Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-20
2003-01-21
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...
C514S269000, C544S253000, C544S315000, C544S316000, C544S319000
Reexamination Certificate
active
06509341
ABSTRACT:
The present invention relates to novel carboxylic acid derivatives, their preparation and use.
Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. “Endothelin” or “ET” hereinafter refers to one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on vessel tone. It is known that this vasoconstriction is caused by binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
Elevated or abnormal release of endothelin causes persistent vasoconstriction in peripheral, renal and cerebral blood vessels, which may result in disorders. As reported in the literature, endothelin is involved in a number of disorders. These include: hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, athersclerosis and asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328, 1732 (1993), Nephron 66, 373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995); Cancer Research 56, 663 (1996)).
At least two endothelin receptor subtypes, ET
A
and ET
B
receptors, are currently described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990)). Accordingly, substances which inhibit the binding of endothelin to the two receptors ought to antagonize the physiological effects of endothelin and therefore represent valuable drugs.
Mixed ET
A
/ET
B
receptor antagonists have been described in DE Patent Application 19636046.3. The spacer Q (see formula II) is important for these compounds, corresponds in length to a C
2
-C
4
-alkyl chain and has the function of producing a defined distance between R
6
and W in compounds of the formula II.
Furthermore, in the patent application WO 97/38980, the following compounds of the formula VII are described as endothelin receptor antagonists:
An advantage of these compounds is -said to be the low plasma binding.
We have now found, surprisingly, that the receptor affinity and selectivity can be influenced using the spacer Q=R
6
CR
7
R
8
(see formula I), as a function of R
6
=amide. Thus, either ET
A
-selective, ET
B
-selective or else mixed receptor antagonists [sic] can be prepared.
The antagonists referred to here as ET
A
(ET
B
)-specific antagonists are those whose affinity for the ET
A
(ET
B
) receptor is at least ten times higher than their affinity for the ET
B
(ET
A
) receptor. Preferred compounds are those whose difference in affinity for the two receptors is at least twenty.
Mixed endothelin receptor antagonists are those compounds which bind with approximately the same affinity to the ET
A
and ET
B
receptors. Approximately the same affinity for receptors exists when the ratio of the affinities is greater than 0.05 (preferably 0.1) and less than 20 (preferably 10).
It is an object of the present invention to identify compounds which belong to one of the three selectivity groups.
We have found that this object is achieved by carboxylic acid derivatives of the formula I
[lacuna] R
1
is tetrazole [sic] or a group
where R has the following meaning:
a) a radical OR
9
where R
9
is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerated organic ammonium ion such as tertiary C
1
-C
4
-alkylammonium or the ammonium ion;
C
3
-C
8
-cycloalkyl, C
1
-C
8
-alkyl, CH
2
-phenyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, hydroxyl, C
1
-C
4
-alkoxy, mercapto, C
1
-C
4
-alkylthio, amino, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
;
a C
3
-C
6
-alkenyl—or a C
3
-C
6
-alkynyl group, it being possible for these groups in turn to carry one to five halogen atoms;
R
9
can also be a phenyl radical which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, hydroxyl, C
1
-C
4
-alkoxy, mercapto, C
1
-C
4
-alkylthio, amino, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
;
b) a 5-membered heteroaromatic system which is linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one or two halogen atoms, or one or two C
1
-C
4
-alkyl or one or two C
1
-C
4
-alkoxy groups.
c) a group
where k can assume the values 0, 1 and 2, p can assume the values 1, 2, 3 and 4, and R
10
is
C
1
-C
4
-alkyl, C
3
-C
8
-cycloalkyl, C
3
-C
6
-alkenyl, C
3
-C
6
-alkynyl or phenyl, which can be substituted by one or more, e.g. one to three, of the following radicals:
halogen, nitro, cyano, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, hydroxyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio, mercapto, amino, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
.
d) a radical
where R
11
is:
C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
3
-C
6
-alkenyl, C
3
-C
6
-alkynyl, C
3
-C
8
-cycloalkyl, it being possible for these radicals to carry a C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio and/or a phenyl radical as specified under c);
phenyl, which can be substituted by one to three of the following radicals: halogen, nitro, cyano, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, hydroxyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio, mercapto, amino, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
The other substituents have the following meanings:
R
2
hydrogen, hydroxyl, NH
2
, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
, halogen, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
2
-C
4
-alkynyl, C
1
-C
4
-hydroxyalkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy or C
1
-C
4
-alkylthio, or CR
2
is linked to CR
10
as indicated under Z to give a 5- or 6-membered ring.
X nitrogen or methine.
Y nitrogen or methine.
Z nitrogen or CR
12
, where R
12
is hydrogen, halogen or C
1
-C
4
-alkyl, or CR
12
forms together with CR
2
or CR
3
a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C
1
-C
4
-alkyl groups and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, —NH or N(C
1
-C
4
-alkyl).
At least one of the ring members X, Y or Z is nitrogen.
R
3
hydrogen, hydroxyl, NH
2
, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
, halogen, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
2
-C
4
-alkynyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy, C
1
-C
4
-hydroxyalkyl, C
1
-C
4
-alkylthio, or CR
3
is linked to CR
12
as indicated under Z to give a 5- or 6-membered ring.
R
4
and R
5
(which can be identical or different):
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
2
-C
4
-alkynyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, phenoxy, carboxyl, C
1
-C
4
-haloalkoxy, C
1
-C
4
-alkylthio, amino, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
or phenyl which can be substituted one or more times, e.g. one to three times, by halogen, nitro, cyano, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy or C
1
-C
4
-alkylthio; or
phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene, or ethenylene group, an oxygen or sulfur atom or an SO
2
, NH or N-alkyl group;
C
3
-C
8
-cycloalkyl.
R
6
a group
R
13
and R
14
(which can be identical or different):
hydrogen, with the proviso that R
13
and R
14
must not simultaneously be hydrogen,
C
1
-C
8
-alkyl, C
3
-C
8
-alkenyl or C
3
-C
8
-alkynyl, it being possible for each of these radicals to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, amino, carboxamide [sic], cyano, C
1
-C
4
-alkoxy, C
3
-C
6
-alkenyloxy, C
3
-C
6
-alkynyloxy, C
1
-C
4
-alkylthio, C
1
-C
4
-haloalkoxy, C
1
-C
4
-alkylcarbonyl, C
1
-C
4
-a
Amberg Wilhelm
Hergenröder Stefan
Jansen Rolf
Raschack Manfred
Unger Liliane
Abbott Laboratories
Balasubramanian Venkataraman
Keil & Weinkauf
Raymond Richard L.
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