WO1998004539A1 - Derives heterocycliques oxygenes - Google Patents

Derives heterocycliques oxygenes Download PDF

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Publication number
WO1998004539A1
WO1998004539A1 PCT/JP1997/002598 JP9702598W WO9804539A1 WO 1998004539 A1 WO1998004539 A1 WO 1998004539A1 JP 9702598 W JP9702598 W JP 9702598W WO 9804539 A1 WO9804539 A1 WO 9804539A1
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WO
WIPO (PCT)
Prior art keywords
salt
solvate
hydrate
alkyl group
methyl
Prior art date
Application number
PCT/JP1997/002598
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English (en)
Japanese (ja)
Inventor
Ryoichi Ando
Hirokazu Masuda
Keiichi Aritomo
Narihiko Yoshii
Ken-Ichi Saito
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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.)
Filing date
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Application filed by Mitsubishi Chemical Corporation filed Critical Mitsubishi Chemical Corporation
Publication of WO1998004539A1 publication Critical patent/WO1998004539A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-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
    • C07D307/18—Heterocyclic compounds containing five-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
    • C07D307/22—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms 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 atoms
    • 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 oxygen-containing heterocyclic derivative. More specifically, the present invention relates to an oxygen-containing heterocyclic derivative, a salt thereof, a solvate thereof or a hydrate thereof, which has a strong inhibitory activity on cysteine protease, especially calpain.
  • cysteine proteases As papain, cathepsin B, cathepsin H, cathepsin L, calpain, interleukin-1 converting enzyme, and other cysteine proteases work in vivo, their abnormal redoxing causes various diseases. Increasingly, cysteine protease inhibitors have been reported to be effective in animal models of these diseases.
  • cysteine proteases such as kyrupain and cathepsin B are involved in early processes such as loss of Z-rays through degradation of muscle fiber proteins. It is considered (Metabolism, Vol. 25, extra edition "Metabolic Disease Highlight", p. 183, 1988). E-64-d, a cysteine protease inhibitor, has been reported to have a prolonged survival effect in muscular dystrophy hamsters (Journa 1 of Pharma cobio Dyn amics, Vol. 10, p. 678). , 1987). Therefore, cysteine protease inhibitors are considered to be therapeutic agents for muscular dystrophy, muscular atrophy and the like.
  • ischemic diseases such as myocardial infarction and stroke
  • the main cause of cell damage after ischemia is active oxygen produced by xanthine oxidase.
  • Converted to oxidase hexane Chin dehydrogenase elevated C a 2 + concentration in the O connexion activated Chikararu z fin is a precursor of xanthine oxidase in the course of ischemia limited proteolysis to There is a theory that there is
  • Amyloid is a protein deposited in the senile plaques specific to the brain of patients with Alzheimer's disease, and it is known that this amyloid is formed by the degradation of the amyloid protein pre-specialized body (APP). I have. Amyloid is not produced by normal metabolism of APP, but amyloid is activated by abnormal metabolism by abnormally increased protease, which is considered to be senile plaque (Scientific American, 1 99 1 year 1 January issue, page 40). Therefore, inhibitors of proteases are expected to be therapeutics for Alzheimer's disease.
  • calpain inhibitors are effective in improving consciousness disorder and movement disorder in head trauma.
  • cataracts are crystallin, a water-soluble protein in the lens. It is said that the lens is opaque due to hydrolysis by the action of the mouth thease. Cataracts in experimental models and certain types of human cataracts have elevated concentrations of calcium in the lens (Inv estigative Opthal mology & Visual Science, Vol. 28, 1702-1). 1987, Experimantal Eye Research, Vol. 34, pp. 413, ⁇ 982), and because the most proteases in the lens are calpain ( L ensand Ey e Toxicity Research, Vol. 6, 725 ⁇ , 1989), it is considered that abnormal dying of calpain is one of the causes of cataract.
  • cysteine protease an enzyme that converts pre-interleukin 1S to interleukin 1/3 (interleukin 1/3 converting enzyme) was found to be a cysteine protease (Nature, 356, 768, (1992), it became clear that activation of cysteine protease plays an important role in the development of inflammation. For these reasons, it is believed that inhibitors of cysteine protease can be used as anti-inflammatory agents. ⁇
  • the type I allergic reaction progresses through immunoglobulin E (IgE) produced by sensitizing a living body to an antigen. It has been reported that essutin A, a cystine protease inhibitor, specifically inhibits IgE production and has no effect on IgG production (The Journal of Antibiotics, Vol. 42). , 1362, 11989). Therefore, it is considered that a cysteine protease inhibitor can be used as an antiallergic agent.
  • IgE immunoglobulin E
  • calpine When hepatocytes are necrotic, damage to the cell membrane increases the permeability of Ca 2+ , increasing the intracellular Ca 2+ concentration and activating calpain. It is thought that cell death occurs as a result of decomposition. Therefore, inhibitors of calpine can be used as therapeutics for fulminant hepatitis.
  • Cathepsins such as cathepsin B and cathepsin L, are involved in the degradation of bone collagen in osteoclasts.
  • Administration of E-64, a cathepsin inhibitor, or Estatin A, to rats with increased bone destruction by administration of parathyroid hormone may decrease blood calcium and hydroxyproline concentrations. It has been reported (Biochemical and Biophysical Research Research, Vol. 125, 1 Page, 1984, JP-A-2-218610). Therefore, inhibitors of cathepsins are considered to be therapeutic agents for osteoporosis and hypertensive lucidemia.
  • calpain substrates examples include sex hormone receptors such as estrogen receptor and androgen receptor. Calpain is known to activate these receptors, and abnormal translation of calpain causes diseases that may be due to abnormal activation of sex hormone receptors, such as breast cancer, prostate cancer, and prostatic hypertrophy. It is said that. Therefore, calpain inhibitors would be therapeutic agents for the above diseases. It is said that epidermal growth factor (EGF) receptor is activated along with canceration of cells, and calpain is known to activate the EGF receptor using the EGF receptor as a substrate.
  • EGF epidermal growth factor
  • calpain inhibitors can be used as platelet aggregation inhibitors.
  • cysteine proteases cause various diseases, and some cysteine protease inhibitors have been reported to be effective in animal models and the like.
  • Known inhibitors include E-64 (Agrica Ituraland Biolo gica 1 Chemistry, Vol. 42, p. 529,] 978), E—64-d (Journalof Biochemistry, Vol. 93, p. 1305, 1983), NC 0-700 (special) Epoxy Succinic Acid Derivatives or Peptide Chloromethyl Ketones (Journa 1 of Biooch), Estatins A and B (The Journal of Antibiotics, Vol. 42, p. 1989) em istry, Vol. 99, p. 173, pp. 1986) Represented by bisoxymethyl ketone (Biooch em istry, Vol. 30, p. 4678, pp. 199). However, most of the irreversible inhibition.
  • irreversible inhibition II is said to be highly toxic because it easily reacts non-specifically with biological constituents other than the target enzyme, and few compounds have been used in clinical practice.
  • reversible inhibitors include leupeptin (The Journal of Antibiotics, Vol. 22, p. 283, 1969), and carpeptin (Journal of Enzyme Inh ibition, Vol. 3, p. 195, Peptidyl aldehyde is known, but it is said to have problems with chemical stability, stability in vivo, and permeability of cell membranes. Disclosure of the invention
  • An object of the present invention is to provide a novel cysteine protease inhibitor that can solve the above-mentioned conventional problems.
  • the gist of the present invention is the following general formula (I)
  • R 4 represents S— (R 4 represents a linear alkyl group of Cu C ⁇ ), and R 2 represents
  • R 3 represents a hydrogen atom or R 5 —C— (R 5 represents an alkyl group of C, to C 10 ), and A may be substituted with an alkyl group of C, to C 3 comprising a carrier acceptable same compounds and pharmaceutically; good maintenance oxygen-containing heterocyclic derivatives represented by an alkylene group of -C 3), a salt thereof, a solvate thereof or a hydrate thereof A pharmaceutical composition; and a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier for a disease caused by cystine protease overactivity.
  • CH to C 2 defined by R 4 in R 1 examples include decdecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and icosyl.
  • straight-chain alkyl groups of 13 to 6 such as a tetradecyl group, a pendecyl group and a hexadecyl group.
  • Examples of the d to C 10 alkyl group defined by R 5 in R 3 include the same groups as defined for R 2 , and preferably include C and C 4 alkyl groups. You.
  • Examples of the d to C 3 alkylene group defined by A include a methylene group, an ethylene group and a propylene group, and such an alkylene group is a d to C 3 alkyl group such as a methyl group, an ethyl group, and a propyl group. ⁇ May be substituted with two.
  • A is preferably a C 1, to C 3 alkylene group.
  • R 1 represents R 4 — C— (R 4 represents a linear alkyl group of CHC! 6 ), R 2 represents C, an alkyl group of 0, R 3 represents hydrogen Atom or
  • R 5 —C— (R 5 represents a C 1 to C 10 alkyl group), and A represents a C 1 to C 3 alkylene group;
  • R 1 is R 4 -0- C - represents the (.
  • R 4 Haji 13-15 an alkyl group of R 2 force "-C 10, R 3 Is a hydrogen atom or
  • R 5 -C— (R 5 represents an alkyl group of d to C 10 ), and A represents a d to C 3 alkylene group;
  • R 1 is R 4 — S— (R 4 represents a C 14 to C 16 linear alkyl group)
  • R 2 represents a C 1, to C 10 alkyl group
  • R 3 represents a hydrogen atom
  • R 5 one C one (R 5 represents an alkyl group having -C 10) represent, compound A represents C, alkylene group of -C 3,
  • the oxygen-containing heterocyclic derivative of the present invention represented by the above general formula (I) can form a salt.
  • Specific examples of such salts include metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt, or ammonium salt, methyl ammonium salt, dimethyl ammonium salt, trimethyl ammonium salt, and disc. Ammonia salts such as oral hexyl ammonium salt can be formed.
  • the oxygen-containing heterocyclic derivative of the present invention represented by the above general formula (I) can also exist as a solvate or hydrate.
  • the oxygen-containing heterocyclic derivative represented by the above general formula (I) can be produced, for example, by the following method.
  • R 1 , R 2 and A are as defined above, and B oc represents a tert-butoxycarbonyl group.
  • the protective group Boc was removed by dissolving in ethyl acetate, 1,4-dioxane, methylene chloride, and other solvents, and adding hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, and other acids.
  • a compound represented by the above formula (VI) is obtained.
  • the compound (VI) is dissolved in a solvent such as methylene chloride, toluene, heptane, tetrahydrofuran and the like, and treated with a reducing agent such as diisobutylaluminum hydride, sodium borohydride / cerium chloride. Is obtained.
  • R 1 , R 2 , R 5 and A are as defined above.
  • the oxygen-containing heterocyclic derivative ( ⁇ ) produced by Production Method 1 is converted to an organic solvent such as methylene chloride, 1,1-dichloroethane, dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, etc. Dissolved in water and reacted with the acid anhydride represented by the above general formula (R 5 CO) 20 in the presence of a base such as pyridine, triethylamine, 4-dimethylaminopyridine, and the like. Is obtained. This reaction can be performed without a solvent.
  • the compound ( ⁇ ) in which R 3 is a hydrogen atom shows strong inhibitory activity against cysteine protease. Also, R 3
  • the compound (VII) of R 5 -C-(R 5 represents an alkyl group of C 1 , to C 10 ) is an oxygen-containing heterocyclic derivative having a strong inhibitory activity against cysteine protease (III) Can be used as a prodrug. That is, when the compound (VII) is orally administered, after being absorbed from the intestinal tract or the like, the oxygen-containing heterocyclic derivative ( ⁇ ), which is an active metabolite, is immediately released by the action of enzymes in the living body.
  • the ratio of the therapeutically active ingredient to the carrier ingredient may be varied between 1% by weight and 90% by weight.
  • the compound of the present invention may be orally administered in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, milks, suspensions or liquids, or injected.
  • the preparation may be administered intravenously, intramuscularly or subcutaneously. It can also be used as a suppository. In addition, it may be used as powder for injection and prepared for business use.
  • Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral, parenteral use can be used to prepare the agents of the present invention.
  • Preparations for parenteral administration i.e., solvents or suspensions used in the manufacture of injections, suppositories, etc. include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like.
  • bases used for suppositories include cocoa butter, emulsified cocoa butter, lauric fat, witepsol and the like.
  • the pharmaceutical preparation may be prepared according to a conventional method.Clinical dose, when used by oral administration, is as a compound of the present invention for an adult, and is generally 0.01 to 100 mg per day for adults.
  • the above-mentioned daily dose of the agent of the present invention may be administered once a day or at appropriate intervals in two or three doses per mouth, or may be administered intermittently.
  • the compound of the present invention When used as an injection, the compound of the present invention is continuously or intermittently administered to an adult in a daily dose of 0.000 to 100 mg / day, preferably 0.01 to 10 mg / day. It is desirable.
  • Example 1 When used as an injection, the compound of the present invention is continuously or intermittently administered to an adult in a daily dose of 0.000 to 100 mg / day, preferably 0.01 to 10 mg / day. It is desirable.
  • Example 2 Production of (3S) -3-((S) -2-dodecanoylamino-4-methylvalerylamino) -12-tetrahydrodrofuranoyl (Compound No. 31 in Table 1) IR (KBr , cm- '): 3 2 7 9, 1 6 4 9, 1 558.
  • the aqueous layer was extracted twice with methylene chloride, and the extract was washed twice with saturated saline, dried with sodium sulfate, filtered to remove the desiccant, and concentrated to give a crude product.
  • Example 9 Production of (2S, 3S) —2-acetoxoxy-3-((S) —2-dodecanoylamino-4-methylvalerylamino) tetrahydrofuran (Compound No. 11 in Table 1-2)
  • Table 3 shows that the compound of the present invention exhibits a strong inhibitory activity against cysteine proteases such as papain, cathepsin B, cathepsin L, and lupain.
  • the oxygen-containing heterocyclic derivative of the present invention has a strong inhibitory effect on cysteine proteins such as papain, cathepsin B, cathepsin H, force tepsin L, calpain, and interleukin 1-converting enzyme, and has an oral absorption property.
  • cysteine proteins such as papain, cathepsin B, cathepsin H, force tepsin L, calpain, and interleukin 1-converting enzyme
  • Muscular dystrophy muscular atrophy, myocardial infarction, stroke, Alzheimer's disease, impaired consciousness and movement at the time of head trauma, multiple sclerosis, peripheral nervous system

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés hétérocycliques oxygénés, de formule générale (I), dans laquelle R1 est (II), où R4 est alkyle C¿11?-C20 ou similaire; R?2¿ est alkyle C¿1?-C10 ou similaire; R?3¿ est H ou (III), où R5 est alkyle C¿1?-C10; et A est alkylène C1-C3 ou similaire; ainsi que leurs sels, leurs solvates ou leurs hydrates. Ces composés ont une puissante activité inhibitrice contre les cystéine protéases telles que la calpaïne.
PCT/JP1997/002598 1996-07-29 1997-07-28 Derives heterocycliques oxygenes WO1998004539A1 (fr)

Applications Claiming Priority (2)

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JP19903796 1996-07-29
JP8/199037 1996-07-29

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998050533A1 (fr) * 1997-05-06 1998-11-12 Smithkline Beecham Corporation Inhibiteurs de proteases
US6426413B1 (en) 1998-03-09 2002-07-30 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US6531474B1 (en) 1998-03-19 2003-03-11 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US6566373B2 (en) 1997-05-06 2003-05-20 Smithkline Beecham Corporation Protease inhibitors
US6635632B1 (en) 1996-12-23 2003-10-21 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
EP1489076A1 (fr) * 2002-03-15 2004-12-22 Senju Pharmaceutical Co., Ltd. Derive de l'hemiacetal cyclique et son utilisation
US6958330B1 (en) 1998-06-22 2005-10-25 Elan Pharmaceuticals, Inc. Polycyclic α-amino-ε-caprolactams and related compounds
US8329662B2 (en) 2000-05-19 2012-12-11 Vertexd Pharmaceuticals Incorporated Prodrug of an ICE inhibitor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO1996025408A1 (fr) * 1995-02-14 1996-08-22 Mitsubishi Chemical Corporation Derives heterocycliques contenant de l'oxygene

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO1996025408A1 (fr) * 1995-02-14 1996-08-22 Mitsubishi Chemical Corporation Derives heterocycliques contenant de l'oxygene

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6635632B1 (en) 1996-12-23 2003-10-21 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
WO1998050533A1 (fr) * 1997-05-06 1998-11-12 Smithkline Beecham Corporation Inhibiteurs de proteases
US6566373B2 (en) 1997-05-06 2003-05-20 Smithkline Beecham Corporation Protease inhibitors
US6426413B1 (en) 1998-03-09 2002-07-30 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US8691848B2 (en) 1998-03-19 2014-04-08 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US7358273B2 (en) 1998-03-19 2008-04-15 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US6531474B1 (en) 1998-03-19 2003-03-11 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US6958330B1 (en) 1998-06-22 2005-10-25 Elan Pharmaceuticals, Inc. Polycyclic α-amino-ε-caprolactams and related compounds
US8329662B2 (en) 2000-05-19 2012-12-11 Vertexd Pharmaceuticals Incorporated Prodrug of an ICE inhibitor
US9156880B2 (en) 2000-05-19 2015-10-13 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
US9487555B2 (en) 2000-05-19 2016-11-08 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
US9994613B2 (en) 2000-05-19 2018-06-12 Vertex Pharmaceuticals Incorporated Prodrug of an ICE inhibitor
EP1489076A1 (fr) * 2002-03-15 2004-12-22 Senju Pharmaceutical Co., Ltd. Derive de l'hemiacetal cyclique et son utilisation
EP1489076A4 (fr) * 2002-03-15 2005-12-21 Senju Pharma Co Derive de l'hemiacetal cyclique et son utilisation
CN1297548C (zh) * 2002-03-15 2007-01-31 千寿制药株式会社 环状半缩醛衍生物及其应用
US7202274B2 (en) 2002-03-15 2007-04-10 Senju Pharmaceutical Co., Ltd. Cyclic hemiacetal derivative and use thereof

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