displaceable group and PG is a protecting group.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that (1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-alkanoic acid hydroxamides possess anti-cell-proliferation properties which arise from their HDAC inhibitory activity. The HDAC inhibitory activity of several (1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) -alkanoic acid hydroxamides of the present invention are shown to be superior to SAHA (suberoylanilide hydroxamic acid), in their HDAC inhibitory activity.
The present invention relates to new compounds of the general formula (I) and their use as antitumor agents:
wherein:
R1 is selected from hydrogen, (1-4C)alkyl, COOH, COO(1-4C)alkyl;
R2, R3, R4, R5 are independently selected from hydrogen, a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, aryloxy-, arylalkyloxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]-amino-, piperidino, morpholino, pyrrolidino, (1-4C)alkanoylamino-, an aryl group, and a heteroaryl group, or R2 and R3 together or R3 and R4 together or R4 and R5 together, respectively, form an (1-3C)alkylenedioxy ring, or R2 and R3 together or R3 and R4 together or R4 and R5 together, respectively, form an (3-5C)alkylene chain;
Y is —CH
2
—CH
2
—;
X is an alkylene chain of 4 to 10 carbon atoms which can be saturated or unsaturated with one or two double bonds or one or two triple bonds or one double and one triple bond, and which can be branched or unbranched or interrupted by a (3-7C) cycoalkyl ring.
The enantiomers of the compounds of formula (I), their diastereoisomers, racemates and mixtures thereof are also included in the present invention, as well as pharmaceutically acceptable salts of the compounds of formula (I) which may be salts formed from contact with pharmaceutically acceptable acids and/or bases.
It is also to be understood that certain derivatives of the formula I can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess anticancer activity. Preferred compounds of formula (I) are those in which R2 and R5 are hydrogen. Particularly preferred compounds of formula (I) are those in which three out of the four radicals R2, R3, R4 and R5 are hydrogen.
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 isopropylamino; 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; when it is (1-3C)alkylenedioxy is, for example, methylenedioxy, ethylenedioxy or propylenedioxy.
An aryl group is a carbocyclic conjugated ring system, for example, phenyl, naphthyl, preferably phenyl, which may be unsubstituted or substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, and an (1-4C)alkanoylamino-group as defined above.
A heteroaryl group is either a 5 or 6 membered cyclic conjugated ring system with one or two hetero atoms independently chosen from nitrogen, oxygen, and sulfur, for example pyridinyl, thiophenyl, furyl or pyrrolyl, or an anulated bicyclic conjugated ring system like indolyl-, quinolyl- or isoquinolyl-, which may be unsubstituted or substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an (1-4C)alkyl-, trifluoromethyl-hydroxy-, (1-4C)alkoxy-, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, and an (1-4C)alkanoylamino-group as defined above.
A preferred value for the arylalkyloxy- radical is benzyloxy.
A preferred (3-7C) cycloalkyl ring is cyclopropyl or cyclobutyl whereby the ring is bound to the chain in a 1,1′-connection.
Preferred values for the chain X are —(CH
2
)
n
— and —CH═CH—(CH
2
)
n-2
—, in which n is an integer from 3 to 7, most preferably from 4 to 6. Other preferred values are —(CH
2
)
n-1
—CH(CH
3
)—, —(CH
2
)
n-1
—C(CH
3
)
2
— and —(CH
2
)
n-1
—C(—CH
2-
CH
2
—)—, in which n is an integer from 3 to 7, most preferably from 4 to 6.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a pharmaceutically effective amount of one or more compounds of formula I or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable

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