Organic compounds

Disclosed are δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amide compounds of formula (I)and the salts thereof, having renin-inhibiting properties. Also disclosed are pharmaceutical compositions comprising these compounds and methods of administering them for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, 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, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.

The invention relates to novel δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides of formula (I)

The compounds of the present invention exhibit inhibitory activity on the natural enzyme renin. Thus, compounds of formula (I) may be employed for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, 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, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.

Listed below are definitions of various terms used to describe the compounds of the present invention. These definitions apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group.

Aryl and aryl in aryl-alkyl, aryl-lower alkoxy, aryl-lower alkyl and the like is, e.g., phenyl or naphthyl that is unsubstituted or mono-, di- or tri-substituted by lower alkyl, lower alkoxy optionally substituted with halogens, hydroxy, lower alkylamino, di-lower alkylamino, halogen and/or by trifluoromethyl.

Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.

Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

Optionally substituted amino refers to a primary or secondary amino group which may optionally be substituted, e.g., by acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, carbamoyl and the like.

Hereinbefore and hereinafter, lower radicals and compounds are to be understood as being, e.g., those having up to and including 7 carbon atoms, preferably up to and including 4 carbon atoms.

Lower alkanoyl-lower alkoxy (oxo-lower alkoxy) carries the lower alkanoyl group in a position higher than the α-position and is, e.g., C1-C7alkanoyl-C1-C4alkoxy, such as 4-acetylbutoxy.

Lower alkanoyloxy-lower alkyl carries the lower alkanoyloxy group in a position higher than the α-position and is, e.g., C1-C7alkanoyloxy-C1-C4alkyl, such as 4-acetoxy-butyl.

Lower alkenyl is, e.g., C1-C7alkenyl, such as vinyl or allyl.

Lower alkylenedioxy is, e.g., methylenedioxy or ethylenedioxy, but can also be 1,3- or 1,2-propylenedioxy.

Depending on whether asymmetric carbon atoms are present, the compounds of the invention can be present as mixtures of isomers, especially as racemates, or in the form of pure isomers, especially optical antipodes.

Salts of compounds having salt-forming groups are especially acid addition salts, salts with bases or, where several salt-forming groups are present, can also be mixed salts or internal salts.

Salts are especially the pharmaceutically acceptable or non-toxic salts of compounds of formula (1).

Such salts are formed, e.g., by compounds of formula (I) having an acid group, e.g., a carboxy group or a sulfo group, and are, e.g., salts thereof with suitable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, IIa and IIb of the Periodic Table of the Elements, e.g., alkali metal salts, especially lithium, sodium or potassium salts; or alkaline earth metal salts, e.g., magnesium or calcium salts; also zinc salts or ammonium salts, as well as salts formed with organic amines, such as unsubstituted or hydroxy-substituted mono-, di- or tri-alkylamines, especially mono-, di- or tri-lower alkylamines; or with quaternary ammonium bases, e.g., with methyl-, ethyl-, diethyl- or triethyl-amine; mono-, his- or tris-(2-hydroxy-lower alkyl)-amines, such as ethanol-, diethanol- or triethanol-amine; tris-(hydroxymethyl)-methylamine or 2-hydroxy-tert-butylamines; N,N-di-lower alkyl-N-(hydroxy-lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)-amine or N-methyl-D-glucamine; or quaternary ammonium hydroxides, such as tetrabutylammonium hydroxide. The compounds of formula (I) having a basic group, e.g., an amino group, can form acid addition salts, e.g., with suitable inorganic acids, e.g., hydrohalic acids, such as hydrochloric acid or hydrobromic acid; or sulfuric acid with replacement of one or both protons; phosphoric acid with replacement of one or more protons, e.g., orthophosphoric acid or metaphosphoric acid; or pyrophosphoric acid with replacement of one or more protons; or with organic carboxylic, sulfonic, sulfo or phosphonic acids; or N-substituted sulfamic acids, e.g., acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, as well as with amino acids, such as the α-amino acids mentioned hereinbefore; and with methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate or N-cyclohexylsulfamic acid (forming cyclamates); or with other acidic organic compounds, such as ascorbic acid. Compounds of formula (I) having acid and basic groups can also form internal salts.

For isolation and purification purposes it is also possible to use pharmaceutically unacceptable salts.

The compounds of the present invention have enzyme-inhibiting properties. In particular, they inhibit the action of the natural enzyme renin. The latter passes from the kidneys into the blood where it effects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to form the octapeptide angiotensinogen II. The octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone, accompanied by an increase in extracellular fluid volume. That increase can be attributed to the action of angiotensin II. Inhibitors of the enzymatic activity of renin bring about a reduction in the formation of angiotensin I. As a result a smaller amount of angiotensin II is produced. The reduced concentration of that active peptide hormone is the direct cause of the hypotensive effect of renin inhibitors.

Thus, the compounds of the present invention may be employed for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, 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, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.

The groups of compounds mentioned below are not to be regarded as exclusive; rather, e.g., in order to replace general definitions with more specific definitions, parts of those groups of compounds can be interchanged or exchanged for the definitions given above, or omitted, as appropriate.

Preferred are the compounds of formula (1), designated as the A group, whereinR9is lower alkyl, optionally substituted cycloalkyl (alkyl, OH, alkoxy, alkoxy-alkyl, halogens), optionally substituted cycloalkyl-alkyl (OH, alkoxy, alkoxy-alkyl, halogens on cycloalkyl), cycloalkyl carboxamides, N-mono or N,N-dialkyl substituted cycloalkyl carboxamides, optionally substituted aryl-alkyl, free or aliphatically esterified or etherified hydroxy-lower alkyl; amino-lower alkyl that is unsubstituted or N-lower alkanoylated or N-mono- or N,N-di-lower alkylated or N,N-di-substituted by lower alkylene, by hydroxy-, lower alkoxy- or lower alkanoyloxy-lower alkylene, by unsubstituted or N′-lower alkanoylated or N′-lower alkylated aza-lower alkylene, by oxa-lower alkylene or by optionally S-oxidised thia-lower alkylene, free or esterified or amidated carboxy-lower alkyl, free or esterified or amidated dicarboxy-lower alkyl, free or esterified or amidated carboxy-(hydroxy)-lower alkyl, free or esterified or amidated carboxycycloalkyl-lower alkyl, cyano-lower alkyl, lower alkanesulfonyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated thiocarbamoyl-lower alkyl, unsubstituted or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkyl, or a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted, or lower alkyl substituted by a heteroaryl radical bonded via a carbon atom and optionally hydrogenated and/or oxo-substituted;
or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the A group whereinR1and R4are hydrogen;R2is lower alkoxy-lower alkoxy;R3is halogen or mono, di or tri-halo-substituted alkyl;
or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the A group wherein the halogen/halo is fluorine or chlorine;

or a pharmaceutically acceptable salt thereof.

More preferred are the compounds in the A group whereinR3is fluorine or trifluoromethyl;
or a pharmaceutically acceptable salt thereof.

Most preferred are the compounds in the A group wherein R2is in the meta position and R3is in the para position;

or a pharmaceutically acceptable salt thereof.

Most preferred are also the compounds in the A group wherein R3is in the ortho position;

or a pharmaceutically acceptable salt thereof.

Most preferred are also the compounds in the A group wherein R3is in the meta position;

or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the A group, designated as the B group, wherein R2is in the meta position and is lower alkoxy-lower alkoxy optionally substituted by halogen(s);

or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the B group wherein the halogen(s) is fluorine or chlorine;

or a pharmaceutically acceptable salt thereof.

More preferred are the compounds in the B group wherein the halogen(s) is fluorine;

or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the B group, designated as the C group, wherein R3is lower alkoxy substituted by halogen(s);

or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the C group wherein the halogen(s) is fluorine or chlorine;

or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the C group wherein the halogen(s) is fluorine;

or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the B group, designated as the D group, wherein R3is in the para position;

or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the D group wherein R3is methoxy;

or a pharmaceutically acceptable salt thereof.

Further preferred are also the compounds in the D group wherein R3is trifluoro-methoxy;

or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds of formula (I) whereinR3is located at the para position and is halogen;
or a pharmaceutically acceptable salt thereof.

Preferred are also the δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amide compounds of formula (I), designated as the E group, having formula (Ia)

Preferred are the compounds in the E group whereinR9is cycloalkyl substituted with alkyl, hydroxy, alkoxy, alkoxy-alkoxy or halogens; cycloalkyl-alkyl optionally substituted with alkyl, hydroxy, alkoxy, alkoxy-alkoxy or halogens on cycloalkyl or halogens on alkyl or halongens on alkoxy; cycloalkyl carboxamides; N-mono or N,N-dialkyl substituted cycloalkyl carboxamides; or optionally substituted aryl-alkyl;
or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the F group whereinR1is hydrogen;R2is C1-C4alkoxy-C1-C4alkoxy or C1-C4alkoxy-C1-C4alkyl;R3is C1-C4alkyl or C1-C4alkoxy;R4is hydrogen;X is methylene;R5is lower alkyl;R6is hydrogen;R7is unsubstituted amino;R8is branched C3-C4alkyl;R9is optionally substituted cycloalkyl-alkyl;
or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the F group whereinR2is 3-methoxypropyloxy;R3is methoxy;R5is isopropyl;R8is isopropyl;
or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the F group, designated as the G group, whereinR1is hydrogen;R2is C1-C4alkoxy-C1-C4alkoxy or C1-C4alkoxy-C1-C4alkyl;R3is C1-C4alkyl or C1-C4alkoxy;R4is hydrogen;X is methylene;R5is lower alkyl;R6is hydrogen;R7is unsubstituted amino;R8is branched C1-C4alkyl;R9is optionally substituted aryl-alkyl; or
a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the G group whereinR2is 3-methoxypropyloxy;R3is methoxy;R5is isopropyl;R8is isopropyl;
or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the G group wherein aryl-alkyl is alkyl substituted with phenyl;

or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the G group wherein aryl-alkyl is methyl substituted with phenyl.

More preferred are the compounds in the G group whereinR2is 3-methoxypropyloxy;R3is methoxy;R5is isopropyl;R8is isopropyl;
or a pharmaceutically acceptable salt thereof.

As a result of the close relationship between the novel compounds in free form and in the form of their salts, hereinabove and hereinbelow any reference to the free compounds and their salts is to be understood as including also the corresponding salts and free compounds, respectively, as appropriate and expedient.

The compounds of the present invention may generally be prepared by those methods disclosed in U.S. Pat. No. 5,559,111, incorporated herein by reference in its entirety as if set forth in full herein.

The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of a pharmacologically active compound of the instant invention, alone or in combination with one or more pharmaceutically acceptable carriers.

The pharmaceutical compositions according to the present invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, to inhibit renin activity, and for the treatment of conditions associated with renin activity. Such conditions include hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, 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, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.

Thus, the pharmacologically active compounds of the invention may be employed in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with:a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets alsoc) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desiredd) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/ore) absorbants, colorants, flavors and sweeteners.

Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.

Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, preferably about 1-50%, of the active ingredient.

Accordingly, the present invention provides pharmaceutical compositions as described above for the treatment of conditions mediated by renin activity, preferably, hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, 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, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.

The pharmaceutical compositions may contain a therapeutically effective amount of a compound of the invention as defined above, either alone or in a combination with another therapeutic agent, e.g., each at an effective therapeutic dose as reported in the art. Such therapeutic agents include:a) antidiabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; peroxisome proliferator-activated receptor (PPAR) ligands; protein tyrosine phosphatase-1B (PTP-1B) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN-194204; sodium-dependent glucose cotransporter inhibitors such as T-1095; glycogen phosphorylase A inhibitors such as BAY R3401; biguanides such as metformin; alpha-glucosidase inhibitors such as acarbose; GLP-1 (glucagon like peptide-1), GLP-1 analogs such as Exendin-4 and GLP-1 mimetics; and DPPIV (dipeptidyl peptidase IV) inhibitors such as LAF237;b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin;c) anti-obesity agents such as orlistat; andd) anti-hypertensive agents, e.g., loop diuretics such as ethacrynic acid, furosemide and torsemide; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; β-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; and aldosterone synthase inhibitors.

Other specific anti-diabetic compounds are described by Patel Mona inExpert Opin Investig Drugs,2003, 12(4), 623-633, in the FIGS. 1to 7, which are herein incorporated by reference. A compound of the present invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.

The structure of the therapeutic agents identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from databases, e.g., Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference.

Accordingly, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a therapeutically effective amount of another therapeutic agent, preferably selected from anti-diabetics, hypolipidemic agents, anti-obesity agents or anti-hypertensive agents, most preferably from antidiabetics, anti-hypertensive agents or hypolipidemic agents as described above.

The present invention further relates to pharmaceutical compositions as described above for use as a medicament.

The present invention further relates to use of pharmaceutical compositions or combinations as described above for the preparation of a medicament for the treatment of conditions mediated by renin activity, preferably, hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, 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, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.

Thus, the present invention also relates to a compound of formula (I) for use as a medicament, to the use of a compound of formula (I) for the preparation of a pharmaceutical composition for the prevention and/or treatment of conditions mediated by renin activity, and to a pharmaceutical composition for use in conditions mediated by renin activity comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier therefor.

The present invention further provides a method for the prevention and/or treatment of conditions mediated by renin activity, which comprises administering a therapeutically effective amount of a compound of the present invention.

A unit dosage for a mammal of about 50-70 kg may contain between about 1 mg and 1000 mg, advantageously between about 5-600 mg of the active ingredient. The therapeutically effective dosage of active compound is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, on the form of administration, and on the compound involved.

In accordance with the foregoing the present invention also provides a therapeutic combination, e.g., a kit, kit of parts, e.g., for use in any method as 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 another therapeutic agent, preferably selected from anti-diabetic agents, hypolipidemic agents, anti-obesity agents or anti-hypertensive agents. The kit may comprise instructions for its administration.

Similarly, the present invention provides a kit of parts comprising: (i) a pharmaceutical composition of the invention; and (ii) a pharmaceutical composition comprising a compound selected from an anti-diabetic, a hypolipidemic agent, an anti-obesity agent, an anti-hypertensive agent, or a pharmaceutically acceptable salt thereof, in the form of two separate units of the components (i) to (ii).

Likewise, the present invention provides a method as defined above comprising co-administration, e.g., concomitantly or in sequence, of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a second drug substance, said second drug substance being an anti-diabetic, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent, e.g., as indicated 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 which responds to modulation of renin activity.

Finally, the present invention provides a method or use which comprises administering a compound of formula (I) in combination with a therapeutically effective amount of an anti-diabetic agent, a hypolipidemic agent, an anti-obesity agent or an anti-hypertensive agent.

Ultimately, the present invention provides a method or use which comprises administering a compound of formula (I) in the form of a pharmaceutical composition as described herein.

As used throughout the specification and in the claims, the term “treatment” embraces all the different forms or modes of treatment as known to those of the pertinent art and in particular includes preventive, curative, delay of onset and/or progression, and palliative treatment.

The above-cited properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, rabbits, dogs, monkeys or isolated organs, tissues and preparations thereof. Said compounds can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10−3molar and 10−10molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.001 and 500 mg/kg, preferably between about 0.1 and 100 mg/kg.

As described above, the compounds of the present invention have enzyme-inhibiting properties. In particular, they inhibit the action of the natural enzyme renin. Renin passes from the kidneys into the blood where it effects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to form the octapeptide angiotensin II. The octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone, accompanied by an increase in extracellular fluid volume which increase can be attributed to the action of angiotensin II. Inhibitors of the enzymatic activity of renin lead to a reduction in the formation of angiotensin I, and consequently a smaller amount of angiotensin II is produced. The reduced concentration of that active peptide hormone is the direct cause of the hypotensive effect of renin inhibitors.

The action of renin inhibitors may be demonstrated inter alia experimentally by means of in vitro tests, the reduction in the formation of angiotensin I being measured in various systems (human plasma, purified human renin together with synthetic or natural renin substrate).

Inter alia the following in vitro tests may be used:

An extract of human renin from the kidney (0.5 mGU [milli-Goldblatt units]/mL) is incubated for one h at 37° C. and pH 7.2 in 1 M aqueous 2-N-(tris-hydroxymethylmethyl)-amino-ethanesulfonic acid buffer solution with 23 μg/mL of synthetic renin substrate, the tetradecapeptide H-Asp-Arg-Val-Tyr-Ile-His-ProPhe-His-Leu-Leu-Val-Tyr-Ser-OH. The amount of angiotensin I formed is determined by radioimmunoassay. Each of the inhibitors according to the invention is added to the incubation mixture at different concentrations. The IC50is defined as the concentration of a particular inhibitor that reduces the formation of angiotensin I by 50%.

Recombinant human renin (expressed in Chinese Hamster Ovary cells and purified using standard methods) at 4 nM concentration is incubated with test compound at various concentrations for 1 h at RT in 0.1 M Tris-HCl buffer, pH 7.4, containing 0.05 M NaCl, 0.5 mM EDTA and 0.05% CHAPS. Synthetic peptide substrate Arg-Glu(EDANS)lle-His-Pro-Phe-His-Leu-Val-IIe_His_Thr-Lys(DABCYL)-Arg9 is added to a final concentration of 2 μM and increase in fluorescence is recorded at an excitation wave-length of 340 nm and at an emission wave-length of 485 nm in a microplate spectro-fluorimeter. IC50values are calculated from percentage of inhibition of renin activity as a function of test compound concentration (Fluorescence Resonance Energy Transfer, FRET, assay).

Recombinant human renin (expressed in Chinese Hamster Ovary cells and purified using standard methods) at 1 nM concentration is incubated with test compound at various concentrations for 1.5 h at 37° C. in 0.1 M Tris/HCl pH 7.4 containing 0.05 M NaCl, 0.5 mM EDTA and 0.025% (w/v) CHAPS. Synthetic peptide substrate Ac-IIe-His-Pro-Phe-His-Leu-Val-IIe-His-Asn-Lys-[DY-505-X5] is added to a final concentration of 5 μM. The enzyme reaction is stopped by adding 6 μL of 1.0% TFA The product of the reaction is separated by HPLC and quantified by spectrophotometric measurement at 505 nM wave-length. IC50values are calculated from percentage of inhibition of renin activity as a function of test compound concentration.

Recombinant human renin (expressed in Chinese Hamster Ovary cells and purified using standard methods) at 3.3 nM concentration, 1251-NVP-AJ1891-NX-1 (0.27 μCi/mL) and streptavidin-SPA (0.67 mg/mL) beads are incubated with test compound at various concentrations for 2.0 h at RT in 0.1 M Tris/HCl pH 7.4 containing 0.5M NaCl and 0.5% (wN) Brij35. At the end of the incubation time, the plates are centrifuged (55g, 60 seconds) and counted in a Wallac MicroBeta reader. IC50values are calculated from percentage of displacement of radioligand binding to renin as a function of test compound concentration.

In animals deficient in salt, renin inhibitors bring about a reduction in blood pressure. Human renin may differ from the renin of other species. In order to test inhibitors of human renin, primates, e.g.,marmosets (Callithrix jacchus) may be used, because human renin and primate renin are substantially homologous in the enzymatically active region. Inter alia the following in vivo tests may be used:

The test compounds are tested on normotensive marmosets of both sexes having a body weight of approximately 350 g that are conscious, allowed to move freely and in their normal cages. The blood pressure and heart rate are measured via a catheter in the descending aorta and recorded radiometrically. The endogenous release of renin is stimulated by the combination of a 1-week low-salt diet and a single intramuscular injection of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid) (5 mg/kg). 16 h after the injection of furosemide the test compounds are administered either directly into the femoral artery using an injection cannula or, in the form of a suspension or solution, via an oesophageal tube into the stomach, and their action on the blood pressure and heart rate are evaluated. In the in vivo test described, the compounds of the present invention have hypotensive action at doses of from approximately 0.003 to approximately 1 mg/kg i.v. and at doses of from approximately 0.3 to approximately 100 mg/kg p.o.

Alternatively, renin inhibitors may be tested on male normotensive marmosets weighing 250 to 500 g that are conscious, allowed to move freely and in their normal cages. The blood pressure, and heart rate are measured via a catheter placed in the descending aorta and recorded radiometrically. Electrocardiogram are obtained by placing electrodes of transmitter in lead II. The endogenous release of renin is stimulated by two intramuscular injection of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid) (10 mg/kg) 43 and 19 hours prior compound application. Test compounds are administered either directly into the femoral artery using an injection cannula or, in the form of a suspension or solution, via an oesophageal tube into the stomach, and their action on the blood pressure, heart rate and ECG are evaluated. In the in vivo test described, compounds of the present invention have hypotensive action at doses of from approximately 0.003 to approximately 0.3 mg/kg i.v. and at doses of from approximately 0.31 to approximately 30 mg/kg p.o.

The compounds of the present invention also have the property of regulating, especially reducing, intra-ocular pressure.

The extent of the reduction in intra-ocular pressure after administration of a pharmaceutical 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 that illustrate the present invention, but are not limited to in any way, are described hereinafter.

The in vivo test on a rabbit of the “Fauve de Bourgogne” type to determine the intra-ocular-pressure-reducing activity of topically applied compositions can be designed, for example, as follows: The intra-ocular pressure (IOP) is measured using an aplanation tonometer both before the experiment and at regular intervals of time. After a local anaesthetic has been administered, the suitably formulated test compound is applied topically in a precisely defined concentration (e.g. 0.000001-5% by weight) to one eye of the animal in question. The contralateral eye is treated, for example, with physiological saline. The measured values thus obtained are evaluated statistically.

The in vivo tests on monkeys of the speciesMacaca Fascicularisto determine the intra-ocular-pressure-reducing activity of topically applied compositions can be carried out, e.g., as follows: The suitably formulated test compound is applied in a precisely defined concentration (e.g. 0.000001-5% by weight) to one eye of each monkey. The other eye of the monkey is treated correspondingly, for example with physiological saline. Before the start of the test the animals are anaesthetised with intramuscular injections of, for example, ketamine. At regular intervals of time, the intra-ocular pressure (IOP) is measured. The test is carried out and evaluated in accordance with the rules of “good laboratory practice” (GLP).

Illustrative of the invention, the compound of Example 29 demonstrates inhibition of renin activity with an IC50value of about 0.3 nM in the FRET assay.

The following Examples are intended to illustrate the invention and are not to be construed as being limitations thereon. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 10 and 100 mmHg (=20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis, melting point (m.p.) and spectroscopic characteristics, e.g., MS, LC/MS, IR, NMR. In general, abbreviations used are those conventional in the art.

General Procedure (I)

A portion thereof (904 mg, 1.24 mmol, 1.0 equiv.) is dissolved in methyl alcohol (MeOH) (20 mL) and 1 M HCl (2 mL, 2 mmol, 1.6 equiv.) is added. The mixture is stirred at RT for 10 minutes before 1 M sodium hydroxide (NaOH) (2 mL) followed by H2O and a 10% citric acid solution are added for workup. Extraction with EtOAc, drying (Na2SO4) of the combined organic extracts and evaporation of the solvent give the crude product which is purified by flash column chromatography [50 g SiO2, CH2Cl2:MeOH (9:1)] to afford the desired product as a colorless oil. MS (LC-MS): 691.3 [M+Na]+; tR(HPLC, C8 column, 5-95% CH3CN/H2O/6.5 minutes, 95% CH3CN/H2O/1 minute, flow: 0.5 mL/min.): 7.63 minutes.

HBTU (400 mg, 1.03 mmol, 1.2 equiv.) is added to a solution of (2S,4S,5S,7S)-5-tert-butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (575 mg, 0.86 mmol, 1.0 equiv.) in acetonitrile (CH3CN) (15 mL) and DMF (1 mL) at 0° C. After 5 minutes, a solution of benzylamine (94 μL, 0.86 mmol, 1.0 equiv.) and Net3(1.2 mL, 8.6 mmol, 10 equiv.) in CH3CN (3 mL) is added and the reaction mixture is stirred at room temperature for 5 minutes. For workup EtOAc is added and the organic layer is washed with 1 N HCl, a saturated solution of sodium bicarbonate (NaHCO3) and brine. Drying (Na2SO4) of the organic phase and evaporation of the solvent affords the crude product which is purified by flash column chromatography [50 g SiO2, hexane:EtOAc (4:1)] to afford the desired product as a colorless foam. MS (LC-MS): 780.4 [M+Na]+; Rf[hexane:EtOAc (1:1)]: 0.65 minutes.

At 0° C. 4 N HCl/dioxane (7 mL, 28 mmol) is added to ((1S,2S,4S)-4-benzylcarbamoyl-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamic acid tert-butyl ester (214 mg, 0.34 mmol, 1.0 equiv.). The resulting solution is stirred at RT for 15 minutes whereupon a saturated solution of NaHCO3is carefully added. The mixture is extracted with EtOAc, the combined extracts are dried (Na2SO4) and the solvent is evaporated. Flash column chromatography [20 g SiO2, CH2Cl2:MeOH (9:1) to CH2Cl2:MeOH (9:1) +1% NEt3] affords the product as a colorless oil. MS (LC-MS): 544.3 [M+H]+; Rf[CH2Cl2:MeOH (9:1)]: 0.19 minutes.

General Procedure (II)

Lithium hydroxide (LiOH).H2O (2.18 g, 52.0 mmol) is added to a solution of (3S,5S)-5-{(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one (20.0 g, 43.3 mmol) in dimethoxyethane (DME) (400 mL) and H2O (200 mL) and the resulting solution is stirred at RT for 2 hours. The solvent is co-evaporated with toluene and the resulting solid is dried under high vacuum.

This residue is dissolved in DMF (160 mL) and NEt3(32 mL, 227.6 mmol), TBDMSOTf (41.8 mL, 182.1 mmol) and DMAP (556 mg, 4.6 mmol) are added sequentially. The mixture is stirred at RT for 16 hours. For workup, EtOAc is added and the mixture is quenched by addition of a saturated solution of NaHCO3. The organic phase is separated and the aqueous phase is extracted with EtOAc. Evaporation of the solvent of the combined organic extracts affords bis-TBDMS protected product (32.4 g) while acidification of the basic aqueous layer with 1 N HCl followed by extraction with EtOAc and evaporation of the solvent yields the corresponding mono-silylated free acid (8.8 g). Both isolated products are combined and subjected to flash column chromatography [hexane:EtOAc (4:1) to hexane:EtOAc (1:1)] to give the desired mono-silylated acid as a viscous oil (complete desilylation of the silyl-protected acid during chromatography). MS (LC-MS): 616.0 [M+Na]+; tR(HPLC, C8 column, 20-95% CH3CN/H2O/3.5 minute, 95% CH3CN/1 minute, flow: 0.8 mL/min.): 3.93 minutes.

HBTU (1.20 g, 3.0 mmol) was added to a solution of (2S,4S,5S,7S)-5-azido-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (1.50 g, 2.5 mmol) in CH3CN (50 mL). Then 2-aminoethylpiperidine (324 mg, 2.5 mmol) and NEt3(3.9 mL) were added and the resulting solution was stirred at RT for 2.5 hours. For workup, EtOAc was added and the organic phase was washed with 1 N HCl, saturated NaHCO3solution and brine. Drying of the organic phase (Na2SO4) and evaporation of the solvent affords the crude product which is purified by flash column chromatography [CH2Cl2:MeOH (95:5)] to give the desired product as a colorless oil. MS (LC-MS): 705.1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 6.82 minutes.

Palladium on carbon (Pd/C) 10% (200 mg) is added to a solution of (2S,4S,5S,7S)-5-azido4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2-piperidin-1-yl-ethyl)-amide (780 mg, 1.32 mmol) in MeOH (40 mL) under Ar. Then the reaction suspension is stirred under a atmosphere of hydrogen (H2) for 8 hours. The catalyst is filtered-off over Celite and washed with MeOH. Evaporation of the solvent gives the crude product which is pure according to anaylsis and used without further purification. MS (LC-MS): 564.1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.31 minutes.

General Procedure (III)

A solution of (3S,5S)-5-{(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one (2.00 g, 4.3 mmol) and cyclopropanemethyl amine (1.9 mL, 21.7 mmol) in acetic acid (0.78 mL) was heated at 100° C. in a sealed tube for 30 minutes. Water was added and the mixture was extracted with CH2Cl2. Drying (Na2SO4) of the combined extracts and evaporation of the solvent afforded the crude product which was used without further purification.

Pd/C 10% (1.10 g, 1.0 mmol) was added to a solution of the crude product (2.58 g) in MeOH (16 mL) and the reaction mixture was stirred under a H2atmosphere for 9 hours. The catalyst was filtered-off over Celite and the solvent was evaporated. Purification of the crude product by flash column chromatography [CH2Cl2to CH2CL2:MeOH (8:2)] afforded the desired product as a colorless foam. MS (LC-MS): 508.1 [M+H]+; tR(HPLC, C18 column, 10-100% CH3CN/H2O/5 minutes, 100% CH3CN/3 minutes, 100-10% CH3CN/H2O/3 minutes, flow: 1.5 mL/min.): 4.91 minutes.

General Procedure (IV)

To a solution of 4-bromo-1-fluoro-2-(3-methoxy-propoxy)-benzene (1.94 g, 13.3 mmol, 1.4 equiv.) and N-methylmorpholine (1.6 mL, 14.7 mmol, 3 equiv.) in THF (20 mL) n-butyl lithium in hexane (1.6 M, 5.5 mL, 8.8 mmol, 1.8 equiv.) is added dropwise at −78° C. The solution is stirred at −78° C. for 1 hour, when a solution of MgBr2(14.7 mmol) in THF (50 mL), freshly prepared from magnesium (0.36 g, 14.7 mmol, 3 equiv.) and 1,2-dibromoethane (1.3 mL, 14.7 mmol, 3 equiv.), is added dropwise at −78° C. The reaction is stirred at the same temperature for 45 minutes, when (S)-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-3-methyl-butyraldehyde (1.4 g, 4.9 mmol, 1 equiv.) in THF (14 mL) is added dropwise at −78° C. The reaction mixture is stirred for an additional hour at the same temperature, before it is quenched with satatured aqueous NH4Cl (20 mL) and warmed to RT. The mixture is extracted with EtOAc, the combined extracts are washed with brine, dried over Na2SO4and the solvent is evaporated. Flash column chromatography [CH2Cl2to CH2Cl2:acetone (9:1)] affords the product as a light yellow oil. MS (LC-MS): 488[M+Na]+; Rf[CH2Cl2:acetone (98:2)]: 0.25 minutes.

The starting material (S)-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxotetrahydro-furan-2-yl)-ethyl]-3-methyl-butyraldehyde is prepared according to the methods described in EP 0 678 503 B1 and EP 0 678 514 A1.

The title compound prepared in accordance with General Procedure (IV).

The title compound prepared in accordance General Procedure (IV).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (III).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (III).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title prepared in accordance with General Procedure (I).

The title prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title prepared in accordance with General Procedure (I).

(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid [(S)-1-(3-methoxy-phenyl)-ethyl]-epared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amide The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (II).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

The title compound prepared in accordance with General Procedure (I).

Gelatin solution

A sterile-filtered aqueous solution, containing 20% cyclodextrins as solubiliser, of one of the compounds of formula (I), mentioned in the preceding Examples, as active ingredient, is so mixed, with the application of heat and under aseptic conditions, with a sterile gelatin solution containing phenol as preservative, that 1.0 mL of solution has the following composition:

Sterile Dry Substance for Injection

Five (5) mg of one of the compounds of formula (I), mentioned in the preceding Examples, as active ingredient, are dissolved in 1 mL of an aqueous solution containing 20 mg of mannitol and 20% cyclodextrins as solubiliser. The solution is sterile-filtered and, under aseptic conditions, introduced into a 2 mL ampoule, deep-frozen and lyophilised. Before being used, the lyophilisate is dissolved in 1 mL of distilled water or 1 mL of physiological saline. The solution is administered intramuscularly or intravenously. The formulation can also be filled into double-chamber disposable syringes.

Nasal Spray

Five hundred (500) mg of finely ground (<5.0 gm) powder of one of the compounds of formula (I), mentioned in the preceding Examples, are suspended as active ingredient in a mixture of 3.5 mL of “Myglyol 8 12” and 0.08 g of benzyl alcohol. The suspension is introduced into a container having a metering valve. Five (5.0) g of “Freon 12” are introduced under pressure through the valve into the container. The “Freon” is dissolved in the Myglyolbenzyl alcohol mixture by shaking. The spray container contains approximately 100 single doses which can be administered individually.

The following constituents are processed for the preparation of 10 000 tablets each containing 100 mg of active ingredient:

A mixture of one of the compounds of formula (I), mentioned in the preceding Examples, as active ingredient, 50 g of corn starch and the colloidal silicic acid is processed into a moist mass with starch paste prepared from 250 g of corn starch and 2.2 kg of demineralised water. The mass is forced through a sieve having a mesh size of 3 mm and dried at 45° C. for 30 minutes in a fluidised bed drier. The dried granules are pressed through a sieve having a mesh size of 1 ram, mixed with a previously sieved mixture (1 mm sieve) of 330 g of corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch and compressed to form slightly biconvex tablets.

Although the present invention has been described in considerable detail with reference to certain preferred versions thereof, other versions are possible without departing from the spirit and scope of the preferred versions contained herein. All references and Patents (U.S. and others) referred to herein are hereby incorporated by reference in their entirety as if set forth in full herein.