Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-11
2004-08-31
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C549S072000, C549S060000, C544S379000, C544S146000, C544S295000, C544S121000, C544S364000, C546S212000, C546S280400, C546S019000, C548S527000, C548S315100, C514S448000, C514S444000, C514S252130, C514S422000, C514S326000, C514S336000, C514S397000, C514S278000, C514S252140, C514S235800, C514S253100
Reexamination Certificate
active
06784173
ABSTRACT:
The invention relates to aromatic dicarboxylic acid derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-cell-proliferation activity such as anti-tumor activity and are accordingly useful in methods of treatment of humans and other animals. The invention also relates to processes for the manufacture of said dicarboxylic acid derivatives, to pharmaceutical compositions containing the derivatives and to their use in the treatment of cell-proliferation disorders.
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. 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 (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., J. Natl. Cancer Inst. 92 (2000) 1210-1216. More specifically, WO 98/55449 and U.S. Pat. No. 5,369,108 report alkanoyl hydroxamates with HDAC inhibitory activity.
It has now been found that certain aromatic dicarboxylic acid derivatives are more potent inhibitors of cell-proliferation than the compounds reported in the aforementioned references. Furthermore, these compounds have HDAC inhibitiory activity.
DESCRIPTION OF THE INVENTION
The invention is directed to an aromatic dicarboxylic acid derivative of the formula I
denotes a phenyl ring 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-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]-amino-, (1-4C)alkanoylamino, a (1-3C)alkylenedioxy-group or an acyl group, or alternatively,
denotes a thiophene ring which may be unsubstituted or substituted by 1 or 2 substituents independently selected from a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]-amino- or a (1-4C)alkanoylamino, a (1-3C)alkylenedioxy-group or an acyl group, and
R1 and R2 are each independently selected from
a hydrogen atom;
a branched or unbranched (1-14C)alkyl group, which may be unsubstituted or substituted with 1 or several substituents independently selected from the group consisting of a halogen-, hydroxy-, nitro-, amino-, carbocyclic- or a heterocyclic group,
and wherein at a chain length of larger than 2 C-atoms one or several non adjacent C-atoms may be replaced by a corresponding number of heteroatoms such as oxygen, nitrogen or sulfur,
and wherein 2 C-atoms may be bound together by a double or triple bond;
a carbocyclic group;
or a heterocyclic group;
or alternatively, R1 and R2 together with the nitrogen atom to which they are attached form a 3-6 membered ring that may contain additional heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring optionally being annulated to a carbocyclic ring or a heterocyclic ring, said —NR
1
R
2
ring being unsubstituted or optionally substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino- or an acyl-group.
An alkyl group may be e.g. pentyl, hexyl or 3-methyl-butyl.
A substituted alkyl group may be e.g. benzyl, phenethyl, tetrahydro-furan-2-yl-methyl or 2-cyclohex-1-enyl-ethyl.
An alkyl group where one or several non adjacent atom groups may be replaced by oxygen, nitrogen or sulfur atoms may be e.g. 3-isopropoxy-propyl or 2-methylsulfanyl-ethyl.
An alkyl group wherein 2 atoms may be bound together by a double or triple bond may be e.g. 1-hexinyl or 2-heptenyl.
“Annulated” as used herein means the fusion of a new ring to a molecule via two new bonds.
A carbocyclic group may be a non-aromatic ring system having 3-7 carbon ring atoms, for example cyclopentane, cyclohexane, cyclohexene or cyclopropane, said ring system being unsubstituted or optionally substituted by 1, 2, or 3 substituents independently selected from a halogen, (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, (1-4)alkanoylamino- or an acyl-group. Said ring atoms optionally may be annulated to an aryl or hetaryl group, to form e.g. an indane or a tetraline. A carbocyclic group as herein defined also may be an aryl group.
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-, (1-4C)alkanoylamino-, carboxyl-, carboxyalkyl- or an acyl-group.
A heterocyclic group may be a non-aromatic ring system having 3-7 ring members, said ring members comprising carbon atoms and one or two hetero atoms independently chosen from nitrogen, oxygen, and sulfur. Examples of heterocyclic groups include piperidino, morpholino, pyrrolidino and piperazino. Said ring system may be unsubstituted or substituted by 1, 2, or 3 substituents independently selected from halogen, (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino, or an acyl-group. Moreover, said ring members optionally may be annulated to an aryl or hetaryl group, to form e.g. a tetrahydrochinoline, tetrahydroisochinoline or a dihydroindole. A heterocyclic group as defined herein also may be a hetaryl group.
A hetaryl 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 annulated 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-, (1-4C)alkanoylamino, or an acyl group.
When R1 and R2 together with the nitrogen atom form a 3-6 membered ring which may contain additional heteroatoms independently selected from nitrogen, oxygen and sulfur, it may be e.g. piperidine, piperazine or morpholine.
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)alk
Leser-Reiff Ulrike
Sattelkau Tim
Zimmermann Gerd
Hoffmann-La Roche Inc.
Johnston George W.
Liu Hong
Raymond Richard L.
Rocha-Tramaloni Patricia S.
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