Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-13
2004-07-06
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S255060, C514S355000, C514S365000, C514S387000, C514S406000, C514S422000, C514S423000, C514S617000, C544S131000, C544S406000, C546S309000, C546S316000, C548S200000, C548S309700, C548S374100, C548S537000, C564S161000
Reexamination Certificate
active
06759412
ABSTRACT:
The present invention relates to acylated 6,7,8,9-tetrahydro-5H-benzocycloheptenyl amines of the general formula (I) with the definitions of R
1
to R
5
and A to D given below in the text, in any of their stereoisomeric forms or mixtures thereof in any ratio or the pharmaceutically acceptable salts thereof, and their use as pharmaceutical agents.
Endothelial NO synthase (eNOS, NOS-1) belongs to a group of three isoenzymes which produce nitric oxide (NO) by oxidation of arginine. Endothelially released NO is of central importance in a number of key cardiovascular mechanisms. It has a vasodilating effect and inhibits the aggregation of platelets, the adhesion of leukocytes to the endothelium and the proliferation of intimal smooth muscle cells.
Endothelial NO synthase is subject to physiological and pathophysiological regulation both at the transcriptional and at the post-transcriptional level. Enzyme already present in the endothelium may undergo calcium-dependent and calcium-independent activation through phosphorylation of specific amino acids, but also by direct interactions with specific proteins. Stimulators of this, usually transient, NO release are, extracellular arginine, 17&bgr;-estrogen and the mechanical stimulus exerted on the luminal surface of the endothelium by the blood flow (shear stress). The latter additionally leads to regulation of eNOS at the transcriptional level. Thus, for example, Sessa et al. (Circ. Research 74 (1994) 349-353) were able by means of exercise training and the increase in shear stress associated therewith to obtain a marked increase in ecNOS.
Whether regulation at the post-transcriptional level is relevant in vivo, is often not unambiguously proved. Thus, for example, administration of a high arginine dose is followed by only a transient improvement in the endothelium-dependent vasorelaxation in patients with coronary heart disease.
On the other hand, the significance of the upregulation of the eNOS protein is scientifically accepted. Thus, there are findings which show that the protective properties of the HMG-CoA reductase inhibitor simivastatin can be attributed, besides the lipid lowering, also in part to an increase in eNOS expression in vivo (Endres et al., Proc. Natl. Acad. Sci. USA 95 (1998) 8880-8885). It is additionally known that single point mutations in the 5′-flanking region of the eNOS gene (“eNOS promoter”), and the reduction in the rate of eNOS gene transcription associated therewith, in the Japanese population is associated with an increase in the risk of coronary spasms (Nakayama et al., Circulation 99 (1999) 2864-2870).
The current assumption therefore is that the transcriptional and post-transcriptional mechanisms of eNOS regulation are seriously disturbed in a large number of disorders, especially in cardiovascular disorders. Even in very early stages of a wide variety of cardiovascular disorders it is possible for a dysfunction of this type in the endothelium lining the blood vessels to lead to a deficiency of bioactive NO, which is manifested as the disorder progresses in the form of measurable pathophysiological and morphological changes. Thus, critical steps in early atherogenesis are speeded up by a decrease in endothelial NO release, such as, for example, the oxidation of low density lipoproteins, the recruitment and deposition of monocytes in the intima of vessels, and the proliferation of intimal cells. A consequence of atherogenesis is the formation of plaques on the inside of the blood vessels, which may in turn lead, through a diminution in the shear stress, to a further decrease in endothelial NO release and a further deterioration in the pathology. Since endothelial NO is also a vasodilator, a decrease thereof frequently also leads to hypertension, which may, as an independent risk factor, cause further organ damage.
The aim of a therapeutic approach to the treatment of these disorders must accordingly be to interrupt this chain of events by increasing the endothelial NO expression. Gene transfer experiments which lead in vitro to overexpression of NO synthase in previously damaged vessels are in fact able to counteract the described processes and are thus evidence of the correctness of this approach (Varenne et al., Hum. Gene Ther. 11 (2000) 1329).
Some low molecular weight compounds which, in cell cultures, may lead to a direct effect on eNOS transcription and expression are disclosed in the literature. The statins which have already been mentioned are, however, the only substances for which it has been possible to date to show such an increase in eNOS in vivo as a side effect. In view of the known range of side effects of this class of substances, however, it is unclear how far this effect is present in a toxicologically unproblematic dose.
Liao et al. claim in WO 99/47153 and WO 00/03746 the use of rhoGTPase inhibitors and agents which influence the organization of the actin cytoskeleton for increasing eNOS in endothelial cells and for the therapy of various disorders such as, for example, strokes or pulmonary hypertension, without, however, indicating a specific way of achieving this.
Thus, there exists a strong need for compounds which upregulate eNOS-expression in endothelial cells. The object of the present invention is to provide compounds showing this ability.
This object is attained by acylated 6,7,8,9-tetrahydro-5H-benzocycloheptenyl amines according to the general formula (I) in any of their stereoisomeric forms or mixtures thereof in any ratio or the pharmaceutically acceptable salts thereof.
In the above formula,
R
1
and R
4
are independently from each other selected from the group consisting of:
H; unsubstituted and at least monosubstituted C
1
C
10
-alkyl, C
2
-C
10
-alkenyl and C
2
-C
10
-alkynyl, the substituents of which are selected from the group consisting of F, OH, C
1
-C
8
-alkoxy, (C
1
-C
8
-alkyl)mercapto, CN, COOR
6
, CONR
7
R
8
, and unsubstituted and at least monosubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogens, pseudohalogens, C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy and CF
3
; unsubstituted and at least monosubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogens, pseudohalogens, C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy and CF
3
; R
9
CO; CONR
10
R
11
; COOR
12
; CF
3
; halogens; pseudohalogens; NR
13
R
14
OR
15
; S(O)
m
R
16
; SO
2
NR
17
R
18
; and NO
2
;
R and R
3
are independently from each other selected from the group consisting of:
H; halogens; pseudohalogens; unsubstituted and at least monosubstituted C
1
-C
10
-alkyl the substituents of which are selected from the group consisting of OH, phenyl, and heteroaryl; OH; C
1
-C
10
-alkoxy; phenoxy, S(O)
m
R
19
; CF
3
; CN; NO
2
; (C
1
-C
10
-alkyl)amino; di(C
1
-C
10
-alkyl)amino; (C
1
-C
6
-alkyl)-CONH—; unsubstituted and at least monosubstituted phenyl-CONH— and phenyl-SO
2
—O—, the substituents of which are selected from the group consisting of halogens, pseudohalogens, CH
3
and methoxy; (C
1
-C
6
-alkyl)SO
2
—O—; unsubstituted and at least monosubstituted (C
1
-C
6
-alkyl)CO, the substituents of which are selected from the group consisting of F, di(C
1
-C
3
-alkyl)amino, pyrrolidinyl and piperidinyl; and phenyl-CO, the phenyl part of which can be substituted by one or more substituents from the group consisting of C
1
-C
3
-alkyl, halogens and methoxy;
A is selected from the group consisting of CH
2
, CHOH and CH—(C
1
-C
3
-alkyl);
B is selected from the group consisting of CH
2
and CH—(C
1
-C
3
-alkyl);
C independently has the same meaning as B;
D independently has the same meaning as B;
R
5
is a group Ar or a group Hetar both of which can be unsubstituted or carry one or more substituents selected from the group consisting of: halogens; pseudohalogens; NH
2
; unsubstituted and at least monosubstituted C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl, C
2
-C
10
-alkynyl, C
1
-C
10
-alkoxy, (C
1
-C
10
-alkyl)amino, di(C
1
-C
10
-alkyl)amino, the substituents of which are selected from the group consisting of F
Strobel Hartmut
Wohlfart Paulus
Aventis Pharma Deutschland GmbH
Parker Raymond S.
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