NEUTRAL ENDOPEPTIDASE (NEP) AND HUMAN SOLUBLE ENDOPEPTIDASE (hSEP) INHIBITORS TO REDUCE DETRIMENTAL EFFECTS OF PERFUSION DEFICIENCY OF PARENCHYMAL ORGANS

Abstract

The invention relates to a novel use of benzazepine, benzoxazepine, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives having both neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP), and endothelin convertase (ECE), inhibitory activity. The compounds of this invention are useful for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases.

Claims

1. Compounds of the general formula (1) wherein: ##STR00008## R1 stands for a group with formula (2) or (3): ##STR00009## A represents CH2, O or S, R2 and R3 independently represent hydrogen or halogen, R4 and R6 independently represent hydrogen or a biolabile carboxylic ester forming group, R5 is selected from the group consisting of (C1-C6)alkoxy(C1-C6)alkyl which may be substituted by a (C1-C6) alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl, (C1-C6)-alkoxy or halogen, and naphtyl-(C1-C6)-alkyl, R7 and R8 independently represent hydrogen or a group forming a biolabile phosphonic acid ester, all stereoisomers, as well as pharmaceutically acceptable salts thereof, for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases selected from the group consisting of diseases such as e.g. (i) diseases of the brain, spinal cord, or peripheral nerves, or parts thereof, and preferably such as e.g. mild cognitive impairment, cognitive dysfunction after chemotherapy, postsurgical 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, Huntington's disease, cerebellar ataxia, spinocerebellar ataxia, Friedreich's ataxia, optic neuritis and spinal cord inflammation, autoimmune encephalitis, central nervous system vasculitis, brain injury in the course of epilepsy, mitochondrial encephalomyopathy, neuronal ceroidolipofuscinosis, lysosomal storage diseases of the central nervous system, leukodystrophies, urea cycle disorders, hepatic encephalopathy, hepatorenal syndrome, toxic-metabolic encephalopathy, chronic traumatic encephalopathy, porphyria, prion diseases, neurotoxic poisoning, Guillain-Barre syndrome, chronic inflammatory or autoimmune neuropathies, brain, spinal and peripheral nerve injury induced 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 e.g. acquired macular disorders such as e.g. age-related macular degeneration; neuropathies of the optic nerve, preferably such as e.g. anterior or posterior ischemic optic neuropathy; hereditary fundus dystrophies, preferably such as e.g. cone dystrophy, cone-rod dystrophy, rod dystrophy, Stargardt's disease, Bietti's crystalline corneoretinal dystrophy, familial benign fleck retina, Best vitelliform macular dystrophy, adult-onset vitelliform dystrophy, North Carolina macular dystrophy, familial dominant drusen, and concentric annular macular dystrophy; myopia and degenerative myopia; all forms of primary and secondary glaucoma, preferably such as e.g. primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, pseudoexfoliation 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 e.g. ischemic heart disease; cardiomyopathies, preferably such as e.g. congestive cardiomyopathy, hypertrophic cardiomyopathy, obstructive cardiomyopathy, right ventricular arrhythmogenic cardiomyopathy, and ischemic, valvular, hypertensive, inflammatory, metabolic, and toxic cardiomyopathy, and cardiomyopathy in the course of systemic diseases, or pregnancy; chronic heart failure; and heart transplant rejection; chronic obstructive pulmonary disease, 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 e.g. silicosis, asbestosis, and anthracosis, or pulmonary transplant rejection; (iv) diseases of the kidneys and urinary tract, and reproductive system, or parts thereof, and preferably such as e.g. polycystic kidney disease, chronic glomerulonephritis, amyloidosis, systemic vasculitides affecting the kidneys, antiphospholipid syndrome; nephropathies, and preferably such as e.g. 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 ischemia, Peyronie's disease, impotence, and male and female infertility; (v) diseases of the digestive system, pancreas, or liver and bile ducts, or parts thereof, and preferably such as e.g. 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 e.g. ischemic, alcoholic and viral hepatitis, and hepatitis in the course of AIDS, metabolic, autoimmune, and radiation-induced hepatitis; cirrhosis, ischemic cholecystitis, ischemic cholangitis, primary sclerosing cholangitis, sclerosing cholangiopathy associated with IgG4, recurrent purulent cholangitis, portal biliopathy, eosinophilic and mastocytic cholangitis, ischemic cholangiopathy, infectious cholangiopathy in the course of AIDS, liver transplant rejection, chronic ischemic pancreatitis, and pancreatic insufficiency; (vi) diseases of the skin, muscles, bones, or joints, or parts thereof, and preferably such as e.g. 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 e.g. Duchenne muscular dystrophy, Becker muscular dystrophy, rim-girdle, facioscapulohumeral, Fukuyama congenital, and myotonic muscular dystrophy; polymyositis, dermatomyositis, fibromyalgia, polymyalgia rheumatica, ankylosing spondylitis, mixed connective tissue disease, systemic lupus erythematosus, rheumatoid arthritis, osteochondrosis, osteoporosis, and osteonecrosis; (vii) diseases of the endocrine glands, or parts thereof, and preferably such as e.g. chronic adrenocortical insufficiency, thymus insufficiency in elderly, pineal gland insufficiency, thyroid goiters, panhypopituitarism, postpartum pituitary gland necrosis (Sheehan's syndrome), diabetes insipidus, premature ovarian failure, premature testicular failure, erectile dysfunction, female sexual arousal disorder, the orgasmic disorder (anorgasmia), and hypoactive sexual desire disorder, with the proviso that said pharmaceutical compositions do not contain an aldosterone receptor antagonist.

2. Use as claimed in claim 1, characterized in that the purpose is to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases, as measured by the elevated concentration of the Endotelin-1 biomarker or its pre-endothelin-1 and Pro-Endothelin precursors (Big Endothelin-1), and/or elevated endothelin-1 converting enzyme (ECE-1), or neutral endopeptidase (NEP), and/or human soluble endopeptidase (hSEP) activity, in one or more body fluids, preferably such as e.g. blood, blood plasma, saliva, tears, sweat, urine, cerebrospinal fluid, bile, gastric juices, lymph, interstitial fluid, semen, or synovial fluid, or in tissue samples, preferably such as e.g. skin clippings, hair samples, organ tissue biopsies, or in swabs, preferably such as e.g. buccal or vaginal swabs.

3. A compound of the general formula (4): ##STR00010## wherein the symbols have the meanings as given in claim 1, all stereoisomers, as well as pharmaceutically acceptable salts thereof, for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases, as claimed in claims 1-2.

4. A compound of the general formula (5): ##STR00011## wherein the symbols have the meanings as given in claim 1, all stereoisomers, as well as pharmaceutically acceptable salts thereof, for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases, as claimed in claims 1-2.

5. Compound (2R)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopent-yl]methyl}-4-phenylbutanoic acid having formula (6): ##STR00012## as well as pharmaceutically acceptable salts thereof, for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases, as claimed in claims 1-2.

6. Compound (2R)-2-{(1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopent-yl]methyl}-4-(1-naphthyl)butanoic acid, having formula (7): ##STR00013## as well as pharmaceutically acceptable salts thereof, for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases, as claimed in claims 1-2.

7. Compound tert-butyl-((3S)-3-{[(1-{[(benzyloxy)(ethoxy)phosphoryl]methyl}cyclopentyl) carbonyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate, having formula (8): ##STR00014## as well as pharmaceutically acceptable salts thereof, for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases, as claimed in claims 1-2.

8. Use as claimed in any of the claims 1-7, characterized in that the pharmaceutically acceptable salt is selected from the group consisting of the lithium salt, the calcium salt, the magnesium salt, and the zinc salt, and that the pharmaceutically acceptable salt is preferably the calcium salt.

9. Use as claimed in any of claims 1-7, characterized in that it is for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases such as e.g. diseases of the brain, spinal cord, or peripheral nerves, or parts thereof, and preferably such as e.g. mild cognitive impairment, cognitive dysfunction after chemotherapy, postsurgical 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, Huntington's disease, cerebellar ataxia, spinocerebellar ataxia, Friedreich's ataxia, optic neuritis and spinal cord inflammation, autoimmune encephalitis, central nervous system vasculitis, brain injury in the course of epilepsy, mitochondrial encephalomyopathy syndrome, neuronal ceroidolipofuscinosis, lysosomal storage diseases of the central nervous system, leukodystrophies, urea cycle disorders, hepatic encephalopathy, hepatorenal syndrome, toxic-metabolic encephalopathy, chronic traumatic encephalopathy, porphyria, prion diseases, neurotoxic poisoning, Guillain-Barre syndrome, chronic inflammatory or autoimmune neuropathies, brain, spinal and peripheral nerve injury induced by radiation and/or chemotherapy, multiple system atrophy, and hereditary spastic paraplegia.

10. Use as claimed in any of the claims 1-7, characterized in that it is for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases such as e.g. diseases of the eyes, and/or optic nerves, or parts thereof, and preferably such as e.g. acquired macular disorders such as e.g. age-related macular degeneration; neuropathies of the optic nerve, preferably such as e.g. anterior or posterior ischemic optic neuropathy; hereditary fundus dystrophies, preferably such as e.g. cone dystrophy, cone-rod dystrophy, rod dystrophy, Stargardt's disease, Bietti's crystalline corneoretinal dystrophy, familial benign fleck retina, Best vitelliform macular dystrophy, adult-onset vitelliform dystrophy, North Carolina macular dystrophy, familial dominant drusen, and concentric annular macular dystrophy; myopia and degenerative myopia; all forms of primary and secondary glaucoma, preferably such as e.g. primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, pseudoexfoliation 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.

11. Use as claimed in any of the claims 1-7, characterized in that it is for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases such as e.g. diseases of the heart, cardiovascular and respiratory systems, or parts thereof, and preferably such as e.g. ischemic heart disease; cardiomyopathies, preferably such as e.g. congestive cardiomyopathy, hypertrophic cardiomyopathy, obstructive cardiomyopathy, right ventricular arrhythmogenic cardiomyopathy, and ischemic, valvular, hypertensive, inflammatory, metabolic, and toxic cardiomyopathy, and cardiomyopathy in the course of systemic diseases, or pregnancy; chronic heart failure; and heart transplant rejection; chronic obstructive pulmonary disease, 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 e.g. silicosis, asbestosis, and anthracosis, or pulmonary transplant rejection.

12. Use as claimed in any of the claims 1-7, characterized in that it is for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases such as e.g. diseases of the kidneys and urinary tract, and of reproductive system, or parts thereof, and preferably such as e.g. polycystic kidney disease, chronic glomerulonephritis, amyloidosis, systemic vasculitides affecting the kidneys, antiphospholipid syndrome; nephropathies, and preferably such as e.g. 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 ischemia, Peyronie's disease, impotence, and male or female infertility.

13. Use as claimed in any of the claims 1-7, characterized in that it is for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases such as e.g. diseases of the digestive system, pancreas, or liver and bile ducts, or parts thereof, and preferably such as e.g. 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 e.g. ischemic hepatitis, alcoholic and viral hepatitis, and hepatitis in the course of AIDS, metabolic, autoimmune, and radiation-induced cirrhosis, ischemic cholecystitis, ischemic cholangitis, primary sclerosing cholangitis, sclerosing cholangiopathy associated with IgG4, recurrent purulent cholangitis, portal biliopathy, eosinophilic and mastocytic cholangitis, ischemic cholangiopathy, infectious cholangiopathy in the course of AIDS, liver transplant rejection, chronic ischemic pancreatitis, and pancreatic insufficiency.

14. Use as claimed in any of the claims 1-7, characterized in that it is for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases diseases, such as e.g. diseases of the skin, or muscles, or bones, or joints, or parts thereof, and preferably such as e.g. 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 e.g. Duchenne muscular dystrophy, Becker muscular dystrophy, rim-girdle, facioscapulohumeral, Fukuyama congenital, and myotonic muscular dystrophy; polymyositis, dermatomyositis, fibromyalgia, polymyalgia rheumatica, ankylosing spondylitis, mixed connective tissue disease, systemic lupus erythematosus, rheumatoid arthritis, osteochondrosis, osteoporosis, and osteonecrosis.

15. Use as claimed in any of the claims 1-7, characterized in that it is for the prevention of biomarker imbalance and/or restoration of biomarker balance and/or for the preparation of pharmaceutical compositions to reduce harmful effects of symptomless progressive disseminated perfusion deficiency of organs, or parts thereof, that may be suggestive of systemic diseases such as e.g. diseases of the endocrine glands, or parts thereof, and preferably such as e.g. chronic adrenocortical insufficiency, thymus insufficiency in elderly, pineal gland insufficiency, thyroid goiters, panhypopituitarism, postpartum pituitary gland 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.

Description

EXAMPLES

[0039] Methods: Wistar rats, 200-250 g, were anesthetized with chloral hydrate, 400 mg/kg, and osmotic minipumps, primed prior to implantation, were filled with either vehicle or example (6), representative for the compounds of the invention, in the dose of 60 mg/kg/d, and were implanted subcutaneously. Subsequently, rats (n=8) were subjected to transient bilateral occlusion of the common carotid artery (BCCA) for 30 min with surgical thread under sodium pentobarbital anaesthesia in the dose of 60 mg/kg i.p. on day 2. The interruption of the blood flow in carotid arteries was visually controlled, after 30 min the threads were removed, and the surgical field closed. In sham-operated control rats (n=8), blood flow in the carotid arteries was not interrupted, but sutures were placed and subsequently removed. The exploratory performance of rats was evaluated in the open field test (M. Fontenay, J. Le Cornec, M. Zaczyska, M. C. Debarle, P. Simon & J. R. Boissier (1970) J. Pharmacol. 1, 243-254). The animals were placed in an open field for a period of 5 min and ambulation, rearing, grooming, episodes of interests in blocks, and number of defecations were counted. The tests were carried out 5 days after BCCA (n=8). Statistical evaluation was performed by means of the Mann-Whitney U test.

[0040] Results: Transient bilateral occlusion of the common carotid artery (BCCA) for 30 min significantly disrupted exploratory behavior of rats as measured in the open field test by the number of rearings (45.12%) and the episodes of interest in blocks (48.64%), while ambulations (105.05) %), grooming (114.53%), and defecations (76.19%) did not significantly change (Table 1). Compound (6) induced statistically significant improvement of exploratory performance in rats subjected to BCCA, as evidenced by the normalization of rearings (104.62%) and the episodes of interest in blocks (103.80%) without affecting ambulations (94.81%), as compared to the sham-operated controls (Table 1).

[0041] Conclusions: The compound of formula (6) induced a significant improvement of exploratory performance reduced by transient deficiency of brain perfusion caused by bilateral occlusion of the common carotid artery (BCCA), as evidenced by the normalization of rearing and episodes of interests in blocks without changing the ambulations, grooming, and defecations in the open field test (Table 1).

TABLE-US-00001 TABLE 1 Effect on exploratory performance of rats in the open field. Ambulation Rearing Blocks Grooming Defecation (n) (n) (n) (n) (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 .sup.5.18 2.05*.sup.a .sup.3.58 1.57*.sup.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 + (6); .sup.aP < 0.05 BCCA vs BCCA + (6); Mann-Whitney U-test; x SEM, BCCA, bilateral occlusion of common carotid arteries.