WO1998001129A1 - Agents de prevention ou de traitement de maladies neurodegeneratives - Google Patents

Agents de prevention ou de traitement de maladies neurodegeneratives Download PDF

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Publication number
WO1998001129A1
WO1998001129A1 PCT/JP1997/002377 JP9702377W WO9801129A1 WO 1998001129 A1 WO1998001129 A1 WO 1998001129A1 JP 9702377 W JP9702377 W JP 9702377W WO 9801129 A1 WO9801129 A1 WO 9801129A1
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Prior art keywords
neurodegenerative disease
methyl
pharmaceutically acceptable
solvent
active ingredient
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PCT/JP1997/002377
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English (en)
Japanese (ja)
Inventor
Narihiko Yoshii
Ken-Ichi Saito
Ryoichi Ando
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Mitsubishi Chemical Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Publication of WO1998001129A1 publication Critical patent/WO1998001129A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to a novel agent for preventing or treating a neurodegenerative disease. More specifically, it relates to a novel preventive or therapeutic agent for a neurodegenerative disease, comprising an oxygen-containing heterocyclic derivative represented by a specific chemical formula, a pharmaceutically acceptable salt thereof, or a solvent or hydrate thereof as an active ingredient. . Background art
  • Known diseases caused by degeneration of nerve cells include Alzheimer's disease, neuropathy of peripheral nerves, diseases caused by demyelination of nerve cells such as multiple sclerosis, and impaired consciousness or movement during head trauma. ing.
  • Alzheimer's disease is a progressive dementia that develops during the old age (45-65 years old), and pathologically shows numerous senile plaques and neurofibrillary tangles in the brain.
  • the number of patients with this disease has increased with the increase in the elderly population, and is now a socially important disease.No drug is currently available to cure Alzheimer's disease, and no drug is being tested in Alzheimer's disease patients.
  • drugs that act on the neurotransmitter system such as cholinesterase inhibitors, and most drugs aim to improve symptoms. Therefore, there is a strong demand for the development of drugs that can reliably treat or prevent Alzheimer's disease.
  • the causes of neuropathy in peripheral nerves are various, such as complications of diabetes and side effects of anticancer drugs.
  • Diabetes patients have increased rapidly in the era of satiation, also stood for a long time from the appearance of cancer in a convex Pukurasu of mortality, and therefore c cancer number of patients is growing as ever, an increasing number of people suffering from the New ⁇ PASSY Therefore, there is a demand for the development of drugs that are effective in neuropathy so that they can live a normal social life as much as possible.
  • Multiple sclerosis is considered to be an autoimmune disease, and neuropathy appears when the myelin of nerve cells collapses.
  • the number of patients in Japan is not very large, it is designated as one of the incurable diseases for which there is no reliable treatment, and the development of an effective drug as soon as possible is desired.
  • the development of a drug that is truly effective against a neurodegenerative disease is desired, and the present invention is intended to meet such a demand.
  • R 1 is R 4 -C-I, R 4 -0-C or R 4 -S- II
  • R is an optionally substituted C 6 -C 14 aryl group which may be substituted with C,-(: an alkyl group of 2 .; a C 3 -C 8 cycloalkyl group; or substituted Represents an aryl group of C 6 to C, 4 which may have a group), and R 2 is d to C 6 0
  • R 3 represents a hydrogen atom or R 5 —C 1 (R 5 represents a C 1 to C 10 alkyl group), and A has a C 1 to C 3 alkyl group oxygen-containing heterocyclic derivatives represented by yet good C, represents an alkylene group having -C 3), a salt thereof a pharmaceutically acceptable or der o present which the solvent or hydrate thereof as an active ingredient, BEST MODE FOR CARRYING OUT THE INVENTION
  • C] to C 2 defined by R 4 examples include methyl, ethyl, propyl, isopropyl, butyl, ybutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, and the like.
  • Xyl group isohexyl group, heptyl group, octyl group, nonyl group, decyl group, pendecyl group, dodecyl group, tridecyl group, tetradecyl group, pendecyl group, hexadecyl group, hexadecyl group, octayl group decyl group, a nonadecyl group, Ikoshiru and the like, preferably a methyl group or preparative Rideshiru group, tetradecyl group, pen evening decyl group, an alkyl group of C 1 3 ⁇ C 1 6 such Kisadeshiru groups to.
  • alkyl groups may be substituted by a C 6 -CH aryl group such as a phenyl group, a naphthyl group and an anthryl group. Further, these aryl groups may further have a substituent as described later.
  • Examples of the cycloalkyl group 8 include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclo CJ heptyl group, a cyclooctyl group, and the like.
  • Examples of the C 6 -C 14 aryl group include a phenyl group, a naphthyl group and an anthryl group.
  • aryl groups further include a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, C, such as a pentyl group, an isopentyl group, a neopentyl group, and a tert-pentyl group; an alkyl group of 5 ; a trifluoromethyl group; a carboxyl group; a nitro group; a hydroxyl group; a methylenedioxy group; Ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy, tert- butoxy group, Penchiruokishi groups, C such as iso Penchiruokishi group may have one or more substituents fort selected from among al
  • R 4 may have a substituent and may be substituted by a C 6 to C 14 aryl group.
  • a is Al Killen group d -C 3
  • Particularly preferred are those wherein R 4 is a C 14 to C 16 alkyl group and A is a C, to C 3 alkylene group.
  • R 4 may have a substituent and may be substituted by a C 6 to C 14 aryl group. ⁇ C 2.
  • A is preferably an alkylene group of C, to (: 3 . Particularly preferred are those wherein R 4 is a C 13 to C 15 alkyl group and A is d to (: 3 alkylene group).
  • R 4 is preferably an alkyl group of ⁇ C 2e or a C 6 -CH aryl group which may have a substituent.
  • Particularly preferred among the alkyl Le group is an alkyl group of C 14 -C 16.
  • the alkyl group -C S methyl group, Echiru group, blanking opening propyl group, an isopropyl group, a butyl group, Isopuchiru group, sec- butyl group, tert one butyl group, a pentyl group, Examples include an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, and an isohexyl group.
  • alkyl group examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-methyl group And hexyl, isohexyl, heptyl, octyl, nonyl, decyl and the like.
  • Examples of the alkylene group of d to (: 3 defined by A include a methylene group, an ethylene group and a propylene group, and such an alkylene group is a d to (: 3 of a methyl group, an ethyl group, a propyl group and the like. It may have 1 to 2 alkyl groups. It is preferably an unsubstituted alkylene group.
  • Particularly preferred compounds include
  • R 1 ′ and R 2 ′ are the same or different and each represents hydrogen or an optionally substituted hydrocarbon group, and R : ′ represents an optionally esterified carboxy group or A ′ represents an alkylene group, B ′ represents hydrogen, an optionally substituted alkyl group or an acyl group, and m ′ and n ′ each represent 0 or 1. However, m ′ and n ′ represent When both are 0, R 3 'represents a carboxyl group or an acyl group having 7 or more carbon atoms which may be esterified.)
  • the preventive or therapeutic agent for a neurodegenerative disease of the present invention represented by the above general formula (I) can be used as a pharmaceutically acceptable salt.
  • Specific examples of such salts include metal salts such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, and a calcium salt, or ammonium salts, methyl ammonium salts, dimethyl ammonium salts, and dimethyl ammonium salts. Salts and ammonium salts such as dicyclohexyl ammonium salt can be formed.
  • the preventive or therapeutic agent for a neurodegenerative disease of the present invention represented by the above general formula (I) can also be used as a solvate or hydrate.
  • the stereochemistry of the asymmetric carbon present in the preventive or therapeutic drug for neurodegenerative diseases of the present invention represented by the above general formula (I) the (R) -form, (S) -form or (RS) Can take body.
  • preventive or therapeutic agent for a neurodegenerative disease of the present invention represented by the above general formula (I) include, when R 3 is a hydrogen atom, compounds shown in Table 11 below, and R 3 is water. When it is not an elementary atom, the compounds shown in Table 12 below can be mentioned.
  • the active ingredient of the preventive or therapeutic agent for a neurodegenerative disease represented by the above general formula (I) can be produced, for example, by the following method. Manufacturing method 1
  • the amino acid derivative represented by the above general formula (II) may be converted, if necessary, in the presence of a base such as triethylamine or pyridine.
  • the carboxylic acid is activated by reacting it with a condensing agent such as dicyclohexylcarposimid, diphenyl phosphoryl azide, carbonyldiimidazole, oxalyl chloride, isobutyl chlorate, or thionyl chloride, and then represented by the general formula (III).
  • a condensing agent such as dicyclohexylcarposimid, diphenyl phosphoryl azide, carbonyldiimidazole, oxalyl chloride, isobutyl chlorate, or thionyl chloride
  • the compound represented by (IV) is obtained.
  • a solvent suitable for each condensing agent may be appropriately selected and used, and the reaction conditions may be performed under conditions suitable for each condensing agent.
  • the obtained compound (IV) is treated with a reducing agent such as dibutyl aluminum hydride, sodium borohydride / cerium chloride, etc.
  • Compound (V) produced by Production Method 1 is converted to an organic compound such as methylene chloride, 1,2-dichloroethane, dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetonitril, and toluene.
  • an acid anhydride represented by the above general formula (R 5 CO) 20 in the presence of a base such as pyridine, tritylamine or 4-dimethylaminopyridine, the above-mentioned formula (R 5 CO) 20 is obtained.
  • the compound represented by VI) can be obtained. This reaction can be performed without a solvent.
  • protection and deprotection of a functional group may be required.
  • a protecting group suitable for the functional group is selected, and an experimental operation is performed using a method known in the literature. Just do it.
  • the compound (V) in which R 3 is a hydrogen atom has a strong inhibitory activity on calpain, one of the cysteine proteases.
  • the compound (VI) in which R 3 is an R 5 —C 1 (representing an alkyl group of R 5 to C,.) Is a prolactone derivative (V) having a strong inhibitory activity against calpain.
  • Calpain is usually present in cells as a stable precursor, and when the intracellular calcium concentration rises for some reason, calcium binds to calpain, changes to an activated form by self-destruction, and acts as a proteolytic enzyme Become like
  • Amyloid is a major component of senile plaque, one of the characteristic pathological findings found in the brain of Alzheimer's disease patients, and its precursor, amyloid precursor protein (APP), is proteolytically degraded. Produced by cleavage by enzymes. As a cleaving enzyme, the involvement of calpain has been suggested. (Biochem i Stry, 33, 455, pp. 1994). As one of the proofs, there is a report that calpain inhibitors suppressed / 3 amyloid secretion from cells overexpressing APP (Neuron, Vol. 14, p. 651, p. 19, 1999). 5 years).
  • MAP2 microtubule-associated protein 2
  • MAP2 is one of the pulmonary skeletal proteins, is present at very high concentrations in dendrites of neurons, is a major component of the cross-link structure between microtubules and between microtubules and neurofilaments, It has a strong relationship with plasticity (Scienti ⁇ ic Ame rican, 259, 56, 1988).
  • MAP2 is one of the very good biological substrates of calpain, and it has been suggested that MAP2 degradation may be an indicator of calpain activation in 8S (Anna 1 softhe New York A cad emy of Sciences.
  • a substance that suppresses MAP2 degradation in the brain is likely to suppress the action of calpain in BS, and for the reasons described above, it is considered that the substance is a prophylactic or therapeutic agent for Alzheimer's disease .
  • calpain inhibitors are thought to be effective for diseases that are said to be caused by demyelination of neuronal cells, such as multiple sclerosis and new ⁇ -pathy of peripheral nerves.
  • calpain inhibitors are considered to be effective in improving consciousness disorder and movement disorder in head trauma.
  • the ratio of the therapeutically active ingredient to the carrier ingredient is usually 1% by weight to 90% by weight.
  • the medicament of the present invention includes granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions and liquids. It may be administered orally in the form of an injection, or it may be administered as an injection intravenously, intramuscularly or subcutaneously. It can also be used as a suppository. It may also be prepared as an injection powder and used. Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral and parenteral use can be used to prepare the agents of the present invention.
  • Liquid preparations for oral administration ie, emulsions, syrups, suspensions, solutions and the like, contain commonly used inert diluents such as water or vegetable oils.
  • the preparation may contain, in addition to the inert diluent, auxiliary substances such as wetting agents, suspending aids, sweetening agents, fragrances, coloring agents or preservatives.
  • Liquid preparations may be contained in capsules of absorbable substances such as gelatin.
  • Solvents or suspensions used in the preparation of parenteral preparations, i.e., injections, suppositories, etc. include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, etc.
  • bases used for suppositories include cocoa butter, emulsified cocoa butter, laurin fat, witetbsol and the like.
  • the preparation method of the preparation may be a conventional method.
  • the clinical dosage when used by oral administration, depends on the strength, age, disease state, and symptom of the compound of the active ingredient for adults, generally in the range of 0.01 to 1 OOOmg daily. It is more preferable to increase or decrease as appropriate.
  • the daily dose of the agent of the present invention may be administered once a day, or divided into two or three times a day at appropriate intervals, or may be administered intermittently.
  • the daily dose of the compound of the present invention for an adult is 0.0001 to! It is desirable to administer 0 O mg continuously or intermittently.
  • the filtrate was washed with saturated brine, dried over magnesium sulfate, and then filtered.
  • the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate containing 30% hexane) to obtain 19 lmg of the desired product.
  • Example 3 to Example 42 were produced in the same manner as in Example 1 and Example 2. The physical properties are described below.
  • Example 8 (3 S)-3-((S) — 4-Methyl-2-pentadecanoylamino novarelylamino) — 2-Tetrahydrofurafuranol (Compounds in Table 1) Manufacture of number 6 4)
  • Example 1 (3 S)-3- ⁇ (S) 1-2-(4-methylbenvylamino)-1-4-Methylvalerylamino ⁇ 1- Manufacture of tetrahydro CJ furanol (compound No. 83 in Table 1)
  • m-calpain was purified from rat brain by the method described in the literature (J0 urna 1 of Biologica 1 Chemistry, vol. 25, p. 310, p. 1984). The inhibitory activity was measured according to the method described in the literature (Journal of Biol ogica 1 Chemistry, Vol. 25, Vol. 128, p. The results are shown in Table 3.
  • Table 13 shows that the compound of the present invention shows a strong inhibitory activity on calpain.
  • Table 1 3 Inhibitory activity of calpain
  • Test Example 2 Production of active metabolites in blood
  • HP LC HP LC
  • Eight-week-old male wister rats were anesthetized with pentobarbital (4 OmgZkg), and kainic acid (0.4 / g) was injected into the lateral ventricle. Drugs were administered orally 60 minutes before and 60 minutes after kainic acid injection. Twenty-four hours after the kainic acid injection, the dorsal half of the hippocampus was excised with 10 mM MT containing 1 mM EDTA, 1 mM EGTA, 1 mM DTT, I mM Benzamidine, 0.1 mM Leptin and 0.1 mM pAPMS F.
  • ris—HC 1 (pH 7.4) was added to 0.3 ml, homogenized, and centrifuged (12000 ⁇ g) at 4 ° C. for 20 minutes. The polypeptide portion was separated from the obtained cytoplasmic fraction by SDS-PAGE, and transferred to a PVDF membrane by Western blotting.
  • MAP2 was immunostained with rat brain MAP2 monoclonal antibody and Alkali phosphatase, and the colored band was laser densitometry overnight (PD-110, MD) Was measured.
  • the active ingredient of the drug of the present invention is suspended in 0.5% CMC-Na aqueous solution on SD male and female rats.
  • the suspension was administered by oral gavage and the symptoms were observed for 7 days.
  • the following components were mixed according to a conventional method, and filled in soft capsules.
  • the following components were mixed according to a conventional method to prepare a 1 ml ampoule.
  • the preventive or therapeutic agent for neurodegenerative diseases of the present invention has an inhibitory activity on calpain and an inhibitory effect on MAP2 degradation, it can be used for Alzheimer's disease and diseases caused by demyelination of neuronal cells (multiple diseases). It is useful as a preventive or therapeutic agent for neurodegenerative diseases such as sclerosis, neuropathy, etc., and head injury (consciousness disorder, movement disorder).

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  • Pharmacology & Pharmacy (AREA)
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Abstract

Agents de prévention ou de traitement de maladies neurodégénératives, renfermant, à titre d'ingrédient actif, des dérivés hétérocycliques oxygénés répondant à la formule générale (I), dans laquelle R1 représente (a), (b) ou (c) (où R4 représente alkyle, aryle ou cycloalkyle); R2 représente alkyle; R3 représente hydrogène ou acyle; et A représente alkylène. Ces médicaments sont efficaces dans la prévention ou le traitement des maladies neurodégénératives telles que la maladie d'Alzheimer, ces maladies étant dues à la démyélinisation dans les cellules nerveuses, par exemple la sclérose en plaques et les neuropathies, et les troubles associés aux traumatismes céphaliques, par exemple les troubles de la conscience et de la motricité.
PCT/JP1997/002377 1996-07-10 1997-07-09 Agents de prevention ou de traitement de maladies neurodegeneratives WO1998001129A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
JP8/180784 1996-07-10
JP18078496 1996-07-10
JP8/200757 1996-07-30
JP20075896 1996-07-30
JP20075796 1996-07-30
JP8/200758 1996-07-30
JP20701296 1996-08-06
JP8/207012 1996-08-06

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WO1998001129A1 true WO1998001129A1 (fr) 1998-01-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000021550A3 (fr) * 1998-10-13 2000-07-27 Harvard College Methodes et compositions de traitement des maladies neurodegeneratives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05246968A (ja) * 1991-07-01 1993-09-24 Mitsubishi Kasei Corp ケトン誘導体
JPH08104685A (ja) * 1993-09-03 1996-04-23 Takeda Chem Ind Ltd ラクトール誘導体、その製造法および用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05246968A (ja) * 1991-07-01 1993-09-24 Mitsubishi Kasei Corp ケトン誘導体
JPH08104685A (ja) * 1993-09-03 1996-04-23 Takeda Chem Ind Ltd ラクトール誘導体、その製造法および用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000021550A3 (fr) * 1998-10-13 2000-07-27 Harvard College Methodes et compositions de traitement des maladies neurodegeneratives

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