Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-16
2002-11-19
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06482820
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the use of benzazepine-N-acetic acid derivatives which contain an oxo-group in the &agr;-position to the nitrogen atom and are substituted in position 3 by a 1-(carboxyalkyl)cyclo-pentylcarbonylamino radical, and their salts and biolabile esters for the treatment of hypertension, particularly of certain forms of secondary hypertension, in larger mammals and particularly humans, and for the production of pharmaceutical compositions suitable for this treatment. The cause of the hypertension to be treated can have a wide variety of origins. In particular, the invention relates to the treatment of those forms of secondary hypertension which may occur as a result of various non-cardiac diseases.
Benzazepine-N-acetic acid derivatives which contain an oxo group in &agr;-position to the nitrogen atom and are substituted in position 3 by a 1-(carboxyalkyl)cyclopentyl-carbonylamino radical, and their salts and biolabile esters fall under the scope of protection of the benzazepine, benzoxazepine and benzothiazepine-N-acetic acid derivatives which contain an oxo group in the &agr;-position to the nitrogen atom and are substituted in position 3 by a 1-(carboxyalkyl)cyclopentyl-carbonylamino radical and have NEP-inhibitory effects on the heart, as described in Waldeck et al., U.S. Pat. No. 5,677,297 (=DE 195 10 566). The benzazepine-N-acetic acid compounds used in the present invention can be produced by the methods described in said U.S. Pat. No. 5,677,297.
SUMMARY OF THE INVENTION
The object of the invention is to develop a novel method for inhibiting hypertension.
In particular, it is an object of the invention to provide a method of treating certain forms of secondary hypertension.
It is especially an object of the invention to develop a method for the treatment of those forms of secondary hypertension which may occur as a result of various non-cardiac diseases.
These and other objects have been achieved in accordance with the present invention by providing a method of inhibiting hypertension in a mammal, said method comprising administering to said mammal an effective hypertension inhibiting amount of a compound corresponding to formula I:
wherein
R
1
stands for a phenyl-lower-alkyl group which can optionally be substituted in the phenyl ring by lower alkyl, lower alkoxy or halogen, or for a naphthyl-lower-alkyl group,
R
2
means hydrogen or a group forming a biolabile ester and
R
3
means hydrogen or a group forming a biolabile group, or a physiologically acceptable salt of an acid of formula I.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
According to the invention compounds of the general formula I
wherein
R
1
stands for a phenyl-lower-alkyl group which can be optionally substituted in the phenyl ring by lower alkyl, lower alkoxy or halogen, or for a naphthyl-lower-alkyl group,
R
2
means hydrogen or a group forming a biolabile ester and
R
3
means hydrogen or a group forming a biolabile ester and physiologically acceptable salts of the acids of formula I are used for the production of pharmaceutical compositions for the treatment of hypertension, particularly for the treatment of certain forms of secondary hypertension, in larger mammals and humans.
Insofar as the substituents in the compounds of formula I are or contain lower alkyl or alkoxy groups, these can be straight-chain or branched and contain, in particular, 1 to 4, preferably 1 to 2, carbon atoms and are preferably methyl or methoxy. Where the substituents contain halogen, particularly suitable are fluorine, chlorine or bromine, preferably fluorine or chlorine.
In the radical R
1
, the lower alkylene chain can contain 1 to 4, preferably 1 to 2, carbon atoms. R
1
in particular is an optionally substituted phenethyl group which can optionally be substituted one or more times by halogen, lower alkoxy or lower alkyl, or is a naphthyl-ethyl group.
The compounds of formula I are optionally esterified dicarboxylic acid derivatives. Depending on the mode of administration, biolabile monoesters, particularly compounds in which R
2
is a group forming a biolabile ester and R
3
is hydrogen, or dicarboxylic acids are preferred, the latter being particularly suitable for i.v. administration.
Suitable R
2
and R
3
groups forming biolabile esters include lower alkyl groups, phenyl or phenyl-lower-alkyl groups which are optionally substituted in the phenyl ring by lower alkyl or by a lower alkylene chain bonded to two adjacent carbon atoms, dioxolanylmethyl groups which are optionally substituted in the dioxolane ring by lower alkyl, or C
2
-C
6
-alkanoyloxymethyl groups optionally substituted on the oxymethyl group by lower alkyl. Where the R
2
or R
3
group forming a biolabile ester is lower alkyl, this can be a preferably unbranched alkyl group with 1 to 4, preferably 2, carbon atoms. Where the group forming a biolabile ester is an optionally substituted phenyl-lower-alkyl group, its alkylene chain can contain 1 to 3, preferably 1, carbon atom. Where the phenyl ring is substituted by a lower alkylene chain, this can contain 3 to 4, particularly 3, carbon atoms. Phenyl, benzyl or indanyl are particularly suitable as phenyl-containing substituents R
2
and/or R
3
. Where R
2
and/or R
3
are an optionally substituted alkanoyloxymethyl group, their alkanoyloxy group can contain 2 to 6, preferably 3 to 5, carbon atoms and is preferably branched and can be, for example, a pivaloyloxymethyl radical tert-butylcarbonyl-oxymethyl radical).
Suitable physiologically acceptable salts of dicarboxylic acids or monoesters of formula I include their alkali metal, alkaline earth metal or ammonium salts, for example sodium or calcium salts or salts with physiologically acceptable, pharmacologically neutral organic amines such as, for example, diethylamine or tert-butylamine.
The compounds of formula I contain two asymmetric or chiral carbon atoms, namely the carbon atom which is in position 3 of the ring framework and carries the amide side-chain, and the carbon atom of the amide side-chain which carries the R
1
group. The compounds can therefore exist in several optically active stereoisomeric forms or as a racemate. According to the present invention both the racemic mixtures and the isomerically pure compounds of formula I may be used.
It has now surprisingly been found that the group of compounds of formula I used according to the invention—particularly with regard to certain secondary forms of hypertension—have a blood pressure-lowering effect in humans and larger mammals. The compounds of formula I and their physiologically acceptable salts of the acids and their biolabile esters are thus suitable for the treatment of hypertension, particularly for the treatment of certain forms of secondary hypertension in which the hypertension to be treated may have a wide variety of origins.
The compounds of formula I, including their salts of acids and their biolabile esters, are advantageously suitable for the treatment of those forms of secondary hypertension which may occur as a result of various non-cardiac diseases.
As used herein, the term “hypertension” (high blood pressure) means an increase in blood pressure beyond the normal level, which mainly becomes evident as arterial hypertension. Bearing in mind the aetiology of the high blood pressure, a distinction is made between two basic forms, namely essential or primary hypertension on the one hand and the forms of secondary hypertension on the other. As a rule, essential hypertension is caused by increased flow resistance resulting from at first purely functional, later organic narrowing of the arterial circulation. Secondary or symptomatic hypertension, conversely, is an organ-related hypertension, i.e. provoked by the disease of an organ, which may take the form of endocrine, renal, pulmonary or cardiovascular hypertension, for example. The diseases causally responsible for secondary hypertension can be of a diverse nature, e.g. chronic obstructive airways diseases or chronic asthma. Normal circulation of the blood in the
Thormaehlen Dirk
Waldeck Harald
Wilkins Martin R.
Crowell & Moring LLP
Solvay Pharmaceuticals GmbH
Spivack Phyllis G.
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