Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-03
2004-04-27
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S567000, C544S171000, C562S456000
Reexamination Certificate
active
06727250
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to carboxylic acid amides that have an inhibitory effect on telomerase, and their use in the treatment of pathophysiological processes which are characterised by an increased telomerase activity, e.g. tumour diseases such as carcinomas, sarcomas and leukaemias.
BACKGROUND OF THE INVENTION
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.
In 1965 Hayflick postulated (Hayflick, Exp. Cell Res. 37, 614-636 (1965)) that the limited proliferative lifespan of normal somatic cells, replicative senescence, can act as a tumour suppressing mechanism. This hypothesis was supported by experimental work which showed that the overcoming of 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 basis for the limited replicative potential of somatic cells, whereas more than 85% of all tumours in humans reactivate an enzyme, telomerase, in order 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 matrix in order to synthesise a strand of telomeric DNA (Morin in Cell 59, 521-529 (1989)). Methods of identifying telomerase activity and also 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 can be used for tumour therapy since 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.
DESCRIPTION OF THE INVENTION
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 inhibitory effect on telomerase.
In 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, a C
1-3
-alkyl, C
3-7
-cycloalkyl or C
1-3
-alkoxy group or also, if R
4
and R
5
each denote a hydrogen atom, R
1
and R
2
together denote an n-C
1-3
-alkylene group optionally substituted by a C
1-3
-alkyl group,
R
3
denotes a hydrogen atom or a C
1-5
-alkyl group,
R
4
and R
5
each denote a hydrogen atom or together denote another carbon-carbon bond, A denotes a phenyl, naphthyl or tetrahydronaphthyl 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,
a 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C
1-3
-alkyl or C
1-3
-alkoxy group, whilst 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 whilst said phenyl ring may also be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom, by a C
1-3
-alkyl or C
1-3
-alkoxy group,
a phenylvinyl group or
R
1
together with A and the carbon atom between them denotes a C
5-7
-cycloalkylidene group to which a phenyl ring may be fused via two adjacent carbon atoms, whilst said phenyl ring may additionally be substituted by one or two C
1-3
-alkyl or C
1-3
-alkoxy groups, whilst the substituents may be identical or different, and
B denotes a 5- or 6-membered heteroaryl group substituted by a carboxy group or capable of being converted into a carboxy group in vivo,
a phenyl or naphthyl group, each of which may be substituted 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, whilst the abovementioned phenyl groups may additionally be substituted
by a fluorine, chlorine, bromine or iodine atom,
by a C
1-3
-alkyl, trifluoromethyl, phenyl, hydroxy, C
1-3
-alkoxy, C
1-3
-alkylsulphonyloxy, phenylsulphonyloxy, carboxy, C
1-3
-alkoxycarbonyl, formyl, C
1-3
-alkylcarbonyl, C
1-3
-alkylsulphonyl, phenylsulphonyl, nitro, pyrrolidino, piperidino, morpholino, N-(C
1-3
-alkyl)-piperazino, aminosulphonyl, C
1-3
-alkylaminosulphonyl or di-(C
1-3
-alkyl)-aminosulphonyl group,
by a C
1-3
-alkyl group which is substituted by a hydroxy, C
1-3
-alkoxy, 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,
by an n-C
2-3
-alkoxy, C
2-3
-alkenyl or C
2-3
-alkynyl group substituted in the 2 or 3 position by a di-(C
1-3
-alkyl)-amino group,
by an amino group, by an N-(C
1-3
-alkyl)-amino or N,N-di-(C
1-3
-alkyl)-amino group wherein the alkyl moiety may in each case be substituted in the 2 or 3 position in relation to the nitrogen atom by a C
1-3
-alkoxy group, by a N-phenylamino, N-(phenyl-C
1-3
-alkyl)-amino or N-(pyridyl-C
1-3
-alkyl)-amino group wherein in each case a hydrogen atom of the abovementioned amino groups may be substituted by a C
1-3
-alkylsulphonyl, phenyl-C
1-3
-alkylsulphonyl or phenylsulphonyl group or by a C
1-7
-alkyl group, which may be replaced in the 2 to 5 position by a C
1-3
-alkoxy, cyano, amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino or tetrazolyl group,
by an aminocarbonyl or C
1-3
-alkylaminocarbonyl group which may in each case be substituted at the amino-nitrogen atom
by a C
1-4
-alkyl group which may be substituted by a vinyl, ethynyl, phenyl, pyridyl, imidazolyl, carboxy
Damm Klaus
Hauel Norbert
Priepke Henning
Schnapp Andreas
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Ramsuer Robert W.
Raymond Robert P.
Stempel Alan R.
LandOfFree
Carboxylic acid amides, pharmaceutical compositions... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Carboxylic acid amides, pharmaceutical compositions..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Carboxylic acid amides, pharmaceutical compositions... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3226261