WO2003030905A1 - Inhibiteur de la dihydroorotate deshydrogenase - Google Patents

Inhibiteur de la dihydroorotate deshydrogenase Download PDF

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Publication number
WO2003030905A1
WO2003030905A1 PCT/JP2002/010030 JP0210030W WO03030905A1 WO 2003030905 A1 WO2003030905 A1 WO 2003030905A1 JP 0210030 W JP0210030 W JP 0210030W WO 03030905 A1 WO03030905 A1 WO 03030905A1
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prodrug
pharmaceutically acceptable
compound according
acceptable salt
solvate
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PCT/JP2002/010030
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English (en)
Japanese (ja)
Inventor
Akinori Arimura
Junji Kishino
Norihiko Tanimoto
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Shionogi & Co., Ltd.
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Priority to JP2003533937A priority Critical patent/JPWO2003030905A1/ja
Publication of WO2003030905A1 publication Critical patent/WO2003030905A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to dihydrorotate dehydrogenase inhibitors.
  • Dihydrorotate dehydrogenase is an enzyme that catalyzes the redox step located at the fourth position of pyrimidine biosynthesis (see Non-Patent Document 1). Rapid cell growth requires new pyrimidine biosynthesis for DNA and MA synthesis, protein glycosylation, membrane lipid biosynthesis, and nucleic acid chain repair.
  • the step catalyzed by dihydro-orotate dehydrogenase is the rate-limiting step in pyrimidine biosynthesis.
  • Dihydrololate dehydrogenase is used for rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, uveitis, myasthenia gravis, bronchial asthma, atopic dermatitis, psoriasis, and viral infections It is known to be associated with bacterial infections, bacterial infections, parasitic infections, cancer, transplant rejection, and graft-versus-host disease. Therefore, dihydrolotate dehydrogenase inhibitors are useful for treating or preventing the above-mentioned diseases (see Non-Patent Documents 2 to 6).
  • the dihidrolotate dehydrogenase inhibitors include the formula:
  • Non-Patent Document 7 wherein R is hydrogen, methyl, tert-butyl, trifluoromethyl, etc. is disclosed (see Non-Patent Document 7).
  • the compound according to the present invention has an inhibitory action on IgE antibody production and an inhibitory action on Th2 differentiation (see Patent Documents 1 and 2).
  • Patent Documents 3 to 28, Non-patent Documents 8 and 9, and the like which have a skeleton similar to the compound of the present invention and have an immunosuppressive effect, an antiallergic effect or an anticancer effect, are disclosed.
  • Patent Document 1 WO 99/38829 Pamphlet
  • Patent Document 2 WO 01/07032 pamphlet
  • Patent Document 3 WO 94/27980 Pamphlet
  • Patent Document 4 WO 95/13067 pamphlet
  • Patent Document 4 WO 96/15123 pamphlet
  • Patent Document 5 WO 95/15318 pamphlet
  • Patent Document 6 WO 96/40659 Pamphlet
  • Patent Document 7 WO 96/40143 Pamphlet
  • Patent Document 8 WO 96/38412 brochure
  • Patent Document 9 WO 96/10012 Pamphlet
  • Patent Document 10 WO 97/24356 Pamphlet
  • Patent Document 11 WO 97/27181 pamphlet
  • Patent Document 1 2 WO 97/24324 Pamphlet
  • Patent Document 13 WO 97/39999 pamphlet
  • Patent Document 14 WO 97/44333 Pamphlet
  • Patent Document 15 WO 97/46524 Pamphlet
  • Patent Document 16 WO 98/04508 pamphlet
  • Patent Document 17 International Publication No. 98/24766 Pamphlet
  • Patent Document 18 WO 98/24782 pamphlet
  • Patent Document 19 International Publication No. 98/56785 Pamphlet
  • Patent Document 20 French Patent Application Publication No. 2301250
  • Patent Document 2 1 U.S. Pat.No. 5,539,991 Patent Document 2 2 Japanese Patent Publication No. 47-7368
  • Patent Document 23 JP-A-51-91259
  • Patent Document 25 JP-A-9-124571
  • Patent Document 27 JP-A-9-124571
  • Patent Document 28 JP-A-11-79993
  • Non-Patent Document 2 Immunopharmacology 2000, Vol. 47, p. .63-83
  • Non-Patent Document 3 Immntopliarinacology 2000, Vol. 47, p.273-289
  • Non-Patent Document 4 Cancer Research 1986, Vol. 46,. 5014-5019
  • Non-Patent Document 5 Biochemistry 1994, Vol. 33, p.5268-5274
  • Non-Patent Document 6 Biochemical Pharmacology
  • Non-Patent Document 7 Tetrahedron Letters 2001, Vol. 42, p.547-551
  • Non-Patent Document 8 Bioorganic & Medicinal Chemistry Letters 1995, Vol. 5, No. 18, p.2143-2146
  • Non-Patent Document 9 Journal Off 'Medicinal Chemistry
  • the present invention provides a novel dihydrolotate dehydrogenase inhibitor.
  • formula (I) we have found that formula (I):
  • R 1 and R 4 are each independently alkyl or alkoxy;
  • R 2 and R 3 are each independently hydrogen or alkyl;
  • R 5 is hydrogen or halogen;
  • R 6 is hydrogen or hydroxy;
  • X 1 and X 2 are each independently —0— or 1 NH 1), and have found that they have a dihydrorotate dehydrogenase inhibitory action, and have completed the following invention.
  • the present invention is a.
  • R 1 and R 4 are each independently alkyl or alkoxy; R 2 and R 3 are each independently hydrogen or alkyl; R 5 is hydrogen or halogen; R 6 is hydrogen or hydroxy X 1 and X 2 are each independently 10-or 1 NH 1), a prodrug thereof, a pharmaceutically acceptable salt thereof or a dihydrorotate containing a solvate thereof.
  • Dehydrogenase inhibitors are each independently alkyl or alkoxy; R 2 and R 3 are each independently hydrogen or alkyl; R 5 is hydrogen or halogen; R 6 is hydrogen or hydroxy X 1 and X 2 are each independently 10-or 1 NH 1), a prodrug thereof, a pharmaceutically acceptable salt thereof or a dihydrorotate containing a solvate thereof.
  • R 1 and R 4 are each independently alkyl; R 2 and R 3 are hydrogen; R 5 is halogen; R 6 is hydrogen; X 1 is 1 NH— ; And the dihydrofluorodehydrogenase inhibitor according to the above (1), wherein X 2 is 10—
  • R 1 and R 4 are each independently alkyl or alkoxy;
  • R 2 and R 3 are each independently hydrogen or alkyl;
  • R 5 is hydrogen or halogen;
  • R 6 is hydroxy;
  • X 1 And X 2 are each independently 111 or 1 NH—), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof,
  • a pharmaceutical composition comprising the compound according to any of (4) to (6) above,
  • a dihydrolotate dehydrogenase inhibitor comprising the compound according to any of (4) to (6) above,
  • dihydrololate dehydrogenase inhibitor according to any one of the above (1) to (3) and (8) which is an agent for treating or preventing cancer
  • dihydrololate dehydrogenase inhibitor according to any of (1) to (3) and (8) above which is a therapeutic or prophylactic agent for a viral infection.
  • dihydrofluorate dehydrogenase inhibitor according to any of (1) to (3) and (8), which is a therapeutic or preventive agent for rheumatoid arthritis; (12) suppression of rejection in transplantation (1) to (3) and
  • the dihydrorotate dehydrogenase inhibitor according to any of (8).
  • Alkyl refers to straight or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. Including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, Isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like. Particularly, methyl is preferred.
  • alkyl part of “alkoxy” is the same as the above “alkyl”.
  • Alkoxy includes linear or branched alkoxy having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms.
  • methoxy is preferred.
  • Halogen includes fluorine, chlorine, bromine and iodine. Particularly, fluorine and chlorine are preferred, and fluorine is more preferred.
  • the compound according to the present invention can be produced according to the methods described in Patent Documents 1 and 2 described above. Hereinafter, the method for producing the compound according to the present invention will be described.
  • R 1 and R 4 are each independently alkyl or alkoxy;
  • R 2 and R 3 are each independently hydrogen or alkyl;
  • R 5 is hydrogen or halogen;
  • R 6 is hydrogen or hydroxy;
  • X 1 and X 2 are each independently — 0— or one NH 1;
  • Y 1 and Y 2 are each independently halogen;
  • a compound represented by the formula (I-A) and a compound represented by the formula (I-I: B) are converted into a suitable solvent (for example, benzene, toluene, N-dimethylformamide, dimethyloxetane, tetrahydrofuran, dioxane, ethanol). or a mixed system or anhydrous systems such as methanol) and ice, a palladium catalyst (e.g.
  • This step can be performed in the same manner as in the first step.
  • R x is derived to a group represented by the formula: — X 1 — CH 2 — CH 2 C (CH 3 ) 2
  • prodrug refers to a group of compounds that can be easily converted in vivo into the active compound of the present invention. The method can also be performed. Methods for selecting and manufacturing suitable prodrug derivatives are described, for example, in the Design of Prodrugs, Elsevier, 0030
  • a group generally used for prodrug formation may be introduced into hydroxy, amino or the like bonded to any position of the compound of the present invention.
  • one CO CH 2 CH 2 CO_ ⁇ _H one CO CH two CH COOH, One C_ ⁇ CH 2 S 0 3 H, one P 0 3 H 2, one CO CH 2 N (CH 3 ) 2 , -C 0 -P yr (P yr represents pyridyl) or the like can be introduced.
  • C When amino is a substituent for example, one C ⁇ 0 CR h R i 0 C 0 CH 2 RJ [R h and R 1 are each independently chromium or lower alkyl, and R j is H, -OH, one CO NHR K , -OCO NH R K ,-(NHCOCR!
  • a prodrug is introduced by introducing the above-mentioned substituted acyloxycarbonyl (1-C ⁇ O CR hR i ⁇ CO CH 2 R j) into an amino present at any position of the compound of the present invention, for example, any of the compounds of the present invention
  • the prodrug compound can be obtained by ⁇ -haloalkoxycarbonylation of the amino present at that position and then reacting it with an appropriate carboxylic acid under appropriate conditions.
  • Such an acyloxyalkyl carbamate can be synthesized according to a known method described in WO96 / 18605 and the like.
  • the compound of the present invention having an amino and an ⁇ -haloalkyl chloroformate are mixed with a base (pyridine, pyridine, or tetrahydrofuran, 1,4-dioxane, ethyl acetate or toluene, etc.) in an inert solvent.
  • a base pyridine, pyridine, or tetrahydrofuran, 1,4-dioxane, ethyl acetate or toluene, etc.
  • the reaction is carried out at 0 ° C to room temperature in the presence of triethylamine or ⁇ -methylmorpholine to obtain a haloalkoxycarbamate compound.
  • a prodrug compound can be obtained by reacting with an earth metal salt, silver salt, mercury salt, etc.) at room temperature to under heating for several hours to several days.
  • the substituent may be protected with an appropriate protecting group in advance, and may be removed by an ordinary method at an appropriate stage.
  • the “pharmaceutically acceptable salt” includes a pharmaceutically acceptable salt of the compound represented by the formula (I) or a prodrug thereof.
  • Pharmaceutically acceptable salts include, for example, salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid; formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, Salts of organic acids such as maleic acid and succinic acid; salts of organic bases such as ammonium, trimethylammonium and triethylammonium; salts of alkali metals such as sodium and potassium or salts of calcium and magnesium Salts of alkaline earth metals can be mentioned.
  • solvate includes a solvate (preferably a hydrate) of the compound represented by the formula (I), a prodrug thereof or a pharmaceutically acceptable salt thereof.
  • Solvates include solvates with organic solvents and / or water. When forming a hydrate, it may be coordinated with any number of water molecules.
  • dihydrolotate dehydrogenase inhibitor refers to a pharmaceutical composition having dihydrorotate dehydrogenase inhibitory activity, i.e., a medicament for treating or preventing a disease associated with the action of dihydrorotate dehydrogenase. Means a composition.
  • a disease associated with the action of dihydrolotate dehydrogenase means a disease that can be treated or prevented by inhibiting the action of dihydrolotate dehydrogenase.
  • rheumatoid arthritis systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, uveitis, myasthenia gravis, bronchial asthma, atopic dermatitis, psoriasis, viral infection, bacterial infection, bacterial infection Disease, parasite infection, cancer, transplant rejection, and graft-versus-host disease.
  • the disease is related to the action of dihydrodrote-to-dehydrogenase. Also included are those diseases.
  • Non-Patent Documents 2 and 3 described above describe the usefulness of a dihydrorotate dehydrogenase inhibitor for autoimmune diseases, allergic diseases, transplant rejection, and the like.
  • Non-Patent Document 3 describes the application of a dihydrololate dehydrogenase inhibitor as an anticancer agent
  • Non-Patent Document 4 describes its usefulness.
  • Non-Patent Documents 5 and 6 described above describe the usefulness of a dihydrololate dehydrogenase inhibitor for bacterial infections, bacterial infections, parasitic infections, and the like.
  • the present invention also includes a method for treating or preventing a disease associated with the action of dihydrololate dehydrogenase by administering the compound of the present invention.
  • a disease associated with the action of dihydrolotrate dehydrogenase is also included.
  • the use of the compound of the formula (I) for the manufacture of a therapeutic or prophylactic agent for is also included.
  • the present invention also provides a method for inhibiting dihydrolotate dehydrogenase by contacting the compound of the present invention with dihydrorotate dehydrogenase. are also included.
  • dihydrolotate dehydrogenase inhibitor in particular, an agent for treating or preventing cancer, an agent for treating or preventing a viral infection, an agent for treating or preventing rheumatoid arthritis, and an agent for suppressing rejection in transplantation are preferable. .
  • Dihydrorotate dehydrogenase inhibitor can function as a kind of nucleic acid metabolizing enzyme inhibitor because it can inhibit pyrimidine biosynthesis by inhibiting dihydrorotate dehydrogenase. Can be. Therefore, a dihydrolotate dehydrogenase inhibitor can inhibit the growth of pathogens based on pyrimidine biosynthesis, and can treat diseases caused by those pathogens. In particular, it is useful as an agent for treating or preventing cancer, or an agent for treating or preventing viral infections, bacterial infections, bacterial infections, and parasitic infections.
  • dihydrorotate dehydrogenase inhibitors can inhibit the nucleic acid synthesis of cells that are active in de novo synthesis (cancer cells, cells in fetal stage), and myeloma (myeloma, for example, multiple myeloma) It can also be used as a remedy for reformers (lymphoma) and leukemia (leukemia).
  • the dihydrorotate dehydrogenase inhibitor of the present invention When administering the dihydrorotate dehydrogenase inhibitor of the present invention, it can be administered either orally or parenterally. Oral administration may be carried out in a usual dosage form such as tablets, granules, powders, capsules, pills, solutions, syrups, buccals, or sublinguals according to a conventional method.
  • a usual dosage form such as tablets, granules, powders, capsules, pills, solutions, syrups, buccals, or sublinguals according to a conventional method.
  • parenteral administration any commonly used dosage form can be suitably administered, for example, injections such as intramuscular administration and intravenous administration, suppositories, transdermal absorbents, and inhalants. In particular, oral administration is preferred.
  • An effective amount of the compound according to the present invention is mixed with various pharmaceutical additives such as excipients, binders, wetting agents, disintegrating agents, lubricants, and diluents, which are suitable for the dosage form, if necessary.
  • lactose lactose, sucrose, pudose, starch, calcium carbonate or crystalline cellulose, etc.
  • a binder methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin or polyvinylpyrrolidone, etc.
  • the disintegrant include carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, sodium alginate, powdered agar or sodium lauryl sulfate
  • examples of the lubricant include talc, magnesium stearate, and macrogol.
  • cocoa butter, macrogol, methyl cellulose or the like can be used as a suppository base.
  • solubilizers when preparing a liquid formulation or an emulsion or suspension injection, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are appropriately added.
  • a flavoring agent In the case of oral administration, a flavoring agent, a fragrance and the like may be added.
  • the dihydrorotate dehydrogenase inhibitor of the present invention may be administered alone, or may be used in combination with other agents as needed.
  • the dose of the dihydrorotate dehydrogenase inhibitor of the present invention is desirably determined in consideration of the patient's age, body weight, type and degree of disease, administration route, and the like. It is usually from 0.05 to 100 mg / kg / day, preferably from 0.1 to 10 mg / kg / day. In the case of parenteral administration, it varies greatly depending on the route of administration, but is usually 0.000 ll Omg / kg g / day, preferably within the range of 0.001 to 1 mg / kg / day. . It may be administered once or several times a day.
  • Example 1 The dose of the dihydrorotate dehydrogenase inhibitor of the present invention
  • Example 1 The compound (I-1) (444 mg, lmmo 1) obtained in Example 1 was dissolved in anhydrous ether (4 OmL), cooled with ice, and stirred under a nitrogen stream while stirring chloromethyl chloroformate (194 mg, lmmol) and triethylamine (210 mL, lmmol) were sequentially added, and the ice bath was removed and stirring was continued for 4 hours.
  • the precipitate in the reaction product was filtered off, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 540 mg of compound (8) as an oil.
  • Human ⁇ -937 cells human histiocytic lymphoma cell line
  • a homogenizing buffer (20 mM Tris-HCl, pH 7.4, containing 2 mM EDTA and protease inhibitor cocktail
  • sonicate 1,200 xg for 15 minutes
  • the cell debris was removed by centrifugation. Further, ultracentrifugation was performed twice at 120,000 X g for 60 minutes to prepare a mitochondrial / microsomal fraction.
  • the obtained fraction was subjected to protein quantification, adjusted to 10 mg / inl, and stored frozen at ⁇ 40 ° C. until measurement.
  • Reaction mixture 50 mM Tris-HC1, pH 7.4, containing 0.1 3 ⁇ 4 Triton X-100, 1 mM KCN, 100 ⁇ , coenzyme Q10, 200 ⁇ MDCIP
  • Compound dilution sequence 10 ⁇ 1 in 150 jl and mitochondrial / microsomal fraction 0.2 mg was added and pre-incubated at 37 ° C for 30 minutes.
  • 20 ⁇ l of a 5 mM DH0 solution final concentration: 500 ⁇ M
  • the absorbance at a measurement wavelength of 620 nm was measured.
  • the inhibition rate of the compound at each concentration against the change in absorbance due to the enzyme reaction was determined, and the concentration ( ICse value) showing 50% inhibition was calculated.
  • the inhibitory activity of the compounds was evaluated.
  • Components other than calcium stearate were uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate was added and compression-molded into tablets.
  • the compound represented by the formula (I) has a dihydrofluorate dehydrogenase inhibitory activity, and is used for chronic rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, uveitis, severe disease
  • chronic rheumatoid arthritis systemic lupus erythematosus
  • multiple sclerosis multiple sclerosis
  • inflammatory bowel disease uveitis
  • severe disease For the treatment or prevention of myasthenia, bronchial asthma, atopic dermatitis, psoriasis, viral infections, bacterial infections, bacterial infections, parasitic infections, cancer, transplant rejection, graft-versus-host disease Can be used.

Abstract

L'invention concerne un composé représenté par la formule (I), dans laquelle R1 et R2 représentent chacun indépendamment alkyle ou alcoxy ; R2 et R3 représentent chacun indépendamment hydrogène ou alkyle ; R5 représente hydrogène ou halogéno ; R6 représente hydrogène ou hydroxy ; et X1 et X2 représentent chacun indépendamment O ou NH . On a découvert que ce composé présentait une activité d'inhibition de la dihydroorotate déshydrogénase.
PCT/JP2002/010030 2001-10-01 2002-09-27 Inhibiteur de la dihydroorotate deshydrogenase WO2003030905A1 (fr)

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JP2003533937A JPWO2003030905A1 (ja) 2001-10-01 2002-09-27 ジヒドロオロテートデヒドロゲナーゼ阻害剤

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JP2001305557 2001-10-01
JP2001-305557 2001-10-01

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Cited By (6)

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WO2006051937A1 (fr) * 2004-11-15 2006-05-18 Shionogi & Co., Ltd. Composés hétérocycliques à cinq chaînons
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
WO2012109329A2 (fr) 2011-02-08 2012-08-16 Children's Medical Center Corporation Méthodes de traitement d'un mélanome
US8686048B2 (en) 2010-05-06 2014-04-01 Rhizen Pharmaceuticals Sa Immunomodulator and anti-inflammatory compounds
CN104030987A (zh) * 2009-04-02 2014-09-10 默克雪兰诺有限公司 二氢乳清酸脱氢酶抑制剂
US9238616B2 (en) 2001-06-11 2016-01-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8168623B2 (en) 2001-06-11 2012-05-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US9238616B2 (en) 2001-06-11 2016-01-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof
WO2006051937A1 (fr) * 2004-11-15 2006-05-18 Shionogi & Co., Ltd. Composés hétérocycliques à cinq chaînons
CN104030987A (zh) * 2009-04-02 2014-09-10 默克雪兰诺有限公司 二氢乳清酸脱氢酶抑制剂
CN104030987B (zh) * 2009-04-02 2017-04-12 默克雪兰诺有限公司 二氢乳清酸脱氢酶抑制剂
US8686048B2 (en) 2010-05-06 2014-04-01 Rhizen Pharmaceuticals Sa Immunomodulator and anti-inflammatory compounds
US9758474B2 (en) 2010-05-06 2017-09-12 Incozen Therapeutics Pvt. Ltd. Immunomodulator and anti-inflammatory compounds
WO2012109329A2 (fr) 2011-02-08 2012-08-16 Children's Medical Center Corporation Méthodes de traitement d'un mélanome

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