MXPA06006219A - Delta-amino-gamma-hydroxy-omega-aryl-alkanoic acid amides and use as renin inhibitors - Google Patents

Abstract

The invention relates to novel ?-amino-&ggr;-hydroxy-&ohgr;-aryl-alkanoic acid amides of formula (I), or a pharmaceutically acceptable salt thereof.

Description

AMIDAS DELTA-AMINO-GAMMA-HYDROXY-OMEGA-ARIL-ALCANOICO ACID. AND ITS USE AS INHIBITORS OF RENIÑA The invention relates to novel amides of the d-amino-α-hydroxy-α-aryl-alkanoic acid of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein: R1, R2, R3, R4, independently of each other, are hydrogen; halogen; hydroxyl, alkanoyloxy of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms; or are alkyl of 1 to 7 carbon atoms which is substituted by: halogen, cyano, hydroxyl, alkanoyloxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms which is substituted by halogen or by hydroxyl, alkenyloxy of 2 to 7 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms S-oxidized, amino, N-mono -alkyl of 1 to 7 carbon atoms -amino, N, N-di-alkyl of 1 to 7 carbon atoms-amino, N-alkanoyl of 1 to 7 carbon atoms-amino, N-alkane of 1 to 7 carbon-sulfonyl-amino atoms, which amino is N, N-disubstituted by alkylene of 2 to 7 carbon atoms, by alkylene of 2 to 7 unsubstituted carbon atoms or N'-alkyl of 1 to 7 carbon atoms or N'- alkanoyl of 1 to 7 carbon atoms-aza-alkylene of 2 to 7 carbon atoms, for oxa-alkylene of 1 to 7 carbon atoms, for thia-alkylene of 1 to 7 atoms carbon atoms, or by thia-alkylene of 1 to 7 carbon atoms S-oxidized, free or esterified or amidated carboxyl, cycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl, hydrogenated heteroaryl, or by oxo; or are alkoxy of 1 to 7 carbon atoms-alkenyl of 2 to 7 carbon atoms; alkoxy of 1 to 7 carbon atoms; or are alkoxy of 1 to 7 carbon atoms which is substituted by: halogen, cyano, hydroxyl, alkanoyloxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms which is substituted by halogen or by hydroxyl, alkenyloxy of 2 to 7 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms S-oxidized, amino, N-mono -alkyl of 1 to 7 carbon atoms-amino, N, N-di-alkyl of 1 to 7 carbon atoms-amino, N-alkanoyl of 1 to 7 carbon atoms-amino, N-alkane of 1 to 7 atoms carbon-sulfonyl-amino, which is N, N-disubstituted by alkylene of 2 to 7 carbon atoms, by unsubstituted carbon atoms of 2 to 7 carbon atoms or N'-alkyl of 1 to 7 carbon atoms - or N ' - alkanoyl of 1 to 7 carbon atoms-aza-alkylene of 2 to 7 carbon atoms, by oxa-alkylene of 1 to 7 carbon atoms, by thia-alkylene of 1 to 7 atoms carbon atoms, or by thia-alkylene of 1 to 7 carbon atoms S-oxidized, free carboxyl or esterified or amidated, cycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl, or by hydrogenated heteroaryl; or are alkenyloxy of 2 to 7 carbon atoms; alkoxy of 1 to 7 carbon atoms-alkenyloxy having 2 to 7 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms; alkanoyl of 1 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; aril; heteroaryl; or hydrogenated heteroaryl; or R3 together with R4 form alkylenedioxyl of 2 to 7 carbon atoms, or a benzo or cyclohexene ring fused thereon; X is methylene; hydroxymethylene; OR; NH; S; SW; or S02; R5 is alkyl of 1 to 7 carbon atoms; alkenyl of 2 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl; R6 is amino; N-mono-amino of 1 to 7 carbon atoms; N, N-di-amino of 1 to 7 carbon atoms; N-alkanoyl of 1 to 7 carbon atoms-amino; N-alkane of 1 to 7 carbon atoms-sulfonyl, or represents a group of the formula -N R 10 COCH R 11 NR 12 R 13, and the latter may be present in either the (D), (L), or (D, L) configuration ) racemic, but preferably in the L form; R7 is alkyl of 1 to 7 carbon atoms, alkenyl of 2 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl; R8 is hydrogen; alkyl of 1 to 7 carbon atoms; or is alkyl of 1 to 7 carbon atoms which is substituted by: halogen, cyano, hydroxyl, alkanoyloxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms which is substituted by halogen or by hydroxyl, alkenyloxy of 2 to 7 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms S-oxidized, amino, N-mono -alkyl of 1 to 7 carbon atoms-amino, N, N-di-alkyl of 1 to 7 carbon atoms-amino, N-alkanoyl of 1 to 7 carbon atoms-amino, N-alkane of 1 to 7 atoms of carbon-sulfonyl-amino, which amino is N, N-disubstituted by alkylene of 2 to 7 carbon atoms, by alkylene of 2 to 7 unsubstituted carbon atoms or N'-alkyl of 1 to 7 carbon atoms- or N '-alkalloy from 1 to 7 carbon atoms-aza-alkyl of 2 to 7 carbon atoms, by oxa-alkylene of 1 to 7 carbon atoms, by thia-alkylene of 1 to 7 atoms of carbon, or by thia-alkylene of 1 to 7 carbon atoms S-oxidized, free carboxyl or esterified or amidated, or is alkanoyl of 1 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl, hydrogenated heteroaryl; cycloalkyl of 3 to 7 carbon atoms; aril; heteroaryl, or hydrogenated heteroaryl; R9 represents alkanoyl of 1 to 7 carbon atoms, alkane of 1 to 7 carbon atoms-sulfonyl, or a group of the formula -COCH R14R11 R12, which may be present in either the (D), (L) configuration , or (D, L) racemic, but preferably in the L form; or a group of the formula -CH20-COR15; R10 is hydrogen; alkyl of 1 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl; R11 is hydrogen; alkyl of 1 to 7 carbon atoms; aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl; R12 and R13, independently of one another, are hydrogen; alkyl of 1 to 7 carbon atoms; alkyl of 1 to 7 carbon atoms which is substituted by: halogen, cycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl, alkoxy of 1 to 7 carbon atoms-carbonyl, thioalkyl of 1 to 7 carbon atoms, by thioalkyl from 1 to 7 carbon atoms S-oxidized, by amino-carbonyl, by N-alkanoyl of 1 to 7 carbon atoms-amino-carbonyl, by N-alkyl of 1 to 7 carbon atoms-amino-carbonyl; by N, N-di-alkyl of 1 to 7 carbon atoms-amino-carbonyl, or by amino-carbonyl which is disubstituted by alkylene of 2 to 7 carbon atoms; or they are cycloalkyl of 3 to 7 carbon atoms; ariio, or heteroari lo; R14 is hydrogen; alkyl of 1 to 7 carbon atoms; aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl; and R15 is alkyl of 1 to 7 carbon atoms, aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl. The salts of the compounds having salt-forming groups are in particular the acid addition salts, the salts with bases, or where several salt-forming groups are present, they can also be the mixed salts or the internal salts. The salts are in particular the pharmaceutically acceptable or non-toxic salts of the compounds of Formula I. In a broader sense, the invention also relates to salts which are not suitable for therapeutic purposes, and which can be used, for example. , in the isolation or purification of the free compounds of Formula (I) or pharmaceutically acceptable salts thereof. Therapeutically, only salts that are pharmaceutically acceptable and non-toxic are used, and therefore, these salts are preferred. The compounds of the present invention possess two or more asymmetric centers, depending on the choice of substituents. However, the present invention encompasses any possible diastereoisomers, enantiomers, and geometric isomers, and mixtures thereof, for example racemates. The general terms used hereinbefore and hereinafter, have the following meanings, unless defined otherwise. Halogen is in particular halogen of an atomic number not greater than 35, such as fluorine, chlorine, or bromine, and also includes iodine. Alkanoyl of 1 to 7 carbon atoms is, for example, formyl, or preferably alkanoyl of 2 to 7 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl, or pivaloyl. Alkanoyl of 2 to 5 carbon atoms is preferred. Alkyl of 1 to 7 carbon atoms is, in particular, alkyl of 1 to 4 carbon atoms, such as methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl. Methyl and ethyl are preferred. Alkoxy of 1 to 7 carbon atoms is, in particular, alkoxy of 1 to 4 carbon atoms, such as methoxy, ethoxy, normal propyloxy, isopropyloxy, normal butyloxy, and tertiary butyloxy. Methoxy and ethoxy are preferred. Alkenyl of 2 to 7 carbon atoms is, in particular, alkenyl of 3 to 7 carbon atoms, and is, for example, 2-propenyl or 1-, 2-, or 3-butenyl. Alkenyl of 3 to 5 carbon atoms is preferred. Cycloalkoxy of 3 to 7 carbon atoms is, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy. Cyclopropyloxy, cyclopentyloxy, and cyclohexyloxy are preferred. S-oxidized C 1 -C 7 -thioalkyl is, for example, alkane of 1 to 7 carbon atoms-sulfinyl, 0 alkane of 1 to 7 carbon atoms-sulfonyl. Alkylene having 2 to 7 carbon atoms is, for example, straight or branched chain, and is in particular methylene, ethylene, propylene, and butylene, and also 1,2-propylene, 2-methyl-1,3-propylene, and 2, 2-dim eti 1-1, 3-propylene. Alkylene of 2 to 5 carbon atoms is preferred. Aza-alkylene of 2 to 7 carbon atoms is, for example, alkylene of 2 to 3 carbon atoms-aza-alkylene of 3 to 4 carbon atoms, such as 3-aza-pentylene. Oxa-alkylene of 2 to 7 carbon atoms is, for example, alkylene of 2 to 3 carbon atoms-oxa-alkylene of 3 to 4 carbon atoms, such as 3-oxa-pentylene. Thia-alkylene of 2 to 7 carbon atoms is, for example, alkylene of 2 to 3 carbon atoms-thia-alkylene of 3 to 4 carbon atoms, such as 3-thia-pentylene. Esterified carboxyl is, for example, alkoxy 1 to 7 carbon atoms - carbonyl, alkoxy of 1 to 7 carbon atoms - alkoxy of 1 to 7 carbon atoms - carbonyl, cycloalkyl of 3 to 7 carbon atoms - alkoxy of 1 to 7 carbon atoms - carbonyl, aryl -alkoxy of 1 to 7 carbon atoms-carbonyl, or heteroaryl-alkoxy of 1 to 7 carbon atoms-carbonyl.

Amidocarboxyl is, for example, amino-carbonyl, N-mono-alkyl of 1 to 7 carbon atoms-amino-carbonyl, N, N-di-amino of 1 to 7 carbon atoms-carbonyl, N-alkanoyl of 1 to 7 carbon atoms-amino-carbonyl, N-alkane of 1 to 7 carbon atoms-sulphonyl-amine-carbonyl, amino-carbonyl which is N, N-disubstituted by alkylene of 2 to 7 carbon atoms , by alkylene of 2 to 7 unsubstituted carbon atoms or N'-alkyl of 1 to 7 carbon atoms- or N'-alkanoyl of 1 to 7 carbon atoms-aza-alkylene of 2 to 7 carbon atoms, by oxa -alkylene of 1 to 7 carbon atoms, by thia-alkylene of 1 to 7 carbon atoms, or by thia-alkylene of 1 to 7 carbon atoms S-oxidized. Cycloalkyl of 3 to 7 carbon atoms is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cyclopropyl, cyclopentyl, and cyclohexyl are preferred. Aryl is, for example, phenyl, biphenylyl, or naphthyl. Aryl is unsubstituted or substituted, for example mono-, di-, or tri-substituted, by a substituent selected from the group consisting of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, hydroxyl, cyano, nitro, alkanoyloxy of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, halogen, and by trifluoromethyl. Heteroaryl is, for example, a 5-membered optionally benzo-fused aza-, diaza-, triaza-, oxadiaza-, or tetra-aza-aryl radical, or a 6-membered aza- or diaza-aryl radical. Suitable 5-membered heteroaryl radicals are, for example, monoaza-, diaza-, triaza-, tetra-aza-, mono-oxa-, or cyclic mono-thia-aryl radicals, such as pyrrolyl, pyrazolyl, imidazolyl. , triazolyl, tetrazolyl, furyl, and thienyl, while suitable and suitable six-member radicals are in particular pyridyl. Heteroaryl is unsubstituted or substituted, for example mono-, di-, or tri-substituted, by a substituent selected from the group consisting of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, hydroxyl, cyano, nitro, alkanoyloxy of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, halogen, and by trifluoromethyl. Pyrrolyl is, for example, 2- or 3-pyrrolyl. Pyrazolyl is 3- or 4-pyrazolyl. Imidazolyl is 2- or 4-imidazolyl. Triazolyl is, for example, 1, 3.5-1 H-triazol-2-yl or 1, 3,4-triazol-2-yl. Tetrazolyl is, for example, 1,2,3,4-tetrazol-5-yl; furyl is 2- or 3-furyl, and thienyl is 2- or 3-thienyl, while the suitable pyridyl is 2-, 3-, or 4-pyridyl. Hydrogenated heteroaryl is, for example, a partially or fully hydrogenated aza-, diaza-, triaza-, oxadiaza-, or tetra-aza-aryl radical of 5 members, optionally benzo-fused, or a radical of aza- or diaza -aril of 6 members. Suitable hydrogenated 5-membered heteroaryl radicals are, for example, monoaza-, diaza-, triaza-, tetra-aza-, mono-oxa-, or cyclic mono-thia-aryl radicals, such as pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, triazolinyl, triazilidinyl, dihydro- or tetrahydro-furyl, and dihydro- or tetrahydro-thienyl, while suitable and suitable 6-membered radicals are in particular pyridinyl or piperidinyl. Hydrogenated heteroaryl is unsubstituted or substituted, for example, mono-, di-, or tri-substituted, by a substituent selected from the group consisting of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, hydroxyl, cyano, nitro, alkanoyloxy of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, halogen, and by trifluoromethyl. Alkylenedioxyl of 2 to 7 carbon atoms is, for example, oxy-alkylene oxyl of 2 to 7 carbon atoms, such as oxy methylene oxide, oxy ethylene oxide, oxy propylene oxide, or oxy butylene oxide. Alkylene dioxy of 2 to 5 carbon atoms is preferred. The compounds of the present invention have enzyme inhibiting properties, either by direct blocking of the enzyme function, or by the release of an active component of the pro-drug prodrug molecule, which inhibits the function of the objective enzyme. In particular, they inhibit, directly and / or indirectly, the action of the natural renin enzyme. The latter passes from the kidneys to the blood, where it dissociates the angiotensinogen, releasing the decapeptide angiotensin I, which then dissociates in the lungs, kidneys, and other organs, to form the octapeptide angiotensinogen II. The octapeptide increases blood pressure, both directly by arterial vasoconstriction, and indirectly by the release from the adrenal glands of the hormone retention of sodium aldosterone, accompanied by an increase in the volume of the extracellular fluid. The increase is attributed to the action of angiotensin II. Inhibitors of the enzymatic activity of renin cause a reduction in the formation of angiotensin I. As a result, a smaller amount of angiotensin II is produced. The reduced concentration of this active peptide hormone is the direct cause of the hypotensive effect of renin inhibitors. The action of renin inhibitors is demonstrated, inter alia, experimentally, by means of in vitro tests, ie, for example, by reducing the formation of angiotensin I from the natural angiotensinogen substrate, or by reducing the dissociation of suitable non-endogenous substrates, measured in several systems (human plasma, purified human renin together with synthetic or natural renin substrate). Among others, the following in vitro tests are used.

Inhibition of human renin determined by a Fluorescence Resonance Energy Transfer (FRET) assay. The recombinant human renin (expressed in Chinese hamster ovary cells, and purified using conventional methods) is incubated at a concentration of 4 nM, with the test compound in different concentrations, for 1 hour at room temperature, in tris-regulator. HCI 0.1M, pH 7.4, containing 0.05M NaCl, 0.5mM EDTA, and 0.05 percent CHAPS. The synthetic peptide substrate Arg-Glu (EDANS) -lle-His-Pro-Phe-His-Leu-Val-lle_His_Thr-Lys (DABCYL) -Arg9 is added to a final concentration of 2 μM, and the increase in fluorescence at an excitation wavelength of 340 nanometers, and at an emission wavelength of 485 nanometers, in a microplate spectrofluorimeter. IC50 values are calculated from the percentage inhibition of renin activity as a function of the concentration of the test compound.

Inhibition of human renin determined by HPLC quantification of the products of enzymatic dissociation. Recombinant human renin (expressed in Chinese hamster ovary cells and purified using conventional methods) is incubated at a concentration of 1 nM, with the test compound in different concentrations, for 1.5 hours at 37 ° C, in Tris / HCl 0.1. M, pH 7.4, containing 0.05M NaCl, 0.5 mM EDTA, and 0.025 percent (weight / volume) CHAPS. Synthetic peptide substrate Ac-I le-H is-Por-Phe-His-Leu-Val-I le-His-Asn-Lys- [DY-505-X5] is added to a final concentration of 5 μM. The enzymatic reaction is stopped by the addition of 6 microliters of 1.0 percent trifluoroacetic acid. The product of the reaction is separated by HPLC, and quantified by spectrophotometric measurement at a wavelength of 505 nanometers. IC50 values are calculated from the percentage inhibition of renin activity as a function of the concentration of the test compound.

Inhibition of human renin by a Cinylation Proximity Assay (SPA). Recombinant human renin (expressed in Chinese hamster ovary cells, and purified using conventional methods) at a concentration of 3.3 nM, 125 I-NVP-AJI891-NX-1 (0.27 μ C / ml); and streptavidin-SPA beads (0.67 milligrams / milliliter), incubated with the test compound in different concentrations for 2.0 hours at room temperature, in 0.1 M Tris / HCl, pH 7.4, containing 0.5 M NaCl and 0.5 Brij35 cent (weight / volume). At the end of the incubation time, the plates are centrifuged (55 g, 60 seconds), and counted in a Wallac MicroBeta reader. The IC 50 values are calculated from the percent displacement of the radioligand that binds to the renin as a function of the concentration of the test compound.

In vivo Test Systems: In animals deficient in salt, renin inhibitors cause a reduction in blood pressure. Human renin differs from the renin of other species. In order to test inhibitors of human renin, primates (marmosets, Callithrix jacchus) are used, because human renin and primate renin are substantially homologous in the enzymatically active region. Among others, the following in vivo test is used: test compounds are tested on normotensive marmosets of both sexes that have a body weight of approximately 350 grams, which are conscious, and are allowed to move freely and in their normal cages. The blood pressure and heart rate are measured by a catheter in the descending aorta, and they are recorded radio-electrically. The endogenous release of renin is stimulated by the combination of a low-salt diet of one week, and a single intramuscular injection of furosemide (5- (amino-sulfonyl) -4-chloro-2 - [(2-furanyl- methyl) -amino] -benzoic acid (5 milligrams / kilogram). Sixteen hours after the injection of furosemide, test compounds are administered either directly into the femoral artery using an injection cannula, or in the form of a suspension or solution, by means of an esophageal tube into the stomach, and its action on blood pressure and heart rate is evaluated. In the described in vivo test, the compounds of the present invention have a hypotensive action in doses of about 0.003 to about 0.3 milligrams / kilogram intravenously, and in doses of about 0.31 to about 30 milligrams / kilogram orally. The compounds of the present invention also have the property of regulating, in particular reducing, the intraocular pressure. The degree of reduction in infra-ocular pressure after administration of a pharmaceutically active ingredient of Formula (I) according to the present invention, can be determined, for example, in animals, for example rabbits or monkeys. Two typical experimental procedures illustrating the present invention are described below, but are not intended to limit it in any way. The in vivo test on a rabbit of the type "Fauve de Bourgogne", to determine the reducing activity of the intraocular pressure of the topically applied compositions, can be designed, for example, as follows. The intraocular pressure (IOP) is measured using a flattening tonometer, both before the experiment and at regular time intervals. After a local anesthetic is administered, the properly formulated test compound in a precisely defined concentration (eg, 0.000001 to 5 weight percent) is applied topically to an eye of the animal in question. The contralateral eye is treated, for example, with physiological saline solution. The measured values thus obtained are statistically evaluated. In vivo tests in monkeys of the species Macaca Fascicularis, to determine the reducing activity of the infraocular pressure of the topically applied compositions, can be carried out, for example, as follows. The suitably formulated test compound is applied in a precisely defined concentration (e.g., 0.000001 to 5 weight percent) to one eye of each monkey. The other eye of the monkey is treated in a corresponding manner, for example, with physiological saline. Before starting the test, the animals are anesthetized with intramuscular injections, for example, of ketamine. At regular time intervals, intraocular pressure (IOP) is measured. The test is carried out and evaluated in accordance with the rules of "good laboratory practice" (GLP). In accordance with the above, the compounds of the present invention can be used in the prevention, treatment, or delay of progress to stop hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy, renal failure (acute and chronic) after infarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, elevated intraocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, Alzheimer's disease, dementia, anxiety states, and cognitive disorders. Accordingly, the compounds of the present invention can be used in the prevention, treatment, or delay of progress to stop hypertension, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy, renal failure (acute and chronic) subsequent to infarction, complications resulting from diabetes, such as nephropathy, vasculopathy, and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, elevated intraocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, anxiety states, and cognitive disorders. The group of compounds mentioned below should not be considered as exclusive; rather, for example, in order to replace the general definitions with more specific definitions, parts of these groups of compounds can be exchanged for the definitions given above, or they can be omitted, as appropriate. Preferred R 1 is hydrogen, alkyl of 1 to 7 carbon atoms, or alkoxy of 1 to 7 carbon atoms. Preferred R2 and R3 are alkoxy of 1 to 7 carbon atoms or alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms. Preferred R 4 is hydrogen, alkyl of 1 to 7 carbon atoms, or alkoxy of 1 to 7 carbon atoms. Preferred R5 and R7 are alkyl of 1 to 7 carbon atoms. Preferred R6 is amino. Preferred R8 is amino-carbonyl-alkyl of 1 to 7 carbon atoms.

Preferred R9 is alkanoyl of 1 to 7 carbon atoms, a group of the formula -COCH R14N R1 R12, which may be present in either the (D), (L), or (D, L) racemic configuration, but preference in the L form; or a group of the formula -CH20-COR15; and R14 is hydrogen, alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 4 carbon atoms; R11 and R12, independently of one another, are hydrogen, alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 4 carbon atoms; and R15 is alkyl of 1 to 7 carbon atoms or phenyl-alkyl of 1 to 4 carbon atoms. Preferred R 10, R 11, R 12, R 3, and R 14 are hydrogen, alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 4 carbon atoms. Preferred R15 is alkyl of 1 to 7 carbon atoms or phenyl-alkyl of 1 to 4 carbon atoms. Preferred X is methylene. The invention relates in particular to a compound of the Formula (I), or a pharmaceutically acceptable salt thereof; wherein: R1 is hydrogen, alkyl of 1 to 7 carbon atoms, or alkoxy of 1 to 7 carbon atoms; R 2 is alkoxy of 1 to 7 carbon atoms or alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms; R3 is alkoxy of 1 to 7 carbon atoms or alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms; R 4 is hydrogen, alkyl of 1 to 7 carbon atoms, or alkoxy of 1 to 7 carbon atoms; R5 is alkyl of 1 to 7 carbon atoms; R6 is amino; R7 is alkyl of 1 to 7 carbon atoms; R8 is am i non-carbon i I-alkyl of 1 to 7 carbon atoms; R9 is alkanoyl of 1 to 7 carbon atoms, a group of the formula -COCH R14N R11 R12, which may be present in either the (D), (L), or (D, L) racemic configuration, but preference in the L form; or a group of the formula -CH20-COR15, and R14 is hydrogen, alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 4 carbon atoms; R12 and R13, independently of one another, are hydrogen, alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 4 carbon atoms; and R15 is alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 4 carbon atoms; and X is methylene.

The invention relates generally to a compound of the Formula (IA): , wherein the variables R1 to R15 and X have the meanings given above; or a pharmaceutically acceptable salt thereof.

The invention relates in particular to a compound of the Formula (IA), or a pharmaceutically acceptable salt thereof, wherein: R1 and R4 are hydrogen; R 2 is alkoxy of 1 to 4 carbon atoms-alkoxy of 1 to 4 carbon atoms, such as 3-methoxy-propyloxy; R3 is alkoxy of 1 to 4 carbon atoms, such as methoxy; R5 and R7, independently of one another, are alkyl of 1 to 7 carbon atoms, such as isopropyl; R6 is amino; R8 is amino-carbonyl-alkyl of 1 to 4 carbon atoms, such as 2-amino-2,2-dimethyl-ethyl; R9 is alkanoyl of 1 to 4 carbon atoms, or a group of the formula -COCH R14NR12R13, wherein R14 is alkyl of 1 to 4 carbon atoms, such as isopropyl or isobutyl, or phenyl-alkyl of 1 to 2 carbon atoms. carbon, such as benzyl; R 2 and R 13 are hydrogen, and X is methylene.

The invention relates especially to a compound of the formula (IB): or a pharmaceutically acceptable salt thereof, wherein R6 and R9 have the meanings given above in each case.

The invention relates to a compound of the Formula (IC): or a pharmaceutically acceptable salt thereof, wherein R9 is alkanoyl of 1 to 4 carbon atoms, or a group of the formula -CQCHR14NH2, wherein R14 is alkyl of 1 to 4 carbon atoms, such as isopropyl or isobutyl, or phenyl-alkyl of 1 to 2 carbon atoms, such as benzyl. When hereinbefore or hereinafter referred to a compound of the Formula (I), a compound of the Formula (IA), (IB), and (IC) is encompassed in the same manner. The invention specifically relates to the compounds of Formula I mentioned in the Examples, and to the salts thereof, especially the pharmaceutically acceptable salts thereof. The present invention also relates to the manufacture of a compound of the Formula (I) or (IA) or (IB) or (IC), respectively, or a salt thereof, wherein the variables R1 to R5 and R7 to R1s and X have the meanings defined above, and R6 is amino, which comprises: reducing a compound of Formula (II a): wherein Y is azido (N3), or a salt thereof, and isolating a compound of the Formula (I) or a salt thereof. The reduction is carried out in the presence of a hydrogenation catalyst. The present invention also relates to the manufacture of a compound of the formula (I) or (IA) or (IB) or (IC), respectively, or a salt thereof, wherein the variables R1 to R8 and R10 to R15 and X have the meanings defined above, which comprises: reacting a compound of the Formula (II b): wherein R6 'is amino or N-mono-amino of 1 to 7 protected carbon atoms; N, N-di-amino of 1 to 7 carbon atoms; N-alkanoyl of 1 to 7 carbon atoms-amino; or represents a group of the formula -NR10COCHR11NR12R13, and the latter may be present in either the (D), (L), or (D, L) racemic configuration, but preferably in the L form; R12 is hydrogen, and R13 is protected amino, or a salt thereof, with a compound of Formula (II c), R9-Y1, wherein Y1 is hydroxyl or a reactive group; or a salt thereof; remove the corresponding protective groups; and isolating a compound of Formula (I) or a salt thereof. The reactions described hereinbefore and hereinafter are carried out in a manner known per se, for example in the absence, or usually in the presence of a suitable solvent or diluent, or a mixture thereof, the operation being carried out as necessary, with cooling, at room temperature, or with heating, for example in a temperature range from about -80 ° C to the boiling temperature of the reaction medium, especially about -10 ° C. C at approximately + 200 ° C, and if necessary, in a closed vessel, under pressure, in an inert gas atmosphere, and / or under anhydrous conditions. The reduction of a compound of the Formula (II a) is carried out, for example, by hydrogenation, in the presence of a hydrogenation catalyst.

A suitable catalyst for hydrogenation is of metals, for example nickel, iron, cobalt, or ruthenium, or of noble metals or their oxides, such as palladium or rhodium or their oxides, optionally supported on a suitable carrier, such as barium sulfate. , aluminum oxide, or activated carbon, or in the form of skeleton catalysts, for example Raney nickel, but especially homogeneous or heterogeneous complexes of metal- or noble metal-ligand. A preferred catalyst is Pd / C. These catalysts are in particular ruthenium complexes or ruthenium salts, such as Ru (ll) halides, such as RuCI2, Ru2CI2, or RuHCI, optionally halogenated lower alkanoylates of Ru (ll), such as Ru (OAc) 2 or Ru (OOC-CF3) 2, with (S) -bis- (2,2'-diphen-1-phosphono) -1,1-biphenyl (S-BINAP) or derivatives thereof, instead of phenyl , substituted phenyl radicals, such as p-tolyl or p-methoxy-phenyl, and also ruthenium complexes with (S) -bis- (2,2'-diphenyl-phosphino) -5,5'-dimethyl-d, phenol, and the like. Hydrogenation with such complexes of preference is carried out in inert solvents or mixtures of solvents, for example alcohols, such as lower alkanols, or alkyl halides, such as methylene chloride, in a pressure range of about 1 to 100 bar, preferably 20 to 30 bar, and in a temperature range of about 10 ° C to 80 ° C, preferably 15 ° C to 25 ° C. The hydrogenation is carried out at temperatures of 0 ° C to 250 ° C, preferably from room temperature to about 100 ° C, and at hydrogen pressures of 1 to 200 bar. The reaction of a compound of the formula (II b) with a compound of the formula (II c) is carried out, for example, following the methods known per se. For the manufacture of a compound of the formula (I), wherein R9 is alkanoyl of 1 to 7 carbon atoms, alkane of 1 to 7 carbon atoms-sulfonyl, or a group of the formula -COCH R14R11 R12, which it may be present in either the (D), (L), or (D, L) racemic configuration, but preferably in the L form; the reaction of a compound of the Formula (II b) with a compound of the Formula (II c) is an acylation, while, for the manufacture of a compound of the Formula (I), wherein R9 is a group of the Formula -CH20-COR15; the reaction of a compound of the Formula (II b) with a compound of the Formula (II c) is an etherification. A corresponding acylation is carried out, for example, in the presence of a suitable base. The proper bases are, for example, hydroxides, hydrides, amides, alkanolates, carbonates, triphenyl-methylides, di-lower alkyl-amides, amino-alkyl-amides, or lower alkyl-silyl-amides, naphthalene-amines, lower alkyl-amines, basic heterocycles , ammonium hydroxides, and carbocyclic amines of alkali metals. Examples which may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium terbutoxide, potassium carbonate, lithium triphenyl-methylide, lithium di-isopropyl amide, - (potassium amine-propyl) amide, potassium bis- (trimethyl-silyl) -amide, dimethylaminophetalene, di- or tri-ethyl-amine, or ethyl-di-isopropyl-amine, N -methyl-piperidine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5-diazabicyclo- [4.3.0] -non-5-ene (DBN), and 1,8-diaza-bicyclo- [5.4.0] -undec-7-ene (DBU). A reactive group Y1 is, for example, halogen, such as chlorine, bromine, or iodine, substituted sulfonyl, or a group of the formula R9-CO-0- or R9-S02-0-. The corresponding acylation is carried out, for example, in the presence of one of the customary condensation agents. The customary condensation agents are, for example, carbodiimides, for example diethyl-, dipropyl-, or N-ethyl-N '- (3-dimethyl-amino-propyl) -carbodi-imide, or in particular bicyclohexyl -carbonyldi-imide, and also suitable carbonyl compounds, for example carbonyl-di-imidazole, 1,2-oxazolium compounds, for example 3'-sulfonate of 2-ethyl-5-f in i-1, 2-oxazolium and 2-tert-butyl-5-methyl-oxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxy-carbonyl-1,2-dihydro-quinoline, and also the acid derivatives activated phosphoric acid, for example diphenyl phosphoryl azide, diethyl phosphoryl cyanide, phenyl N-phenyl-phosphoramidochloride, bis- (2-oxo-3-oxazolidinyl) -phosphinoyl chloride, or hexafluoro-phosphate of 1 - benzotriazolyloxytris- (dimethylamino) -phosphonium. If desired, an organic base is added, for example a tri-lower alkyl-amine having bulky radicals, for example ethyl-di-isopropylamine, or a heterocyclic base, "for example pyridine, 4-dimethylamino- pyridine, or preferably N-methyl-morpholine A corresponding etherification is carried out, for example, following the methods known per se.Etherification can be carried out, for example, in the presence of a base, a hydride , alkali metal hydroxide, or carbonate, or an amine, conversely, the corresponding ethers, such as the lower alkoxy compounds, can be dissociated, for example, by means of strong acids, such as mineral acids, for example the acids Hydrochloric or hydroiodic acid hydrochlorides, which may conveniently be present in the form of pyridinium halides, or by means of Lewis acids, for example the halides of the elements of the main group III, or the sub-groups corresponding pos. These reactions can be carried out, if necessary, with cooling or heating, for example in a temperature range from about -20 ° C to about 100 ° C, in the presence or absence of a solvent or diluent, under a Inert gas and / or under pressure, and if appropriate, in a closed container. The removal of the amino protecting groups is carried out following, for example, the methods known per se, in particular using the methods that are applied to the manufacture of peptides or proteins. For example, the Boc group is removed in the presence of an acid, such as hydrochloric acid, in an inert solvent or in a mixture of solvents, such as in an ether, for example dioxane. The isolation of a compound of the Formula (I) is carried out according to conventional isolation methods, such as by crystallization of the resulting compound of the Formula (I) from the reaction mixture, or by chromatography of the reaction mixture. The process for the manufacture of the compounds of the Formula (I) and the salts thereof, for example, it can be illustrated by the processing examples that, in the same way, together with the method for preparing the compounds of the Formula (I), is another aspect of the present invention. The starting material of the compounds of the formulas (II a), (II b), and (II c) is known or can be prepared using and applying the methods known per se in the art. The manufacture of the compounds of Formula (II a), for example, is described in the processing examples. The compounds of the Formulas (II a) and (II b) can be prepared, for example, using the methods described in European Patent Number EP 678503A1; the subject matter concerned in connection with the manufacture of this starting material is incorporated herein by reference. In view of the close relationship between the novel compound in the free form and in the form of its salts, in the above text and below, it should be understood that the free compound or its salts also mean, in a corresponding and convenient manner, the corresponding salts or the free compound. The salts of the compounds of the Formula (I) can be prepared in a manner known per se. For example, the acid addition salts of the compounds of Formula (I) are obtained by treatment with an acid or with an appropriate ion exchange reagent. The acid addition salts can be converted into the free compounds in the customary manner, for example, by treatment with a suitable basic agent. The resulting acid addition salts can be converted to other salts in a manner known per se, for example by treatment with a suitable metal salt, such as a sodium, barium, or silver salt, of a different acid, in a suitable solvent in which the formed inorganic salt is insoluble, and which is consequently removed from the equilibrium of the reaction. The compounds of Formula (I), including a salt thereof, may also be obtained in the form of a hydrate, or may include the solvent used for crystallization (solvates). As a result of the close relationship between the novel compounds in free form and in the form of their salts, hereinafter and hereinafter, any reference to the free compounds and their salts, should be understood to also include the salts and corresponding free compounds, respectively, as appropriate and convenient. The invention relates in particular to a combination, such as a combined preparation or a pharmaceutical composition, respectively, which comprises a compound of the Formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutic agent selected from of the group consisting of: (i) an ATi receptor antagonist, or a pharmaceutically acceptable salt thereof, (ii) an angiotensin-converting enzyme (ACE) inhibitor, or a pharmaceutically acceptable salt thereof, (iii) a beta blocker, or a pharmaceutically acceptable salt thereof, (iv) a calcium channel blocker, or a pharmaceutically acceptable salt thereof, (v) an aldosterone synthase inhibitor, or a pharmaceutically acceptable salt thereof, (vi) ) an aldosterone receptor antagonist, or a pharmaceutically acceptable salt thereof, (vii) a double inhibitor of angiotensin converting enzyme / neutral endopeptidase (ACE / NE P), or a pharmaceutically acceptable salt thereof, (viii) an endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof, (ix) a diuretic, or a pharmaceutically acceptable salt thereof, (x) an endopeptidase inhibitor. neutral (NEP), or a pharmaceutically acceptable salt thereof, (xi) a membrane pump inhibitor of Na-K-ATPase, or a pharmaceutically acceptable salt thereof, (xii) an anti-diabetic agent, or a pharmaceutically acceptable salt thereof, (xiii) a hypolipidemic agent, or a pharmaceutically acceptable salt thereof, and (xiv) an anti-obesity agent, or a pharmaceutically acceptable salt thereof. The invention relates in particular to a combination, such as a combined preparation or a pharmaceutical composition, respectively, which comprises a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, at least one therapeutic agent selected from of the group consisting of: (i) an ATT receptor antagonist, or a pharmaceutically acceptable salt thereof, (ii) an angiotensin converting enzyme (ACE) inhibitor, or a pharmaceutically acceptable salt thereof, (iii) a beta blocker, or a pharmaceutically acceptable salt thereof, (iv) a calcium channel blocker, or a pharmaceutically acceptable salt thereof, (v) an aldosterone synthase inhibitor, or a pharmaceutically acceptable salt thereof, (vi) ) an aldosterone receptor antagonist, or a pharmaceutically acceptable salt thereof, (vii) a double inhibitor of angiotensin converting enzyme / neutral endopeptidase (ACE / NEP) ), or a pharmaceutically acceptable salt thereof, (viii) an endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof, (ix) a diuretic, or a pharmaceutically acceptable salt thereof. The combination according to the present invention in the same manner comprises at least one pharmaceutically acceptable carrier. The term "at least one therapeutic agent" will mean that, in addition to the compound of Formula (I), one or more, for example two, and in addition three, active ingredients, as specified in accordance with the present invention, may be combined. . It is understood that AT receptor antagonists! (also referred to as angiotensin II receptor antagonists) are the active ingredients that bind to the AT ^ receptor subtype of the angiotensin II receptor, but which do not result in receptor activation. As a consequence of the inhibition of the AT-i receptor, these antagonists, for example, can be used as anti-hypertensives, or for the treatment of congestive heart failure. The class of ATT receptor antagonists comprises compounds having different structural characteristics, and those which are non-peptidic are essentially preferred. For example, mention may be made of the compounds that are selected from the group consisting of Walloon (see European Patent Number EP 443983), losartan (see European Patent Number EP 253310), candesartan (see European Patent Number EP). 459136), eprosartan (see European Patent Number EP 403159), irbesartan (see European Patent Number EP 454511), olmesartan (see European Patent Number EP 503785), tasosartan (see European Patent Number EP 539086), telmisartan (see European Patent Number EP 522314), the compound with the designation E-1477 of the following formula: the compound with the designation SC-52458 of the following formula and the compound with the designation ZD-8731 of the following formula: or in each case, a pharmaceutically acceptable salt thereof.

Preferred ATT receptor antagonists are the agents that have been marketed, and more preferably are mercarase, or a pharmaceutically acceptable salt thereof. The interruption of the enzymatic degradation of angiotensin II to angiotensin II with the so-called ACE inhibitors (also known as angiotensin-converting enzyme inhibitors), is a successful variant for the regulation of blood pressure, and also a method therapy for the treatment of congestive heart failure. The class of angiotensin-converting enzyme inhibitors comprises compounds having different structural characteristics. For example, mention may be made of the compounds which are selected from the group consisting of alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapri !, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, moveltopril, perindopril, quinapril , quinapriiate, ramipril, ramiprilat, espirapril, temocapril, trandolapril, and zofenopril, or in each case, a pharmaceutically acceptable salt thereof. Preferred angiotensin-converting enzyme inhibitors are the agents that have been marketed, and more benazepril, enalapril, lisinopril, and especially ramipril are preferred. A beta-blocker in this combination of preference is a representative selected from the group consisting of a selective β-blocker 1 such as atenolol, bisoprolol (especially its fumarate), metoprolol (especially its hemi- (R, R) - fumarate or its fumarate), in addition acetutolol (especially its hydrochloride), esmolol (especially its hydrochloride), celiprolol (especially its hydrochloride), taliprolol, or acebutolol (especially its hydrochloride), a nonselective β-blocker, such such as oxprenolol (especially its hydrochloride), pindolol, propanolol (especially its hydrochloride), bupranolol (especially its hydrochloride), penbutolol (especially its sulfate), mepindolol (especially its sulphate), carteolol (especially its hydrochloride) ), or nadolol, and a β-blocker with a blocked oral activity, such as carbedilol; or in each case, a pharmaceutically acceptable salt thereof. The class of calcium channel blockers (CCBs) essentially comprises dihydro-pyridine (DHPs), and those that are not dihydro-pyridines, such as calcium channel blockers of the diltiazem type and the verapamil type. A calcium channel blocker useful in this combination is preferably a representative of dihydro-pyridine selected from the group consisting of amlodipine, felodipine, riosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine. , and nivaldipine, and preferably is a representative other than dihydro-pyridine, selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil, and verapamil, and in each case, a pharmaceutically acceptable salt thereof. All of these calcium channel blockers are used therapeutically, for example, as anti-hypertensive, anti-angina, or anti-arrhythmic drugs. Preferred calcium channel blockers comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, for example, depending on the specific calcium channel blocker, a pharmaceutically acceptable salt thereof. Especially preferred are dihydropyridines, amlodipine or a pharmaceutically acceptable salt thereof, especially its besylate, and also the maleate thereof. An especially preferred representative of those which are not dihydro-pyridines is verapamil, or a pharmaceutically acceptable salt, especially its hydrochloride. Aldosterone synthase is an enzyme that converts corticosterone to aldosterone by the hydroxylation of corticosterone to form 18-OH-corticosterone, and from 18-OH-corticosterone to aldosterone. It is known that the class of aldosterone synthase inhibitors is applied for the treatment of hypertension and primary aldosteronism, and comprises both the steroidal and non-spheroidal aldosterone synthase inhibitors, with the latter being more preferred. Preference is given to commercially available aldosterone synthase inhibitors, or to aldosterone synthase inhibitors that have been approved by health authorities. The class of aldosterone synthase inhibitors comprises compounds having different structural characteristics. For example, mention may be made of the compounds that are selected from the group consisting of anastrozole, fadrozole (including its (+) enantiomer, as well as exemestane, or, where applicable, a pharmaceutically acceptable salt of the The most preferred non-spheroidal aldosterone synthase inhibitor is the (+) enantiomer of fadrozole (U.S. Patent Nos. 4617307 and 4889861) of the Formula: or a pharmaceutically acceptable salt thereof, for example, its hydrochloride. A preferred spheroidal aldosterone receptor antagonist is epierenone (see European Patent Number EP 122232 A) of the Formula: or spironolactone. Compounds that have an inhibitory effect on both angiotensin converting enzyme and neutral endopeptidase, referred to as dual inhibitors of ACE / NEP, can be used for the treatment of cardiovascular pathologies. A preferred double inhibitor of angiotensin converting enzyme / neutral endopeptidase (ACE / NEP) is, for example, omapatrilate (see European Patent Number EP 629627), fasidotril, or fasidotrilate (see European Patent Number EP 419327), or Z 13752A (see International Publication Number WO 97/24342), or if appropriate, a pharmaceutically acceptable salt thereof. A preferred endothelin antagonist is, for example, bosentan (see European Patent Number EP 526708 A), enrasentan (see International Publication Number WO 94/25013), atrasentan (see International Publication Number WO 96/06095), especially atrasentan hydrochloride, darusentan (see European Patent Number EP 785926 A), BMS 193884 (see European Patent Number EP 702012 A), sitaxentan (see U.S. Patent Number US 5594021), especially sitaxsentan sodium, YM 598 (see European Patent Number EP 882719 A), S 0139 (see International Publication Number WO 97/27314), J 104132 (see European Patent Number EP 714897 A or International Publication Number WO 97/37665), and they also tezosentan (see International Publication Number WO 96/19459), or in each case, a pharmaceutically acceptable salt thereof. A diuretic is, for example, a thiazide derivative selected from the group consisting of amiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorothalidone. Hydrochlorothiazide is preferred. An inhibitor of the membrane pump of Na-K-ATPase is, for example, digoxin. An anti-diabetic agent or a pharmaceutically acceptable salt thereof is, for example, insulin, insulin derivatives, and mimetics; insulin secretagogues, such as the sulfonyl-ureas, for example glipizide, glyburide, and Amaril; insulinotropic sulfonyl urea receptor ligands, such as meglitinides, for example nateglinide and repaglinide; the ligands of the peroxisome proliferator-activated receptor (PPAR); inhibitors of protein tyrosine-1B phosphatase (PTP-1B), such as PTP-112; inhibitors of GSK3 (glycogen synthase kinase-3), such as SB-517955, SB-4195052, SB-216763, NN-57-05441, and NN-57-05445; the RXR ligands, such as GW-0791 and AGN-194204; inhibitors of the sodium-dependent glucose co-transporter, such as T-1095; inhibitors of glycogen phosphorylase A, such as BAY R3401; biguanides, such as metformin; alpha-glucosidase inhibitors, such as acarbose; GLP-1 (glucagon-1 peptide), GLP-1 analogs, such as Exendin-4 and GLP-1 mimetics; and inhibitors of DPP-IV (dipeptidyl-peptidase IV), such as LAF237. Other specific anti-diabetic compounds are described by Patel Mona in Expert Opin Investig Drugs, 2003, 12 (4), 623-633, in Figures 1 to 7, which are incorporated herein by reference. A hypolipidemic agent or a pharmaceutically acceptable salt thereof is, for example, that of the inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (H MG-CoA) -reductase, for example lovastatin, pitavastatin, simvastatin, pravastatin , cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin, and rivastatin; inhibitors of squalene synthase; the ligands of FXR (receptor farnesojde X) and LXR (receptor of liver X); cholestyramine; fibrates; nicotinic acid, and aspirin. An agent against obesity is, for example, orlistat. A compound of the present invention can be administered either in a simultaneous manner, before, or after the other active ingredient, either separately, by the same or different route of administration, or together in the same pharmaceutical formulation. In accordance with the foregoing, the present invention also provides a therapeutic combination, for example a kit, a kit of parts, for example, for use in any method defined herein, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to be used concomitantly or in sequence with at least one pharmaceutical composition comprising at least one other therapeutic agent, preferably selected from anti-diabetic agents, hypolipidemic agents, anti-obesity agents, or agents against hypertension. The parts kit may comprise instructions for its administration. In a similar manner, the present invention provides a kit of parts comprising: (i) a pharmaceutical composition of the invention; and (ii) a pharmaceutical composition comprising at least one therapeutic agent, especially a compound selected from the above-specified combination components, such as an anti-diabetic, a hypolipidemic agent, an anti-obesity agent, an anti-obesity agent, and an anti-obesity agent. hypertension, or a pharmaceutically acceptable salt thereof, in the form of two separate units of components (i) to (ii). In the same manner, the present invention provides a method as defined above, which comprises the co-administration, for example in a concomitant or sequential manner, of a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one therapeutic agent, with this drug substance being especially selected from the above specified combination components, such as an antidiabetic, a hypolipidemic agent, an anti-obesity agent, or an anti-obesity agent. hypertension, for example as indicated in the above. Preferably, a compound of the invention is administered to a mammal in need thereof. Preferably, a compound of the invention is used for the treatment of a disease responsive to the modulation of renin activity. Accordingly, the present invention also relates to a compound of Formula (I) for use as a medicament. In the same way, the present invention relates to a method for the inhibition of renin activity in mammals, or for the prevention, treatment, or delay of progress to stop a disease or condition as specified above, which method comprises administering to a mammal in need thereof, a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, either alone or together with at least one therapeutic agent. The structure of the active agents identified by generic or commercial names, can be taken from the current edition of the standard compendium "The Merck Index", or from the databases, for example LifeCycle Patents International (for example, IMS World Publications). The corresponding content thereof is incorporated herein by reference. Any person skilled in the art is absolutely qualified to identify the active agents, and, based on these references, in the same way is able to manufacture and test the indications and pharmaceutical properties in conventional test models, both in vitro and in vitro. alive. The novel compounds of Formula (I) may be present, for example, in the form of pharmaceutical preparations, which comprise a therapeutically effective amount of the active substance, if necessary together with inorganic or organic carriers, solid or liquid, pharmaceutically acceptable, and which are suitable for enteral, for example oral, or parenteral administration, especially for the prevention and treatment of a condition or disease as described hereinabove and hereinbelow. The present pharmaceutical preparations which, if desired, may contain other pharmacologically active substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving, or lyophilizing processes, and may contain from about 0.1 percent to 100 percent, especially from about 1 percent to about 50 percent of lyophilized, to about 100 percent of the active substance. In the same way, the invention relates to the use of the compounds of the Formula (I), preferably for the preparation of pharmaceutical compositions, especially for the prevention and treatment of a condition or disease as described hereinabove and later in the present. In the same way, the invention relates to a method for the prevention or treatment of a condition or disease as disclosed hereinbefore and hereinafter, which comprises administering to a patient (including a human) that in need thereof, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of a pharmacologically active compound of the present invention, alone or in combination with one or more pharmaceutically acceptable carriers. The dosage may depend on several factors, such as the route of administration, the species, the age, and / or the condition of the individual. The daily doses to be administered are between about 0.25 and about 10 milligrams / kilogram in the case of oral administration, and preferably between about 20 milligrams and about 500 milligrams for warm-blooded animals with a body weight of about 70 kilograms .

The following Examples illustrate the invention described above; however, they are not intended to limit your scope in any way. Temperatures are indicated in degrees Celsius.

The process for the manufacture of the compounds of the Formula (I) and the salts thereof, for example, can be illustrated by means of the following reaction scheme: Hydrogenation of the azide group to the free primary amine: Example 1 Example 2 Example 1 (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4 -methoxy-3- (3-methoxy-propoxy) benzyl] -5-methyl-hexyl ester of acetic acid.

? ^ Pd / C is added to 10 percent (20 milligrams, Engelhard 4505) to a solution of (1S, 2S, 4S) -2-azido-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] - 4- [4- Methoxy-3- (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl-acetic acid ester (55 milligrams, 0.09 mmol) in MeOH (3 milliliters) and 1 N HCl (1 milliliter) under Ar. Then the suspension is stirred under an atmosphere of H2 for 5 hours. The reaction mixture is filtered over Celite, and the solvent is evaporated. After the addition of diethyl ether, the desired hydrochloride salt of (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl) is obtained. carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3- (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl ester of acetic acid as a colorless solid. MS (LC / MS): 594.3 [M + H] +. Rf (CH2Cl2 / MeOH, 9: 1): 0.09.

The starting material can be prepared, for example, as follows: (1S, 2S, 4S) -2-azido-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3- (3-methoxy-propoxy) -benzyl] -5-m-ethylhexyl ester of acetic acid.

Add triethylamine (37 microliters, 0.26 millimoles, 1.5 equivalents), acetic anhydride (25 microliters, 0.26 millimoles, 1.5 equivalents), and DMAP (0.3 milligrams, 0.002 millimoles, 0.01 equivalents) to a solution of (2-carbamoyl) (2S, 4S, 5S, 7S) -5-azido-4-hydroxy-2-isopropyl-7- [4-methoxy-3- (3-methoxy-propoxy) - 2-methyl-propyl) -amide benzyl] -8-methyl-nonanoic acid (100 milligrams, 0.17 mmol) in tetrahydrofuran (2 milliliters) under Ar. After stirring at room temperature for 3 hours, water is added, and the mixture is extracted with ethyl acetate. Drying of the combined extracts (Na2SO4) and evaporation of the solvent provide the crude product, which is purified by flash column chromatography (10 grams of SiO2, CH2Cl2 / MeOH, 95: 5), to give the product desired as a colorless oil. MS (LC / MS): 620.1 [M + H] + - R, (CH 2 C 12 / M eO H, 9: 1): 0.36.

The following compounds are prepared according to the experimental procedures described above: (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3 -methyl-butyl] -4- [4-methoxy-3- (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl-ester of propionic acid.

MS (LC / MS): 608.1 [M + H] + - R, (CH 2 Cl 2 / M eOH, 9: 1): 0.20. (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy] -3- (3-methoxy-propox?) Benzyl] -5-methyl-hexyl ester of propionic acid i co.

MS (LC / MS): 622.2 [M + H] + - Rf (CH 2 C 12 / M eO H, 9: 1): 0.19. (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3 - (3-methoxy-propoxy) bencyl] -5-m ethylhexyl ester of butyric acid.

MS (LC / MS): 636.3 [M + H] + - Rf (C H 2 C 12 / M eO H, 9: 1): 0.19. (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3 - (3-methoxy-propoxy) benzyl] -5-methyl-hexyl-ester of isobutyric acid.

MS (LC / MS): 622.2 [M + H] + - Rf (C H2C 12 / M eO H, 9: 1): 0.21. (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3 - (3-methoxy-propoxy) -ben cyl] -5-m ethyl-hexyl-l-ester of 2,2-dimethyl-propionic acid.

S (LC / MS): 636.3 [M + H] + - R, (CH 2 Cl 2 / eO H, 9: 1): 0.28.

Example 2 (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4 - (S) -2-amino-3-methyl-butyric acid [4-methoxy-3- (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl ester.

% Pd / C (9 milligrams, Engelhard 4505) is added to a solution of (1S, 2S, 4S) -2-azido-1 - [(S) -2- (2-carbamoyl-2-methyl) -propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3- (3-methoxy-propoxy!) -benzyl] -5-methyl-hexyl ester of (S) -2- amino-3-methyl-butyric acid (32 milligrams, 0.05 mmol) in MeOH (2 milliliters) and 1 N HCl (1 milliliter) under Ar. Then the suspension is stirred under an atmosphere of H2 for 14 hours. The reaction mixture is filtered over Celite, and the solvent is evaporated. After the addition of diethyl ether, the product is isolated as a colorless solid. MS (LC / MS): 651.3 [M + H] + - tR (HPLC, column C18, 20 to 100 percent CH3CN / H20): 3.27 minutes.

The starting material can be prepared, for example, as follows: (1S, 2S, 4S) -2-azido-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl) l-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3- (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl ester of (S) -2-terbutoxy-carbonyl -amino-3-met i I-butyric.

Dicyclohexyl-carbodiimide (39 milligrams, 0.19 millimoles, 1.1 equivalents) is added to a mixture of N-Boc-valine (38 milligrams, Q.17 millimoles), (2-carbamoyl-2-methyl-propyl) -amide. (2S.4S, 5S, 7S) -5-azido-4-hydroxy-2-isopropyl-7- [4-methoxy-3- (3-methoxy-propoxy) -benzyl] -8-methyl-nonanoic acid (100 milligrams, 0.17 mmol), and 4-dimethyl-amino-pyridine (21 milligrams, 0.17 mmol) in CH2Cl2 (2 milliliters) at 0 ° C under Ar. The reaction mixture is stirred for 14 hours, a saturated solution of NaHCO 3 is added, and the mixture is extracted with CH 2 Cl 2. The combined extracts are dried (Na2SO4), and the solvent is evaporated. Purification of the residue by flash column chromatography (10 grams of SiO 2, CH 2 Cl 2 to CH 2 Cl 2 / MeOH, 95: 5) gives the desired product as a colorless oil. tR (HPLC, column C18, 20 to 100 percent CH3CN / H20): 6.70 minutes - Rf (C H2CI2 / M eO H, 9: 1): 0.55. (1S, 2S, 4S) -2-azido-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3 - (3-methoxy-propoxy) -benzyl] -5-m-ethyl-l-hexy-l-ester of (S) -2-amino-3-methyl-butyric acid.

At 0 ° C, 2M HCl (0.47 milliliters, 0.93 millimole, 12 equivalents) is added to a solution of (1S, 2S, 4S) -2-azido-1 - [(S) -2- (2-carbamoyl-2 -methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3- (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl ester of (S) -2- Terbutoxy-carbonyl-amino-3-methyl-butyric acid (60 milligrams, 0.077 mmol) in MeOH (2 milliliters). After stirring at room temperature for 14 hours, a saturated solution of NaHCO 3 is added, and the mixture is extracted with CH 2 Cl 2. Drying (Na2SO4) and evaporation of the solvent provide the crude product, which is subjected to flash column chromatography (10 grams of Si02, CH2Cl2 / MeOH, 9: 1), to give the product as a colorless oil. MS (LC / MS): 677.4 [M + H] + - tR (HPLC, column C18, 20 to 100 percent CH3CN / H20): 4.67 minutes.

The following compounds are prepared according to the experimental procedures described above: (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3 -methyl-butyl] -4- [4-methoxy-3- (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl ester of (S) -2-am ino-4-methyl-pentanoic acid.

MS (LC / MS): 665.3 [M + H] + - tR (HPLC, column C18, 20 to 100 percent CH3CN / H20): 3.47 minutes. (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy] 3- (3-Methoxy-propoxy) benzyl] -5-methyl-hexyl-ester of (S) -2-amino-3-f-propyl ester.

MS (LC / MS): 699.3 [M + H] + - tR (HPLC, column C18, from 20 to 100 percent CH3CN / H20): 3.51 minutes.

Claims (10)

REVITALIZATION E S
1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: R1, R2, R3, R4, independently of each other, are hydrogen; halogen; hydroxyl, alkanoyloxy of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms; or are alkyl of 1 to 7 carbon atoms which is substituted by: halogen, cyano, hydroxyl, alkanoyloxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms which is substituted by halogen or by hydroxyl, alkenyloxy of 2 to 7 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms S-oxidized, amino, N-mono -alkyl of 1 to 7 carbon atoms-amino, N, N-di-alkyl of 1 to 7 carbon atoms-amino, N-alkanoyl of 1 to 7 carbon atoms-amino, N-alkane of 1 to 7 atoms of carbon-sulfonyl-amino, amino which is N, N-disubstituted by alkylene of 2 to 7 carbon atoms, by alkylene of 2 to 7 unsubstituted carbon atoms or N'-alkyl of 1 to 7 carbon atoms- or N - alkanoyl of 1 to 7 carbon atoms-aza-alkylene of 2 to 7 carbon atoms, by oxa-alkylene of 1 to 7 carbon atoms, by thia-alkylene of 1 to 7 atoms carbon, or by thia-alkylene of 1 to 7 carbon atoms S-oxidized, free carboxyl or esterified or amidated, cycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl, hydrogenated heteroaryl, or by oxo; or are alkoxy of 1 to 7 carbon atoms-alkenyl of 2 to 7 carbon atoms; alkoxy of 1 to 7 carbon atoms; or are alkoxy of 1 to 7 carbon atoms which is substituted by: halogen, cyano, hydroxyl, alkanoyloxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms which is substituted by halogen or by hydroxyl, alkenyloxy of 2 to 7 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms S-oxidized, amino, N-mono -alkyl of 1 to 7 carbon atoms-amino, N, N-di-alkyl of 1 to 7 carbon atoms-amino, N-alkanoyl of 1 to 7 carbon atoms-amino, N-alkane of 1 to 7 atoms carbon-sulfonyl-amino, which is N, N-disubstituted by alkylene of 2 to 7 carbon atoms, by unsubstituted carbon atoms of 2 to 7 carbon atoms or N'-alkyl of 1 to 7 carbon atoms - or N ' - alkanoyl of 1 to 7 carbon atoms-aza-alkylene of 2 to 7 carbon atoms, by oxa-alkylene of 1 to 7 carbon atoms, by thia-alkylene of 1 to 7 atoms carbon, or by thia-alkylene of 1 to 7 carbon atoms S-oxidized, free carboxyl or esterified or amidated, cycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl, or by hydrogenated heteroaryl; or are alkenyloxy of 2 to 7 carbon atoms; alkoxy of 1 to 7 carbon atoms-alkenyloxy having 2 to 7 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms; alkanoyl of 1 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; aril; heteroaryl; or hydrogenated heteroaryl; or R3 together with R4 form alkylenedioxyl of 2 to 7 carbon atoms, or a benzo or cyclohexene ring fused thereon; X is methylene; hydroxymethylene; OR; NH; S; SW; or S02; R5 is alkyl of 1 to 7 carbon atoms; alkenyl of 2 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl; R6 is amino; N-mono-amino of 1 to 7 carbon atoms; N, N-di-amino of 1 to 7 carbon atoms; N- alkanoyl of 1 to 7 carbon atoms-amino; N-alkane of 1 to 7 carbon atoms-sulfonyl, or represents a group of the formula -N R1 ° COCH R11 N R12R13, and the latter may be present in either the (D), (L), or ( D, L) racemic, but preferably in the L form; R7 is alkyl of 1 to 7 carbon atoms, alkenyl of 2 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl; R8 is hydrogen; alkyl of 1 to 7 carbon atoms; or is alkyl of 1 to 7 carbon atoms which is substituted by: halogen, cyano, hydroxyl, alkanoyloxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms which is substituted by halogen or by hydroxyl, alkenyloxy of 2 to 7 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms, thioalkyl of 1 to 7 carbon atoms S-oxidized, amino, N-mono -alkyl of 1 to 7 carbon atoms-amino, N, N-di-alkyl of 1 to 7 carbon atoms-amino, N-alkanoyl of 1 to 7 carbon atoms-amino, N-alkane of 1 to 7 atoms of carbon-sulfonyl-amino, which amino is N, N-disubstituted by alkylene of 2 to 7 carbon atoms, by alkylene of 2 to 7 unsubstituted carbon atoms or N'-alkyl of 1 to 7 carbon atoms- or N - alkanoyl of 1 to 7 carbon atoms-aza-alkylene of 2 to 7 carbon atoms, by oxa-alkylene of 1 to 7 carbon atoms, by thia-alkylene of 1 to 7 carbon atoms carbon, or by thia-alkylene of 1 to 7 carbon atoms S-oxidized, free carboxyl or esterified or amidated, or is alkanoyl of 1 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl, hydrogenated heteroaryl; cycloalkyl of 3 to 7 carbon atoms; aril; heteroaryl, or hydrogenated heteroaryl; R9 represents alkanoyl of 1 to 7 carbon atoms, alkane of 1 to 7 carbon atoms-sulfonyl, or a group of the formula -COCH R14R11 R12, which may be present in either the (D), (L) configuration , or (D, L) racemic, but preferably in the L form; or a group of the formula -CH20-COR15; R10 is hydrogen; alkyl of 1 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; cycloalkyl of 3 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl; R1 is hydrogen; alkyl of 1 to 7 carbon atoms; aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl; R12 and R13, independently of one another, are hydrogen; alkyl of 1 to 7 carbon atoms; alkyl of 1 to 7 carbon atoms which is substituted by: halogen, cycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl, alkoxy of 1 to 7 carbon atoms-carbonyl, thioalkyl of 1 to 7 carbon atoms, by thioalkyl from 1 to 7 carbon atoms S-oxidized, by amino-carbonyl, by N-alkanoyl of 1 to 7 carbon atoms-amino-carbonyl, by N-alkyl of 1 to 7 carbon atoms-amino-carbonyl; by N, N-di-alkyl of 1 to 7 carbon atoms-amino-carbonyl, or by amino-carbonyl which is substituted by alkylene of 2 to 7 carbon atoms; or they are cycloalkyl of 3 to 7 carbon atoms; aryl, or heteroaryl; R14 is hydrogen; alkyl of 1 to 7 carbon atoms; aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl; and R15 is alkyl of 1 to 7 carbon atoms, aryl-alkyl of 1 to 7 carbon atoms; heteroaryl-alkyl of 1 to 7 carbon atoms; aryl or heteroaryl.
2. 2. A compound according to claim 1, of Formula (I), or a pharmaceutically acceptable salt thereof; wherein: R1 is hydrogen, alkyl of 1 to 7 carbon atoms, or alkoxy of 1 to 7 carbon atoms; R 2 is alkoxy of 1 to 7 carbon atoms or alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms; R3 is alkoxy of 1 to 7 carbon atoms or alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms; R 4 is hydrogen, alkyl of 1 to 7 carbon atoms, or alkoxy of 1 to 7 carbon atoms; R5 is alkyl of 1 to 7 carbon atoms; R6 is amino; R7 is alkyl of 1 to 7 carbon atoms; R8 is amino-carbonyl-alkyl of 1 to 7 carbon atoms; R9 is alkanoyl of 1 to 7 carbon atoms, a group of the formula -COCHR14N R11 R12, which may be present in either the (D), (L), or (D, L) racemic configuration, but preferably in the L form; or a group of the formula -CH20-COR15, and R14 is hydrogen, alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 4 carbon atoms; R12 and R13, independently of one another, are hydrogen, alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 4 carbon atoms; and R15 is alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 4 carbon atoms; and X is methylene.
3. 3. A compound according to claim 1 or 2, of the Formula (IA): wherein the variables R1 to R15 and X have all the meanings defined in claim 1 or 2; or a pharmaceutically acceptable salt thereof.
4. 4. A compound according to any of claims 1 to 3, of the Formula (IA), or a pharmaceutically acceptable salt thereof, wherein: R1 and R4 are hydrogen; R 2 is alkoxy of 1 to 4 carbon atoms-alkoxy of 1 to 4 carbon atoms, such as 3-methoxy-propyloxy; R3 is alkoxy of 1 to 4 carbon atoms, such as methoxy; R5 and R7, independently of one another, are alkyl of 1 to 7 carbon atoms, such as isopropyl; R6 is amino; R8 is amino-carbonyl-alkyl of 1 to 4 carbon atoms, such as 2-amino-2,2-dimethyl-ethyl; R9 is alkanoyl of 1 to 4 carbon atoms, or a group of the formula -COCHR14NR12R13, wherein R14 is alkyl of 1 to 4 carbon atoms, such as isopropyl or isobutyl, or phenyl-alkyl of 1 to 2 carbon atoms , such as benzyl; R12 and R13 are hydrogen, and X is methylene.
5. 5. A compound according to claim 4, of Formula (IB): or a pharmaceutically acceptable salt thereof, wherein R9 is alkanoyl of 1 to 4 carbon atoms, or a group of the formula -COCHR14NH2, wherein R 14 is alkyl of 1 to 4 carbon atoms, such as isopropyl or isobutyl, or phenyl-alkyl of 1 to 2 carbon atoms, such as benzyl.
6. 6. A compound according to any of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3- (3-methoxy-propoxy) -benzyl] -5-methyl- hexyl ester of acetic acid; (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyI-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy] -3- (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl ester of propionic acid; (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3 - (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl ester of butyric acid; (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3 - (3-methoxy-propoxy!) -benzyl] -5-methyl-hexyl-ester of isobutyric acid; (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3 - 2,2-dimethyl-propionic acid (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl ester; (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3 - (S) -2-amino-3-methyl-butyric acid (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl ester; (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy-3 - (S) -2-amino-4-methyl-pentanoic acid (3-methoxy-propoxy) -benzyl] -5-methyl-hexyl ester; and (1S, 2S, 4S) -2-amino-1 - [(S) -2- (2-carbamoyl-2-methyl-propyl-carbamoyl) -3-methyl-butyl] -4- [4-methoxy- 3- (3-methoxy-propoxy!) -benzyl] -5-methyl-hexyl-ester of (S) -2-amino-3-phenyl-propionic acid.
7. 7. A compound according to any of claims 1 to 6, for the treatment of the animal and human body.
8. 8. The use of a compound according to any of claims 1 to 7, for the preparation of a medicament for the treatment or prevention or delay of progress to stop hypertension, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy , renal failure (acute and chronic) after myocardial infarction, complications resulting from diabetes, such as nephritis, vasculopathy, and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, elevated intraocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, states of anxiety, and cognitive disorders.
9. 9. A pharmaceutical composition, which comprises a compound according to any of claims 1 to 8, and a carrier. A composition according to claim 9, which further comprises at least one therapeutic agent selected from the group consisting of: (i) an AT receptor antagonist or a pharmaceutically acceptable salt thereof, (ii) an inhibitor of the angiotensin converting enzyme (ACE), or a pharmaceutically acceptable salt thereof, (iii) a beta blocker, or a pharmaceutically acceptable salt thereof, (iv) a calcium channel blocker, or a pharmaceutically acceptable salt thereof. , (v) an aldosterone synthase inhibitor, or a pharmaceutically acceptable salt thereof, (vi) an aldosterone receptor antagonist, or a pharmaceutically acceptable salt thereof, (vii) a double inhibitor of the angiotensin converting enzyme. / neutral endopeptidase (ACE / NEP), or a pharmaceutically acceptable salt thereof, (viii) an endothelin receptor antagonist, or a pharmaceutically acceptable salt thereof, (ix) a diuretic, or a pharmaceutically acceptable salt thereof, (x) a neutral endopeptidase inhibitor (NEP), or a pharmaceutically acceptable salt thereof, (xi) an inhibitor of the membrane pump of Na-K-ATPase, or a salt pharmaceutically acceptable thereof, (xii) an anti-diabetic agent, or a pharmaceutically acceptable salt thereof, (xiii) a hypolipidemic agent, or a pharmaceutically acceptable salt thereof, and (xiv) an anti-obesity agent, or a pharmaceutically acceptable salt thereof.