Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-03-31
2002-08-27
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, C514S275000, C544S323000, C544S324000, C544S326000, C544S328000, C544S330000, C544S331000, C544S332000
Reexamination Certificate
active
06440975
ABSTRACT:
The present invention relates to novel amino acid derivatives and to their preparation and use.
Endothelin is a peptide which is composed of 21 amino acids and which is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms ET-1, ET-2 and ET-3. “Endothelin” or “ET” hereinafter means one or all endothelin isoforms. Endothelin is a potent vasoconstrictor and has a strong effect on vascular 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).
Elevated or abnormal release of endothelin causes a persistent vasoconstriction in the peripheral, renal and cerebral blood vessels, which may lead to illnesses. As reported in the literature, elevated plasma endothelin levels are found in patients with hypertension, acute myocardial infarct, pulmonary hypertension, Raynaud's syndrome, atherosclerosis and in the airways of asthmatics (Japan J. Hypertension 12 (1989) 79, J. Vascular Med. Biology 2 (1990) 207, J. Am. Med. Association 264 (1990) 2868).
Accordingly, substances which specifically inhibit the binding of endothelin to the receptor ought also to antagonize the various abovementioned physiological effects of endothelin and therefore be valuable drugs.
We have found that certain amino acid derivatives are good inhibitors of endothelin receptors.
The invention relates to amino acid derivatives of the formula I
where R is formyl, tetrazolyl, cyano, COOH or a radical which can be hydrolyzed to COOH, for example R is
where R
1
has the following meanings:
a) hydrogen
b) succinimedyl
c) a 5-membered heteroaromatic ring which is linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and 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;
d) R
1
is furthermore
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. from 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
is furthermore 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,
C
3
-C
6
-alkenyl or C
3
-C
6
-alkynyl, it being possible for these groups in turn to carry from one to five halogen atoms;
R
10
can furthermore be a phenyl radical which can carry from one to five halogen atoms and/or from 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 ring which is linked via a nitrogen atom and contains from one to three nitrogen atoms and can 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, in particular 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-dichloro-1-imidazolyl;
f) R
1
is furthermore
where R
1
is: C
1
-C
4
-alkyl, C
3
-C
6
-alkenyl, C
3
-C
6
-alkynyl, C
3
-C
8
-cycloalkyl as mentioned above in particular, 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 above;
phenyl which is unsubstituted or substituted, in particular as mentioned above;
g) R
1
is
where R
12
has the same meaning 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
-alkenyl, 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 form a ring and is unsubstituted or substituted, eg. by C
1
-C
4
-alkyl, and which 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
—;
a tetrazole group or a nitrile group.
The other substituents have the following meanings:
W is nitrogen or C—NO
2
, and W can furthermore be a CH group when one or more of the substituents R
2
, R
3
, R
15
and/or R
16
are nitro;
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, unsubstituted or mono- to trisubstituted 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; or a five- or six-membered heteroaromatic ring which contains from one to three nitrogen atoms and/or one sulfur or oxygen atom and which carries from 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 ring in which, in each case, one or two carbon atoms can be replaced by a hetero atom such as nitrogen, sulfur or oxygen, and which can be mono- to trisubstituted 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 or C
1
-C
5
-alkyl, C
1
-C
5
-alkoxy, C
1
-C
5
-alkylthio, nitro, phenyl, hydroxyl, mercapto, halogen, amino, C
1
-C
4
-alkylamino, C
1
-C
4
-dialkylamino or cyano,
or CR
15
is linked to R
2
to form a 5- or 6-membered ring as described above, and furthermore CR
15
can form together with R
3
and its adjacent carbon atom a 5- or 6-membered ring as described above;
R
3
can have the same meaning as R
2
and furthermore form together with the adjacent carbon atom and Y a 5- or 6-membered alkylene or alkylidene ring in which, in each case, one or two carbon atoms can be replaced by nitrogen, oxygen or sulfur; the 5- or 6-membered ring can be unsubstituted or mono- to trisubstituted 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 or C
1
-C
3
-dialkylamino; nitrogen in the 5-membered ring can also be substituted by a formyl or acetyl group; R
2
and R
3
can be identical or different;
Y is nitrogen or CR
16
where R
16
is hydrogen, C
1
-C
5
-alkyl, C
1
-C
5
-alkoxy, C
1
-C
5
-alkylthio, nitro, phenyl, hydroxyl, halogen, cyano, amino, C
1
-C
4
-alkylamino, C
1
-C
4
-dialkylamino or mercapto, or CR
16
forms together with R
3
and its adjacent carbon atom a 5- or 6-membered ring as described above;
R
4
is hydrogen, C
1
-C
7
-alkyl, C
3
-C
7
-cycloalkyl; or phenyl or naphthyl which can be
Amberg Wilhelm
Kling Andreas
Klinge Dagmar
Raschack Manfred
Riechers Hartmut
Abbott Laboratories
Balasubramanian Venkataraman
Keil & Weinkauf
Raymond Richard L.
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