Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2001-12-19
2002-12-10
Kumar, Shailendra (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C548S567000, C548S568000, C514S408000, C514S428000, C514S563000
Reexamination Certificate
active
06492547
ABSTRACT:
The last decade of oncological research has made it possible for the first time to achieve a molecular understanding of the regulatory mechanisms involved in the formation of tumours. These include, for example, the function of oncogenes, tumour suppressor genes, growth factors, receptors, signal transduction cascades, pro- and anti-apoptotic genes in controlling cell growth, differentiation, migration and cell death. These new findings have also shown, however, that cancer is a multifactorial disease at the molecular level, during the onset of which tissues may undergo malignant degeneration as a result of different mechanisms. This heterogeneity of the malignant cells in turn explains the clinical problems of tumour therapy.
As long ago as 1965 Hayflick postulated (Hayflick, Exp. Cell Res. 37, 614-636 (1965)) that the limited proliferative lifespan of normal somatic cells, replicative senescence, may act as a tumour suppressor mechanism. This hypothesis was supported by experimental work which showed that overcoming replicative senescence is a prerequisite for the malignant transformation of cells (Newbold et al. in Nature, 299, 633-636 (1989); Newbold and Overell in Nature, 304, 648-651 (1983)).
However, only in the last few years has there been any understanding of the molecular mechanisms by which somatic cells achieve the state of replicative senescence.
The ends of eukaryotic chromosomes, the telomers, consist of simple repetitive sequences the integrity of which is essential for the function and structure of the chromosomes. However, linear chromosomes lose a certain length of their telomers in each round of DNA replication, a phenomenon which was recognised by Watson back in 1972 (Watson in Nature New Biol. 239, 197-201 (1972)). The cumulative loss of telomeric DNA over numerous cell divisions constitutes the reason for the limited replicative potential of somatic cells, whereas more than 85% of all tumours in humans reactivate an enzyme, telomerase, to compensate for the loss of telomers and thus become immortal (see Shay and Bacchetti in European Journal of Cancer, 33, 787-791 (1997)).
Telomerase in humans is a ribonucleoprotein (RNP) which is made up of at least one catalytic subunit (hTERT), and one RNA (hTR). Both components have been molecularly cloned and characterised. Biochemically, telomerase is a reverse transcriptase which uses a sequence fragment in hTR as a matrix in order to synthesise a strand of telomeric DNA (Morin in Cell 59, 521-529 (1989)). Methods of identifying telomerase activity as well as methods of diagnosing and treating replicative senescence and immortality by modifying telomers and telomerase have already been described (Morin in Cell 59, 521-529 (1989); Kim et al. in Science 266, 2011-2014 (1994)).
Inhibitors of telomerase may be used for tumour therapy, as somatic cells, unlike tumour cells, are not dependent on telomerase.
Moreover, U.S. Pat. No. 3,940,422 inter alia describes the compound trans-3,4-dimethoxy-cinnamic acid-N-anthranilic acid-amide, which has antiallergenic properties, in particular.
It has now been found that the carboxylic acid amides of general formula
the isomers thereof, particularly the trans-isomers thereof, and the salts thereof, particularly the physiologically acceptable salts thereof, surprisingly have an inhibiting effect on telomerase.
The present invention relates to the new carboxylic acid amides of the above general formula I and the salts thereof, particularly the physiologically acceptable salts thereof, which have an inhibiting effect on telomerase, processes for preparing them, pharmaceutical compositions containing these compounds and the use thereof.
The invention further relates to the use of the above carboxylic acid amides of general formula I in inhibiting telomerase and the preparation of a suitable pharmaceutical preparation.
In the new carboxylic acid amides of the above general formula I
R
1
denotes a hydrogen atom, a C
1-3
-alkyl or trifluoromethyl group,
R
2
denotes a hydrogen, fluorine, chlorine or bromine atom or a C
1-3
-alkyl group,
R
3
denotes a hydrogen atom or a C
1-5
-alkyl group,
A denotes a phenyl or naphthyl group substituted by a fluorine, chlorine, bromine or iodine atom, by a C
1-6
-alkyl, C
3-7
-cycloalkyl, phenyl, C
1-3
-alkoxy, cyano, trifluoromethyl or nitro group, whilst the abovementioned monosubstituted phenyl and naphthyl groups may additionally be substituted by a fluorine, chlorine or bromine atom, by a C
1-3
-alkyl or C
1-3
-alkoxy group and the abovementioned disubstituted phenyl groups may additionally be substituted by a C
1-3
-alkyl or C
1-3
-alkoxy group,
a naphthyl group,
a chromane or chromene group wherein a methylene group may be replaced by a carbonyl group,
or a 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by a C
1-3
-alkyl or C
1-3
-alkoxy group, while the 6-membered heteroaryl groups contain one, two or three nitrogen atoms and the 5-membered heteroaryl groups contain an imino group optionally substituted by a C
1-3
-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C
1-3
-alkyl group and an oxygen or sulphur atom, or one or two nitrogen atoms and additionally a phenyl ring may be fused to the abovementioned monocyclic heteroaryl groups via two adjacent carbon atoms and may also be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by a C
1-3
-alkyl or C
1-3
-alkoxy group, and
B denotes a phenyl or naphthyl group which is substituted in each case by a carboxy group, by a group which may be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions and may optionally additionally be substituted by a fluorine, chlorine, bromine or iodine atom or by a C
1-3
-alkyl, trifluoromethyl or methoxy group, whilst the abovementioned phenyl groups are additionally substituted
by a C
1-3
-alkyl group which is substituted by an amino, C
1-4
-alkylamino, di-(C
1-4
-alkyl)-amino, C
3-7
-cycloalkylamino, pyrrolidino, piperidino, morpholino, piperazino or N-(C
1-3
-alkyl)-piperazino group,
while the amino and imino groups mentioned in the definition of the abovementioned groups may additionally be substituted by a group which can be cleaved in vivo.
By a group which can be converted in vivo into a carboxy group is meant, for example, a hydroxmethyl group, a carboxy group esterified with an alcohol, wherein the alcoholic moiety preferably denotes a C
1-6
-alkanol, a phenyl-C
1-3
-alkanol, a C
3-9
-cycloalkanol, whilst a C
5-8
-cycloalkanol may additionally be substituted by one or two C
1-3
-alkyl groups, a C
5-8
-cycloalkanol wherein a methylene group in the 3 or 4 position is replaced by an oxygen atom or by an imino group optionally substituted by a C
1-3
-alkyl, phenyl-C
1-3
-alkyl, phenyl-C
1-3
-alkoxycarbonyl or C
2-6
-alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C
1-3
-alkyl groups, a C
4-7
-cycloalkenol, a C
3-5
-alkenol, a phenyl-C
3-5
-alkenol, a C
3-5
-alkynol or phenyl-C
3-5
-alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C
3-8
-cycloalkyl-C
1-3
-alkanol, a bicycloalkanol having a total of 8 to 10 carbon atoms which may additionally be substituted by one or two C
1-3
-alkyl groups in the bicycloalkyl moiety, a 1,3-dihydro-3-oxo-1-isobenzfuranol or an alcohol of formula
R
a
—CO—O—(R
b
CR
c
)—OH,
wherein
R
a
denotes a C
1-8
-alkyl, C
5-7
-cycloalkyl, phenyl or phenyl- C
1-3
-alkyl group,
R
b
denotes a hydrogen atom, a C
1-3
-alkyl, C
5-7
-cycloalkyl or a phenyl group and
R
c
denotes a hydrogen atom or a C
1-3
-alkyl group,
by a group which is negatively charged under physiological conditions is meant a carboxy, hydroxysulphonyl, phosphono, tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C
1-6
-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, C
1-6
-alkylsulphonyla
Damm Klaus
Hauel Norbert
Priepke Henning
Schnapp Andreas
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Kumar Shailendra
Raymond Robert P.
Stempel Alan R.
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