Pharmaceutically active compounds, their preparation and use...

Details Pharmaceutically active compounds, their preparation and use... Pharmaceutically active compounds, their preparation and use...

2000-04-10

2002-10-22

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C514S566000, C514S569000, C514S616000, C562S459000, C568S306000

Reexamination Certificate

active

06469056

ABSTRACT:

The invention relates to novel pharmaceutically active compounds, their preparation and use for producing pharmaceutical preparations for treating diseases.
Endothelin is a peptide which is composed 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 refers to one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a strong effect on vessel muscle 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).
Elevated or abnormal release of endothelin causes persistent vasoconstriction 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, 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, 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 one or to both receptors ought to antagonise the physiological effects of endothelin and therefore represent valuable drugs.
However, the disadvantage of these receptor antagonists is that endothelin has already formed and the effect of endothelin must be antagonized after its production. Substances which prevent formation of endothelin from its precursor, which is called big endothelin, intervene at an earlier stage in the effect of endothelin and thus represent a desired alternative to the endothelin receptor antagonists because they ought to have a more direct and better effect, as shown, for example, by inhibitors of ACE (ACE=“angiotensin converting enzyme”, Szelke et al. Nature, 299, 555) or of ANP (ANP=,Sybertz et al., J. Pharmacol. Exp. Ther. 250, 1989, 624).
It is an object of the present invention to provide inhibitors of endothelin converting enzyme (=ECE).
We have found that this object is achieved by compounds of the formula I:
its physiolically active salts or combination thereof, where the substituents have the following meanings:
R
1
and R
2
independently of one another substituted or unsubstituted, branched or unbranched C
1
-C
8
-alkyl, C
1
-C
8
-alkylaryl or C
1
-C
8
-alkylhetaryl, substituted or unsubstituted aryl or hetaryl
R
3
a group of the formula a, b or c:
R
4
substituted or unsubstituted C
4
-C
14
-aryl, C
4
-C
14
-hetaryl, with one or more rings containing one or more hetero atoms selected from the group of O, S and N,
R
5
C
1
-C
8
-alkyl, C
1
-C
8
-alkylaryl, aryl or hetaryl.
The invention further relates to a process for preparing the abovementioned compounds of the formula I, which comprises condensing a compound of the formula II:
with a compound of the formula III
and reducing with a reducing agent to a compound of the formula IV:
and reacting with an acylating agent R
4
COCl (V) and eliminating the protective group SG
1
to give the abovementioned compounds of the formula I, where the substituents R
1
, R
2
, R
3
and R
4
, have the meanings mentioned above, and SG
1
is a protective group.
The invention further relates to the use of compounds of the formula I for inhibiting endothelin converting enzyme (=ECE), for producing pharmaceutical preparations for treating diseases and to the use of these pharmaceutical preparations in combination with at least one other active substance or drug which lowers blood pressure.
The substituents R
1
and R
2
in the abovementioned formulae I, II, III and IV have the following meanings:
R
1
and R
2
independently of one another substituted or unsubstituted, branched or unbranched C
1
-C
8
-alkyl, C
1
-C
8
-alkylaryl or C
1
-C
8
-alkylhetaryl, substituted or unsubstituted aryl or hetaryl, where
alkyl branched or unbranched C
1
-C
8
-alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl or n-octyl;
alkylaryl branched-chain or unbranched-chain C
1
-C
8
-alkylaryl such as C
1
-C
8
-alkylphenyl or C
1
-C
8
-alkylnaphthyl radicals, such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropylphenyl, 2-methylpropylphenyl, 1,1-dimethylethylphenyl, pentylphenyl, 1-methylbutylphenyl, 2-methylbutylphenyl, 3-methylbutylphenyl, 2,2-dimethylpropylphenyl, 1-ethylpropylphenyl, hexylphenyl, heptylphenyl, octylphenyl, methylnaphthyl, ethylnaphthyl, propynaphthyl, 1-methylethylnaphthyl, butylnaphthyl, 1-methylpropylnaphthyl, 2-methylpropylnaphthyl, 1,1-dimethylethylnaphthyl, pentylnaphthyl, 1-methylbutylnaphthyl, 2-methylbutylnaphthyl, 3-methylbutylnaphthyl, 2,2-dimethylpropylnaphthyl, 1-ethylpropylnaphthyl, hexylnaphthyl, heptylnaphthyl or octylnaphthyl;
alkylhetaryl branched-chain or unbranched-chain C
1
-C
8
-alkylhetaryl radicals which [lacuna] simple or fused aromatic ring systems with one or more heteroaromatic 3- to 8-membered rings which may, where appropriate, contain one or more hetero atoms such as S, N or O;
aryl such as phenyl, naphthyl, anthranyl or phenanthryl;
hetaryl simple or fused aromatic ring systems with one or more heteroaromatic 5- to 8-membered rings which may, where appropriate, contain one or more heteroatoms such as S, N or O, such as thienyl, pyridyl or indoyl [sic].
All said radicals R
1
or R
2
may, where appropriate, be substituted by one or more of the radicals —NH
p
(C
1
-C
8
-alkyl)
2−p
, —QH
n
(C
1
-C
8
-alkyl)
1−n
, —SS-t-butyl, —CN, —NO
2
or halogen such as fluorine, chlorine, bromine or iodine, where p is 0, 1 or 2, Q is sulfur or oxygen, n is 0 or 1, and C
1
-C
8
-alkyl has the abovementioned meaning.
Preferred radicals for R
1
and R
2
are those derived from natural or unnatural amino acids, it being possible for functional groups in these radicals to be protected or unprotected. Since the radicals R
1
and R
2
are advantageously derived from natural or unnatural amino acids, the stereocenters adjacent to the radicals may exist both in the D and in the L configuration (=R- or S-form). Further preferred radicals for R
1
and R
2
are substituted or unsubstituted, branched or unbranched C
1
-C
4
-alkyl, C
1
-C
4
-alkylaryl or C
1
-C
4
-alkylhetaryl, substituted or unsubstituted aryl or hetaryl, and C
1
-C
4
-alkylaryl is particularly preferred.
It is possible in principle, in a less preferred form, for the radicals R
1
or R
2
also to be hydrogen. However, compounds with these radicals show only very little or no biological effect.
The substituent R
3
in the abovementioned formulae I, III and IV has the following meaning:
R
3
a group of the formula a, b or c:
 Formulae a, b and c may, where appropriate, have other substituents. R
5
in formula b has the meaning mentioned below.
The substituent R
4
in the abovementioned formulae I and V has the following meaning:
R
4
substituted or unsubstituted C
4
-C
14
-aryl, C
4
-C
14
-hetaryl with one or more rings containing

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