TW200522974A - 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 10 and EP 0 916 679, and can be described by the general formulae (1): , wherein the symbols have the meanings as given above in the description.

Description

200522974 IX. Description of the invention: [The field of rhyme ^ Ming ^ technology] The present invention relates to known benzoazepines with neutral endopeptidase (NEP) and / or human soluble endopeptidase (hSEP) inhibitory activity. A new use of pyrene, benzoxaZepme, benzothiazepine-N-acetic acid and phosphono-substituted benzazepinone derivatives . The compounds of the present invention prepare pharmaceutical compositions for the prevention and treatment of neurological diseases. -The present invention relates to the use of a compound disclosed herein for the preparation of amusement which provides beneficial effects. The beneficial effects are disclosed herein or will be apparent to those skilled in the art from the specification and common general knowledge in the art. The invention also relates to the use of the compounds of the invention for the preparation of a treatment or condition. More specifically, the present invention relates to a disease or I5 symptom for treating a disease disclosed herein or known to those skilled in the art based on the description and well known in the art. In embodiments of the invention, the specific compounds disclosed herein are used in the preparation of a medicament. I would like to thank you in advance for the patented towels, which are the materials for treating neurodegeneration = matrix_metalloproteinase inhibitors for diseases. The problems related to the invention are firstly a qualitative-metalloproteinase inhibitor comprising a broad group of protease inhibitors, and the first metalloprotease according to this declaration must be ... a pharmaceutical composition of a preparation. It also contains N-NOS inhibitory content of the invention. 3 An enzyme inhibitor, which has therapeutic value when administered as a monotherapy as a target of the present invention 20 200522974. It is remarkable that benzonitrogen, benzoweiza, benzopyrazine and benzopyrazine have been found to have neutral endopeptidase (NEp) and / or human soluble endopeptidase_P) inhibitory activity. -N-acetic acid and phosphino substituted benzoazepinone derivatives have protective effects in animal models of traumatic brain injury. This property makes them useful for preparing pharmaceutical compositions for the prevention and treatment of neurodegenerative diseases.

[Formula; J The compounds of the present invention are known according to European patents EP 0 733 642, EP 0 910 679 and EP 1 468 010, including their detailed synthesis, and can be described by 10 general formula (1):

among them:

Ri represents a group of formula (2) or (3):

Re (2) (3) A represents CH2, O or S, R2 and R3 independently represent hydrogen or halogen, R4 and Re independently represent hydrogen or a group that forms a biologically unstable carboxylic acid ester; only 5 are free (CrQ ) Alkoxy (crC6) alkynyl, which can be substituted by (crc6) alkoxy 200522974, benzyl- (CrC6) -alkyl and phenoxy- (CrC6> alkyl, where phenyl can be replaced by (CrQ) A group consisting of an alkyl group, a (CrC6) -alkyloxy group, or an oxo group, and an ethyl group- (CrC6) -alkyl group, and Rs independently represent hydrogen or a group that forms a biolabile phosphonate. 5 All have the formula (1) Compounds, racemates, diastereomeric mixtures and individual stereoisomers belong to the present invention; and also include their pharmacologically acceptable salts. Therefore, the Compounds with a substituent in the R-configuration or ^ configuration belong to the present invention. Prodrugs are 10 therapeutic agents that are themselves inactive but are converted into one or more active metabolites. Prodrugs are used to overcome certain uses of the parent drug molecule Bioreversible derivatives of drug molecules that are barriers. These barriers include, but are not limited to, solubility, permeability, stability, pre-systemic Presystemic metabolism and targeting restriction (Medicinal Chemistry Principles and Practice, 1994, ISBN 0-85186-494-5, Ed .: F. D. King, p. 215; J. Stella, "Prodmgs as

15 therapeutics' Expert Opin. Ther. Patents. 14 (^) 277-280, 2004 · P

Ettmayer et al., "Lessons learned from marketed and investigational prodrugs ,, J. Med. Chem., 47, 2393-2404, 2004). Prodrugs are metabolized to have the formula (1) when administered to a human by any known route. The compound of the compound) belongs to the present invention. Specifically, this relates to the compound 20 having a hydroxyl group. This compound can be reacted with an organic acid to give a compound having the formula (1), in which there is an additional compound that is easily removed after administration. Groups, including, but not limited to, glutinous rice, crocetin, chinesyl domains, meridian-methylene derivatives, 0- (acyloxymethylene carbamate) derivatives, carbamates , Esters, amides, or enaminones. Pharmaceutically acceptable salts can be obtained by standard methods well known in the art 200522974, for example by mixing a compound of the invention with a suitable metal ion or organic domain such as an amine. The metal salt of the compound of the general formula (1) can be prepared by preparing a metal salt of the towel which is a rotor or a divalent gold linseed. A preferred divalent metal salt is a raw material. The most preferred is a feed salt. Invention Don't involve compounds with general formula (4)

The symbols have the meanings given above. More particularly, the invention relates to compounds having the general formula (5)

The symbols have the meanings given above. The most preferred active substances according to the invention are: • (2R) -2-{[H {[(3S) -H carboxyfluorenyl) -2-oxo-2,3,4,5-tetrahydro_1 1.Benzoazepine-3-yl] amino} carbonyl) cyclopentyl] methylbuthenyl 4-phenylbutyrate:

8 15 200522974 • (2R) -2-{[l-({[((3S) -l- (Weiranyl) -2-oxo-2,3,4,5-tetrahydro-111-1-benzonitrogen Hetero-3-yl] amino} carbonyl) cyclopentyl] methyl} _4naphthyl) fluorene butyrate:

• ((3S) -3-{[(l-{[(benzyloxy) (ethoxy) filled acyl] methyl} cyclopentyl) supper 5-yl] oxo-2,3,4 , 5-tetrahydro-111-1-benzoazepine small group) tert-butyl acetate (8):

Pharmaceutical composition 10 The compound of the present invention can be formed into a form suitable for administration by a conventional method using an excipient such as a liquid or solid carrier material. The present pharmaceutical composition can be administered enterally, sigma, parenterally (intramuscularly or intravenously), rectally or locally (or icaily). They can be in the form of solutions, powders, tablets, capsules (including microcapsules), soft t (creams or gels) or suppositories. Suitable excipients for this formulation are-conventional tinctures or solid fillers and extenders, solvents, emulsifiers, flavoring agents, colorants and / or buffering substances. Can be mentioned often: " ::: ^ stone, gift protein, gelatin, starch, oils such as A, vegetarian and its clothing, animals and plants' Yang Xiang Yue Cai oil, peanut oil or sesame oil, polyethylene glycol and solvents 15 200522974 Such as sterile water and mono- or polyhydric alcohols such as glycerin. The compounds of the invention are generally administered as pharmaceutical compositions. The types of pharmaceutical compositions that can be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and others disclosed herein or otherwise known to those skilled in the art based on 5 instructions and common general knowledge in the art Types of. In an embodiment of the present invention, a medicinal package or kit is provided, which comprises one or more cereals filled with one or more ingredients of the pharmaceutical composition of the present invention. Associated with these containers are various written materials, such as instruction manuals, or notices in the form designated by government agencies that regulate the production, use, or sale of pharmaceuticals. The 'σ' notice reflects the approval of the production and use of Longchain for human sickle applications. 0 Very specific formulations suitable for the compounds of this invention have been disclosed in patent applications WO 03/068266 and WO 04/062692. The specific compounds described above are intended to further illustrate the present invention in more detail, and therefore should not be construed as limiting the invention in any way. Other implementations of the invention will be apparent to those skilled in the art from the following months and after the practice of the invention disclosed herein. Therefore, it is to be considered that the specification and the examples are merely examples, and the true scope and spirit of the present invention are not the same as the scope of patent application. 20 Traumatic thin scallop injury · Delayed neuron death Method Contusion device · Contusion device consists of a stainless steel tube with a length of 40cm and perforations at a distance of 1cm to prevent empty money from shrinking in the tube. Xianhe trichloroacetic acid was used to anesthetize Wistar rats with a size of 23-270 g, and performed in the right hemisphere. 200522974 Gu Yuedao operation will guide the weight of the fall to the f of the pedal on the dura mater. Placed perpendicular to the recording surface of the head, choose to generate the monthly self-contusion in the transfer gxc_ generated by 2 tons. Allow writing on the surface of the brain with a maximum of 2 · 5 faces to avoid mechanical thorns of the dura mater. The center of the foot pedal is placed stereotactically at the U leg and the side 5 2 · 5 mm after the anterior food point. Use 40% in phosphate buffer. The paraformaldehyde solution allowed the rats to undergo perfusion fixation 3 days after the injury. Brain-to-intravenous (ιχ · ν ·) injection: Intraventricular administration of the compound was performed by a Hamitoon syringe with a volume of 5-15 µ1. After the trauma was caused, injection was performed with the following stereotactic coordinates over 5 minutes, 15 minutes, and 8 hours: Αρ = _〇 · 5 mm, L = _2mm, and 10 V & 5.5, relative to the anterior iliac point (SwansOn, L w (1992) Brain Maps:

Structure of the Rat Brain, Elsevier, Amsterdam). Intravenous injection: The compound was administered intravenously using an imi syringe connected to a 26 gauge needle. A needle is inserted into the left femoral vein along a small incision in the skin. Compound administration was performed in a volume of 1 ml / kg body weight within 30 seconds. 15 Hippocampal morphometric analysis. Three days after traumatic injury, the damage in the hippocampal CA3 subregion was determined stereoscopically at five different rostrocaudal levels extending from 10.21 mm to 11.21 mm (Sw anson, LW (1992 ) Brain Maps: Structure of the Rat Brain, Elsevier, Amsterdam). In order to quantitatively evaluate neuronal loss in the hippocampus, three-dimensional stripping technique (Cruz-Orive, L.M. & Weibel, E.R. (1990) Am. J. Physiol. 258, L148-L156) was used to evaluate the cone. Numeric Density (Nv) of the neuron. An unbiased counting frame (0.05 mm X 0.05 mm; stripper height 0.01 mm) and a high-aperture objective lens (x40) were used for sampling. Normal nerves were identified by the presence of a typical nucleus surrounded by cytoplasm containing Nissl matter with a clear nucleus and clear nucleoli. The boundary between the CA2 and CA3 subregions is considered to be the point where the looser arrangement of large cones leads to the cones of the subregions. Arbitrary lines connecting the lateral ends of the faceted cell layer are considered to be the connection between the subregions ㈤ and ㈤. 5 Shuming compounds are used to prevent and treat neuronal degenerative diseases, such as missing stroke, traumatic brain injury, acute disseminated encephalomyelitis, amyotrophic lateral sclerosis (ALS), pigmented retinitis, mild Cognitive Impairment, Alzheimer's Disease, Pick's Disease, Alzheimer's Disease, Progressive Supranuclear Leukemia, Subcortical Cancer Dementia, Wilson's Disease, Multiple Infarction Disease, Arteriosclerotic Dementia, Aids-related Dementia, Cerebellar degeneration, spinal cerebellar degeneration syndrome, Friedreich ataxia, ataxia · capillary telangiectasia, thin-related brain injury, spinal cord injury, t-movement ',' 5 signs, ·? Tinton's disease and Parkinson's disease, striatum nigra degeneration, cerebral arthritis, mitochondrial encephalomyopathy, neuronal cerebellolipidosis, spinal muscular atrophy, lysosomal storage involving the central nervous system Disease, malnutrition of the brain, 15 deficiencies in urea loop, hepatic encephalopathy, renal encephalopathy, metabolic encephalopathy, porphyria, bacterial or viral meningitis and meningoencephalitis, prion disease, neurotoxic compound poisoning, Gaubach syndrome, chronic inflammatory neuropathy, polymyositis, dermatomyositis, and radiation-induced brain damage. The dose administered should preferably be 0.001 · 1000 mg / kg, with an optimal body weight of -1 to 100 mg / kg. Pharmacological test results In the above-mentioned traumatic brain injury model, compounds having formulae 6 and 7 caused a dose-dependent neuroprotective effect. These effects are still significant when the compounds having formulae 6 and 7 are administered intraventricularly up to 8 hours after trauma. 12 * 200522974 ‘Nerve protection of weaving compounds as ㈣ dose response / 15 minutes after trauma in adult Wistar rats with compounds of formulae 6 and 7: ^ Dose response of intraventricular administration of Risi ’s neurological 蒦 effect. As described in the method, 'sense neuron density in CA3 hippocampal region. The 6 stereotactic levels of CA3 were measured on the non-damaged left side of the 5 major machines treated with excipients and the injured right side of rats treated with excipients and in rats treated with compounds having formulae 6 and 7 Density of neurons ± standard deviation (= SED). The results are shown in Table 丨 below. In all the tables below, the number ("η") indicates the number of rats in each group when used. Density of hippocampal A3 neurons, cell X 1 stereotactic level 3 left side of the vehicle ^ (n = 8) right side of the vehicle (n = 8) compound Yang formula (6) (N = 8) compound formula (7) 10.21 148.5712.23 90.29 ± 5.54 112.5111.40 107.25115.19 10.41 154.29 ± 3.73 84.86 ± 7.29 103 · 75 ± 11 · 80 100.25114.71 10.61 158.86 ± 3.44 77.7115.82 101.75114.80 93.50 ± 16.96 10.81 155.71 ± 4.07 76.57 ± 13.45 98.50 ± 10.68 93.50 ± 12.36 11.01 150.86 ± 1.95 85 · 71 ± 10.0 · 98 96.75 ± 13.98 101.50 ± 18.81 11.21 148.29 ± 1.38 Γ 92.86 ± 8.71 101.75 ± 15.17 107.75 ± 16.51 10 Injection of excipients to those who have suffered head trauma In the right ventricle of rats, the CA3 hippocampal neuron density was reduced to 48% of the control value, and the injection of a compound of tannic formula 或 or a compound of formula (7) partially prevented hippocampal neuron loss. Analysis of variance ("ANOVA") showed that the two test substances had a significant protective effect on neuronal loss in the CA3 hippocampus. 15 Active intravenous excipients after intravenous (iv) administration resulted in a decrease in CA3 hippocampal neuron density to a control value of 53 ° / 〇, while injection of a test substance of 30 or 300 mg / kg formula ⑺ partially prevented hippocampal nerves The most effective was a 300 mg / kg dose. Analysis of variance ("ANOVA") shows that the two test substances are affected by the nerves of the CA3 hippocampus 13 * 200522974

V loss had significant protective treatment effects (P <0.001; n = 8 / group). ANOVA also showed that a dose of 300 mg / kg resulted in a significantly better neuroprotective effect than a dose of 30 mg / kg. Neuron density in the hippocampus of stupid 2LCA3 丨 fine infusion ^ i〇3 / mm3), intravenously administered stereotactic horizontal excipients left Cn = 8) excipients right (η = 8) IV / 111111 factory nr Formula ⑺ 300MG / KG (N = 8) τϊτ Chemical correction type 30MG / KG (N = 8) 10.21 150.50 ± 1 · 41 97 · 50 ± 7.39 126 · 50 ± 5 · 53 107.50 ± 6.99 10.41 154.25 ± 1.67 90 25 ± 5 · 60 117 · 75 ± 4 · 95 102.25 ± 7.89 10.61 157.2512.38 84 · 75 ± 7.09 110 · 00 ± 7.01 100.75 ± 9.91 10.81 154.00 ± 1.85 88 · 00 ± 7.17 106.75 ± 7.48 101 · 75 ± 9 · 65 11.01 149.00 ± 1.07 94 · 00 ± 5 · 45 116 · 50 ± 9 · 06 111 · 25 ± 7.55 11.21 146.00 ± 1.51 99.75 ± 8.24 125.25 ± 5.01 117.75 ± 10.11 5 [Brief description of the drawing] (None) [Main] Component symbol description] (none)

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Claims (1)

200522974 10. Scope of patent application: L-Use of compounds of general formula ⑴, all stereoisomers thereof, and pharmacologically acceptable salts and prodrugs, for preparing pharmaceutical compositions for preventing and treating neurodegenerative diseases: Wherein: R! Represents a group of formula (2) or (3): Rs r6 / 〇 (2) 〇II R70〇 or8 15 200522974 r 2. If the application is the oldest in the scope of patent application, it is characterized by the drug combination The compound contains a compound of the general formula (4), all stereoisomers thereof, and at least one of a pharmacologically acceptable salt and a prodrug (4) 0 The symbols in it have the meaning given by the patented patent. 3. The use according to item 1 of the scope of patent application, characterized in that the pharmaceutical composition contains a compound of the general formula (5), all stereoisomers thereof, and at least one of a pharmacologically acceptable salt and a prodrug (5) The symbol φ 10 has the meaning given in item 1 of the scope of patent application. 4. The use of item 1 in the scope of patent application, characterized in that the compound is (2R > 2) [H {[(3SH- (Weimethyl) oxo_2,3,4,5, hydrogen -1H-1-Benzazine_3.yl] aminopropyl) cyclopentyl] methylbutylenyl butyric acid: 16 15 • 200522974 and its pharmacologically acceptable salts and prodrugs. 5. If applying for a patent, Wu Zheng, Qian Zheng lies in the fact that the compound is a compound with formula 该 called the methyl group> 2_oxo_23,4,5 ~ -m ] Amino group) Cyclofluorenyl group] Butyric acid: V is not And its pharmacologically acceptable salts and prodrugs. 6. The oldest application in the scope of patent application, which is characterized in that the compound is of the formula (called 3-{[((1_lyticoxy) (ethoxy) phosphorusyl] methyl) cyclopentyl group) ] Aminob 2-oxo_2,3,4,5_ A brief talk about tert-butyl acetate of benzogas: And its pharmacologically acceptable salts and prodrugs. 7. The use of any of the 6 items in the scope of application for patent red, characterized in that the pharmacologically acceptable salt is selected from the group consisting of lye, good salt, town salt, and rhenium salt, and the pharmacologically acceptable salt is preferably Calcium salt. 8. The use of "Gu Gu Hong 7 She Ren" is characterized in that the neurodegenerative disease is ischemic stroke, traumatic brain injury, acute disseminated brain 17 15 200522974 10 15 Myelitis, amyotrophic lateral sclerosis (ALS), pigmented retinitis, mild cognitive impairment, Alzheimer's disease, Pick's disease, Alzheimer's disease, progressive epilepsy, subcortical dementia, Wilson Disease, multiple infarction, arteriosclerotic dementia, AIDS-related dementia, cerebellar degeneration, spinal cerebellar degeneration syndrome, ataxia, continuous dysfunction, capillary telangiectasia, brain damage related to epilepsy, spinal cord Injuries, ADHD, Utinton's disease and Parkinson's disease, striatum nigra degeneration, cerebral vasculitis, mitochondrial encephalomyopathy, neuronal waxy lipofuscinosis, spinal muscular atrophy , Lysosomal storage disorders involving the central nervous system, white matter malnutrition, urea loop defects, hepatic encephalopathy, renal encephalopathy, metabolic encephalopathy, porphyria, bacterial or viral meningitis and meningoencephalitis, Prion disease, neurotoxic compound poisoning, Gaba syndrome, chronic inflammatory neuropathy, polymyositis, dermatomyositis, and radiation-induced brain damage. 9. The use according to item 8 of the scope of patent application, characterized in that the neurodegenerative disease is ischemic stroke. 10. The use according to item 8 of the scope of patent application, characterized in that the neurodegenerative disease is traumatic brain injury. u. The use of item 8 of the scope of patent application ', characterized in that the neurodegenerative disease is senile dementia. 12. The use according to item 8 of the scope of patent application, characterized in that the neurodegenerative disease is Alzheimer's disease. C. The use according to item 8 of the scope of patent application, characterized in that the neurodegenerative disease is spinal cord injury. '@ 14. If the application in the scope of patent application No. 8 is used, it is characterized in that the neurodegenerative disease 20 200522974 is a hyperactive leg syndrome. 15. The use according to item 8 of the scope of patent application, characterized in that the neurodegenerative disease is Parkinson's disease. 19 200522974 ^ VII. Designated Representative Map: (1) The designated representative map in this case is: (). (None) (b) Brief description of the component symbols in this representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: