RU2782919C2 - Inhibitors of neutral endopeptidase (nep) and human soluble endopeptidase (hsep) for reduction in harmful effects of perfusion organ deficiency - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to the use of a compound of the general formula (1), or its stereoisomer, or pharmaceutically acceptable salt for the preparation of a pharmaceutical composition intended for prevention of biomarker disbalance and/or recovery of biomarker balance, and reduction in harmful effects of asymptomatic progressive disseminated perfusion deficiency (blood flow deficiency) of organs or their parts, which may indicate systemic diseases, which is indicated by increased concentration of a biomarker of endothelin-1 (hereinafter – ET-1) or precursors of pre-endothelin-1 and pro-endothelin (hereinafter – big endothelin-1, Big ET-1) and/or increased activity of endothelin-1-converting enzyme (hereinafter – ECE-1) or neutral endopeptidase (hereinafter – NEP). In the general formula (1), R₁ is a group of the formula (2) or (3), A is CH₂; R₂ and R₃ are independently hydrogen; R₄ and R₆ are independently hydrogen or tert-butyl; R₅ is naphthyl-(C1-C6)alkyl or phenyl-ethyl; R₇ and R₈ are independently ethyl or benzyl.

EFFECT: use of compounds of the formula (1) for the preparation of a pharmaceutical composition intended for prevention of biomarker disbalance and/or recovery of biomarker balance, and reduction in harmful effects of asymptomatic progressive disseminated perfusion deficiency (blood flow deficiency) of organs or their parts.

5 cl, 1 tbl, 1 ex

Description

FIELD OF THE INVENTION

[0001] Described are dual inhibitors of neutral endopeptidase (NEP) and/or soluble human endopeptidase (REPh), as well as endothelin converting enzyme-1 (EPF-1), used for the preparation of pharmaceutical compositions and serving to reduce the harmful effects of asymptomatic progressive disseminated perfusion deficiency ( lack of blood flow) of organs or their parts, which may indicate systemic diseases.

SCIENTIFIC BACKGROUND OF THE INVENTION

[0002] Deficiency in blood flow through the organs is one of the main risk factors for the development of systemic diseases in humans. Progressive diffuse organ perfusion deficiency is usually asymptomatic or with mild symptoms for many months or even years, and is not associated with a specific disease. For this reason, preventive or curative actions are not taken until the first specific clinical symptoms of the disease appear and the physician makes a diagnosis of a systemic disease. Well-known examples illustrating this situation include, for example, ischemic heart disease, ischemic stroke, age-related macular degeneration, or chronic neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease. In all these conditions, long before the onset of any specific symptoms of the disease, there is a period of slowly progressive, disseminated decrease in perfusion of various organs. During this phase, perfusion deficiency cannot be attributed to any specific disease. Diseases of the brain, spinal cord or peripheral nerves, diseases of the eyes and / or optic nerves, diseases of the heart, cardiovascular or respiratory systems, diseases of the kidneys and urinary tract, reproductive system, diseases of the digestive system, pancreas, liver and biliary tract, diseases of the skin, muscles, bones or joints, as well as diseases of the endocrine glands or their parts, are the most common systemic diseases in humans, the pathogenesis of which is associated in part with a progressive decrease in perfusion of certain organs. Currently, there is no therapy that reduces the deficit of diffuse blood flow through the organs, or therapy that limits the consequences of asymptomatic progressive disseminated perfusion deficiency of organs or parts of them, which may indicate a systemic disease.

[0003] Endothelium is a 21 amino acid peptide that is synthesized and released by the endothelium. Endothelium is produced by cleavage of the Trp-Val bond in the large endothelial precursor peptide (Big Endothelin, Big ET-1). Endothelin converting enzyme-1 (ECE-1, ECP-1), a membrane-bound metalloprotease, catalyzes the proteolytic activation of Big ET-1 to ET-1 and is a regulatory site that controls the production of the active peptide. The endothelium is the most potent vasoactive peptide in the human body known to date. Possessing a vasoconstrictor property, the endothelium is involved in the regulation of blood pressure in parenchymal organs. When released, it causes a decrease in blood flow through the organs, followed by hypofunction of the organs involved in the pathological process,

[0004] Endothelium, in addition to affecting intraocular blood pressure and regulating intraocular fluid pressure, affects retinal ganglion cell apoptosis through ETv receptors, and induces the proliferation of human optic nerve head astrocytes through ET _A and ET _B receptors (G. Prasanna , R. Krishnamoorthy, A. F. Clark, R. J. Wordinger, & T. Yorio (2002) Invest. Ophthalmol. Vis. Sci. 43, 2704-2713).

[0005] Neutral endopeptidase (NEP), a zinc metallopeptidase, degrades atrial natriuretic peptide type C (NPS) and forms a regulatory site that controls the concentration of the active peptide. In serum-free cells, NPS inhibits apoptosis by causing an increase in cGMP levels. The natriuretic peptide receptor NprB regulates the intracellular concentration of cGMP by stimulating dispersed guanylyl cyclase (pGC), which activates the cGMP-dependent G protein kinase pathway.

[0006] Publications that upregulation of ET-1 receptors and downregulation of NPS receptors occur in cells exposed to oxidative stress prompted us to study the effect of dual inhibition of LEP and EPF on the manifestation of cerebral perfusion deficit in rats, similar to asymptomatic progressive disseminated deficiency of cerebral perfusion, manifested in humans due to carotid stenosis.

BACKGROUND OF THE INVENTION

[0007] The invention relates to a novel use of benzazepine, benzoxazepine, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives having the ability to inhibit neutral endopeptidase (NEP) and/or human soluble endopeptidase (REPh). The compounds of this new invention can be used in the preparation of pharmaceutical compositions intended to reduce the harmful effects of asymptomatic progressive disseminated perfusion deficit (blood flow deficiency) of organs or parts thereof, which may be indicative of systemic diseases.

[0008] The invention relates to the use of the compounds disclosed in patent EP 1706121 B1, for the manufacture of medicines that have a positive effect. The beneficial effect is disclosed herein or is obvious to a person skilled in the art from the specification and general knowledge in this field. The invention relates to the use of the compounds of the invention for the manufacture of theranostic medicaments aimed not at a specific disease, but at a person predisposed to this disease. This is a procedure in which the appropriate type of drug is selected based on the result of an appropriate diagnostic test in a particular individual in the context of personalized medicine. At the time of taking the theranostic drug, the person has not yet been diagnosed with the disease or condition. More specifically, the invention relates to a novel use of the compounds to restore functional balance in parenchymal organs as measured by the diagnostic biomarkers disclosed herein or apparent to one of skill in the art from the specification and general knowledge in the art. In embodiments of the present invention, the specific compounds disclosed herein are used in the manufacture of theranostic drugs.

[0009] Patent EP1706121 B1 relates to the use of certain compounds with combined inhibitory activity against both neutral endopeptidase and/or soluble human endopeptidase (REPh), as well as endothelin converting enzyme (EPF) for the treatment and/or prevention of neurodegenerative diseases, such as traumatic brain injury, acute disseminated encephalomyelitis, brain damage due to epilepsy, spinal cord injury, bacterial or viral meningitis and meningoencephalitis, prion diseases, poisoning by neurotoxic compounds, radiation-induced brain damage, as well as for the prevention of ischemic stroke, provided that that said pharmaceutical compositions do not contain an aldosterone receptor antagonist.

[0010] WO 2004/082637, filed March 18, 2004 and published September 30, 2004, discloses a method for the prevention or treatment of numerous pathological conditions, comprising the administration of an aldosterone receptor antagonist and an endothelin converting enzyme (ECF) inhibitor. Among these pathological conditions are systemic diseases. However, the usefulness of the preferred compounds in such indications has not been disclosed, nor have methods for the manufacture of theranostic preparations whose effects are distributed unrelated to a specific disease have been disclosed.

[0011] The aim of the present invention was to identify specific metalloprotease inhibitors that have a beneficial effect and have a theranostic value when administered to individuals with an altered diagnostic biomarker, but not suffering from a specific disease, and these inhibitors should not contain aldosterone receptor antagonists.

[0012] Surprisingly, benzazepine, benzoxazepine, benzothiazepine-N-acetic acid, and phosphono-substituted benzazepinone derivatives with neutral endopeptidase (NEP) and/or soluble human endopeptidase (REPh) inhibitory activity were found to exhibit protective activity in a rat model of deficiency brain perfusion, which is not indicative of a specific disease, can be measured using a diagnostic biomarker and may indicate disease of the central nervous system, as in humans. This property makes them useful for reducing the harmful effects of asymptomatic progressive disseminated perfusion deficiency of organs or parts thereof and/or for the preparation of pharmaceutical compositions intended to reduce the harmful effects of asymptomatic progressive disseminated perfusion deficiency of organs or parts thereof, which may be a sign of systemic diseases selected by them. a group consisting of such diseases as, for example, (i) diseases of the brain, spinal cord or peripheral nerves or parts thereof, and preferably such as, for example: mild cognitive impairment, cognitive dysfunction after chemotherapy, post-surgical cognitive impairment, Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, senile dementia, AIDS dementia complex, progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, pain Huntington's disease, cerebellar ataxia, spinocerebellar ataxia, Friedreich's ataxia, optic neuritis and inflammation of the spinal cord, autoimmune encephalitis, central nervous system vasculitis, traumatic brain injury in epilepsy, mitochondrial encephalomyopathy, neuronal ceroidolipofuscinosis, lysosomal diseases of the central nervous system, leukodystrophy, disorders urea cycle, hepatic encephalopathy, hepatorenal syndrome, toxic-metabolic encephalopathy, chronic traumatic encephalopathy, porphyria, prion diseases, neurotoxic poisoning, Guillain-Barré syndrome, chronic inflammatory or autoimmune neuropathies, damage to the brain, spinal and peripheral nerves caused by radiation and / or chemotherapy, multiple system atrophy and hereditary spastic paraplegia; (i) diseases of the eyes and/or optic nerves or parts thereof, and preferably such as, for example, acquired macular disorders, such as, for example, age-related macular degeneration; optic neuropathies, preferably such as, for example, anterior or posterior ischemic optic neuropathy; hereditary dystrophies of the fundus, preferably such as, for example, age-related macular degeneration, cone dystrophy, cone-rod dystrophy, rod dystrophy, Stargardt's disease, Bietti's crystalline corneal dystrophy, Fleck's familial benign retina, Best's vitelliform macular dystrophy, adult-onset vitelliform dystrophy , North Carolina macular degeneration, familial dominant Drusus, and concentric annular macular degeneration; myopia and degenerative myopia; all forms of primary and secondary glaucoma, preferably such as, for example, primary open-angle glaucoma, normal tension glaucoma, primary angle-closure glaucoma, pseudoexfoliative syndrome and glaucoma, pigment dispersion syndrome and glaucoma, neovascular glaucoma, inflammatory glaucoma, lens-related glaucoma, traumatic glaucoma , primary congenital glaucoma, iatrogenic induced glaucoma and malignant glaucoma; (iii) diseases of the heart, cardiovascular or respiratory systems, or parts thereof, and preferably such as, for example, ischemic heart disease; cardiomyopathies, preferably such as, for example, congestive cardiomyopathy, hypertrophic cardiomyopathy, obstructive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, as well as ischemic, valvular, hypertensive, inflammatory, metabolic and toxic cardiomyopathy and cardiomyopathy during systemic disease or pregnancy; chronic heart failure and rejection of a heart transplant .; chronic obstructive pulmonary disease, pulmonary emphysema, bronchiectasis, bronchiolitis obliterans, bronchopulmonary dysplasia, cystic fibrosis, alpha-1 antitrypsin deficiency, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, pulmonary fibrosis, lymphangioleiomyosis, sarcoidosis, pneumoconiosis and preferably such as, for example, silicosis, asbestosis and anthracosis, or lung transplant rejection; (iv) diseases of the kidneys and urinary tract, as well as of the reproductive system or parts thereof, and preferably such as, for example, polycystic kidney disease, chronic glomerulonephritis, amyloidosis, systemic vasculitis affecting the kidneys, antiphospholipid syndrome; nephropathy, and preferably such as, for example, hypertensive, ischemic, diabetic, autoimmune, obstructive, drug-induced, toxic or lupus nephropathy; nephrotic syndrome, diffuse renal glomerulosclerosis, hemolytic uremic syndrome, preeclampsia, renal artery stenosis, renal sarcoidosis, renal transplant rejection, polycystic ovary syndrome, chronic ovarian ischemia, chronic uterine ischemia, endometriosis, chronic testicular ischemia, chronic penile ischemia, chronic ischemia prostate, Peyronie's disease, impotence, male and female infertility; (v) diseases of the digestive system, pancreas, liver and bile ducts or parts thereof, and preferably such as, for example, ischemic esophagitis, ischemic gastritis, ischemic duodenitis, chronic mesenteric ischemia, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ischemic or ulcerative colitis, necrotizing enterocolitis, pseudomembranous enterocolitis, radiation-induced enteritis, gastritis and colitis, celiac disease and chronic gastritis; hepatitis, and preferably such as, for example: ischemic, alcoholic and viral hepatitis, as well as hepatitis in AIDS, metabolic, autoimmune and radiation-induced hepatitis; liver cirrhosis, ischemic cholecystitis, ischemic cholangitis, primary sclerosing cholangitis, IgG4-associated sclerosing cholangiopathy, recurrent purulent cholangitis, portal biliopathy, eosinophilic and mast cell cholangitis, ischemic cholangiopathy, infectious cholangiopathy in AIDS, liver transplant rejection, chronic ischemic pancreatitis; (vi) diseases of the skin, muscles, bones or joints, or parts thereof, and preferably such as, for example, pemphigus vulgaris, bullous pemphigoid, eczema, acne, psoriasis, ischemic onycholysis, ischemic dermatopathy, acantholysis, dermatosis, cutaneous lupus erythematosus, scabies, vitiligo, hair loss, alopecia areata; muscular dystrophies, and preferably such as, for example, Duchenne muscular dystrophy, Becker muscular dystrophy, colon, girdle, faciocapulohumeral, Fukuyama congenital and myotonic muscular dystrophy; polymyositis, dermatomyositis, fibromyalgia, polymyalgia rheumatica, ankylosing spondylitis, mixed connective tissue diseases, systemic lupus erythematosus, rheumatoid arthritis, osteochondrosis, osteoporosis and osteonecrosis; (vii) diseases of the endocrine glands or parts thereof, and preferably such as, for example, chronic adrenal insufficiency, thymus insufficiency in the elderly, pineal insufficiency, thyroid goiter, panhypopituitarism, postpartum pituitary necrosis (Sheehan's syndrome), diabetes insipidus, premature ovarian failure, premature testicular failure, erectile dysfunction, female sexual arousal disorder, female orgasm disorder (anorgasmia), and female hypoactive sexual desire disorder.

[0013] The compounds of the present invention are known from European patents EP 0733642, EP 0916679 and EP 1468010 containing detailed descriptions of the synthesis, and can be described by the general formula (1):

where:

R1 means a group of formula (2) or (3):

A is CH2, O or S,

R2 and R3 are independently hydrogen or halogen,

R4 and R6 independently represent hydrogen or a group forming a biolabile carboxylic acid ester;

R5 is selected from the group consisting of (C1-C6)alkoxy(C1-C6)alkyl which may be substituted with (C1-C6)alkoxy; phenyl-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl, where the phenyl group may be substituted by (C1-C6) alkyl, (C1-C6)-alkoxy or halogen; and naphthyl-(C1-C6)-alkyl,

R7 and R8 independently represent hydrogen or a group forming a biolabile phosphonic acid ester.

[0014] The invention includes all compounds having formula (1), racemates, mixtures of diastereomers and individual stereoisomers, as well as their pharmaceutically acceptable salts. Thus, the invention includes compounds in which the substituents on the potentially asymmetric carbon atoms are either in the R-configuration or in the S-configuration.

[0015] Pharmaceutically acceptable salts can be obtained using standard techniques well known in the art, for example, by mixing the compounds of the present invention with the appropriate metal cation or organic base, such as an amine.

[0016] This object can be achieved by preparing a metal salt of the general formula (1) as above, wherein the metal ion is a lithium ion or a divalent metal ion. Preferred divalent metal salts are calcium, magnesium and zinc salts. Most preferred is the calcium salt.

[0017] The invention relates to the use of a compound of general formula (1) as defined above to reduce the harmful effects of asymptomatic progressive disseminated perfusion deficiency of organs or parts thereof, and/or for the preparation of pharmaceutical compositions intended to reduce the harmful effects of asymptomatic progressive disseminated perfusion deficiency organs or parts thereof, which may be indicative of systemic diseases selected from the group including, for example, diseases such as (i) diseases of the brain, spinal cord or peripheral nerves or parts thereof, and preferably such as, for example: mild cognitive impairment, post-chemotherapy cognitive dysfunction, post-surgical cognitive impairment, Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, senile dementia, AIDS complex dementia, progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, cerebellar ataxia, spinocerebellar ataxia, Friedreich's ataxia, optic neuritis and spinal cord inflammation, autoimmune encephalitis, central nervous system vasculitis, traumatic brain injury in epilepsy, mitochondrial encephalomyopathy, neuronal ceroidolipofuscinosis, lysosomal diseases central nervous system, leukodystrophy, urea cycle disorders, hepatic encephalopathy, hepatorenal syndrome, toxic-metabolic encephalopathy, chronic traumatic encephalopathy, porphyria, prion diseases, neurotoxic poisoning, Guillain-Barré syndrome, chronic inflammatory or autoimmune neuropathies, brain, spinal and peripheral injuries nerves caused by radiation and/or chemotherapy, multiple system atrophy and hereditary spastic paraplegia; (ii) diseases of the eyes and/or optic nerves or parts thereof, and preferably such as, for example, acquired macular disorders, such as, for example, age-related macular degeneration; optic neuropathies, preferably such as, for example, anterior or posterior ischemic optic neuropathy; hereditary dystrophies of the fundus, preferably such as, for example, age-related macular degeneration, cone dystrophy, cone-rod dystrophy, rod dystrophy, Stargardt's disease, Bietti's crystalline corneal dystrophy, Fleck's familial benign retina, Best's vitelliform macular dystrophy, adult-onset vitelliform dystrophy , North Carolina macular degeneration, familial dominant Drusus, and concentric annular macular degeneration; myopia and degenerative myopia; all forms of primary and secondary glaucoma, preferably such as, for example, primary open-angle glaucoma, normal tension glaucoma, primary angle-closure glaucoma, pseudoexfoliative syndrome and glaucoma, pigment dispersion syndrome and glaucoma, neovascular glaucoma, inflammatory glaucoma, lens-related glaucoma, traumatic glaucoma , primary congenital glaucoma, iatrogenic induced glaucoma and malignant glaucoma; (iii) diseases of the heart, cardiovascular or respiratory systems, or parts thereof, and preferably such as, for example, ischemic heart disease; cardiomyopathies, preferably such as, for example, congestive cardiomyopathy, hypertrophic cardiomyopathy, obstructive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, as well as ischemic, valvular, hypertensive, inflammatory, metabolic and toxic cardiomyopathy and cardiomyopathy during systemic disease or pregnancy; chronic heart failure and rejection of a heart transplant .; chronic obstructive pulmonary disease, pulmonary emphysema, bronchiectasis, bronchiolitis obliterans, bronchopulmonary dysplasia, cystic fibrosis, alpha-1 antitrypsin deficiency, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, pulmonary fibrosis, lymphangioleiomyosis, sarcoidosis, pneumoconiosis and preferably such as, for example, silicosis, asbestosis and anthracosis, or lung transplant rejection (iv) diseases of the kidneys and urinary tract, as well as the reproductive system or parts thereof, and preferably such as, for example, polycystic kidney disease, chronic glomerulonephritis, amyloidosis, systemic vasculitis affecting the kidneys, antiphospholipid syndrome; nephropathy, and preferably such as, for example, hypertensive, ischemic, diabetic, autoimmune, obstructive, drug-induced, toxic or lupus nephropathy; nephrotic syndrome, diffuse renal glomerulosclerosis, hemolytic uremic syndrome, preeclampsia, renal artery stenosis, renal sarcoidosis, renal transplant rejection, polycystic ovary syndrome, chronic ovarian ischemia, chronic uterine ischemia, endometriosis, chronic testicular ischemia, chronic penile ischemia, chronic ischemia prostate, Peyronie's disease, impotence, male and female infertility; (v) diseases of the digestive system, pancreas, liver and bile ducts or parts thereof, and preferably such as, for example, ischemic esophagitis, ischemic gastritis, ischemic duodenitis, chronic mesenteric ischemia, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ischemic or ulcerative colitis, necrotizing enterocolitis, pseudomembranous enterocolitis, radiation-induced enteritis, gastritis and colitis, celiac disease and chronic gastritis; hepatitis, and preferably such as, for example: ischemic, alcoholic and viral hepatitis, as well as hepatitis in AIDS, metabolic, autoimmune and radiation-induced hepatitis; liver cirrhosis, ischemic cholecystitis, ischemic cholangitis, primary sclerosing cholangitis, IgG4-associated sclerosing cholangiopathy, recurrent purulent cholangitis, portal biliopathy, eosinophilic and mast cell cholangitis, ischemic cholangiopathy, infectious cholangiopathy in AIDS, liver transplant rejection, chronic ischemic pancreatitis; (vi) diseases of the skin, muscles, bones or joints, or parts thereof, and preferably such as, for example, pemphigus vulgaris, bullous pemphigoid, eczema, acne, psoriasis, ischemic onycholysis, ischemic dermatopathy, acantholysis, dermatosis, cutaneous lupus erythematosus, scabies, vitiligo, hair loss, alopecia areata; muscular dystrophies, and preferably such as, for example, Duchenne muscular dystrophy, Becker muscular dystrophy, colon, girdle, faciocapulohumeral, Fukuyama congenital and myotonic muscular dystrophy; polymyositis, dermatomyositis, fibromyalgia, polymyalgia rheumatica, ankylosing spondylitis, mixed connective tissue diseases, systemic lupus erythematosus, rheumatoid arthritis, osteochondrosis, osteoporosis and osteonecrosis; (vii) diseases of the endocrine glands or parts thereof, and preferably such as, for example, chronic adrenal insufficiency, thymus insufficiency in the elderly, pineal insufficiency, thyroid goiter, panhypopituitarism, postpartum pituitary necrosis (Sheehan's syndrome), diabetes insipidus, premature ovarian failure, premature testicular failure, erectile dysfunction, female sexual arousal disorder, female orgasmic disorder (anorgasmia), and female hypoactive sexual desire disorder, provided that said pharmaceutical compositions do not contain an aldosterone receptor antagonist.

[0018] Further embodiments of the invention are defined in the dependent claims. prevention and / or restoration of the balance of biomarkers and / or for the preparation of pharmaceutical compositions to reduce the harmful effects of asymptomatic progressive disseminated perfusion deficiency of organs or their parts. An imbalance of biomarkers may indicate systemic diseases, as indicated by an increased concentration of the biomarker endothelin- 1 or precursors of pre-endothelin-1 and pro-endothelin (large endothelin-1), and / or increased activity of endothelin-1-converting enzyme (EPF-1), or neutral endopeptidase (NEP) and / or soluble human endopeptidase (REPh) in one or more several body fluids, preferably blood, plasma, saliva, tears, sweat, urine, cerebrospinal fluid, bile, gastric juice, lymph, interstitial fluid, semen or synovial fluid, or in tissue samples, preferably, such as skin samples, hair samples, tissue samples of organs taken for biopsy, or samples in swabs, preferably, such as buccal or vaginal swabs. The use of a compound of formula (1) is intended to prevent biomarker imbalance, and/ or restoring the balance of a biomarker and/or for the preparation of pharmaceutical compositions to reduce the harmful effects of asymptomatic progressive disseminated perfusion deficiency of organs or parts thereof, which may be indicative of systemic diseases such as diseases of the brain, spinal cord or peripheral nerves or parts thereof.

[0019] The invention particularly relates to the use of compounds having the general formula (4):

where the symbols have the meanings given above.

[0020] More specifically, the invention relates to the use of compounds of general formula (5):

where the symbols have the meanings given above.

[0021] The most preferred active substances used in the present invention are the following:

• (2R)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin -3-yl]amino} carbonyl)cyclopentyl]methyl}-4-phenylbutanoic acid (6):

• (2R)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1 H -1-benzazepin -3-yl]amino }carbonyl)cyclopentyl]methyl }-4-(1-naphthyl)butanoic acid (7):

• tert-butyl-((3S)-3-{[(1-{[(benzyloxy)(ethoxy)phosphoryl]methyl}cyclopentyl)-carbonyl]amino)-2-oxo-2,3,4,5-tetrahydro -1 H -1-benzazepin-1-yl)acetate (8):

PHARMACEUTICAL COMPOSITIONS

[0022] The compounds of the invention may be brought into forms suitable for administration by conventional processes using excipients such as liquids or carrier materials. The pharmaceutical compositions of the invention may be administered systemically and/or topically, and in particular, for example, they may be administered enterally, orally, parenterally (intramuscularly or intravenously), subcutaneously or rectally, vaginally or locally (topically), as well as externally and in the eye. , periocular, including subconjunctival, subtenonal, retrobulbar or peribulbar and intraocular into the eye. They can be administered as solutions, suspensions, ointments (creams, gels, gelling solutions, sprays, eye inserts/deposits, contact lenses), ocular implants, as well as tablets, capsules, softgels, powders, suppositories, nanocompositions, or with using iontophoresis, or using pharmaceutical compositions based on nanoparticle carrier systems. Suitable excipients for such formulations are pharmaceutically common liquid or solid excipients and diluents, solvents, emulsifiers, lubricants, flavoring agents, coloring agents and/or buffering agents. Commonly used excipients include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as, for example, fish oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols, such as, for example, glycerol.

[0023] The compounds of the present invention are usually administered as pharmaceutical compositions. Possible types of pharmaceutical compositions used include, but are not limited to, solutions, suspensions, ointments (creams, gels or sprays), as well as tablets, chewable tablets, capsules, softgels, parenteral solutions, suppositories and other types disclosed herein or obvious to a person skilled in the art from the specification and general knowledge in the field. The pharmaceutical compositions of the invention do not contain an aldosterone receptor antagonist.

[0024] Embodiments of the invention provide a pharmaceutical package or kit containing one or more containers filled with one or more ingredients of the pharmaceutical composition of the invention. Such container(s) may be accompanied by various written materials, such as, for example, instructions for use or a notice in the form prescribed by a government agency that regulates the manufacture, use or sale of medicines; such notification informs about the authorization by the state body of the production, use and sale of these medicinal products for human treatment and veterinary use.

[0025] Formulations suitable for the compounds of the invention are described in detail in patent applications WO 03/068266 and WO 04/062692.

[0026] The specific compounds described above are intended to further illustrate the invention in more detail and therefore do not limit the scope of the invention in any way.

ASSYMPTOM PROGRESSIVE DISSEMINATED ORGANIUM PERFUSION DEFICIENCY INDICATING SYSTEMIC DISEASES

[0027] Asymptomatic progressive disseminated deficiency of blood flow through organs or parts thereof is an important factor that can be a sign of disease of the brain, spinal cord or peripheral nerves or parts thereof, and preferably such as: mild cognitive impairment, cognitive dysfunction after chemotherapy, post-surgical cognitive impairment, Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, senile dementia, complex AIDS dementia, progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis , Huntington's disease, cerebellar ataxia, spinocerebellar ataxia, Friedreich's ataxia, optic neuritis and inflammation of the spinal cord, autoimmune encephalitis, central nervous system vasculitis, traumatic brain injury in epilepsy, mitochondrial encephalomyopathy, neuronal ceroid lipofuscinosis, lysosomal diseases diseases of the central nervous system, leukodystrophy, urea cycle disorders, hepatic encephalopathy, hepatorenal syndrome, toxic-metabolic encephalopathy, chronic traumatic encephalopathy, porphyria, prion diseases, neurotoxic poisoning, Guillain-Barré syndrome, chronic inflammatory or autoimmune neuropathies, injuries brain, spinal and peripheral nerves induced by radiation and/or chemotherapy, multiple system atrophy and hereditary spastic paraplegia (WR Brown & CR Thore (2011) Neuropathol. Appl. neurobiol. 37, 56-74); (ii) diseases of the eyes and/or optic nerves or parts thereof, and preferably such as, for example, acquired macular disorders, such as, for example, age-related macular degeneration; optic neuropathies, preferably such as, for example, anterior or posterior ischemic optic neuropathy; hereditary dystrophies of the fundus, preferably such as, for example, age-related macular degeneration. cone dystrophy, cone rod dystrophy, rod dystrophy, Stargardt's disease, Bietti's crystalline corneal dystrophy, Fleck's familial benign retina, Best's vitelliform macular dystrophy, adult-onset vitelliform dystrophy, North Carolina macular dystrophy, familial dominant Drusus and

concentric annular macular degeneration; myopia and degenerative myopia; all forms of primary and secondary glaucoma, preferably such as, for example, primary open-angle glaucoma, normal tension glaucoma, primary angle-closure glaucoma, pseudoexfoliative syndrome and glaucoma, pigment dispersion syndrome and glaucoma, neovascular glaucoma, lens-related inflammatory glaucoma glaucoma, traumatic glaucoma, primary congenital glaucoma, iatrogenic induced glaucoma, and malignant glaucoma (Y. Zhang, J. M. Harrison, O. San Emeterio Nateras, S. Chalfin, & T. Q. Duong (2013) Doc. Ophthalmol. 126, 187–197 ); (iii) diseases of the heart, cardiovascular or respiratory systems, or parts thereof, and preferably such as, for example, ischemic heart disease; cardiomyopathies, preferably such as, for example, congestive cardiomyopathy, hypertrophic cardiomyopathy, obstructive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, as well as ischemic, valvular, hypertensive, inflammatory, metabolic and toxic cardiomyopathy and cardiomyopathy during systemic diseases or pregnancy; chronic heart failure and heart transplant rejection; chronic obstructive pulmonary disease, pulmonary emphysema, bronchiectasis, bronchiolitis obliterans, bronchopulmonary dysplasia, cystic fibrosis, alpha-1 antitrypsin deficiency, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, pulmonary fibrosis, lymphangioleiomyosis, sarcoidosis, pneumoconiosis and preferably such as, for example, silicosis, asbestosis and anthracosis, or lung transplant rejection (P. Abete, D. Della-Morte, G. Gargiulo, C. Basile, A. Langellotto, G. Galizia, G. Testa, V. Canonico , D. Bonaduce & F. Cacciatore (2014) Ageing Res. Rev. 18, 41-52); (iv) diseases of the kidneys and urinary tract, as well as of the reproductive system or parts thereof, and preferably such as, for example, polycystic kidney disease, chronic glomerulonephritis, amyloidosis, systemic vasculitis affecting the kidneys, antiphospholipid syndrome; nephropathy, and preferably such as, for example, hypertensive, ischemic, diabetic, autoimmune, obstructive, drug-induced, toxic or lupus nephropathy; nephrotic syndrome, diffuse renal glomerulosclerosis, hemolytic uremic syndrome, preeclampsia, renal artery stenosis, renal sarcoidosis, renal transplant rejection, polycystic ovary syndrome, chronic ovarian ischemia, chronic uterine ischemia, endometriosis, chronic testicular ischemia, chronic penile ischemia, chronic prostate cancer, Peyronie's disease, impotence, male and female infertility (A. Saad, S. M. Herrmann & S. C. Textor (2015) Physiology (Bethesda) 30, 175-182); (v) diseases of the digestive system, pancreas, liver and bile ducts or parts thereof, and preferably such as, for example, ischemic esophagitis, ischemic gastritis, ischemic duodenitis, chronic mesenteric ischemia, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ischemic or ulcerative colitis, necrotizing enterocolitis, pseudomembranous enterocolitis, radiation-induced enteritis, gastritis and colitis, celiac disease and chronic gastritis; hepatitis, and preferably such as, for example: ischemic, alcoholic and viral hepatitis, as well as hepatitis in AIDS, metabolic, autoimmune and radiation-induced hepatitis; liver cirrhosis, ischemic cholecystitis, ischemic cholangitis, primary sclerosing cholangitis, IgG4-associated sclerosing cholangiopathy, recurrent suppurative cholangitis, portal biliopathy, eosinophilic and mast cell cholangitis, ischemic cholangiopathy, infectious cholangiopathy in AIDS, liver transplant rejection, chronic ischemic pancreatitis M. Björck & A. Wanhainen (2010) Semin Vasc Surg 23, 54-64); (vi) diseases of the skin, muscles, bones or joints, or parts thereof, and preferably such as, for example, pemphigus vulgaris, bullous pemphigoid, eczema, acne, psoriasis, ischemic onycholysis, ischemic dermatopathy, acantholysis, dermatosis, cutaneous lupus erythematosus, scabies, vitiligo, hair loss, alopecia areata; muscular dystrophies, and preferably such as, for example, Duchenne muscular dystrophy, Becker muscular dystrophy, colon. girdle, faciocapulohumeral, congenital Fukuyama and myotonic muscular dystrophy; polymyositis, dermatomyositis, fibromyalgia, polymyalgia rheumatica, ankylosing spondylitis, mixed connective tissue diseases, systemic lupus erythematosus, rheumatoid arthritis, osteochondrosis, osteoporosis and osteonecrosis (M.C. Dalakas (2010) Curr. Opin. Pharmacol. 10, 346-352); (vii) diseases of the endocrine glands or parts thereof, and preferably such as, for example, chronic adrenal insufficiency, thymus insufficiency in the elderly, pineal insufficiency, thyroid goiter, panhypopituitarism, postpartum pituitary necrosis (Sheehan's syndrome), diabetes insipidus, premature ovarian failure, premature testicular failure, erectile dysfunction, female sexual arousal disorder, female orgasm disorder (anorgasmia) and female hypoactive sexual desire disorder (H.J. Schneider, P.G. Sämann, M. Schneider, C.G. Croce, G. Corneli, C. Sievers, F. Ghigo, G. K. Stalla, & G. Aimaretti (2007) J. Endocrinol Invest. 30, RC9-RC12). To simulate an asymptomatic progressive disseminated deficiency of blood flow in the brain in an animal experiment, rats were subjected to bilateral transient occlusion of the carotid arteries while maintaining the patency of the vertebral arteries and maintaining normal blood pressure. To determine whether exemplary compounds of the present invention protect the brain from the harmful effects of perfusion deficiency, we used the normotensive rat model of transient bilateral common carotid artery occlusion (BCCA) (C. Heim, M. Sieklucka, F. Block, R. Schmidt-Kastner, R. Jaspers & K.-H. Sontag (1990) Pharmacology of cerebral ischemia, J. Krieglstein & H. Oberpichler, WVG, Stuttgart, pp. 53-61), which is the experimental equivalent of brain perfusion deficiency caused by carotid stenosis in humans.

EXAMPLES

[0028] Methods: Wistar rats weighing 200-250 g were anesthetized with chloral hydrate at a dose of 400 mg/kg, and osmotic mini-pumps, primed before implantation, were filled with either a vehicle or a compound (6), representative of the compounds of the invention, at a dose of 60 mg/kg / day and implanted subcutaneously. On day 2, transient bilateral occlusion of the common carotid artery (BCCA) was intraperitoneally induced with a surgical thread under sodium pentobarbital anesthesia in rats (n=8) for 30 min at a dose of 60 mg/kg. Interruption of blood flow in the carotid arteries was monitored visually, after 30 min the threads were removed, and the surgical field was closed. In sham-operated control rats (n=8), blood flow in the carotid arteries was not interrupted, but sutures were applied and subsequently removed. The behavior of rats was evaluated in the open field test (M. Fontenay, J. Le Cornec, M. Zaczyńska, MC Debarle, P. Simon & JR Boissier (1970) J. Pharmacol. 1, 243-254). Animals were placed in an open field for 5 min and then the number of visited squares (ambulations), uprights, acts of grooming, manifestations of interest in the group, and defecations were counted. Testing was performed 5 days after bilateral clamping of the carotid artery (n = 8). Statistical evaluation was carried out using the Mann-Whitney U-test.

[0029] Results: As measured in the open field test, transient bilateral occlusion of the common carotid artery (BCCA) for 30 minutes significantly changed the exploratory behavior of rats in such parameters as vertical

standing (45.12%) and showing interest in blocks (48.64%), while ambulations (105.05%), grooming (114.53%) and defecation (76.19%) did not change significantly (Table 1). Compound (6) introduced a statistically significant improvement in the exploratory behavior of rats undergoing bilateral common carotid artery occlusion, as evidenced by the normalization of vertical stances (104.62%) and interest in blocks (103.80%) with a virtually unchanged number of ambulations (94.81%) compared with with sham-operated control animals (Table 1).

[0030 ] Conclusions: Compound of formula (6) produced a statistically significant improvement in exploratory behavior in rats, which worsened as a result of transient cerebral perfusion deficit caused by bilateral common carotid artery (BCCA) occlusion, as evidenced by normalization of uprights and instances of interest. to blocks with unchanged parameters of ambulations, grooming and defecation in the open field test (Table 1).

Table 1.Influence at exploratory behavior of rats in an open field

Ambulation
(n) Vertical stand (n) Blocks
(n) Grooming
(n) defecation
(n) Control+(6) 28.91 ± 5.13 11.48 ± 3.51 7.36 ± 2.85 5.30±1.57 1.26±0.45 % 100 100 100 100 100 BCCA 30.37 ± 3.22 5.18±2.05*ª 3.58±1.57*ª 6.07 ± 1.38 0.96 ± 0.31 % 105.05 45.12 48.64 114.53 76.19 BCCA+(6) 2741±4.25 12.01 ± 3.86 7.64 ± 2.54 5.98 ± 1.06 1.04±0.45 % 94.81 104.62 103.80 112.83 82.54

^* P<0.05 BCCA vs control group+(6); ^ª P<0.05 BCCA versus BCCA+(6); U-test Mann-Whitney; x̄±SOS, BCCA, bilateral occlusion of the common carotid arteries.

Claims (21)

1. Use of the compound of general formula (1)

where R ₁ means a group of formula (2) or (3)

A is CH ₂ ; R ₂ and R ₃ are independently hydrogen; R ₄ and R ₆ independently represent hydrogen or tert-butyl; R ₅ means naphthyl-(C1-C6) alkyl or phenyl-ethyl; R ₇ and R ₈ are independently ethyl or benzyl; or a stereoisomer or pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition intended to prevent biomarker imbalance and/or restore biomarker balance and reduce the harmful effects of asymptomatic progressive disseminated perfusion deficiency (blood flow deficiency) of organs or their parts, which may indicate systemic diseases, as indicated by an increased concentration of the endothelin-1 biomarker or precursors of preendothelin-1 ET-1 and proendothelin (large endothelin-1 Big ET-1) and/or increased activity of endothelin-1-converting enzyme (ECE-1, EPF-1) or neutral endopeptidase (NEP, NEP). 2. Use according to claim 1, wherein the systemic disease is a disease of the brain, heart, cardiovascular or respiratory systems, or parts thereof. 3. Use according to any one of claims 1 or 2, wherein the compound of formula (1) is (2R)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3, 4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-phenylbutanoic acid of formula (6)

as well as a pharmaceutically acceptable salt thereof. 4. Use according to any one of claims 1 or 2, wherein the compound of formula (1) is (2R)-2-{(1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3, 4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(1-naphthyl)butanoic acid of formula (7)

as well as a pharmaceutically acceptable salt thereof. 5. Use according to any one of claims 1 or 2, wherein the compound of formula (1) is t-butyl-((3S)-3-{[(1-{[(benzyloxy)(ethoxy)phosphoryl]methyl}cyclopentyl)- carbonyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate of formula (8)

as well as a pharmaceutically acceptable salt thereof.