Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-30
2003-11-18
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S183000, C514S237800, C514S237800, C514S238800, C514S239500, C514S277000, C514S425000, C544S386000, C544S398000, C544S402000, C544S403000, C544S162000, C544S170000, C544S176000, C546S001000, C546S304000, C546S329000, C546S339000
Reexamination Certificate
active
06649616
ABSTRACT:
The present invention relates to substituted phenylcyclohexanecarboxamides, to a process for their preparation and to their use in medicaments, in particular for the prevention and/or treatment of cardiovascular disorders, for example for the acute and chronic treatment of ischaemic disorders.
Adenosine is an endogenic effector with cell-protective activity, in particular under cell-damaging conditions with limited oxygen supply, such as, for example, in the case of ischaemia. Adenosine is a highly effective vasodilator. It increases ischaemic “preconditioning” (R. Strasser, A. Vogt, W. Scharper, Z. Kardiologie 85, 1996, 79-89) and can promote the growth of collateral vessels. It is released under hypoxic conditions, for example in the case of cardiac or peripheral occlusive diseases (W. Makarewicz “Purine and Pyrimidine Metabolism in Man”, Plenum Press New York, 11, 1998, 351-357). Accordingly, adenosine protects against the effects of disorders caused by ischaemia, for example by increasing the coronary or peripheral circulation by vasodilation, by inhibiting platelet aggregation and by stimulating angiogenesis. Compared to systemically administered adenosine, the adenosine-uptake inhibitors have the advantage of selectivity for ischaemia. Moreover, systemically administered adenosine has a very short half-life. Systemically administered adenosine causes a strong systemic lowering of the blood pressure, which is undesirable, since circulation into the ischaemic regions may be reduced even further (“steal phenomenon”, L. C. Becker, Circulation 57, 1978, 1103-1110). The adenosine-uptake inhibitor increases the effect of the adenosine which is formed locally owing to the ischaemia and thus only dilates the vessels in the ischaemic regions. Accordingly, orally or intravenously administered adenosine-uptake inhibitors can be used for preventing and/or treating ischaemic disorders.
Furthermore, there have been various indications of a neuroprotective, anticonvulsive, analgesic and sleep-inducing potential of adenosine-uptake inhibitors, since they increase the intrinsic effects of adenosine by inhibiting its cellulare re-uptake (K. A. Rudolphi et al., Cerebrovascular and Brain Metabolism Reviews 4, 1992, 364-369; T. F. Murray et al., Drug Dev. Res. 28, 1993, 410-415; T. Porkka-Heiskanen et al., Science 276, 1997, 1265-1268; ‘Adenosine in the Nervous System’, Ed.: Trevor Stone, Academic Press Ltd. 1991, 217-227; M. P. DeNinno, Annual Reports in Medicinal Chemistry 33, 1998, 111-120).
It is an object of the present invention to provide novel substances for preventing and/or treating cardiovascular disorders, the substances having improved administration properties.
The present invention relates to compounds of the formula
in which
D represents a radical
in which
R
2
represents hydrogen, halogen, hydroxyl, carboxyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy or (C
1
-C
6
)-alkoxycarbonyl,
A represents an oxygen atom or a group of the formula N—R
5
or CH—R
6
,
in which
R
5
represents hydrogen, (C
1
-C
6
)-alkyl, (C
3
-C
7
)-cycloalkyl, where alkyl and cycloalkyl for their part may be substituted up to three times independently of one another by hydroxyl or mono- or di-(C
1
-C
6
)-alkylamino, represents (C
6
-C
10
)-aryl, 5- to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S or 5- or 6-membered heterocyclyl having up to three heteroatoms from the group consisting of N, O and S, where aryl, heteroaryl and heterocyclyl for their part may be substituted up to three times independently of one another by halogen, hydroxyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxycarbonyl or mono- or di-(C
1
-C
6
)-alkylamino,
R
6
represents hydrogen, (C
1
-C
6
)-alkoxycarbonyl or carboxyl,
R
1
represents hydrogen, (C
1
-C
6
)-alkyl, which for its part may be substituted by hydroxyl or (C
1
-C
4
)-alkoxy, represents (C
3
-C
7
)-cycloalkyl, (C
6
-C
10
)-aryl, 5- to 10-membered heteroaryl having up to two heteroatoms from the group consisting of N, O and S, where aryl and heteroaryl for their part may be substituted independently of one another by halogen, or represents a radical of the formula —NR
7
R
8
or —OR
9
,
in which
R
7
and R
8
independently of one another represent hydrogen, (C
6
-C
10
)-aryl, adamantyl, (C
1
-C
8
)-alkyl, whose chain may be interrupted by one or two oxygen atoms and which may be substituted up to three times independently of one another by hydroxyl, phenyl, trifluoromethyl, (C
3
-C
8
)-cycloalkyl, (C
1
-C
6
)-alkoxy, mono- or di-(C
1
-C
6
)-alkylamino, 5- or 6-membered heterocyclyl having up to three heteroatoms from the group consisting of N, O and S or by 5- to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S, represent (C
3
-C
8
)-cycloalkyl, which may be substituted up to three times independently of one another by (C
1
-C
4
)-alkyl, hydroxyl or oxo, or represent 5- or 6-membered heterocyclyl having up to two heteroatoms from the group consisting of N, O and S, where N is substituted by hydrogen or (C
1
-C
4
)-alkyl, or
R
7
and R
8
together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which is optionally substituted by hydroxyl, oxo or (C
1
-C
6
)-alkyl, which for its part may be substituted by hydroxyl, and
R
9
represents (C
6
-C
10
)-aryl, adamantyl, (C
1
-C
8
)-alkyl, whose chain may be interrupted by one or two oxygen atoms and which may be substituted up to three times independently of one another by hydroxyl, phenyl, trifluoromethyl, (C
3
-C
8
)-cycloalkyl, (C
1
-C
6
)-alkoxy, mono- or di-(C
1
-C
6
)-alkylamino, 5- or 6-membered heterocyclyl having up to three heteroatoms from the group consisting of N, O and S or by 5- to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S, represents (C
3
-C
8
)-cycloalkyl, which may be substituted up to three times independently of one another by (C
1
-C
4
)-alkyl, hydroxyl or oxo, or represents 5- or 6-membered heterocyclyl having up to two heteroatoms from the group consisting of N, O and S, where N is substituted by hydrogen or (C
1
-C
4
)-alkyl,
R
3
represents (C
1
-C
8
)-alkyl, whose chain may be interrupted by a sulphur or oxygen atom or an S(O) or SO
2
group, represents phenyl, benzyl or 5- or 6-membered heteroaryl having up to two heteroatoms from the group consisting of N, O and S, where phenyl, benzyl and heteroaryl may be substituted up to three times independently of one another by halogen, trifluoromethyl, cyano, nitro, hydroxyl, (C
1
-C
6
)-alkyl or (C
1
-C
6
)-alkoxy, and
R
4
represents a radical of the formula —C(O)—NR
10
R
11
,
in which
R
10
and R
11
independently of one another represent hydrogen or (C
1
-C
6
)-alkyl,
and their salts, hydrates, hydrates of the salts and solvates.
Salts of the compounds according to the invention are physiologically acceptable salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particular preference is given, for example, to salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acids, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Salts can also be physiologically acceptable metal or ammonium salts of the compounds according to the invention. Particularly preferred are alkali metal salts (for example sodium salts or potassium salts), alkaline earth metal salts (for example magnesium salts or calcium salts), and also ammonium salts, which are derived from ammoia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or
Bischoff Erwin
Krahn Thomas
Müller Stephan-Nicholas
Paulsen Holger
Schuhmacher Joachim
Bayer Aktiengesellschaft
Patel Sudhaker B.
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