Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives,...

Details Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives,... Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives,...

1999-03-01

2003-12-30

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...

C544S298000, C544S299000, C544S309000, C544S310000

Reexamination Certificate

active

06670367

ABSTRACT:

The present invention relates to novel carboxylic acid derivatives, their preparation and use.
Endothelin is a peptide which consists 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 means one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a great effect on vessel tone. It is known that this vasoconstriction is caused by 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 persistent vasoconstriction in peripheral, renal and cerebral vessels, which may lead to 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, 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, have been described in the literature (Nature 348, (1990) 730, Nature 348, (1990) 732). Accordingly, substances which inhibit the binding of endothelin to the two receptors ought to antagonize the physiological effects of endothelin and therefore be valuable drugs.
WO 96/11914 describes carboxylic acid derivatives which, however, bind with high affinity to the ET
A
receptor and with considerably less affinity to the ET
B
receptor (called ET
A
-specific antagonists).
ET
A
-specific antagonists mean here those antagonists whose affinity for the ET
A
receptor is at least twenty times higher than their affinity for the ET
B
receptor.
It is an object of the present invention to provide endothelin receptor antagonists which bind with approximately the same affinity to the ET
A
and ET
B
receptors (called mixed antagonists).
Approximately the same affinity for the receptors means that the ET
A
:ET
B
affinity ratio is greater than 0.1 and less than 20, preferably less than 10.
We have found that this object is achieved by carboxylic acid derivatives of the formula I
where R
1
is tetrazole [sic] or a group
where R has the following meaning:
a) a radical OR
7
where R
7
is:
hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerated organic ammonium ion such as 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, carboxyl, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
;
C
3
-C
6
-alkenyl or C
3
-C
6
-alkynyl, it being possible for these groups in turn to carry one to five halogen atoms;
R
7
can furthermore 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 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 is 0, 1 and 2, p is 1, 2, 3 and 4 and R
8
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, 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, carboxyl, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
;
d) a radical
 in which R
9
is:
C
1
-C
4
-alkyl, C
3
-C
6
-alkenyl, C
3
-C
6
-alkynyl, C
3
-C
8
-cycloalkyl, C
1
-C
4
-haloalkyl, 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);
phenyl, unsubstituted or substituted, in particular as mentioned above,
e) R
1
can furthermore be
 where R
13
and R
14
can be identical or different and have the following meanings:
hydrogen, C
1
-C
8
-alkyl, C
3
-C
8
-cycloalkyl, C
3
-C
8
-alkenyl, C
3
-C
8
-alkynyl, benzyl, phenyl 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
,
or R
13
and R
14
together form a C
4
-C
7
-alkylene chain which is closed to form a ring and which may be substituted by C
1
-C
4
-alkyl and in which an alkylene group may be replaced by oxygen, sulfur or nitrogen, such as —(CH
2
)
4
—, —(CH
2
)
5
—, —(CH
2
)
6
—, —(CH
2
)
2
—O—(CH
2
)
2
—, —(CH
2
)
7
—, —CH
2
—S—(CH
2
)
2
—, —CH
2
—NH—(CH
2
)
2
—, —(CH
2
)
2
—N—(CH
2
)
2
—;
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 below to give a 5- or 6-membered ring.
X nitrogen or methine.
Y nitrogen or methine.
Z nitrogen or CR
10
, where R
10
is hydrogen or C
1
-C
4
-alkyl, or CR
10
forms together with CR
2
or CR
3
a 5- or 6-membered alkylene or alkenylene ring which may 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)
2
.
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 or C
1
-C
4
-alkylthio, or CR
3
is linked to CR
10
as indicated above to give a 5- or 6-membered ring.
R
4
and R
5
(which may be identical or different):
phenyl or naphthyl, which may 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
1
-C
4
-hydroxyalkyl, 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, eg. 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 linked together in the 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
C
3
-C
8
-Cycloalkyl, it being possible for these radicals in each case to be substituted one or more times by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C
1
-C
4
-alkoxy, C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
2
-C
4
-alkynyl, 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
-alkyl-carbonylalkyl, NH(C
1
-C
4
-alkyl), N(C
1
-C
4
-alkyl)
2
, or phenyl which can be substituted one or more times, eg. 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;
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, R
15
, nitro, mercapto, carboxyl, cyano

Affiliated with

Also associated with

Rating

Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives,... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives,..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Azinyloxy, and phenoxy-diaryl-carboxylic acid derivatives,... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3152995