Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-19
2003-12-09
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S031000, C549S307000, C514S469000
Reexamination Certificate
active
06660764
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.
In the new carboxylic acid amides of the above general formula I
R
1
denotes a hydrogen atom or a C
1-3
-alkyl 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 chromane or chromene group linked via a fused-on phenyl ring wherein a methylene group may be replaced by a carbonyl group,
or a bicyclic heteroaryl group consisting of
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, wherein 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 a phenyl ring fused to the abovementioned monocyclic heteroaryl groups via two adjacent carbon atoms, by means of which the bicyclic heteroaryl group is linked to the R
1
-substituted alkene-carbon atom and which 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 5- or 6-membered heteroaryl group substituted by a carboxy group or by a group which may be converted into a carboxy group in vivo
or 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, while the abovementioned phenyl group 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
-alkyl-sulphonyloxy, 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 an n-C
2-3
-alkoxy 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 in the 2 or 3 position relative to the nitrogen atom may be substituted in each case by a C
1-3
-alkoxy group, by an N-phenylamino, N-(phenyl-C
1-3
-alkyl)-amino or N-(pyridyl-C
1-3
-alkyl)-amino group,
by an aminocarbonyl group which may be mono- or disubstituted at the amino-nitrogen atom by a C
1-3
-alkyl group,
by a pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl or N—(C
1-3
-alkyl)-piperazinocarbonyl group,
by a sulphonyl group substituted by an amino, C
1-3
-alkylamino, di-(C
1-3
-alkyl)-amino, pyrrolidino, piperidino, morpholino or N—(C
1-3
-alkyl)-piperazino group,
by an amino or N—(C
1-3
-alkyl)-amino group which is substituted in each case at the amino-nitrogen atom by an aminocarbonyl, C
1-3
-alkylaminocarbonyl, phenyl-C
1-3
-alkylaminocarbonyl, phenylaminocarbonyl, pyridylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl or N—(C
1-3
-alkyl)-piperazinocarbonyl group, whilst in the abovementioned aminocarbonyl groups any hydrogen atom present may additionally be replaced by a C
1-3
-alkyl group,
or by a 5 or 6-membered heteroaryl group,
whilst the abovementioned phenyl groups may additionally be substituted by another fluorine, chlorine or bromine atom or by another C
1-3
-alkyl or C
1-3
-alkoxy group and two C
1-3
-alkoxy groups in the o position may be replaced by a methylenedioxy group,
and the abovementioned 6-membered heteroaryl groups contain one, two or three nitrogen atoms and the abovementioned 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,
the isomers thereof and the salts thereof.
An essential feature of the invention is the fact that A denotes a bicyclic heteroaryl group which is linked via the phenyl ring to the R
1
-substituted olefinic carbon atom.
By a group which can be converted in vivo into a carboxy group is meant, for example, a hydroxmethyl group, a carboxy
Damm Klaus
Hauel Norbert
Priepke Henning
Schnapp Andreas
Boehringer Ingelheim Pharma KG
Seaman D. Margaret
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-3154493