&agr;-hydrdroxylic acid derivatives, their production and use

Details &agr;-hydrdroxylic acid derivatives, their production and use &agr;-hydrdroxylic acid derivatives, their production and use

1998-10-08

2004-02-03

Shah, Mukund J. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S315000, C544S318000, C544S319000

Reexamination Certificate

active

06686369

ABSTRACT:

The present invention relates to novel &agr;-hydroxy acid derivatives, their preparation and use.
Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. “Endothelin” or “ET” hereinafter signifies one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a great effect on vascular tone. It is known that this vasoconstriction is caused by the 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).
Increased or abormal [sic] release of endothelin causes a persistent contraction in peripheral, renal and cerebral blood vessels, which may lead to disorders. As reported in the literature, endothelin is involved in a number of disorders; these include hypertension, myocardial infarct, heart failure, kidney failure, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasms, atherosclerosis, stroke, benign prostate hypertrophy and asthma (Japan J. Hyperteusion [sic] 12, 79 (1989), 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), Nephton [sic] 66, 373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardist. 27, A234 (1995), Cancer Research 56, 663 (1996)).
A compound having the formula A
is mentioned in the European patent application with the file number P 44 36 851.8 (page 32, compound I-28). However, this compound cannot be prepared by the preparation process mentioned in this patent application.
Compounds of the formula B where R
3
can be, for example, phenyl, and R
2
and R
4
can be hydrogen or C
1
-C
4
-alkyl, are described in the European patent with the number 0 347 811 B1 as substances with herbicidal activity.
The invention relates to the &agr;-hydroxy carboxylic acid derivatives of the formula I
where R is formyl, a tetrazole [sic], nitrile [sic], a group COOH or a radical which can be hydrolyzed to COOH. R is, for example, a group
where R
1
has the following meanings:
a) hydrogen
b) a succinylimidoxy [sic] group
c) a 5-membered heteroaromatic system, such as pyrrolyl, pyrazolyl-[sic] imidazolyl and triazolyl, which is linked via a nitrogen atom and which may carry one or two halogen atoms or one or two C
1
-C
4
-akyl or one or two C
1
-C
4
-alkoxy groups;
d) R
1
furthermore a group
where k can assume the values 0, 1 and 2, p can assume the values 1, 2, 3 and 4, and R
9
is C
1
-C
4
-alkyl, C
3
-C
7
-cycloalkyl, C
3
-C
6
-alkenyl, C
3
-C
6
-alkynyl or unsubstituted or substituted 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, C
1
-C
4
-alkylamino, C
1
-C
4
-dialkylamino;
e) R
1
furthermore a radical OR
10
, where R
10
is:
hydrogen, the cation of an alkali metal such as lithium, sodium, potassium or the cation of an alkaline earth metal such as calcium, magnesium and barium, and physiologically tolerated alkylammonium ion or the ammonium ion;
C
3
-C
8
-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
C
1
-C
8
-alkyl, in particular C
1
-C
4
-alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl;
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, C
1
-C
4
-alkylamino, C
1
-C
4
-dialkylamino,
a C
3
-C
6
-alkenyl or C
3
-C
6
-alkynyl group, it being possible for this group in turn to carry one to five halogen atoms;
R
10
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, C
1
-C
4
-alkylamino, C
1
-C
4
-dialkylamino;
a 5-membered heteroaromatic system which is linked via a nitrogen atom and contains one to three nitrogen atoms, and which may carry one or two halogen atoms and/or one or two of the following radicals: C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, phenyl, C
1
-C
4
-haloalkoxy and/or C
1
-C
4
-alkylthio. Particular mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3,4-dichloroimidazol-1-yl;
f) R
1
furthermore a radical
where R
11
is:
C
1
-C
4
-alkyl, 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;
phenyl which is unsubstituted or substituted, in particular as mentioned above;
g) R
1
a radical
where R
12
has the same meanings as R
11
;
h) 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
7
-alkyl, C
3
-C
7
-cycloalkyl, C
3
-C
7
-alkanyl [sic], C
3
-C
7
-alkynyl, benzyl, phenyl, unsubstituted or substituted, as described above
or R
13
and R
14
together form a C
4
-C
7
-alkylene chain which is closed to a ring, is unsubstituted or substituted by C
1
-C
4
-alkyl, for example, and may contain a hetero atom, eg. oxygen, nitrogen 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
—, —CH
2
—NH—(CH
2
)
2
—, —(CH
2
)
2
—NH—(CH
2
)
2
—.
The other substituents have the following meanings:
W nitrogen or C—NO
2
, furthermore W can be a CH group when one or more of the substituents R
2
, R
3
, R
15
and/or R
16
are a nitro group, or when X and/or Y are nitrogen;
R
2
is hydrogen, halogen, C
1
-C
4
-alkyl, C
1
-C
4
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkoxy, hydroxyl, mercapto, C
1
-C
4
-alkylthio, nitro, amino, C
1
-C
4
-alkylamino or C
1
-C
4
-dialkylamino, cyano, phenyl, optionally substituted once to three times by halogen, hydroxyl, amino, mono- or dialkyl (C
1
-C
3
)-amino, C
1
-C
3
-alkyl, C
1
-C
3
-alkoxy, mercapto or C
1
-C
3
-alkylthio, carboxyl, C
1
-C
3
-alkylcarboxyl;
or
a five- or six-membered heteroaromatic system containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which carries one to three substituents as described above;
R
2
can furthermore form, with the adjacent carbon atom and X, a 5- or 6-membered alkylene or alkylidene [sic] ring in each of which one or two carbon atoms can be replaced by a hetero atom such as nitrogen, sulfur or oxygen, and which can be substituted once to three times by the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C
1
-C
3
-alkyl, C
1
-C
3
-haloalkyl, C
1
-C
3
-alkoxy, C
1
-C
3
-alkylthio, amino, C
1
-C
3
-alkylamino, C
1
-C
3
-dialkylamino;
X is nitrogen or CR
15
where R
15
is hydrogen, nitro, C
1
-C
5
-alkyl or C
2
-C
5
-alkenyl, optionally substituted once or twice by hydroxyl, carboxyl or phenyl, which in turn can be substituted by C
1
-C
3
-alkyl, hydroxyl or carboxyl; C
1
-C
6
-alkoxy, C
1
-C
6
-alkylthio, phenyl, hydroxyl, mercapto, nitro, amino, C
1
-C
4
-alkylamino, C
1
-C
4
-dialkylamino, cyano or carboxyl;
it is furthermore possible for CR
15
to be linked to R
2
to give a 5- or 6-membered ring as described above, or CR
15
can form with R
3
and its adjacent carbon atom a 5- or 6-membered alkylene or alkylidene [sic] ring in each of which one or two carbon atoms can be replaced by nitrogen, oxygen or sulfur, and the 5- or 6-membered ring may optionally be substituted once to three times by the following radicals:
halogen, nitro, cy

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