MXPA06007933A - Neutral endopeptidase (nep) and human soluble endopeptidase (hsep) inhibitors for prophylaxis and treatment of neurodegenerative disorders - Google Patents

Abstract

The invention relates to a novel use of known benzazepine, benzoxazepine, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives having neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP) inhibitory activity. The compounds of the invention are useful for the preparation of pharmaceutical compositions for prophylaxis and treatment of neurodegenerative disorders. The compounds of the invention are known from the European patents EP 0 733 642 and EP 0 916 679, and can be described by the general formula (1) wherein the symbols have the meanings as given above in the description.

Description

INHIBITORS OF NEUTRAL ENDOPEPTIDASE (NEP) AND ENDOPEPTIDESA HUMAN SOLUBLE (hSEP) FOR PROPHYLAXIS AND TREATMENT OF NEURODEGENERATIVE DISORDERS DESCRIPTIVE MEMORY The invention relates to a novel use of known benzazepine, benzoxazepine, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives having neutral endopeptidase (NEP) and / or human soluble endopeptidase (hSEP) inhibitory activity. The compounds of the invention are useful for the preparation of pharmaceutical compositions for the prophylaxis and treatment of neurodegenerative disorders. The invention relates to the use of a compound, use disclosed herein for the manufacture of a medicament having a beneficial effect. A beneficial effect is set forth herein or is apparent to one skilled in the art based on the specification and general knowledge of the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition. More particularly, the invention relates to a novel use for the treatment of a disease or condition, use disclosed herein or apparent to one skilled in the art as described in the specification and general knowledge of the art. In embodiments of the invention, specific compounds set forth herein are used for the manufacture of a medicament. In the patent application of E.U.A. 20030045449 it is described that matrix-metalloprotease inhibitors are useful for the treatment of neurodegenerative disorders. Problems associated with this invention are, first, that matrix-metalloprotease inhibitors comprise a broad group of protease inhibitors and, secondly, that according to such a request the metalloproteases should be used in a pharmaceutical composition that also contains a N-NOS inhibitor. It was the object of the present invention to identify specific metalloprotease inhibitors that have a therapeutic value when administered as monotherapy. Surprisingly, it has now been found that benzazepine, benzoxazepine, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives that have neutral endopeptidase (NEP) inhibitory activity and / or human soluble endopeptidase (hSEP) are protective in the damage model. traumatic brain This property makes them useful for the preparation of pharmaceutical compositions for the prophylaxis and treatment of neurodegenerative disorders. The compounds of the invention are known from the European patents EP 0 733 642, EP 0 916 679 and EP 1 468 010, which contain detailed synthesis methods, and the compounds can be described by the general formula (1): where: R-i represents a group of formula (2) or (3): (2) (3) A represents CH2, O or S, R2 and R3 independently represent hydrogen or halogen, R4 and R6 independently represent hydrogen or a group forming a biolabile carboxylic ester; R5 is selected from the group consisting of (C6-C6 alkoxy) C- | -C6 alkyl which may be substituted by CrC6 alkoxy, CrC6 phenylalkyl and C6 phenyloxyalkyl wherein the phenyl group may be substituted with CrC6 alkyl, CrC6 or halogen, and naphthylalkyl of CrC6, R7 and R8 independently represent hydrogen or a group forming a biolabile phosphonic acid ester.

The invention encompasses all compounds of formula (1), their racemates, mixtures of diastereomers and individual stereoisomers, and also includes pharmacologically acceptable salts thereof. Therefore, compounds in which substituents of potentially asymmetric carbon atoms are in the R configuration or in the S configuration belong to the invention. Prodrugs are therapeutic agents that are inactive per se, but that are transformed into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules, used to overcome some barriers that limit the utility of the parent drug molecule. These barriers include, without limitation, solubility, permeability, stability, presystemic metabolism and target limitations (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed .: F. D. King, p.; J. Stella, "Prodrugs as therapeutics", expert Opin. Ther. Patents, 14 (3), 277-280, 2004; P. Ettmayer et al., "Lessons learned from marketed and research prodrugs", J. Med. Chem., 47, 2393-2404, 2004). The prodrugs, ie the compounds that when administered to humans by any known route are metabolized to compounds having the formula (1), belong to the invention. This relates in particular to compounds with hydroxy groups. Such compounds can be reacted with organic acids to provide compounds having the formula (1) which have an additional group which can be easily separated after administration, for example, but without limitation, an amidino, enamino, a Mannich base. , a hydroxylmethylene derivative, an O- (acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone. The pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable metal cation or an organic base, for example an amine. This object can be achieved by preparing the metal salt of the compounds of general formula (1) mentioned above where the metal ion is a lithium ion or a divalent metal ion. The preferred bivalent metal salts are the calcium, magnesium and zinc salts. The most preferred is the calcium salt. The invention relates particularly to compounds of general formula (4): where the symbols have the meanings indicated above. More particularly, the invention relates to compounds of general formula (5): wherein the symbols have the meanings indicated above. The most preferred active substances according to the present invention are: (2R) -2- acid. { [1- ( { [(3S) -1- (carboxymethyl) -2-oxo-2,3,4,5-tetrahydro-1 H-1-benzazepin-3-yl] amino.} Carbonyl) cyclopentyl ] methyl} -4-phenylbutanoic (6): • Acid (2R) -2-. { [1- ( { [(3S) -1- (carboxymethyl) -2-oxo-2, 3,4,5-tetrahydro-1 H-1 -benzazepin-3-yl] amino.} Carbonyl) cyclopentyl ] metl} -4- (1-naphthyl) butanoic (7): • Tert-butyl acetate ((3S) -3- { [(1- {[[(benzyloxy) (ethoxy) phosphoryl] methyl} - cyclopentyl) carbonyl] amino.} -2-oxo -2,3,4,5-tetrahydro-1 H-1-benzazepin-1-yl) (8): Pharmaceutical Compositions The compounds of the invention can be taken to forms suitable for administration by usual processes using auxiliary substances such as liquid or solid carrier materials. The pharmaceutical compositions of the invention can be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or locally (topically). They can also be administered in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gels) or suppositories. Suitable excipients for such formulations are liquid or solid fillers and solvents, solvents, emulsifiers, lubricants, flavors, colorants and / or pH regulating substances normally used for pharmaceutical purposes. Frequently used auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, peanut or sesame, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol. The compounds of the present invention are generally administered as pharmaceutical compositions. Types of pharmaceutical compositions that may be used include, without limitation, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and other types discussed herein or apparent to one skilled in the art based on this specification and general knowledge of the technique. In embodiments of the invention, a package or pharmaceutical equipment comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention is provided. With such a container (such containers) may be associated several written materials, such as instructions for use or a note required by a government agency that regulates the manufacture, use or sale of pharmaceutical products, note that reflects the approval by the agency of the manufacture, use or sale for human or veterinary administration. Very specific formulations suitable for the compounds of the invention were described in patent applications WO 03/068266 and WO 04/062692. The specific compounds described above are for the purpose of further illustrating the invention in greater detail, and therefore are not considered to restrict the scope of the invention in any way. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention set forth herein. Therefore, the descriptive memory and the examples are for the sole purpose of serving as an example, the true scope and spirit of the invention being indicated by the claims.

Traumatic brain damage: delayed neuronal death Methods Contusion device: The contusion device consists of a 40 cm long stainless steel tube, drilled at 1 cm intervals to prevent air compression in the tube. Wistar rats, 230-270 g, were anesthetized with doral hydrate, 400 mg / kg ip, a craniotomy was performed in the right hemisphere, the device that guides a weight that falls on the platform resting on the surface of the encephalic dura was placed , perpendicular to the surface of the skull, and a force of 380 gx cm produced by a 20 g weight was selected to produce cerebral contusion. A maximum brain depression of 2.5 mm was allowed to avoid mechanical puncture of the dura mater. The center of the platform was placed stereotaxically in a position of 1.5 mm posterior and 2.5 mm lateral of the bregma. 3 days after the brain damage, the rats were subjected to perfusion fixation with a solution containing 4% paraformaldehyde in phosphate buffer.

Intracerebroventricular injections (i.c.v.): The compounds were administered intracerebroventricularly (i.c.v.) by a Hamilton syringe in a volume of 5-15 μl. The injections were administered for 5 min, 15 min - 8 hours after the trauma, using the following stereotaxic coordinates in relation to the bregma: AP = -0.5 mm, L = -2 mm and V = -5.5 (Swanson, LW (1992 ) Brain Maps: Structure of the Rat Brain, Elsevier, Amsterdam). Intravenous injections: the compounds were administered i.v. using a 1 ml syringe attached to a 26 gauge needle. After a small incision in the skin the needle was inserted into the left femoral vein. The compounds were administered in a volume of 1 ml / kg of body weight for 30 sec. Morphometric analysis in the hippocampus: Three days after traumatic injury, damage in the CA3 subfield of the hippocampus was determined stereologically at 5 different rostrocaudal levels ranging from 10.21 to 11.21 mm (Swanson, LW (1992) Brain Maps: Structure of the Rat Brain, Elsevier, Amsterdam) and through its lateral mid-axis. To quantitatively evaluate the neuronal loss in the hippocampus, the stereological dissector technique was used (Cruz-Orive, LM &Weibel, ER (1990) Am. J. Physiol. 258, L148-156) to stimulate the numerical density (Nv ) of pyramidal neurons. For the sampling, a counting frame without inclination (0.05 mm x 0.05 mm, dissector height 0.01 mm) and a high opening objective (x40) was used. Normal neurons were identified by the presence of typical nuclei with transparent nucleoplasm and clear nucleoli surrounded by cytoplasm containing Nissl substance. As a limit between subfields CA2 and CA3, the point where the looser disposition of large pyramidal cells is transformed into densely packed pyramidal cells of subfield CA3 was considered. An arbitrary line connecting the lateral ends of the layers with serrated granulated cells was considered as a junction between subfields CA3 and CA4. The compounds of the invention are useful in the prophylaxis and treatment of neurodegenerative disorders such as, for example, attack of ischemia, traumatic brain injury, acute disseminated encephalomyelitis, amyotrophic lateral sclerosis (ALS), retinitis pigmentosa, mild cognitive impairment, Alzheimer's, Pick's disease, senile dementia, progressive supranuclear palsy, subcortical dementias, Wilson's disease, multiple heart disease, arteriosclerotic dementia, dementia associated with AIDS, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedreich's ataxia, ataxia telangiectasia, brain damage related to epilepsy, spinal cord injury, restless legs syndrome, Huntington's disease and Parkinson's disease, striatonigral degeneration, cerebral vasculitis, mitochondrial encephalomyopathies, neuronal ceroid lipofuscinosis, spinal muscular atrophy, lyosome storage disorders l with involvement of the central nervous system, leukodystrophies, disorders of a defective urea cycle, hepatic encephalopathies, renal encephalopathies, metabolic encephalopathies, porphyria, meningitis and bacterial or viral meningoencephalitis, prion diseases, poisonings with neurotoxic compounds, Guillain Barre syndrome, chronic inflammatory neuropathies, polymyositis, dermatomyositis and radiation-induced brain damage. The dosage administered conveniently is 0.001-1000 mg / kg, preferably 0.1-100 mg / kg of the patient's body weight.

Results of pharmacological tests In the traumatic brain injury model described above, the compounds of formula 6 and 7 caused dose-dependent neuroprotective effects. These effects were still evident when formulas 6 and 7 were administered intracerebroventricularly until 8 hours after the trauma.

Response to a given dose of the test compounds with neuroprotective effect The response to a given dose of the test compounds of formula 6 and 7 with neuroprotective effect administered i.c.v. 15 minutes after the trauma to adult Wistar rats. Neuronal densities were determined in the CA3 subfield of the hippocampus as described in the methods. The densities of neurons CA3 ± standard deviation (= SED) were measured in 6 stereotactic levels on the non-traumatized left side of vehicle-treated rats, the right side of traumatized rats treated with vehicle and in rats treated with compounds of formulas 6 and 7, and the results are indicated in table 1 below. In all the following tables, numbers ("n") indicate the number of rats per group, if applicable.

TABLE 1 The injection of vehicle into the right cerebral ventricle of rats subjected to a head trauma resulted in the decrease of neuronal densities in the CA3 hippocampus of up to 48% with respect to the control values, while the injection of 10 μg of a any compound of formula 6 or formula 7 partially prevented neuronal loss in the hippocampus. The analysis of variance ("ANOVA") revealed that treatment with either of the two test substances had a significant protective effect against neuronal loss in the CA3 hippocampus.

Activity after intravenous administration (iv) Vehicle injection resulted in the reduction of neuronal densities in the CA3 hippocampus of up to 53% with respect to the control values, while the injection of 30 or 300 mg / kg of the Test substance of formula (7) partially prevented neuronal loss in the hippocampus, the dose being 300 mg / kg more effective. The analysis of variance ("ANOVA") revealed that the treatment with both tested doses of the test substance had a significant protective effect against neuronal loss in the CA3 hippocampus (PO.001; n = 8 per group). ANOVA also revealed that the 300 mg / kg dose conferred significantly better neuroprotection than the 30 mg / kg dose.

TABLE 2 Neuronal densities in hippocampus CA3, (cells x 103 / mm3), i.v.

Claims (10)

1. NOVELTY OF THE INVENTION CLAIMS 1.- The use of a compound of general formula (1) where R-i represents a group of formula (2) or (3): .. (2) O) A represents CH2, O or S, R2 and R3 independently represent hydrogen or halogen, R4 and R6 independently represent hydrogen or a group forming a biolabile carboxylic ester; R5 is selected from the group consisting of (CiC alkoxy) Jalkyl of C-pCß which may be substituted by C6 alkoxy, phenylalkyl of C6 and phenyloxyalkyl of C-? - C6 where the phenyl group may be substituted with CrC6 alkyl , C6 alkoxy or halogen, and naphthylalkyl of C -? - C6, R and Rs independently represent hydrogen or a group forming a biolabile phosphonic acid ester, all stereoisomers, as well as pharmacologically acceptable salts and prodrugs thereof , for the preparation of pharmaceutical compositions for the prophylaxis and treatment of conditions selected from the group consisting of traumatic brain injury, acute disseminated encephalomyelitis, brain damage related to epilepsy, spinal cord injury, meningitis and bacterial or viral meningoencephalitis, prion diseases , poisoning with neurotoxic compounds and radiation-induced brain damage, and for ischemia attack prophylaxis and neurological damage induced by ischemia attack.
2. 2. The use as claimed in claim 1, wherein said pharmaceutical compositions contain at least one compound of the general formula (4) wherein the symbols have the meanings given in claim 1, all the stereoisomers, as well as the pharmacologically acceptable salts and prodrugs thereof.
3. 3. The use as claimed in claim 1, wherein said pharmaceutical compositions contain at least one compound of the general formula (5) wherein the symbols have the meanings given in claim 1, all the stereoisomers, as well as the pharmacologically acceptable salts and prodrugs thereof.
4. 4, - The use as claimed in claim 1, wherein said compound is (2R) -2- acid. { [1- ( { [(3S) -1- (carboxymethyl) -2-oxo-2, 3,4,5-tetrahydro-1H-1-benzazepin-3-yl] amino.} Carbonyl) cyclopentyl] methyl } -4-phenylbutanoic of formula (6): as well as pharmacologically acceptable salts and prodrugs thereof.
5. 5. The use as claimed in claim 1, wherein said compound is (2R) -2- acid. { [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 of formula (7): as well as pharmacologically acceptable salts and prodrugs thereof.
6. 6. - The use as claimed in claim 1, wherein said compound is tert-butyl acetate ((3S) -3-. {[[(1- {[[(benzyloxy) (ethoxy) phosphoryl] methyl} cyclopentyl) carbonyl] amino} -2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) of formula (8): as well as pharmacologically acceptable salts and prodrugs thereof.
7. 7. The use as claimed in any of the claims 1-6, wherein the pharmacologically acceptable salt is selected from the group consisting of the lithium salt, the calcium salt, the magnesium salt and the zinc salt, the pharmacologically acceptable salt being preferably the calcium salt.
8. 8. The use as claimed in any of the claims 1-6, wherein said treatment is for traumatic brain injury or spinal cord injury.
9. 9. The use as claimed in any of the claims 1-6, wherein said treatment is for acute disseminated encephalomyelitis, brain damage related to epilepsy, meningitis and bacterial or viral meningoencephalitis, prion diseases, poisonings with neurotoxic compounds and radiation-induced brain damage.
10. 10. - The use as claimed in any of claims 1-6, wherein said prophylaxis is for ischemia attack and neurological damage induced by ischemia attack.