Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-27
2002-03-19
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S187000, C548S213000, C548S221000, C548S230000, C548S243000, C548S165000, C514S369000, C514S372000, C514S375000, C514S376000, C514S380000
Reexamination Certificate
active
06358983
ABSTRACT:
The present invention relates to novel carboxylic acid derivatives, their preparation and use.
Endothelin is a peptide constructed from 21 amino acids, which is synthesized and released by vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following text, “endothelin” or “ET” designates one or all isoforms of endothelin. Endothelin i s a potent vasoconstrictor and has a strong effect on the vascular tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332 (1988), 411-415; FEBS Letters, 231 (1988), 440-444 and Biochem. Biophys. Res. Commun., 154 (1988), 868-875).
Increased or abnormal release of endothelin causes a lasting vascular contraction in peripheral, renal and cerebral blood vessels, which can lead to diseases. As reported in the literature, endothelin is involved in a number of diseases. These include: hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis, asthma and prostate cancer (J. Vascular Med. Biology 2 (1990), 207, J. Am. Med. Association 264 (1990), 2868, Nature 344 (1990), 114, N. Engl. J. Med. 322 (1989), 205, N. Engl. J. Med. 328 (1993), 1732, Nephron 66 (1994), 373, Stroke 25 (1994), 904, Nature 365 (1993), 759, J. Mol. Cell. Cardiol. 27 (1995), A234; Cancer Research 56 (1996), 663, Nature Medicine 1 (1995), 944).
At least two endothelin receptor subtypes, ETA and ETB receptors, have at present been described in the literature (Nature 348 (1990), 730, Nature 348 (1990), 732). Accordingly, substances which inhibit the binding of endothelin to one or both receptors should antagonize physiological effects of endothelin and therefore be useful pharmaceuticals.
It is an object of the present invention to provide endothelin receptor antagonists which bind to the ET
A
and/or the ET
B
receptor.
We have found that this object is achieved by heterocyclically substituted a-hydroxycarboxylic acid derivatives of the formula I
R
1
being tetrazole or a group
where R has the following meanings:
a) a radical OR
5
, where R
5
is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerable 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, 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
8
-alkenyl or a C
3
-C
8
-alkynyl group, it being possible for these groups for their part to carry one to five halogen atoms;
R
5
can furthermore be a phenyl radical which can 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 linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl or triazolyl, which can 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 or 2, p the values 1, 2, 3 or 4 and R
6
is
C
1
-C
4
-alkyl, C
3
-C
8
-cycloalkyl, C
3
-C
8
-alkenyl, C
3
-C
8
-alkynyl or phenyl, which can be mono- to trisubstituted by: halogen, nitro, cyano, C
1
-C
4
-alkyl, hydroxyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio, amino, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
, mercapto.
d) a radical
where R
7
is:
C
1
-C
4
-alkyl, C
3
-C
8
-alkenyl, C
3
-C
8
-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 mentioned under c);
C
1
-C
4
-haloalkyl or phenyl, which can be substituted as mentioned under c).
The other substituents have the following meanings:
A is NR
8
R
9
, azido, OR
10
, SR
10
or C
1
-C
4
-alkyl.
X is oxygen, sulfur, CR
11
or NR
12
; with the proviso that if X=CR
11
, then Y=oxygen or sulfur or NR
14
.
Y is oxygen, sulfur, CR
13
or NR
14
; with the proviso that if Y=oxygen or sulfur or NR
14
, then X=CR
11
.
R
2
and R
3
(which can be identical or different):
are phenyl or naphthyl, 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, 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 mono- or polysubstituted, e.g. mono- to trisubstituted, 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 to one another in the ortho-position via a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO
2
, NH or N(C
1
-C
4
-alkyl) group;
C
5
-C
6
-cycloalkyl, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
2
-C
4
-alkynyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio, C
1
-C
4
-haloalkoxy.
and R
11
(which can be identical or different):
are hydrogen, halogen, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy, C
3
-C
6
-alkenyloxy, C
3
-C
6
-alkynyloxy, C
1
-C
4
-alkylthio, C
1
-C
4
-alkylcarbonyl, C
1
-C
4
-alkoxycarbonyl, hydroxyl, NH
2
, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
; p
2
C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
2
-C
4
-alkynyl, it being possible for these radicals to be substituted by halogen, hydroxyl, mercapto, carboxyl, cyano;
or CR
4
, together with CR
11
, forms a 5- or 6-membered alkylene or alkenylene ring which can be unsubstituted or substituted, 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).
R
8
is hydrogen, C
1
-C
8
-alkyl, C
3
-C
8
-alkenyl or C
3
-C
8
-alkynyl, C
1
-C
5
-alkylcarbonyl, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, amino, 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
-alkoxycarbonyl, C
3
-C
8
-alkylcarbonylalkyl, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
, C
3
-C
8
-cycloalkyl, phenoxy or phenyl, it being possible for the aryl radicals mentioned for their part to be mono- or polysubstituted, e.g. mono- to trisubstituted, by halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy, amino, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
, phenyl or C
1
-C
4
-alkylthio;
phenyl or naphthyl, which in each case can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy, phenoxy, C
1
-C
4
-alkylthio, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
, dioxomethylene or dioxoethylene;
C
3
-C
8
-cycloalkyl, it being possible for these radicals in each case to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
2
-C
4
-alkynyl, C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio, C
1
-C
4
-haloalkoxy;
or R
8
, together with R
9
, forms a C
3
-C
7
-alkylene chain closed to give a ring, which can be mono- or polysubstituted by C
1
-C
4
-alkyl, C
1
-C
4
-alkylthio, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkyl, C
1
-C
4
-haloalkoxy, and in which an alkylene group can be replaced by oxygen or sulfur, such as —(CH
2
)
4
—, —(CH
2
)
5
—, —(CH
2
)
6
—, —(CH
2
)
7
—, —(CH
2
)
2
—O—(CH
2
)
2
—, —(CH
2
)
2
—S—(CH
2
)
2
—.
R
9
is hydrogen, C
1
-C
4
-alkyl;
or R
9
is as indicated under R
8
linked with R
8
to give a ring.
R
10
is hydrogen, C
1
-C
8
-alkyl,
Amberg Wilhelm
Hergenröder Stefan
Hillen Heinz
Jansen Rolf
Raschack Manfred
Abbott Laboratories
Gerstl Robert
Keil & Weinkauf
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