Use of 4-substituted tetrahydropyridines for making...

Details Use of 4-substituted tetrahydropyridines for making... Use of 4-substituted tetrahydropyridines for making...

2000-04-10

2002-01-29

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S357000, C546S329000, C546S339000, C546S340000

Reexamination Certificate

active

06342505

ABSTRACT:

This application is a 371 of PCT/FR98/01000 filed May 20, 1998.
The present invention relates to the use of certain 1,2,3,6-tetrahydropyridine derivatives, and to their pharmaceutically acceptable salts and solvates for the preparation of medicaments capable of increasing the levels of TGF-&bgr;1 (Transforming growth factors &bgr;1).
TGF-&bgr;1 is a multifunctional and ubiquitous peptide which is constituted, in its active form, by two identical sub-units linked by a disulphide bridge. As illustrated by P. Bedesse and V. Paradis (Journal of Hepatology, 1995, 22, 37-42), TGF-&bgr;1 has been identified as a factor which induces cell growth in transformed fibroblasts, but many other cell functions have been discovered successively.
The WO 93/09808 application describes the use of TGF-&bgr;1 for the treatment of damages to the central nervous system.
The WO 96/34881 and WO 94/17099 applications claim novel peptides which have a similar activity to that of TGF-&bgr;1 and which may be used for the treatment of several pathologies.
TGF-&bgr;1 is for example implicated in the control of the cell cycle, in angiogenesis, in cellular differentiation, in embryogenesis, in tissue repair, as well as in apoptosis.
Amongst these activities, the anti-apoptotic effect of TGF-&bgr;1 is very important due to its pharmacological implications.
“Apoptosis”, or “programmed cell death”, indicates the whole of the physiological processes linked to cell death. In its terminal phase, apoptosis is characterised by an activation of the endonucleases which cleave double-stranded DNA in the internucleosomal regions, thus generating mono- and oligo-nucleosomes which complex with histones. An enrichment in oligo- and mono-nucleosomes linked to histones is thus observed in the cytoplasm of the apoptotic cells.
Although this phenomenon is physiological, in contrast to necrosis, it may also be caused by pathological stimulations.
D. A. Carson and J. M. Ribeiro report (The Lancet 1993, 341, 1251-1254) the role of apoptosis in certain pathologies such as immuno-depression, immune deficiencies in patients suffering from AIDS, cell aging, and degenerative illnesses.
J. Mathieu et al. (Ann. pharmaceutics frangaises 1996, 54, 5, 193-201) demonstrated that the pathological effects caused by chemical and physical agents such as free radicals and ionising radiation are caused by the pro-apoptotic effects of these agents.
The apoptosis-regulating products were described in the WO 96/21449 patent application. The general formula includes both inhibitors and stimulators of apoptosis, without the means of distinguishing them from one another being given.
It has now been found that certain tetrahydropyridines increase circulating and cellular and extracellular levels of TGF-&bgr;1.
Thus, the object of the present invention is the use of a 4-substituted 1,2,3,6-tetrahydropyridine of formula (I):
in which:
R
1
represents a halogen or a CF
3
, (C
1
-C
4
)alkyl or (C
1
-C
4
)alkoxy group;
Y represents a nitrogen atom or a CH group;
Z′ and Z″ each represent hydrogen or a (C
1
-C
3
)alkyl group, or one represents hydrogen and the other a hydroxy group, or both, together, represent an oxo group;
Z represents
a phenyl radical;
a phenyl radical monosubstituted with a substituent X, X being
a) a (C
1
-C
6
)alkyl; (C
1
-C
6
)alkoxy; (C
3
-C
7
)carboxyalkyl; (C
1
-C
4
)alkoxycarbonyl(C
1
-C
6
)alkyl; (C
3
-C
7
)carboxyalkoxy or (C
1
-C
4
)-alkoxycarbonyl(C
1
-C
6
)alkoxy group;
b) a group selected from a (C
3
-C
7
)cycloalkyl, (C
3
-C
7
)cycloalkyloxy, (C
3
-C
7
)cycloalkylmethyl, (C
3
-C
7
)cycloalkylamino and cyclohexenyl group, it being possible for said group to be substituted with a halogen, hydroxy, (C
1
-C
4
)alkoxy, carboxy, (C
1
-C
4
)alkoxycarbonyl, amino, mono- or di-(C
1
-C
4
)alkylamino;
c) a group selected from a phenyl, phenoxy, phenylamino, N-(C
1
-C
3
)alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulphonyl, phenylsulphinyl or styryl, it being possible for said group to be mono- or poly-substituted on the phenyl group with a halogen, CF
3
, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, cyano, amino, mono- or di-(C
1
-C
4
)alkylamino, (C
1
-C
4
)acylamino, carboxy, (C
1
-C
4
)alkoxycarbonyl, aminocarbonyl, mono- or di-(C
1
-C
4
)alkylaminocarbonyl, amino(C
1
-C
4
)alkyl, hydroxy(C
1
-C
4
)alkyl or halo(C
1
-C
4
)alkyl;
a phenyl radical disubstituted with a substituent R
2
, R
2
being a halogen or a hydroxy, methyl, ethyl, (C
3
-C
6
)alkyl, (C
1
-C
4
)alkoxy or trifluoromethyl group and with a substituent X, X being as defined above;
a 1-naphthyl or 2-naphthyl radical;
a 1-naphthyl or 2-naphthyl radical substituted in positions 5, 6, 7 and/or 8 with one or two hydroxyl groups, one or two (C
1
-C
4
)alkoxy groups or a 6,7-methylenedioxy group;
or Z″ is hydrogen and Z and Z′ represent, each independently, a non-substituted or mono-, di- or tri-substituted phenyl group;
or of one of its pharmaceutically acceptable salts and solvates, for the preparation of pharmaceutical compositions capable of increasing circulating and cellular and extracellular levels of TGF-&bgr;
1
.
According to an advantageous aspect, the object of the invention is the use of the compound of formula (I) in which Y is CH and R
1
is o- or m-CF
3
.
According to a preferred aspect, Y is CH, R
1
is o- or m-CF
3
and Z′ and Z″ are hydrogen.
According to another preferred aspect, Y is CH, R
1
is o- or m-CF
3
, Z′ and Z″ represent an oxo group and Z is 4-biphenyl.
According to a further advantageous aspect, the object of the invention is the use of the compound of formula (I) wherein Y is CH, R
1
is o- or m-CF
3
, Z′ and Z″ are hydrogen and Z represents a phenyl radical monosubstituted with a substituent X, X being a), b), c) or one of its pharmaceutically acceptable salts and solvates.
According to another preferred aspect, the invention relates to the use of the compound of formula (I) in which Y is CH, R
1
is o- or m-CF
3
, Z′ and Z″ are hydrogen and Z represents either a phenyl radical monosubstituted with a group X′, X′ being a phenyl non-substituted or substituted with 1 to 3 halogens, 1 to 3 CF
3
, 1 to 3 (C
1
-C
4
)alkyl, 1 to 3 (C
1
-C
4
)alkoxy, 1 to 3 cyano, 1 to 3 amino, 1 to 3 mono- or di-(C
1
-C
4
)alkylamino, 1 to 3 (C
1
-C
4
)acylamino, 1 to 3 carboxy, 1 to 3 (C
1
-C
4
)alkoxycarbonyl, 1 to 3 aminocarbonyl, 1 to 3 mono- or di-(C
1
-C
4
)alkylaminocarbonyl, 1 to 3 amino(C
1
-C
4
)alkyl, 1 to 3 hydroxy(C
1
-C
4
)alkyl or 1 to 3 halo(C
1
-C
4
)alkyl groups; or a phenyl radical disubstituted with a substituent R
2
, R
2
being a halogen or a hydroxy, methyl, ethyl, (C
3
-C
6
)alkyl, (C
1
-C
4
)alkoxy or trifluoromethyl group and with a substituent X′, X′ being as defined above, or of one of its pharmaceutically acceptable salts and solvates.
According to another preferred aspect, the invention relates to the use of the compound of formula (I) in which Y is CH, R
1
is o- or m-CF
3
, Z′ and Z″ are hydrogen and Z is a phenyl group substituted in positions 3 and 4 with a (C
1
-C
6
)alkyl group, or of one of its pharmaceutically acceptable salts and solvates.
According to another preferred aspect, the invention relates to the use of the compound of formula (1) in which Y is CH, R
1
is o- or m-CF
3
, Z″ is hydrogen and Z and Z′, identical, each represent a phenyl group; a phenyl group substituted in position 2, 3 or 4 with a fluorine or chlorine atom or with a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, cyano, methoxy, methylthio, methylsulphonyl, ethoxy, ethylthio, ethylsulphonyl, (C
1
-C
3
)alkoxycarbonyl or di(C
1
-C
3
)alkylaminocarbonyl group; a phenyl group disubstituted in positions 2,4 ; 3,4; 3,5 or 2,6 with a chlorine or fluorine atom, or with a methyl, ethyl, trifluoromethyl, cyano or methoxy group ; or a phenyl group trisubstituted in positions 3,4,5 ; 2,4,5 or 2,4,6 with a chlorine or fluorine atom, or with a methyl, ethyl, trifluoromethyl, cyano or

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