Heterocyclic carboxylic acid derivatives, the production and...

Details Heterocyclic carboxylic acid derivatives, the production and... Heterocyclic carboxylic acid derivatives, the production and...

1999-06-14

2002-09-10

Rao, Deepak R. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S243000, C544S182000, C544S183000, C544S184000

Reexamination Certificate

active

06448248

ABSTRACT:

The present invention relates to novel carboxylic acid derivatives, their preparation and use.
Endothelin is a peptide made up of 21 amino acids, which is synthesized and released by vascular endothelin. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following, endothelin or ET designates one or all isoforms of endothelin. Endothelin is 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 illnesses. As reported in the literature, endothelin is involved in a number of illnesses. These include: hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's Syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis and asthma (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).
At least two endothelin receptor subtypes, ET
A
and ET
B
receptors, are at present described in the literature (Nature 348 (1990), 730, Nature 348 (1990), 732). Accordingly, substances which inhibit the binding of endothelin to one or to both receptors should antagonize physiological effects of endothelin and therefore be useful pharmaceuticals.
It is an object of the present invention to make available endothelin receptor antagonists which bind to the ET
A
and/or the ET
B
receptors.
The invention relates to carboxylic acid derivatives of the formula I
[lacuna] R
1
is tetrazole or a group
where R has the following meanings:
a) a radical OR
6
, where R
6
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 in turn to carry one to five halogen atoms;
R
6
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 to two halogen atoms, or one to two C
1
-C
4
-alkyl or one to two C
1
-C
4
-alkoxy groups;
c) a group
where k [lacuna] assume the values 0, 1 and 2, p can assume the values 1, 2, 3 and 4 and R
7
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 substituted by one or more, eg. 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
8
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 unsubstituted or substituted phenyl, in particular as mentioned under c).
The other substituents have the following meanings:
X is nitrogen or methine; with the proviso that if X=nitrogen then Z=nitrogen and if X=methine then at least one of the ring members Y or Z is nitrogen;
Y is nitrogen or CR
9
;
Z is nitrogen or CR
10
;
R
2
is C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
2
-C
4
-alkynyl, it being possible for these radicals each to be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, cyano, amino, C
1
-C
4
-alkoxy;
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, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2,
hydroxyl, carboxyl, cyano, amino, mercapto;
or CR
2
together with CR
9
or CR
10
forms a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C
1
-C
4
-alkyl groups, and where in each case one or more methylene groups can be replaced by oxygen, sulfur, —NH or —N(C
1
-C
4
-alkyl);
R
3
and R
4
(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, eg. 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-alkyl group;
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;
R
5
is hydrogen, C
1
-C
8
-alkyl, C
3
-C
8
-alkenyl or C
3
-C
8
-alkynyl, 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
-alkylcarbonyl, 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, heteroaryloxy or heteroaryl, which is five-or six-membered, comprising one to three nitrogen atoms and/or a sulfur or oxygen atom, phenoxy or phenyl, it being possible for the aryl radicals mentioned in turn to be mono- or polysubstituted, eg. 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
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, C
1
-C
4
-alkylamino, C
1
-C
4
-dialkylamino, dioxomethylene or dioxoethylene;
a five- or six-membered heteroaromatic, comprising one to three nitrogen atoms and/or a sulfur or oxygen atom, which can carry one to four halogen atoms and/or one to two of the following radicals: C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy, C
1
-C
4
-alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy and/or C
1
-C
4
-alkylthio;
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

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