MXPA01008164A - Medicament for treating hypertension - Google Patents

Abstract

The invention relates to the use of benzazepine-N ethanoic acid derivatives, containing an oxo group bonded to the nitrogen atom in the&agr;-position and which are substituted by a 1-(carboxy alkyl)-cyclopentyl-carbonyl amino radical in position 3. It also relates to the use of the salts and unstable esters of these derivatives in the treatment of hypertension, particularly to the treatment of certain types of secondary hypertension in large mammals and humans and to the production of suitable medicaments for this treatment. The origins of the hypertension which should be treated can vary greatly. The invention relates specifically to those types of secondary hypertension which may arise as a result of various non-cardiac diseases.

Description

MEDICINE FOR THE TREATMENT OF BLOOD HYPERTENSION DESCRIPTION The present invention relates to the use of benzazepin-N-acetic acid derivatives, which in the o-position; they contain in the nitrogen atom an oxo group and in the 3-position they are substituted by means of a 1- (carboxyalkyl) cyclopentylcarbonyl-amino radical, and their salts and esters biologically unstable for the treatment of blood hypertension, especially in certain ways of secondary hypertension, in higher mammalian animals and especially in humans and for the preparation of suitable drugs for its treatment. The cause of hypertension to treat can have different origins. In particular, the invention relates to the treatment of those forms of secondary blood hypertension that may occur as a consequence of non-cardiac diseases. The benzazepine-N-acetic acid derivatives in which in position a is contained in the nitrogen atom an oxo group and in the 3-position are substituted with a radical 1- (carboxylalkyl) -cyclopent and 1-carbonyl-amino , and their biologically unstable salts and esters fall under the scope of protection of the benzazepine-, benzoxazepine- and benzothiazepine-N-acetic acid derivatives described in the German patent application DE 195 10 566, which in the 3-position are substituted by means of a 1- (carboxyalkyl) -cyclopentylcarbonyl-amino radical, have NEP inhibitory effects on hearts. The benzazepine-N-acetic acid compounds used in the context of the present invention can be prepared according to the method described in DE 195 10 566. The invention proposes the task of developing new pharmaceutical preparations for the treatment of hypertension blood, especially for the treatment of certain forms of secondary hypertension. Preferably the task of the invention consists in the development of new pharmaceutical preparations for the treatment of those forms of secondary hypertension that may occur as a consequence of different non-cardiac diseases. According to the invention, the compounds of the general formula I are now used in which R 1 means a phenylalkyl lower group, which may optionally be substituted on the phenyl ring by means of lower alkyl, lower alkoxy or halogen, or may be a naphthyl lower alkyl group, hydrogen R2 or a biologically unstable ester forming group, and hydrogen R3 or a biologically unstable ester forming group, and and physiologically acceptable salts of the acids of the formula I, to prepare pharmaceutical preparations for the treatment of the hypertension, especially for the treatment of certain forms of secondary hypertension, in higher mammals and humans. As long as the compounds of the formula I use or contain the lower alkyl or lower alkoxy groups, they can be straight-chain or branched and in particular contain 1 to 4, preferably 1 to 2, carbon atoms and represent preferentially methyl or ethoxy. As long as the substituents contain halogen, fluorine, chlorine or bromine, preferably fluorine or chlorine, are particularly suitable. In the radical R 1 it may contain the lower alkyl chain, 1 to 4, preferably 1 to 2 carbon atoms. In particular, R 1 represents an optionally substituted phenethyl group, which may optionally be substituted one or more times by means of halogen, lower alkoxy or lower alkyl, or a naphthylethyl group. The compounds of the formula I optionally represent dicarboxylic acid derivatives which are typed. Depending on the form of application, biologically unstable monoesters are preferred, in particular compounds in which R 2 is a group forming biologically unstable esters and R 3 is hydrogen, or dicarboxylic acids, the latter being especially suitable for the application i.v. The lower alkyl groups are suitable as forming groups of biologically unstable esters R2 and R3.optionally lower phenyl or phenylalkyl groups substituted on the phenyl ring by means of lower alkyl or by a chain, lower alkyl linked to two neighboring carbon atoms, dioxolanylmethyl groups optionally substituted on the dioxolane ring by means of lower alkyl or alkanoyloxymethyl groups substituted with 2 to 6 carbon atoms. As long as one of the biologically unstable ester forming groups R2 and R3 means lower alkyl, the ester may preferably be an unbranched alkyl group of 1 to 4 carbon atoms, preferably 2 carbon atoms. As long as the biologically unstable ester forming group represents an optionally substituted phenylalkyl group, the alkylene chain may contain from 1 to 3 carbon atoms, preferably 1. As long as the phenyl ring is substituted by a lower alkylene chain , this may contain from 3 to 4 carbon atoms, especially 3. Substituents containing phenyl R2 and / or RJ are especially suitable phenyl, benzyl or indanyl. As long as R 2 and / or R 3 represent optionally alkanoyloxymethyl groups, their alkanoyloxy group 2 to 6, preferably 3 to 5 carbon atoms can be preferably taken and can be a pivaloyloxymethyl radical (butylcarbonyloxymethyl radical tert.). Suitable physiologically acceptable salts of dicarboxylic acids or monoesters of the formula I are alkali metal, alkaline earth metal or calcium salts or salts with pharmacologically neutral and physiologically acceptable organic amines such as, for example, diethylamine or butyl ina tert. The compounds of the formula I contain two chiral carbon atoms, in fact the carbon atom carrying the amide side chain in the 3-position of the ring structure and the carbon atom carrying the radical R 1 of the amide side chain . The compounds can thus be found in various optically active stereoisomeric forms or as a racemate. According to the present invention, both the racemic mixtures and also the isomerically pure compounds of the formula I can be used. It was now surprisingly found that the group of compounds of the formula I used according to the invention, especially also in view of the fact that Several secondary forms of blood hypertension - a hypotensive effect in humans and higher mammals. The compounds of the formula I and their physiologically acceptable salts of the acids and their biologically unstable esters are thus suitable for the treatment of blood hypertension, in particular for the treatment of certain forms of secondary blood hypertension, the blood hypertension to treat, have different origins. The compounds of the formula I, including their acid salts and their biologically unstable esters, are advantageously used here for the treatment of those forms of secondary blood hypertension, which may occur as a consequence of different non-cardiac diseases. Under high blood pressure (hypertonia) is an increase in blood pressure beyond the norm, which mainly presents as arterial hypertension. With regard to the cause of the origin of hypertension, there is a distinction between two basic forms, essential or primary blood hypertension on the one hand and forms of secondary blood hypertension on the other hand. The essential blood pressure is usually caused by the high resistance to flow as a consequence of the reduction at the beginning of purely functional, and later organic, blood vessels. Secondary or symptomatic hypertension, on the other hand, is of an organic nature, a blood hypertension provoked by the disease of an organ, which, inter alia, can be expressed, for example, as endocrine, renal, pulmonary or cardiovascular hypertonia. The diseases responsible for secondary blood pressure can be of multiple types, for example chronic obstructive diseases of the lungs or airways or chronic asthma. Then normal blood circulation in the lungs in adult humans is presented in the case of low pressure and reduced resistance. An existing chronic hypoxia, such as that which may occur, for example, in the case of chronic obstructive respiratory diseases, leads, however, to pulmonary artery hypertension and remodeling of the pulmonary arteries (increased growth of vascular muscle cells) and the right ventricle (increased growth of cardiac muscle cells). In a particularly advantageous manner, the compounds of the formula I can be used, including their acid salts and their biologically unstable esters for the treatment of pulmonary hypertension, especially also of non-cardiac origin. Pulmonary hypertension may be presented here as a primary form (of unknown origin) or secondary pulmonary hypertension and are treated with the compounds of formula I and their salts of physiologically acceptable acids and their biologically unstable esters. Under pulmonary (secondary) hypertension (elevated pressure in a small circulation) means a constant increase in the mean pressure in the arterial system of the lungs to values >; 22 mmHg at rest. This increase in mean pressure can, for example, be due to congestion in small circulation circuits (for example, in nitral valves, left ventricular insufficiency), vascular contraction of the capillary zones (for example as a consequence of hypoxia in the case of pulmonary emphysema). prolonged obstructive, after reducing operations of the lungs), secondary vascular damage (in the case of pulmonary fibrosis, destructive pulmonary emphysema), over-irrigation, this is hypercirculation in the pulmonary circulatory system (for example in the case of cardiac damage with large right-left anastomosis), persistent pulmonary embolism, as a secondary effect as a consequence of primary pulmonary vascular anomalies (= idiopathic = primary pulmonary vascular hypertension). For the treatment according to the invention of blood hypertension, the compounds of the formula I and their physiologically acceptable salts and their biologically unstable esters can be administered in conventional pharmaceutical preparations, whether orally, intravenously or transdermally. Thus the compounds of the formula I and their physiologically acceptable salts of the acids and their biologically unstable esters can be used in an effective amount as a pressure reducer together with additives and / or pharmaceutical excipients customary in solid or liquid pharmaceutical preparations. Examples of solid preparations are oral preparations such as tablets, dragees, capsules, powders or granules, or also suppositories or patches (transdermal therapeutic systems). These solid preparations may contain pharmaceutically customary organic and / or inorganic excipients, for example lactose, talc or starch, as well as pharmaceutically customary additives, for example lubricants or disintegrators for tablets. Liquid preparations such as solutions, suspensions or emulsions of the active ingredient may contain the usual diluents such as water, oils and / or suspending agents such as polyethylene glycols and the like. In addition, other additives may be added, such as preservatives, flavor correctors and the like. The active ingredients can be mixed or formulated with the pharmaceutical additives and / or excipients in a manner known per se. For the preparation of solid medicaments the active ingredients with the additives and / or excipients can be mixed in the usual way and granulated in wet or dry. The granulate or powder can be used directly to fill capsules or present in the usual manner in the form of tablet cores. These may, if desired, be coated in the known manner. The liquid preparations can be obtained in the form of solutions or suspensions by dissolving or dispersing the active ingredients and optionally other additives in a suitable liquid carrier. The blood pressure lowering effect of the compounds of the formula I used according to the invention can be demonstrated in vivo in chronically hypoxic rats by measuring the effect of the substance in relation to the pharmacological indicators suitable for this purpose, example by measuring pulmonary artery pressure and right ventricular weight, as well as by means of the study of pulmonary vascular remodeling in hypoxic rats.

Description of Test Methods and Results As the test substance, usable substances according to the invention of formula I were used (3S, 2R ') - 3- [1 - (2' - (carboxy-4'-phenyl- butyl) -cyclopentan-1-carbonylamino] -2, 3, 4, 5-te trahydro-2-oxo-1H-1-benzazepin-1-acetic The administered dose of the substance was 40 mg / kg per day (enough to reduce the readjustment of the pressure in the large endothelium.) As test animals, we used Sprague-Dawley rats (260 to 310 g, n = 6 to 10 per test group). The animals were placed in a pressure chamber under acutely hypoxic conditions.A control group was maintained under normal air conditions and another control group under hypoxic conditions.

The tests were carried out in the following way: The test animals were treated with the active substance or with a vehicle by means of osmotic minipumps. The osmotic minipumps were implanted intraperitoneally to the animals, before 3 of subjecting the animals 24 hours later to a pressure chamber for 2 weeks. Animals were kept there at normal pressure either under hypoxic conditions (10% of 02) or under normal air. After 2 weeks the animals were prepared for hemodynamic studies and measurements were made.

Hemodynamic studies: The animals were anesthetized and then a pre-prepared cannula was introduced into the pulmonary artery through the jugular vein, the atrium and the ventricle. A catheter was inserted into the left jugular vein, in order to administer the active substance intravenously. The left carotid artery was provided with a cannula to measure systemic blood pressure. After awakening the animals, the pulmonary artery pressure (PAP = pulmonary artery pressure) was determined. Then the rats were again subjected to hypoxic conditions (10% 0) and the increase in pulmonary artery pressure was measured and recorded equally. The effects of the test substance on PAP under normoxic and hypoxic conditions are shown in Table 1 in comparison to the d-e control tests. The given data are the mean values + _ the standard deviation and were statistically evaluated by means of ANOVA.

Measurement of the antihypertrophic effect: At the end of the hemodynamic studies the animals were sacrificed and the hearts were extracted. The weights of the right and left ventricles were determined and the relationship to body weight was obtained. The effects of the test substance on body weights under normoxic and hypoxic conditions are shown in Table 1 in comparison with the control tests. The given data are the mean values + _ the standard deviation and were statistically evaluated by means of ANOVA.

Studies on the effect on arterial-pulsed remodeling: After sacrificing rats in addition to hearts, the lungs were also isolated. The latter were examined histologically, that is, the extent of the measurement of pulmonary vascular muscularization was determined by means of dyeing according to "van Gieson" by means of a microscope with an increase of 400x. The effects of the test substance on pulmonary artery remodeling (that is on the musculari zation of the distal pulmonary vessels) during hypoxia for 2 weeks are shown in Table 2 in comparison with the hypoxic control tests. The given data are the mean values + _ the standard deviation and were statistically evaluated by means of ANOVA.

Results: In the described test methods, it led the treatment with the test substance in hypoxic animals, to a statistically significant reduction of the pulmonary artery pressure (PAP), compared with the hypoxic control animals (Table 1). Here the systemic blood pressure was not influenced, that is, hypotensive properties were not determined. This represents a special advantage, since in the case of normotensive people with high pulmonary pressure there is no fear of a reduction in blood pressure under normal values.

Table 1: Effects of the substance used according to the invention (40 mg / kg / day for 14 days) on the pulmonary artery pressure and the weights of the left and right ventricles of the rats after 14 days under normotoxic and hypoxic conditions.

In the table they mean: * significantly different compared to the normoxic control tests (p <0.05) # significantly different compared to the hypoxic control tests (p <0.05) PAP = pulmonary artery pressure: pulmonary artery pressure RtHWt = weight of the left ventricle (mg); proportion Rt / LtHWt from the weight of the right ventricle to the left; RtHWt / BW = ratio of left ventricular weight to body weight.

The reduction of pulmonary artery pressure by means of the test substance led to a statistically significant reduction in the weight of the right ventricle of the rats (antihypertrophic effect) compared to the hypoxic control tests (Table 1). There was also a tendency to reduce the weight proportions of the weight from the right heart to the left and from the weight of the right ventricle to the body weight. In addition, the test substance was statistically significantly reduced by the muscularization of the distal pulmonary vessels of the rats (Table 2). This reduced pulmonary-artery remodeling is also a consequence of the statistically significant reduction of pulmonary hypertension.

Table 2: Effects of the substance used according to the invention (40 mg / kg / day for 14 days) on the muscularization of the distal pulmonary vessels of rats during 14 days of hypoxia compared to the hypoxic control tests * significantly different compared to the hypoxic control tests (p <0.05) Due to its previously described effect the compounds of the formula I and their biologically unstable salts and esters are sble as medicaments for higher mammals and humans, for the treatment of hypertension, especially for the treatment of certain forms of secondary hypertension. The compounds used according to the invention are sble in particular for the treatment of those forms of secondary blood hypertension, which can occur as a consequence of different non-cardiac diseases, such as, for example, for the treatment of pulmonary blood hypertension of non-cardiac etiology. The substances used according to the invention thus offer an advantageous application for the treatment and / or prophylaxis in particular of pulmonary blood hypertension caused by hypoxia and its complications, however without influencing the normal systemic blood pressure. Here, dicarboxylic acids of the formula I and their salts are advantageously used for the parenterally applicable drugs, in particular i.v., and mono- or diester of the formula I, advantageously in orally applicable medicaments. The doses used can be individually different and vary naturally according to the state to be treated, the substance used and the method of application. For example, parenteral formulations containing less active substance than oral preparations are used. In general, however, they are sble for applications in higher mammals, especially in humans, with an active ingredient content of 1 to 200 mg per individual dose. The compounds of the formula I including their acid salts and their biologically unstable esters can be administered here both with immediate release and also delayed, in a controlled and / or controllable manner.

The following examples should illustrate the invention in more detail, however they should not limit its scope in any way. The following examples 1 and 2 describe pharmaceutical preparations according to the invention containing an active ingredient of the formula I as well as the preparation of these pharmaceutical preparations. The compounds used according to the invention of formula I can be produced by means of the methods described in the aforementioned German patent application DE 195 10 566. Example 3 mentions preferred compounds for use according to the invention.

E j Example 1: Tablets containing (3S, 2 'R) -3- acid. { 1 - [2'-ethoxycarbonyl) -4 '-phenyl-butyl] -cyclopentan-1-carbonylamino} -2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzacepin-1-acetic Tablets are prepared with the following composition per tablet: Acid (3S, 2'R) -3-. { 1- [2'-ethoxycarbonyl) -4'-phenyl-butyl] -cyclopentane-1-carbonyl-amino} -2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzacepin-1-acetic acid 20 mg Starch Le. corn 60 mg Lactose 135 mg Gelatin (as a 10% solution) 6 mg The active ingredient, corn starch and lactose are thickened with a 10% solution of gelatin. The pulp is crushed, and the formed granulate is poured on a sble sheet and dried at 45 ° C. The dried granulate was conducted through a crusher and mixed in a mixer with the following additional additives: Talc 5 mg Magnesium stearate 5 mg Corn starch 9 mg and thus 240 mg tablets are pressed Step 2: Injectable solution containing (3S, 2'R) -3- acid. { l- [2'- (Carboxy-4'-phenyl-butyl] -cyclopentan-1-carbonylamino.) -2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic prepare a solution for injection with the following composition for every 5 ml: Acid (3S, 2'R) -3- { 1- [2 '- (carboxy-4' -phenyl-butyl] -cyclopentan-1-carbonylamino .} -2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzacepin-l-acetic 10 mg Na2HP04.7H20 43.24 mg NaH2P04.2H20 7.72 mg NaCl 30.00 mg Purified water 4948.00 mg The solids are dissolved in water, the solution is sterilized and used to fill ampules in portions of 5 ml trails.

Example 3: Preferred compounds of the formula I for use according to the invention for preparing medicaments for the treatment of hypertension, in particular for the treatment of secondary forms of blood hypertension such as for example pulmonary hypertension, are for example (including salts of acids): Butyl ester tert. of acid 3-. { l- [2- (Ethoxycarbonyl) -4'-phenyl-butyl] -cyclopentan-1-carbonyllamino} -2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzacepin-1 -acetic acid 3-. { 1- [2- (Ethoxycarbonyl) -4 '-phenyl-butyl] -cyclopent-a-n-1-carbonylamino} -2, 3, 4, 5-tetrahydro-2-oxo-lH-1-benzazepin-1-acetic butyl ester tert. of acid (3S, 2 'R) -3-. { 1- [2-R-ethoxycarbonyl) -4 '-phenyl-butyl] -cyclopentan-1-carbonyl amino} -2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzacepin-1-acetic acid (3S, 2'R) -3-. { l- [2'-ethoxycarbonyl) -4'-phenyl-butyl] -cyclopentan-1 -carbonylamino} -2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzazepin-1-acetic acid (3S, 2'R) -3-. { 1- [2 '- (carboxy-4' -phenyl-butyl] -cyclopentan-1-carbonylamino.) -2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzacepin-1-acetic ester butyl tert., 3-, {l- [2'- (butoxycarbonyl) -4'-phenyl-butyl] -cyclopentan-1-carbonylimide} -2, 3, 4, 5-tetrahydro-2 -oxo-lH-l-benzazepin-1-acetic acid 3- {1- [2'-carboxy-phenyl-butyl] -cyclopentan-1-carbonyl-lamino} -2, 3, 4, 5 -tetrahydro-2 -oxo-lH-l-benzacepin-l-acetic acid Benzyl ester of 3- (l-l- [2'- (butoxy carboni 1) -4 '-phenyl-butyl] -cyclopentan- 1- carboni lamino.} -2, 3, 4, 5-tetrahydro-2-oxo-lH-l-benzacepin-1-acetic acid benzyl ester 3- { 1 - [2 '-carboxy-4' - phenyl-butyl] -cyclopentan-1-carbonylamino.) -2, 3, 4, 5-te t-rahydr-o-2-oxo-lH-1-benzazepin-1-acetic Acid benzyl ester {. l- [2 '- (Butylcarbonyloxymethoxycarbonyl) -4' -phenyl-butyl] -cyclopentan-1-carbonyl-lamino} -2, 3, 4, 5-tetrahydro-2-oxo-1H-1-benzacepin - 1- acetic Acid 3-. [1- (2 '- (piva1o i loxymethoxycarboni 1) -4' • phenyl-butyl] -cyclopentan-1 -carbonylamino} -2,3,4,5-tetrahydro-2 -oxo-1H-1-benzacepin-1 -acetic

Claims (7)

1. - CLAIMS 1. Use of compounds of the general formula I wherein R1 means a phenylalkyl lower group, which may optionally be substituted on the phenyl ring by means of lower alkyl, lower alkoxy or halogen, or it may be a lower naphthylalkyl group, R 'hydrogen or a biologically unstable ester forming group. , and R 'hydrogen or a biologically unstable ester forming group, and and physiologically acceptable salts of the acids of the formula I, for preparing pharmaceutical preparations for the treatment of hypertension, in particular for the treatment of certain forms of secondary hypertension which are caused by non-cardiac diseases, in higher mammals and humans.
2. 2. Use of compounds according to claim 1, wherein the secondary blood hypertension not caused by heart disease is a pulmonary arterial hypertension.
3. 3. Use of compounds according to claim 1 or 2, wherein R2 and / or R3 mean a group forming biologically unstable esters.
4. 4. Use of compounds according to one of the preceding claims wherein a group forming biologically unstable esters is a lower alkyl group, phenyl or lower phenylalkyl groups substituted on the phenyl ring by means of lower alkyl or by a lower alkyl chain attached to two neighboring carbon atoms are preferably phenyl, benzyl or indanyl, a dioxolanylmethyl group optionally substituted on the dioxolane ring by means of lower alkyl, is in particular (2,2-dimethy1,3-dioxolan-4) -yl) -methyl, or represents an alkanoylmethyl group of 2 to 6 carbon atoms optionally substituted in the oxymethyl group by means of lower alkyl.
5. 5. Use of compounds according to one of the preceding claims wherein R 'means a biologically unstable ester forming group and R3 is hydrogen
6. 6. Use of compounds according to claim 5, wherein the (3S, 2 'R) -3- acid is used. { 1- [2'-ethoxycarbonyl) -4'-phenyl-butyl] -cyclopentan-1-carbonyllamino} -2, 3, 4, 5-tetrahydro-2-oxo-lH-1-benzazepin-1-acetic acid or its physiologically acceptable salts.
7. 7. Procedures for the preparation of pharmaceutical preparations for the treatment of hypertension, especially here the forms of secondary blood hypertension that are caused by non-cardiac diseases, in higher mammals and humans, wherein an amount effective to reduce the blood pressure of a compound of the formula I according to claim 1 or of physiologically acceptable salts of acids of the formula I together with customary pharmaceutical additives are transformed into a suitable medicament form.