WO2004004703A1 - m-PHENYLENEDIAMINE DERIVATIVE - Google Patents

m-PHENYLENEDIAMINE DERIVATIVE Download PDF

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WO2004004703A1
WO2004004703A1 PCT/JP2003/008320 JP0308320W WO2004004703A1 WO 2004004703 A1 WO2004004703 A1 WO 2004004703A1 JP 0308320 W JP0308320 W JP 0308320W WO 2004004703 A1 WO2004004703 A1 WO 2004004703A1
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group
general formula
substituted
carbon atoms
hydrogen atom
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PCT/JP2003/008320
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French (fr)
Japanese (ja)
Inventor
Takashi Tsuruo
Tsuneji Suzuki
Katsutoshi Tsuchiya
Toshiyuki Shimazaki
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Mitsui Chemicals, Inc.
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Priority to AU2003281198A priority Critical patent/AU2003281198A1/en
Publication of WO2004004703A1 publication Critical patent/WO2004004703A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • 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
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • telomeres are present at the ends of chromosomes in eukaryotes and play an important role in stabilizing chromosomes. In normal cells, telomeres are shortened by 50-200 bases each time cell division takes place, and if they are shortened to a certain length or less, cell division stops, and it is thought that they play a role in determining the life span of cells. I have. Therefore, normal cells do not grow indefinitely.
  • telomeres are shortened due to division, and growth is stopped or cell death occurs. Absent.
  • telomerase inhibitors it is known that when those cells express the telomerase-prolonging enzyme telomerase, they become immortalized and become cancer cells. Therefore, if the infinite growth of cancer cells can be suppressed by telomerase inhibitors, it is expected to become a new anticancer drug with low toxicity.
  • catechins Biochem. Biophys. Res. Cobalt un., 249, P391-396, 1998)
  • porphyrin derivatives J. Am. Chem.
  • telomerase is involved in various diseases related to cell proliferation other than cancer, and telomerase inhibitors are expected to have broad potential as drugs. Have been. Despite much research, no effective drug has been found that can inhibit telomerase and treat various diseases.
  • An object of the present invention is to provide a compound having telomerase inhibitory activity represented by the general formula (1) as a medicament for treating and / or improving various diseases.
  • Another object of the present invention is to provide a compound represented by the general formula (5).
  • the present inventors have found a strong telomerase inhibitory activity in a metaphenylenediamine derivative having a polyhydroxy group, and have completed the present invention.
  • Z represents a substituted phenyl group or a heterocyclic group.
  • R1, R2, R3, R4, and R7 represent a hydrogen atom or OR5 group, an alkoxy group, an acyloxy group, an amino group, and the number of carbon atoms.
  • R 1 and R 2 represents an OR 5 group
  • R 5 is a hydrogen atom or a hydroxyl-protecting group
  • R 6 is a hydrogen atom or an alkyl or benzyl group having 1 to 5 carbon atoms which may be substituted.
  • a telomerase inhibitor comprising a compound represented by the formula or a pharmacologically acceptable salt thereof,
  • R 1, R 2, R 3, R 4, R 5, R 6, and R 7 are the same as described above (provided that one of R 1 and R 2 represents an OR 5 group.)
  • R 8, R 9, R 10, R 11 is each independently a hydrogen atom or an OR 5 group, an alkoxy group, an acyloxy group, an amino group, an amino group, a nitro group, and a carboxyl group which may be substituted with an alkyl group having 1 to 5 carbon atoms.
  • a telomerase inhibitor comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof,
  • telomerase inhibitor comprising the compound according to claim 3 or a pharmaceutically acceptable salt thereof
  • a medicament comprising at least one telomerase inhibitor according to any one of claims 1 to 4, wherein
  • Z represents a substituted phenyl group or a heterocyclic group.
  • R3, R4, and R7 each independently represent a hydrogen atom or an OR5 group, an alkoxy group, an alkoxy group, an amino group, a carbon number.
  • An amino group optionally substituted with 1 to 5 alkyl groups R 5 is a hydrogen atom or a hydroxyl-protecting group, R 6 is a hydrogen atom or a nitro group, a carbonyl group having 1 to 5 carbon atoms, a halogen atom, a sulfonyl group which may be substituted.
  • R 12 represents a hydrogen atom or an alkoxy group, an acyloxy group, an amino group, or an amino group which may be substituted with an alkyl group having 1 to 5 carbon atoms.
  • R8, R9, R10, and R11 are each independently a hydrogen atom or an OR5 group, an alkoxy group, an acyloxy group, Amino group, amino group which may be substituted with alkyl group having 1 to 5 carbon atoms, nitro group, carbonyl group, alkoxycarbonyl group having 1 to 5 carbon atoms, halogen atom, sulfonyl group which may be substituted (Wherein R8, R9, R10, and R11 are not hydrogen atoms at the same time), or a pharmacologically acceptable salt thereof,
  • the substituted phenyl group for Z may be a substituent at any of the 2-, 3-, and 4-positions on the phenyl group. Substituents may be present at multiple positions. When it has a plurality of substituents, the types of the substituents may be the same or different. Examples of the substituent include an alkyl group such as a methyl group, an ethyl group and an isopropyl group, an alkyloxy group such as a methoxy group, an ethoxy group, an n-propyloxy group and an i-propyloxy group, a hydroxy group, a nitro group, an amino group, and a methylamino group.
  • amide group such as an acyl group such as a propionyl group and a benzoyl group; an acyloxy group such as a formyloxy group and an acetyloxy group; a propionyloxy group and a benzoyloxy group; a formamide group, an acetoamide group and a benzamide group.
  • substituted phenyl group examples include 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2,3-dihydroxyphenyl group, and 3,4-dihydroxyphenyl group.
  • Group, 2,3,4-trihydroxyphenyl group, 3,4,5-trihydroxyphenyl group Phenyl, 2,4,5—trihydroxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 3,4-diaminophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3,4-dimethoxyphenyl group, 2,3-dimethoxyphenyl group, 2,3 , 4,1-Trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl
  • substituents that can be further substituted such as hydroxyl group and amino group, various groups that control fat-solubility, stability, water solubility, translocation into the body, absorption in the intestinal tract, etc. Substituents can also be introduced.
  • the hydroxyl-protecting group in R 5 may be any substituent that protects a phenolic or alcoholic hydroxyl group.
  • various partial structures can be added to the substituent to control fat-solubility, water-solubility, translocation into the body, and absorption in the intestinal tract.
  • the substituent in the R5 group include an alkyl group optionally substituted with another functional group, a silyl group optionally substituted with another functional group, an alkylacyl group optionally substituted with another functional group, Examples thereof include an aromatic acyl group that may be substituted with another functional group, a hydroxycarbonyl group that may be substituted with another functional group, and an aminocarbonyl group that may be substituted with another functional group.
  • alkylacyl group which may be substituted include a formyl group, an acetyl group, a pionyl group, an n-butyryl group, an i-butyryl group, an n-pentenyl group, an n-hexanoyl group, and an n-hepnoyl group And n-octanol groups, methoxypropionyl groups, and phenylacetyl groups.
  • esters of amino acids such as glycine, alanine, palin, leucine, isoleucine, serine, threonine, phenylalanine, tryptophan, lysine, methionine and the like can be mentioned.
  • aromatic acyl group which may be substituted by another functional group include benzoyl group, 2-methylbenzoyl group, 3-methylbenzoyl group, 4-methylbenzoyl group, 2-methoxybenzoyl group, and 3-methoxybenzoyl group.
  • hydroxycarbonyl group which may be replaced by another functional group include: methoxycarbonyl group, ethoxycarbonyl group, n-propyloxycarbonyl group, i_propyloxycarbonyl group, n-butyloxycarbonyl.
  • the aminocarbonyl group which may be substituted with another functional group include an aminocarbonyl group, an N-methylaminocarbonyl group, an N, N-dimethylaminocarbonyl group, an N-ethylaminocarbonyl group, and an N-propyl group.
  • examples thereof include an aminocarbonyl group, an N-phenylaminocarbonyl group, and an N-benzylaminocarbonyl group.
  • the alkoxy group is a methoxy group, an ethoxy group, a propoxy group, or an isopropoxy group.
  • acyloxy group examples include a formyloxy group, an acetoxy group, a propionyloxy group, a bivaloyloxy group, and a benzoyloxy group.
  • An amino group which may be substituted with an alkyl group having 1 to 5 carbon atoms means that a nitrogen atom on the amino group may be substituted with an alkyl group.
  • methylamino group, ethylamino group, n-propylamino group, butylamino group, dimethylamino group Group getylamino group, diisopropylamino group, cyclopropylamino group, benzylamino group and the like.
  • the alkoxycarbonyl group having 1 to 5 carbon atoms includes a methoxycarbonyl group, an ethoxycarbonyl group, an n-propyloxycarbonyl group, a benzyloxycarbonyl group and the like.
  • Examples of the sulfonyl group which may be substituted include a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a benzenesulfonyl group and the like.
  • Halogen atoms include fluorine, chlorine, bromine and iodine.
  • R6 include a hydrogen atom, a methyl group, an ethyl group, an n_propyl group, an n-butyl group, a benzyl group, a methoxyethyl group, an acetyloxymethyl group, an acetoxethyl group, and the like.
  • the pharmaceutically acceptable salts of the compounds include alkali metals such as lithium, sodium and potassium, alkaline earth metals such as magnesium and calcium, methylammine, ethylamine, dimethylamine, trimethylamine, and the like, which are commonly used in this field. Salts with organic bases such as triethylamine, benzylamine, cyclohexylamine and the like, and inorganic bases such as ammonia can be mentioned as salts of the compounds.
  • the compound of the general formula (1) When the compound of the general formula (1) has a basic property such as an amino group, it may be an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, fumaric acid, maleic acid, citrate, Salts with organic acids such as benzoic acid, trifluoroacetic acid, P-toluenesulfonic acid and methanesulfonic acid can also be mentioned as salts of the compounds.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, fumaric acid, maleic acid, citrate, Salts with organic acids such as benzoic acid, trifluoroacetic acid, P-toluenesulfonic acid and methanesulfonic acid can also be mentioned as salts of the compounds.
  • the compound represented by the general formula (1) can also be used as a prodrug by masking a hydroxyl group or a diamino group for use as a pharmaceutical.
  • the compound represented by the general formula (1) When the compound represented by the general formula (1) has an asymmetric carbon, it can exist in a form of a mixture of different stereoisomeric forms or stereoisomeric forms including racemic forms. That is, the present invention includes various forms defined as above, and these can be similarly used as active ingredient compounds.
  • To be contained as an active ingredient means to contain one or more compounds represented by the general formula (1) in the preparation.
  • Pharmaceuticals are useful as therapeutic and / or ameliorating agents for diseases associated with telomerase. More specifically, diseases related to cell proliferation and diseases related to homeostasis, i.e., malignant tumors, autoimmune diseases, skin diseases, infectious diseases, vascular diseases, blood diseases, allergic diseases, gastrointestinal tract It is useful as a therapeutic and / or ameliorating agent for injuries, hormonal diseases, metabolic diseases, diabetes and the like.
  • Malignant tumors include hematopoietic tumors such as acute leukemia, chronic leukemia, malignant lymphoma, multiple myeloma, macroglobulinemia, colorectal cancer, brain tumor, head and neck cancer, breast cancer, lung cancer, esophageal cancer, stomach cancer, liver cancer, Gallbladder cancer, bile duct cancer, Teng cancer, hepatocellular carcinoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, prostate cancer, testicular tumor, ovarian cancer, uterine cancer, choriocarcinoma, thyroid cancer, malignant rutinoid tumor, skin cancer , Malignant melanoma, osteosarcoma, soft tissue sarcoma, neuroblastoma, Wilms tumor, retinoblastoma and other solid tumors.
  • hematopoietic tumors such as acute leukemia, chronic leukemia, malignant lymphoma, multiple myeloma, macroglobulin
  • Autoimmune diseases include rheumatism, nephritis, diabetes, systemic lupus erythematosus, human autoimmune lymphoproliferative lymphadenopathy, immunoblastic lymphadenopathy, Crohn's disease, ulcerative colitis and the like.
  • Skin diseases include psoriasis, acne, eczema, atopic dermatitis, parasitic skin diseases, alopecia, purulent skin diseases, and skin sclerosis.
  • Infectious disease means a disease caused by infection with various bacteria, viruses or parasites.
  • the vascular disease includes arteriosclerosis and the like.
  • the target disease of the present invention is not limited to these.
  • the formulations are prepared using commonly used diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and lubricants.
  • diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and lubricants.
  • Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment. Representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, injections (solutions) , Suspensions, etc.) and suppositories.
  • a carrier In the form of tablets, it is well known in the art as a carrier.
  • quaternary ammonium base such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal keic acid, talc, stearic acid salts, polyethylene glycol Etc. It may be used agents.
  • tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets, or multilayer tablets.
  • a wide variety of carriers conventionally known in this field can be used. Examples include excipients such as crystalline cellulose, lactose, starch, hardened vegetable oils, kaolin, talc, binders such as gum arabic, powdered tragacanth, gelatin, disintegrants such as carmellose calcium, agar and the like.
  • No. Capsules are prepared by mixing the active ingredient compound with the various carriers exemplified above and filling the resulting mixture into hard gelatin capsules, soft capsules, and the like, according to a conventional method. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals can be contained in the pharmaceutical preparation.
  • the amount of the active ingredient compound to be contained in these pharmaceutical preparations of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 70% by weight, preferably about The content is preferably 5 to 50% by weight.
  • the compound of the present invention can be synthesized, for example, by the following method.
  • R 13 represents a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom
  • the compounds represented by the general formulas (9) to (12) are commercially available, are known compounds, can be easily synthesized, or can be obtained by combining known reactions.
  • the condensation reaction of (a) or (b) can be carried out by a usual amide bond forming reaction, for example, a method using an acid halide, a mixed acid anhydride or an active ester.
  • a compound represented by the general formula (10) or the general formula (12) (where R 13 represents a hydroxyl group), 2,4,5_trichlorophenol, pentachlorophenol or 412trophenol, etc.
  • Phenols or N-hydroxy compounds such as N-hydroxysuccinimide and N-hydroxybenztriazole are condensed in the presence of dicyclohexylcarposimide to form an active ester, and then converted to an active ester form by the general formula (9)
  • it can be obtained by reacting with a compound represented by the general formula (11).
  • a compound represented by the general formula (10) or (12) (wherein R 13 represents a hydroxyl group) and methyl chlorocarbonate, ethyl ethyl carbonate, benzyl carbonate, isobutyl carbonate or A mixed acid anhydride is obtained by reacting with methanesulfonyl chloride, trifluoroacetic anhydride, etc., and then represented by the general formula (9) or (11). Can also be obtained by condensation with the compound to be prepared.
  • condensation reaction can also be carried out using a peptide condensation reagent such as dicyclohexylcarposimide, N, N'-carbonyldiimidazole, diphenylphosphoric acid azide, or cytyl phosphate.
  • a peptide condensation reagent such as dicyclohexylcarposimide, N, N'-carbonyldiimidazole, diphenylphosphoric acid azide, or cytyl phosphate.
  • the reaction is usually carried out at 120 to 150 ° C. for 0.5 to 48 hours.
  • solvent used examples include aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, dioxane and ethyl ether, halogenated hydrocarbons such as dichloromethane and chloroform, N, N-dimethylformamide ⁇ ⁇ Alcohols such as DMI, methanol, ethanol, and isopropyl alcohol, or mixtures thereof.
  • aromatic hydrocarbons such as benzene and toluene
  • ethers such as tetrahydrofuran, dioxane and ethyl ether
  • halogenated hydrocarbons such as dichloromethane and chloroform
  • Alcohols such as DMI, methanol, ethanol, and isopropyl alcohol, or mixtures thereof.
  • the reaction rate can also be increased by adding an organic base such as triethylamine or pyridine, 4- (N, N-dimethyl) amino
  • This reaction may be accelerated by the presence of a base.
  • a base examples include organic bases such as triethylamine and pyridine, 4-N, N-dimethylaminopyridine, N-methylmorpholine and N-methylpiperidine, and alkoxide bases such as sodium methoxide and sodium methoxide.
  • organic bases such as triethylamine and pyridine, 4-N, N-dimethylaminopyridine, N-methylmorpholine and N-methylpiperidine
  • alkoxide bases such as sodium methoxide and sodium methoxide.
  • inorganic bases such as carbon dioxide, sodium carbonate and lithium carbonate.
  • the compound represented by the general formula (1) can be synthesized by deprotecting the protecting group.
  • deprotection appropriate conditions can be used depending on the protecting group. For example, Protective Groups in ORGANIC SYNTHESIS, TEHODORA W. , INC.) Etc. can be used for deprotection.
  • the compound represented by the general formula (1) can easily form a salt with a pharmacologically acceptable base.
  • the base include inorganic bases such as lithium, sodium, potassium, magnesium, calcium, and ammonium, and organic bases such as methylamine, ethylamine, and benzylamine. These salts can also be used as the active ingredient compound of the present invention in the same manner as the molecular compound of the general formula (1).
  • the compound represented by the general formula (1) can be isolated and purified from the reaction mixture by a usual separation means, for example, an extraction method, a recrystallization method, a column chromatography and the like.
  • the compound represented by the general formula (1) or a salt thereof of the present invention does not show toxicity at a pharmacologically effective dose.
  • N- (3-aminophenyl) _3,4,5-tribenzyloxybenzamide was obtained.
  • Oxalyl chloride (0.18 ml) was added to a suspension of (2--2) 4-benzyloxybenzoic acid (0.34 g, 1.5 mmol) in dichloromethane (10 ml), and then DMF was added. One drop was added and the mixture was stirred at 45 for 2 hours. After the solvent was distilled off, the residue was dissolved in dichloromethane (1 Om 1).
  • N- (3-Aminophenyl) -1,3,4,5-tribenzyloxybenzamide (0.53 g, 1.
  • the present invention provides a compound having a telomerase inhibitory action, a pharmacologically acceptable salt thereof, and a telomerase inhibitor containing them.
  • the compound according to the present invention is effective as a therapeutic composition and / or amelioration of telomerase-related diseases, and thus is useful as a pharmaceutical composition for treating such diseases, particularly as an anticancer agent.

Abstract

A novel m-phenylenediamine derivative having telomerase inhibitory activity; and a medicine such as a therapeutic agent or ameliorant for diseases which is based on the activity. The m-phenylenediamine derivative is represented by the general formula (1). This compound or a pharmacologically acceptable salt thereof is used in a medicine. By using the m-phenylenediamine derivative and telomease inhibitor in or as a medicine, treatments for or prevention of various diseases to which cell proliferation relates is possible. (1)

Description

明細書 メタフエ二レンジァミン誘導体 技術分野 本発明は、 新規なメタフエ二レンジァミン誘導体のテロメラーゼ阻害作用に基 づく医薬品への利用に関する。 背景技術 テロメァは真核生物の染色体末端に存在し、 染色体を安定化するために重要な 役割を果たしている。 通常の細胞では、 細胞***を行うごとにテロメァが 50— 20 0 b a s e短縮し、 ある長さ以下に短縮すると細胞***を停止するため、 細 胞の寿命を決定する役割を果たしていると考えられている。 そのため、 通常の細 胞は無限に増殖を続けることはない。 たとえば、 P53 などの癌抑制遺伝子に変異 が生じ、 細胞が異常に***を続けるようになっても、 ***に伴いテロメァが短縮 することにより、 増殖停止あるいは細胞死が起こるため、 癌になることはない。 しかし、 それらの細胞がテロメァを延長する酵素テロメラーゼを発現すると、 不 死化し癌細胞となることが知られている。 そこで、 テロメラーゼの阻害剤によ り癌細胞の無限増殖を抑えることが出来れば、 毒性の低い新しい制癌剤となるこ とが期待されている。実際、カテキン類（Biochem. Biophys. Res. Co匪 un.、 249、 P391-396, 1998)、 ポルフィリン誘導体 (J. Am. Chem. Soc.、 120、 3261-3262, 1998)、 核酸誘導体 （Biochemistry, 35、 15611、 1996)、 アントラキノン誘導 体 （J. Med. Chem.、 40、 2113、 1997) 等がテロメラーゼ阻害剤として報告さ れている。 さらに、 2, 4—ジォキソチアゾリジン誘導体 （特開 20 0 1— 7 2 5 9 2公報）、フラポマンナン（特開 2 00 1 - 3 1 5 64公報）、 Spiro[benzo[l， 2-b:5, 4- c']dipyran-2(3H)- naphtofuran]誘導体 (特開 2 0 0 1 _ 8 1 0 2 9公 報）、 ピリジン誘導体 （特開平 1 1— 496 7 6号公報、 特開平 1 1— 4 9 6 7 8 号公報、特開平 1 1一 4 9 7 6 9号公報、特開平 1 1一 4 9 7 7 7号公報）、 トリ ァジン誘導体 （特開平 1 1—6 0 5 7 3号公報） などの特許が知られている。 さらに、 癌以外の細胞増殖に関わる様々な疾患においても、 テロメラ一ゼが関 与していることが知られており、 テロメラ一ゼの阻害薬は、 医薬品として広い可 能性を持つ薬剤として期待されている。 し力 ^し、 多くの研究が行われているにも 関わらず、 テロメラーゼを阻害して様々な疾患を治療できる、 有効な薬剤は見い 出されていない。 TECHNICAL FIELD The present invention relates to use of a novel metaphenylenediamine derivative in a drug based on a telomerase inhibitory action of the metaphenylenediamine derivative. Background Art Telomeres are present at the ends of chromosomes in eukaryotes and play an important role in stabilizing chromosomes. In normal cells, telomeres are shortened by 50-200 bases each time cell division takes place, and if they are shortened to a certain length or less, cell division stops, and it is thought that they play a role in determining the life span of cells. I have. Therefore, normal cells do not grow indefinitely. For example, even if a mutation occurs in a tumor suppressor gene such as P53 and cells continue to divide abnormally, telomeres are shortened due to division, and growth is stopped or cell death occurs. Absent. However, it is known that when those cells express the telomerase-prolonging enzyme telomerase, they become immortalized and become cancer cells. Therefore, if the infinite growth of cancer cells can be suppressed by telomerase inhibitors, it is expected to become a new anticancer drug with low toxicity. In fact, catechins (Biochem. Biophys. Res. Cobalt un., 249, P391-396, 1998), porphyrin derivatives (J. Am. Chem. Soc., 120, 3261-3262, 1998), nucleic acid derivatives (Biochemistry , 35, 15611, 1996), anthraquinone derivatives (J. Med. Chem., 40, 2113, 1997), and the like have been reported as telomerase inhibitors. Furthermore, 2,4-dioxothiazolidine derivatives (Japanese Patent Application Laid-Open No. 2001-72592), flapomannans (Japanese Patent Application Laid-Open No. 2001-315564), Spiro [benzo [l, 2-b] : 5,4-c '] dipyran-2 (3H) -naphtofuran] derivative (Japanese Patent Application Laid-Open No. 2001-81929), pyridine derivative (Japanese Patent Application Laid-Open No. 11-49676, Kaiping 1 1— 4 9 6 7 8 Patents, Japanese Patent Application Laid-Open No. 11-49769, Japanese Patent Application Laid-Open No. 11-97777, and Triazine Derivatives (Japanese Patent Application Laid-Open No. 11-65773) It has been known. It is also known that telomerase is involved in various diseases related to cell proliferation other than cancer, and telomerase inhibitors are expected to have broad potential as drugs. Have been. Despite much research, no effective drug has been found that can inhibit telomerase and treat various diseases.
また、 ポリヒドロキシ化合物が様々な効果を発揮することは良く知られている が、 メタフエ二レンジァミン誘導体がテロメラーゼを阻害することは、 全く知ら れていなかった。 メタフエ二レンジァミン誘導体のポリヒドロキシ化合物として 知られているのは、 N. Raymond ら （JACS, 2001， 123, 8923) の Supramo l ecu l ar Cl us t erに関してのみである。 さらに、 その作用を発揮するためには、 2， 3 - ジヒドロキシベンズアミド構造が重要であることが明らかであり、 また、 ポリヒ ドロキシ基を有するメタフエ二レンジァミン誘導体の医薬用途への有用性は全く 知られていない。 発明の開示 本発明の課題は、 一般式 （1 ) で表されるテロメラ一ゼ阻害活性を有する化合 物を、 様々な疾患の治療および または改善剤などの医薬品として提供すること にある。  Although it is well known that polyhydroxy compounds exert various effects, it has never been known that metaphenylenediamine derivatives inhibit telomerase. The only known polyhydroxy compound of the metaphenylenediamine derivative is only with respect to Supramo eccu lar Cluster of N. Raymond et al. (JACS, 2001, 123, 8923). Further, it is clear that the 2,3-dihydroxybenzamide structure is important for exerting its effect, and the usefulness of the metaphenylenediamine derivative having a polyhydroxy group for pharmaceutical use is completely known. Not. DISCLOSURE OF THE INVENTION An object of the present invention is to provide a compound having telomerase inhibitory activity represented by the general formula (1) as a medicament for treating and / or improving various diseases.
また、 本発明の別の課題は、 一般式 （5 ) で表される化合物を提供することに ある。  Another object of the present invention is to provide a compound represented by the general formula (5).
本発明者は上記課題を解決すべく鋭意検討した結果、ポリヒドロキシ基を有す るメタフエ二レンジァミン誘導体に、 強いテロメラ一ゼ阻害活性を見いだし、 本 発明を完成させた。  As a result of intensive studies to solve the above problems, the present inventors have found a strong telomerase inhibitory activity in a metaphenylenediamine derivative having a polyhydroxy group, and have completed the present invention.
すなわち、 本発明は、 That is, the present invention
[ 1 ] 一般式 （1 )
Figure imgf000005_0001
[1] General formula (1)
Figure imgf000005_0001
(式中、 Zは置換されているフエニル基、 あるいは複素環基を表す。 R l、 R2、 R3、 R4、 R 7は水素原子あるいは OR 5基、 アルコキシ基、 ァシルォキシ基、 アミノ基、 炭素数 1〜5のアルキル基で置換されてもよいアミノ基、 ニトロ基、 カルボキシル基、 炭素数 1〜 5のアルコキシカルボ二ル基、 ハロゲン原子、 置換 されてもよいスルホ二ル基を （ただし、 R 1と R 2のいずれか一方は OR 5基を 表す）、 R 5は水素原子または水酸基の保護基を、 R 6は水素原子または炭素数 1 〜 5の置換されてもよいアルキル基またはベンジル基を表す。）で表される化合物 あるいはその薬理'学的に許容される塩を含むテロメラーゼ阻害剤であり、  (In the formula, Z represents a substituted phenyl group or a heterocyclic group. R1, R2, R3, R4, and R7 represent a hydrogen atom or OR5 group, an alkoxy group, an acyloxy group, an amino group, and the number of carbon atoms. An amino group, a nitro group, a carboxyl group, an alkoxycarbonyl group having 1 to 5 carbon atoms, a halogen atom, a sulfonyl group which may be substituted One of R 1 and R 2 represents an OR 5 group), R 5 is a hydrogen atom or a hydroxyl-protecting group, and R 6 is a hydrogen atom or an alkyl or benzyl group having 1 to 5 carbon atoms which may be substituted. A telomerase inhibitor comprising a compound represented by the formula or a pharmacologically acceptable salt thereof,
[2] 一般式 （2)  [2] General formula (2)
Figure imgf000005_0002
Figure imgf000005_0002
(式中、 R l、 R2、 R3、 R4、 R5、 R6、 R 7は前記に同じ （ただし、 R 1と R 2のいずれか一方は OR 5基を表す。） R8、 R9、 R 10、 R 1 1はそれ ぞれ独立して水素原子あるいは OR 5基、 アルコキシ基、 ァシルォキシ基、 アミ ノ基、 炭素数 1〜 5のアルキル基で置換されてもよいアミノ基、 ニトロ基、 カル ボキシル基、 炭素数 1〜5のアルコキシカルポニル基、 ハロゲン原子、 置換され てもよいスルホ二ル基を表す （ただし、 R8、 R9、 R 10、 R 11は同時に水 素原子にならない。）） で表される請求項 1に記載の化合物又はその薬理学的に許 容される塩を含むテロメラ一ゼ阻害剤であり、  (Wherein, R 1, R 2, R 3, R 4, R 5, R 6, and R 7 are the same as described above (provided that one of R 1 and R 2 represents an OR 5 group.) R 8, R 9, R 10, R 11 is each independently a hydrogen atom or an OR 5 group, an alkoxy group, an acyloxy group, an amino group, an amino group, a nitro group, and a carboxyl group which may be substituted with an alkyl group having 1 to 5 carbon atoms. Represents an alkoxycarbonyl group having 1 to 5 carbon atoms, a halogen atom, or an optionally substituted sulfonyl group (however, R8, R9, R10, and R11 are not simultaneously hydrogen atoms). A telomerase inhibitor comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof,
[3] —般式 （3)
Figure imgf000006_0001
[3] — General formula (3)
Figure imgf000006_0001
(式中、 R l、 R2、 R3、 R 5は前記に同じ （ただし、 1と!^2のぃずれか 一方は OR 5基を表す。）で表される請求項 2に記載の化合物又はその薬理学的に 許容される塩を含むテロメラーゼ阻害剤であり、  3. The compound according to claim 2, wherein R 1, R 2, R 3, and R 5 are the same as described above (however, any one of 1 and! ^ 2 represents an OR 5 group). Telomerase inhibitors, including their pharmacologically acceptable salts,
[4] 一般式 （4)  [4] General formula (4)
Figure imgf000006_0002
Figure imgf000006_0002
(式中、 R 5は前記に同じ。）で表される請求項 3に記載の化合物又はその薬理学 的に許容される塩を含むテロメラ一ゼ阻害剤であり、  (Wherein R 5 is the same as defined above), or a telomerase inhibitor comprising the compound according to claim 3 or a pharmaceutically acceptable salt thereof,
[5] 請求項 1から請求項 4の何れか一項に記載の、 少なくともひとつのテロメ ラ一ゼ阻害剤を含む医薬品であり、  [5] A medicament comprising at least one telomerase inhibitor according to any one of claims 1 to 4, wherein
[6] 請求項 1から請求項 4の何れか一項に記載の、 少なくともひとつのテロメ ラーゼ阻害剤を含む制癌剤であり、  [6] An anticancer agent comprising at least one telomerase inhibitor according to any one of claims 1 to 4, wherein
[7] 一般式 （5)  [7] General formula (5)
Figure imgf000006_0003
Figure imgf000006_0003
(式中、 Zは置換されているフエニル基、あるいは複素環基を表す。 R3、 R4、 R7は、 それぞれ独立して水素原子あるいは OR 5基、 アルコキシ基、 ァシルォ キシ基、 アミノ基、 炭素数 1〜5のアルキル基で置換されてもよいアミノ基、 二 トロ基、 力ルポキシル基、 炭素数 1〜5のアルコキシカルボ二ル基、 ハロゲン原 子、置換されてもよいスルホニル基を、 R 5は水素原子または水酸基の保護基を、 R 6は水素原子または炭素数 1〜 5の置換されてもよいアルキル基またはべンジ ル基を、 R 12は水素原子あるいはアルコキシ基、 ァシルォキシ基、 アミノ基、 炭素数 1〜 5のアルキル基で置換されてもよいアミノ基、 ニトロ基、 カルポキシ ル基、 炭素数 1〜5のアルコキシカルボニル基、 ハロゲン原子、 置換されてもよ いスルホ二ル基を表す。）で表される化合物又はその薬理学的に許容される塩であ り、 (In the formula, Z represents a substituted phenyl group or a heterocyclic group. R3, R4, and R7 each independently represent a hydrogen atom or an OR5 group, an alkoxy group, an alkoxy group, an amino group, a carbon number. An amino group optionally substituted with 1 to 5 alkyl groups, R 5 is a hydrogen atom or a hydroxyl-protecting group, R 6 is a hydrogen atom or a nitro group, a carbonyl group having 1 to 5 carbon atoms, a halogen atom, a sulfonyl group which may be substituted. R 12 represents a hydrogen atom or an alkoxy group, an acyloxy group, an amino group, or an amino group which may be substituted with an alkyl group having 1 to 5 carbon atoms. A nitro group, a carboxyl group, an alkoxycarbonyl group having 1 to 5 carbon atoms, a halogen atom, and a sulfonyl group which may be substituted. ) Or a pharmacologically acceptable salt thereof,
[8] 一般式 （6)  [8] General formula (6)
Figure imgf000007_0001
Figure imgf000007_0001
(式中、 R3、 R4、 R5、 R6、 R7、 R 12は前記に同じ。 R8、 R9、 R 10、 R 1 1はそれぞれ独立して水素原子あるいは OR 5基、 アルコキシ基、 ァ シルォキシ基、 アミノ基、 炭素数 1〜5のアルキル基で置換されてもよいアミノ 基、 ニトロ基、 力ルポキシル基、 炭素数 1〜 5のアルコキシカルポニル基、 ハロ ゲン原子、 置換されてもよいスルホ二ル基を表す（ただし、 R8、 R9、 R 10、 R 1 1は同時に水素原子にならない））で表される請求項 7に記載の化合物又はそ の薬理学的に許容される塩であり、 (Wherein, R3, R4, R5, R6, R7, and R12 are the same as above. R8, R9, R10, and R11 are each independently a hydrogen atom or an OR5 group, an alkoxy group, an acyloxy group, Amino group, amino group which may be substituted with alkyl group having 1 to 5 carbon atoms, nitro group, carbonyl group, alkoxycarbonyl group having 1 to 5 carbon atoms, halogen atom, sulfonyl group which may be substituted (Wherein R8, R9, R10, and R11 are not hydrogen atoms at the same time), or a pharmacologically acceptable salt thereof,
[9] 一般式 （7)  [9] General formula (7)
Figure imgf000007_0002
Figure imgf000007_0002
(式中、 R3、 R5、 R 12は前記に同じ。） で表される請求項 8に記載の化合物 又はその薬理学的に許容される塩であり、 (Wherein, R3, R5, and R12 are the same as described above). Or a pharmacologically acceptable salt thereof,
[ 1 0 ] 一般式 ( 8 )  [10] General formula (8)
Figure imgf000008_0001
Figure imgf000008_0001
(式中、 R 5は前記に同じ。）で表される請求項 9に記載の化合物又はその薬理学 的に許容される塩である。 発明を実施するための最良の形態 以下、 本発明を詳細に説明する。  (Wherein R 5 is the same as defined above), or a pharmacologically acceptable salt thereof according to claim 9. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
一般式 （1 ) で表される化合物において、 Zにおける置換されているフエニル 基とは、 フエニル基上の 2位、 3位、 4位のいずれの位置に置換基があってもよ く、 また複数の位置に置換基があってもよい。 複数の置換基を有する場合、 置換 基の種類は同一であっても別の置換基であってもよい。 置換基としては例えば、 メチル基、 ェチル基、 イソプロピル基などのアルキル基、 メトキシ基、 エトキシ 基、 n—プロピルォキシ基、 i —プロピルォキシ基などのアルキルォキシ基、 ヒ ドロキシ基、 ニトロ基、 アミノ基、 メチルァミノ基、 ェチルァミノ基、 n—プロ ピルアミノ基、 i—プロピルアミノ基、 ジメチルァミノ基、 ジェチルァミノ基な どの置換もしくは無置換アミノ基、 フルォロ原子、 クロ口原子、 ブロモ原子など のハロゲン原子、 ホルミル基、 ァセチル基、 プロピオニル基、 ベンゾィル基など のァシル基、 ホルミルォキシ基、 ァセチルォキシ基、 プロピオニルォキシ基、 ベ ンゾィルォキシ基などのァシルォキシ基、 ホルムアミド基、 ァセトアミド基、 ベ ンズアミド基などのアミド基等が挙げられる。 置換されているフエニル基の例と しては、 2 —ヒドロキシフエニル基、 3 —ヒドロキシフエニル基、 4ーヒドロキ シフエ二ル基、 2， 3 —ジヒドロキシフエニル基、 3， 4—ジヒドロキシフエ二 ル基、 2 , 3 , 4—トリヒドロキシフエニル基、 3 , 4 , 5 —トリヒドロキシフ ェニル基、 2 , 4 , 5 —トリヒドロキシフエニル基、 2 —メチルフエニル基、 3 一メチルフエニル基、 4 _メチルフエニル基、 2—ァミノフエ二ル基、 3 _アミ ノフエ二ル基、 4—ァミノフエニル基、 3 , 4—ジァミノフエニル基、 2—メト キシフエニル基、 3—メトキシフエ二ル基、 4—メトキシフエ二ル基、 3， 4— ジメトキシフエ二ル基、 2， 3 —ジメトキシフエ二ル基、 2， 3， 4一トリメト キシフエニル基、 3， 4， 5 —トリメトキシフエ二ル基、 2—クロ口フエ二ル基、 3 —クロ口フエ二ル基、 4—クロ口フエ二ル基、 2—ブロモフエニル基、 3—ブ ロモフエニル基、 4—ブロモフエニル基、 3 , 4—ジクロロフェニル基、 3 , 4 一ジブロモフエニル基、 2 —ホルムアミドフエ二ル基、 3 _ホルムアミドフエ二 ル基、 4—ホルムアミドフエ二ル基、 2 —ァセトキシフエ二ル基、 3—ァセトキ シフエ二ル基、 4ーァセトキシフエ二ル基、 3 , 4—ァセトキシフエ二ル基、 2 , 3—ァセトキシフエニル基、 4—ヒドロキシ _ 3—アミノフェニル基等が挙げら れる。 また、 ヒドロキシル基、 アミノ基などのさらなる置換が可能な置換基の先 には、 脂溶性、 安定性、 水溶性、 体内への移行性、 腸管での吸収性などをコント ロールするような種々の置換基を導入することもできる。 In the compound represented by the general formula (1), the substituted phenyl group for Z may be a substituent at any of the 2-, 3-, and 4-positions on the phenyl group. Substituents may be present at multiple positions. When it has a plurality of substituents, the types of the substituents may be the same or different. Examples of the substituent include an alkyl group such as a methyl group, an ethyl group and an isopropyl group, an alkyloxy group such as a methoxy group, an ethoxy group, an n-propyloxy group and an i-propyloxy group, a hydroxy group, a nitro group, an amino group, and a methylamino group. Group, ethylamino, n-propylamino, i-propylamino, dimethylamino, dimethylamino, substituted or unsubstituted amino, halogen, fluoro, chloro, bromo, etc., formyl, acetyl And an amide group such as an acyl group such as a propionyl group and a benzoyl group; an acyloxy group such as a formyloxy group and an acetyloxy group; a propionyloxy group and a benzoyloxy group; a formamide group, an acetoamide group and a benzamide group. Examples of the substituted phenyl group include 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2,3-dihydroxyphenyl group, and 3,4-dihydroxyphenyl group. Group, 2,3,4-trihydroxyphenyl group, 3,4,5-trihydroxyphenyl group Phenyl, 2,4,5—trihydroxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 3,4-diaminophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3,4-dimethoxyphenyl group, 2,3-dimethoxyphenyl group, 2,3 , 4,1-Trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl Group, 3-bromophenyl group, 4-bromophenyl group, 3,4-dichlorophenyl group, 3,4-dibromophenyl group, 2-formamidophenyl group, 3-formamidophenyl group, 4-formamidophenyl group Group, 2 Acetoxyphenyl group, 3-acetoxyphenyl group, 4-acetoxyphenyl group, 3,4-acetoxyphenyl group, 2,3-acetoxyphenyl group, 4-hydroxy_3-aminophenyl group and the like. Is received. In addition to the substituents that can be further substituted, such as hydroxyl group and amino group, various groups that control fat-solubility, stability, water solubility, translocation into the body, absorption in the intestinal tract, etc. Substituents can also be introduced.
R 5基における水酸基の保護基とは、 フエノール性あるいはアルコール性の水 酸基を保護するような置換基であれば良い。 また、 置換基においては脂溶性、 水 溶性、 体内への移行性、 腸管での吸収性をコントロールするような種々の部分構 造を加える事ができる。 R 5基における置換基の例としては、 他の官能基により 置換されても良いアルキル基、 他の官能基により置換されても良いシリル基、 他 の官能基により置換されても良いアルキルァシル基、 他の官能基により置換され ても良い芳香族ァシル基、 他の官能基により置換されても良いヒドロキシカルボ ニル基、 他の官能基により置換されても良いアミノカルポニル基などが挙げられ る。  The hydroxyl-protecting group in R 5 may be any substituent that protects a phenolic or alcoholic hydroxyl group. In addition, various partial structures can be added to the substituent to control fat-solubility, water-solubility, translocation into the body, and absorption in the intestinal tract. Examples of the substituent in the R5 group include an alkyl group optionally substituted with another functional group, a silyl group optionally substituted with another functional group, an alkylacyl group optionally substituted with another functional group, Examples thereof include an aromatic acyl group that may be substituted with another functional group, a hydroxycarbonyl group that may be substituted with another functional group, and an aminocarbonyl group that may be substituted with another functional group.
他の官能基により置換されても良いアルキル基の具体例としては、 メチル基、 ェチル基、 n—プロピル基、 i—プロピル基、 n—ブチル基、 i —ブチル基、 ベ ンジル基 （B n )、 ジフエニルメチル基、 トリフエニルメチル基 （T r )、 メトキ シメチル基 （M〇M)、 エトキシメチル基、 メトキシェチル基、 ベンジルォキシメ チル基、 トリメチルシリルォキシェチル基などが挙げられる。 他の官能基により 置換されても良いアルキルァシル基の例としては、 ホルミル基、 ァセチル基、 プ 口ピオニル基、 n—プチリル基、 i 一プチリル基、 n—ペンテノィル基、 n—へ キサノィル基、 n—ヘプ夕ノィル基、 n—ォク夕ノィル基、 メトキシプロピオ二 ル基、 フエニルァセチル基が挙げられる。 また、 グリシン、 ァラニン、 パリン、 ロイシン、 イソロイシン、 セリン、 スレオニン、 フエ二ルァラニン、 トリプトフ アン、 リジン、 メチォニンなどのアミノ酸のエステル類が挙げられる。 他の官能 基により置換されても良い芳香族ァシル基の例としては、 ベンゾィル基、 2—メ チルベンゾィル基、 3 _メチルベンゾィル基、 4—メチルベンゾィル基、 2—メ トキシベンゾィル基、 3—メトキシベンゾィル基、 4—メトキシベンゾィル基、 2 —ヒドロキシベンゾィル基、 3 —ヒドロキシベンゾィル基、 4—ヒドロキシべ ンゾィル基、 ピリジン— 2—ィルカルポニル基、 ピリジン— 3—ィルカルボニル 基、 ピリジン一 4—ィルカルポニル基、 4 _ニトロベンゾィル基、 4一フエニル ベンゾィル基、 4 _アミノベンゾィル基などが挙げられる。 他の官能基により置 換されても良いヒドロキシカルボニル基の例としては、 メトキシカルポニル基、 ェトキしカルボ二ル基、 n—プロピルォキシカルポニル基、 i _プロピルォキシ カルポニル基、 n—ブチルォキシカルポニル基、 フエニルォキシカルボニル基、 フエニルメチルォキシカルボニル基、 などが挙げられる。 他の官能基により置換 されても良いアミノカルポニル基の例としては、 ァミノカルボニル基、 N—メチ ルァミノカルポニル基、 N、 N—ジメチルァミノカルボニル基、 N—ェチルアミ ノカルポニル基、 N—プロピルアミノカルボ二ル基、 N—フエニルァミノカルボ ニル基、 N—ベンジルァミノ力ルポニル基などが挙げられる。 Specific examples of the alkyl group which may be substituted with another functional group include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a benzyl group (Bn ), A diphenylmethyl group, a triphenylmethyl group (Tr), a methoxymethyl group (M〇M), an ethoxymethyl group, a methoxyethyl group, a benzyloxymethyl group, and a trimethylsilyloxethyl group. By other functional groups Examples of the alkylacyl group which may be substituted include a formyl group, an acetyl group, a pionyl group, an n-butyryl group, an i-butyryl group, an n-pentenyl group, an n-hexanoyl group, and an n-hepnoyl group And n-octanol groups, methoxypropionyl groups, and phenylacetyl groups. In addition, esters of amino acids such as glycine, alanine, palin, leucine, isoleucine, serine, threonine, phenylalanine, tryptophan, lysine, methionine and the like can be mentioned. Examples of the aromatic acyl group which may be substituted by another functional group include benzoyl group, 2-methylbenzoyl group, 3-methylbenzoyl group, 4-methylbenzoyl group, 2-methoxybenzoyl group, and 3-methoxybenzoyl group. Group, 4-methoxybenzoyl group, 2-hydroxybenzoyl group, 3-hydroxybenzoyl group, 4-hydroxybenzoyl group, pyridine-2-ylcarbonyl group, pyridine-3-ylcarbonyl group, pyridine-1 4 —Ylcarbonyl group, 4-nitrobenzoyl group, 4-phenylbenzoyl group, 4-aminobenzoyl group and the like. Examples of the hydroxycarbonyl group which may be replaced by another functional group include: methoxycarbonyl group, ethoxycarbonyl group, n-propyloxycarbonyl group, i_propyloxycarbonyl group, n-butyloxycarbonyl. A phenyloxycarbonyl group, a phenylmethyloxycarbonyl group, and the like. Examples of the aminocarbonyl group which may be substituted with another functional group include an aminocarbonyl group, an N-methylaminocarbonyl group, an N, N-dimethylaminocarbonyl group, an N-ethylaminocarbonyl group, and an N-propyl group. Examples thereof include an aminocarbonyl group, an N-phenylaminocarbonyl group, and an N-benzylaminocarbonyl group.
R l、 R 2、 R 3、 R 4、 R 7、 R 8、 R 9、 R 1 0、 R l l、 R 1 2におい て、 アルコキシ基とは、 メトキシ基、 エトキシ基、 プロポキシ基、 イソプロポキ シ基、 ブトキシ基、 ベンジルォキシ基などが挙げられる。  In Rl, R2, R3, R4, R7, R8, R9, R10, Rll, and R12, the alkoxy group is a methoxy group, an ethoxy group, a propoxy group, or an isopropoxy group. Group, butoxy group, benzyloxy group and the like.
ァシルォキシ基とは、ホルミルォキシ基、ァセトキシ基、プロピオニルォキシ基、 ビバロイルォキシ基、 ベンゾィルォキシ基などが挙げられる。 Examples of the acyloxy group include a formyloxy group, an acetoxy group, a propionyloxy group, a bivaloyloxy group, and a benzoyloxy group.
炭素数 1〜 5のアルキル基で置換されてもよいアミノ基とは、 アミノ基上の窒 素原子にアルキル基が置換されても良い事をあらわす。 具体的にはメチルァミノ 基、 ェチルァミノ基、 n—プロピルアミノ基、 プチルァミノ基、 ジメチルァミノ 基、 ジェチルァミノ基、 ジイソプロピルアミノ基、 シクロプロピルアミノ基、 ベ ンジルァミノ基などが挙げられる。 An amino group which may be substituted with an alkyl group having 1 to 5 carbon atoms means that a nitrogen atom on the amino group may be substituted with an alkyl group. Specifically, methylamino group, ethylamino group, n-propylamino group, butylamino group, dimethylamino group Group, getylamino group, diisopropylamino group, cyclopropylamino group, benzylamino group and the like.
炭素数 1〜5のアルコキシカルボニル基とは、 メトキシカルボニル基、 ェトキ シカルポニル基、 n—プロピルォキシカルボニル基、 ベンジルォキシカルボニル 基などが挙げられる。  The alkoxycarbonyl group having 1 to 5 carbon atoms includes a methoxycarbonyl group, an ethoxycarbonyl group, an n-propyloxycarbonyl group, a benzyloxycarbonyl group and the like.
置換されてもよいスルホニル基とは、 メタンスルホニル基、 エタンスルホニル 基、 プロパンスルホニル基、 ベンゼンスルホニル基などが挙げられる。  Examples of the sulfonyl group which may be substituted include a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a benzenesulfonyl group and the like.
ハロゲン原子としてはフッ素原子、 塩素原子、 臭素原子、 ヨウ素原子をあらわ す。  Halogen atoms include fluorine, chlorine, bromine and iodine.
R 6の例としては具体的には、 水素原子、 メチル基、 ェチル基、 n _プロピル 基、 n—ブチル基、 ベンジル基、 メトキシェチル基、 ァセトキシメチル基、 ァセ トキシェチル基などが挙げられる。  Specific examples of R6 include a hydrogen atom, a methyl group, an ethyl group, an n_propyl group, an n-butyl group, a benzyl group, a methoxyethyl group, an acetyloxymethyl group, an acetoxethyl group, and the like.
薬学的に許容される化合物の塩とは、 この分野で常用されるリチウム、 ナトリ ゥム、 カリウムなどのアルカリ金属、 マグネシウム、 カルシウムなどのアルカリ 土類金属、 メチルァミン、 ェチルァミン、 ジメチルァミン、 トリメチルァミン、 トリェチルァミン、 ベンジルァミン、 シクロへキシルァミンなどの有機塩基、 ァ ンモニァなどの無機塩基との塩を化合物の塩として挙げることができる。  The pharmaceutically acceptable salts of the compounds include alkali metals such as lithium, sodium and potassium, alkaline earth metals such as magnesium and calcium, methylammine, ethylamine, dimethylamine, trimethylamine, and the like, which are commonly used in this field. Salts with organic bases such as triethylamine, benzylamine, cyclohexylamine and the like, and inorganic bases such as ammonia can be mentioned as salts of the compounds.
また一般式 （1 ) の化合物がアミノ基などの塩基性を有する場合は、 塩酸、 臭 化水素酸、 硫酸、 燐酸などの無機酸の他、 酢酸、 酒石酸、 フマル酸、 マレイン酸、 クェン酸、 安息香酸、 トリフルォロ酢酸、 P—トルエンスルホン酸、 メタンスル ホン酸などの有機酸との塩も化合物の塩として挙げることができる。  When the compound of the general formula (1) has a basic property such as an amino group, it may be an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, fumaric acid, maleic acid, citrate, Salts with organic acids such as benzoic acid, trifluoroacetic acid, P-toluenesulfonic acid and methanesulfonic acid can also be mentioned as salts of the compounds.
一般式 （1 ) で表される化合物は医薬品として用いるために水酸基ゃァミノ基 などをマスクする事でプロドラッグとして用いる事も出来る。  The compound represented by the general formula (1) can also be used as a prodrug by masking a hydroxyl group or a diamino group for use as a pharmaceutical.
一般式 （1 ) で表される化合物において不斉炭素を有する場合は、 異なった立 体異性形態またはラセミ形態を含む立体異性形態の混合物の形態で存在すること ができる。 すなわち、 本発明はこのように規定した種々の形態をも包含するが、 これらも同様に有効成分化合物として用いることができる。  When the compound represented by the general formula (1) has an asymmetric carbon, it can exist in a form of a mixture of different stereoisomeric forms or stereoisomeric forms including racemic forms. That is, the present invention includes various forms defined as above, and these can be similarly used as active ingredient compounds.
有効成分として含有するとは、 製剤中に一般式 （1 ) で表される化合物を一つ または複数含有することである。 医薬品とは、 テロメラーゼに関係する疾病の治療および/または改善剤として 有用である。 より具体的には、 細胞の増殖に関わる疾患や生体の恒常性に関わる 疾患、 すなわち悪性腫瘍、 自己免疫性疾患、 皮膚病、 感染症、 血管性疾患、 血液 性疾患、 アレルギー性疾患、 消化管傷害、 ホルモン性疾患、 代謝性疾患、 糖尿病 などの治療および/または改善剤として有用である。 To be contained as an active ingredient means to contain one or more compounds represented by the general formula (1) in the preparation. Pharmaceuticals are useful as therapeutic and / or ameliorating agents for diseases associated with telomerase. More specifically, diseases related to cell proliferation and diseases related to homeostasis, i.e., malignant tumors, autoimmune diseases, skin diseases, infectious diseases, vascular diseases, blood diseases, allergic diseases, gastrointestinal tract It is useful as a therapeutic and / or ameliorating agent for injuries, hormonal diseases, metabolic diseases, diabetes and the like.
悪性腫瘍とは急性白血病、 慢性白血病、 悪性リンパ腫、 多発性骨髄腫、 マクロ グロブリン血症などの造血器腫瘍の他、 大腸癌、 脳腫瘍、 頭頸部癌、乳癌、 肺癌、 食道癌、 胃癌、 肝癌、 胆嚢癌、 胆管癌、 滕癌、 塍島細胞癌、 腎細胞癌、 副腎皮質 癌、 膀胱癌、 前立腺癌、 睾丸腫瘍、 卵巣癌、 子宮癌、 絨毛癌、 甲状腺癌、 悪性力 ルチノイド腫瘍、 皮膚癌、 悪性黒色腫、 骨肉腫、 軟部組織肉腫、 神経芽細胞腫、 ウィルムス腫瘍、 網膜芽細胞腫などの固形腫瘍が挙げられる。  Malignant tumors include hematopoietic tumors such as acute leukemia, chronic leukemia, malignant lymphoma, multiple myeloma, macroglobulinemia, colorectal cancer, brain tumor, head and neck cancer, breast cancer, lung cancer, esophageal cancer, stomach cancer, liver cancer, Gallbladder cancer, bile duct cancer, Teng cancer, hepatocellular carcinoma, renal cell carcinoma, adrenocortical carcinoma, bladder cancer, prostate cancer, testicular tumor, ovarian cancer, uterine cancer, choriocarcinoma, thyroid cancer, malignant rutinoid tumor, skin cancer , Malignant melanoma, osteosarcoma, soft tissue sarcoma, neuroblastoma, Wilms tumor, retinoblastoma and other solid tumors.
自己免疫性疾患とはリウマチ、 腎炎、 糖尿病、 全身性エリテマトーデス、 ヒト 自己免疫性リンパ球増殖性リンパ節症、 免疫芽細胞性リンパ節症、 クローン病、 潰瘍性大腸炎などが挙げられる。  Autoimmune diseases include rheumatism, nephritis, diabetes, systemic lupus erythematosus, human autoimmune lymphoproliferative lymphadenopathy, immunoblastic lymphadenopathy, Crohn's disease, ulcerative colitis and the like.
皮膚病とは乾せん、 ァクネ、 湿疹、 アトピー性皮膚炎、 寄生性皮膚疾患、 脱毛 症、 化膿性皮膚疾患、 皮膚硬化症などが挙げられる。  Skin diseases include psoriasis, acne, eczema, atopic dermatitis, parasitic skin diseases, alopecia, purulent skin diseases, and skin sclerosis.
感染症とは、 様々な細菌、 ウィルスあるいは寄生虫などの感染によって引き起 こされる疾患を意味する。  Infectious disease means a disease caused by infection with various bacteria, viruses or parasites.
血管性疾患とは、 動脈硬化症などが挙げられる。  The vascular disease includes arteriosclerosis and the like.
なお、 本発明の対象疾患はこれらに限定されることはない。  The target disease of the present invention is not limited to these.
さらに、 医薬品ばかりでなく動物用薬、 健康を維持するための食品や機能性食 品としても有用であり、 食品への添加やそれ自体を医療用製剤と同様な形態で用 いられる。  In addition, it is useful not only as a pharmaceutical product but also as a veterinary drug, a food for maintaining health and a functional food, and can be used in foods or in its own form in the same form as a medical preparation.
製剤は通常使用される充填剤、 増量剤、 結合剤、 保湿剤、 崩壊剤、界面活性剤、 滑沢剤等の希釈剤あるいは賦形剤を用いて調製される。 この医薬製剤としては各 種の形態が治療目的に応じて選択でき、 その代表的なものとして錠剤、 丸剤、 散 剤、 液剤、 懸濁剤、 乳剤、 顆粒剤、 カプセル剤、 注射剤 （液剤、 懸濁剤等） およ び坐剤等が挙げられる。  The formulations are prepared using commonly used diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and lubricants. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment. Representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, injections (solutions) , Suspensions, etc.) and suppositories.
錠剤の形態に成形するに際しては、 担体としてこの分野で従来からよく知られ ている各種のものを広く使用することができる。 その例としては、 例えば乳糖、 ブドウ糖、 デンプン、 炭酸カルシウム、 カオリン、 結晶セルロース、 ケィ酸等の 賦形剤、 水、 エタノール、 プロピルアルコール、 単シロップ、 ブドウ糖液、 デン プン液、 ゼラチン溶液、 カルポキシメチルセルロース、 セラック、 メチルセル口 ース、ポリビニルピロリドン等の結合剤、乾燥デンプン、アルギン酸ナトリゥム、 カンテン末、 カルメロースカルシウム、 デンプン、 乳糖等の崩壊剤、 白糖、 力力 ォバター、 水素添加油等の崩壊抑制剤、 第 4級アンモニゥム塩基、 ラウリル硫酸 ナトリウム等の吸収促進剤、 グリセリン、 デンプン等の保湿剤、デンプン、乳糖、 カオリン、 ベントナイト、 コロイド状ケィ酸等の吸着剤、 タルク、 ステアリン酸 塩、 ポリエチレングリコール等の滑沢剤等を使用することができる。 さらに錠剤 については、 必要に応じ通常の剤皮を施した錠剤、 例えば糖衣錠、 ゼラチン被包 錠、 腸溶性被包錠、 フィルムコーティング錠あるいは二層錠、 多層錠とすること ができる。 In the form of tablets, it is well known in the art as a carrier. Can be widely used. Examples include excipients such as lactose, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, caffeic acid, water, ethanol, propyl alcohol, simple syrup, dextrose, starch, gelatin, carboxy. Binders such as methylcellulose, shellac, methylcellulose, polyvinylpyrrolidone, etc., disintegrants such as dried starch, sodium alginate, agar powder, carmellose calcium, starch, lactose, etc. Agents, quaternary ammonium base, absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal keic acid, talc, stearic acid salts, polyethylene glycol Etc. It may be used agents. Furthermore, tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets, or multilayer tablets.
丸剤の形態に成形するに際しては、 担体として従来この分野で公知のものを広 く使用できる。 その例としては、 例えば結晶セルロース、 乳糖、 デンプン、 硬化 植物油、 カオリン、 タルク等の賦形剤、 アラビアゴム末、 トラガント末、 ゼラチ ン等の結合剤、 カルメロースカルシウム、 カンテン等の崩壊剤等が挙げられる。 カプセル剤は、 常法に従い通常有効成分化合物を上記で例示した各種の担体と 混合して、 硬質ゼラチンカプセル、 軟質カプセル等に充填して調製される。 さらに必要に応じて着色剤、 保存剤、 香料、 風味剤、 甘味剤等や他の医薬品を 医薬製剤中に含有させることもできる。  In molding into a pill form, a wide variety of carriers conventionally known in this field can be used. Examples include excipients such as crystalline cellulose, lactose, starch, hardened vegetable oils, kaolin, talc, binders such as gum arabic, powdered tragacanth, gelatin, disintegrants such as carmellose calcium, agar and the like. No. Capsules are prepared by mixing the active ingredient compound with the various carriers exemplified above and filling the resulting mixture into hard gelatin capsules, soft capsules, and the like, according to a conventional method. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals can be contained in the pharmaceutical preparation.
本発明のこれらの医薬製剤中に含有されるべき有効成分化合物の量は、 特に限定 されずに広範囲から適宜選択されるが、 通常製剤組成物中に約 1〜7 0重量％、 好ましくは約 5〜 5 0重量％とするのがよい。 The amount of the active ingredient compound to be contained in these pharmaceutical preparations of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 70% by weight, preferably about The content is preferably 5 to 50% by weight.
以下、 本発明の式 （1 ) で示される化合物の代表的構造を表 1から表 7に具体 的に例示する。
Figure imgf000014_0001
Hereinafter, typical structures of the compound represented by the formula (1) of the present invention are specifically shown in Tables 1 to 7.
Figure imgf000014_0001
化合物番号 R1 R2 R3 R4 R8 R10 R11Compound number R1 R2 R3 R4 R8 R10 R11
101 OH H H H H H H101 OH H H H H H H
102 OH OH H H H H H102 OH OH H H H H H
103 H OH H H H H H103 H OH H H H H H
104 H OH OH H H H H104 H OH OH H H H H H
105 OH H OH H H H H105 OH H OH H H H H
106 H OH OH OH H H H106 H OH OH OH H H H
107 OH H H H OH H H107 OH H H H OH H H
108 OH OH H H OH H H108 OH OH H H OH H H
109 H OH H H OH H H109 H OH H H OH H H
110 H OH OH H OH H H110 H OH OH H OH H H
111 OH H OH H OH H H111 OH H OH H OH H H
112 H OH OH OH OH H H112 H OH OH OH OH H H
113 OH H H H H OH H113 OH H H H H OH H
114 OH OH H H H OH H114 OH OH H H H OH H
115 H OH H H H OH H115 H OH H H H OH H
116 H OH OH H H OH H116 H OH OH H H OH H
117 OH H OH H H OH H117 OH H OH H H OH H
118 H OH OH OH H OH H118 H OH OH OH H OH H
119 OH H H H H OH OH119 OH H H H H OH OH
120 OH OH H H H OH OH120 OH OH H H H OH OH
121 H OH H H H OH OH121 H OH H H H OH OH
122 H OH OH H H OH OH122 H OH OH H H OH OH
123 OH H OH H H OH OH123 OH H OH H H OH OH
124 H OH OH OH H OH OH124 H OH OH OH H OH OH
125 OH H H H OH OH H125 OH H H H OH OH H
126 OH OH H H OH OH H126 OH OH H H OH OH H
127 H OH H H OH OH H127 H OH H H OH OH H
128 H OH OH H OH OH H128 H OH OH H OH OH H
129 OH H OH H OH OH H129 OH H OH H OH OH H
130 H OH OH OH OH OH H
Figure imgf000015_0001
Figure imgf000016_0001
表 4 130 H OH OH OH OH OH H
Figure imgf000015_0001
Figure imgf000016_0001
Table 4
Figure imgf000017_0001
表 5
Figure imgf000017_0001
Table 5
Figure imgf000018_0001
表 6
Figure imgf000018_0001
Table 6
Figure imgf000019_0001
Figure imgf000019_0001
表 7 Table 7
Figure imgf000020_0001
本発明の化合物は例えば下記のような方法により合成する事ができる。
Figure imgf000020_0001
The compound of the present invention can be synthesized, for example, by the following method.
(a) 一般式 （9)  (a) General formula (9)
Figure imgf000021_0001
Figure imgf000021_0001
(式中、 R 1〜R7、 は前記に同じ） で表される化合物と一般式 （10) (Wherein, R 1 to R 7 are the same as described above) and a compound represented by the general formula (10)
R13 Z (10) R13 Z (10)
(式中、 Zは前記に同じ、 R 13は水酸基、 フッ素原子、 塩素原子、 臭素原子、 ヨウ素原子をあらわす） で表される化合物とを縮合する事により得られるか、 ま たは、 (Wherein, Z is the same as described above, and R 13 represents a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), or
(b) —般式 （1 1)  (b) — General formula (1 1)
Figure imgf000021_0002
Figure imgf000021_0002
(式中、 R6、 R7は前記に同じ） で表される化合物と一般式 （12)
Figure imgf000022_0001
(Wherein R6 and R7 are the same as described above) and a compound represented by the general formula (12)
Figure imgf000022_0001
(式中、 R 1〜R5、 R 13は前記に同じ） で表される化合物を縮合する事によ り得られる。 この際、 一般式 （9) 〜 （12) に表される化合物が反応性の官能 基を有する場合は、 その官能基を保護の後反応させ、 更に脱保護する事により一 般式 （1) で表される化合物に変換することができる。  (Wherein, R 1 to R 5 and R 13 are the same as described above). At this time, when the compounds represented by the general formulas (9) to (12) have a reactive functional group, the functional group is protected and then reacted, and further deprotected to obtain the general formula (1) Can be converted to the compound represented by
一般式 （9) から一般式 （12) で表される化合物は、 市販されているか、 既 知の化合物であり容易に合成できるか、 公知の反応を組みあわせる事により得る 事ができる。  The compounds represented by the general formulas (9) to (12) are commercially available, are known compounds, can be easily synthesized, or can be obtained by combining known reactions.
(a) または （b) の縮合反応において、 通常のアミド結合形成反応、 例えば 酸ハロゲン化物または混合酸無水物または活性エステルなどの方法によって実施 する事ができる。  The condensation reaction of (a) or (b) can be carried out by a usual amide bond forming reaction, for example, a method using an acid halide, a mixed acid anhydride or an active ester.
例えば一般式 （10) または一般式 （12) で表される化合物 （ただし R 13 は水酸基を表す） と、 2， 4, 5 _トリクロ口フエノール、 ペンタクロロフエノ —ルまたは 4一二トロフエノールなどのフエノール類または N—ヒドロキシスク シイミド、 N—ヒドキシベンズトリアゾールなどの N—ヒドロキシ化合物を、 ジ シクロへキシルカルポジイミドの存在下に縮合させ、 活性エステル体に変換した 後、 一般式 （9) または一般式 （1 1) で表される化合物と反応させることによ り得られる。  For example, a compound represented by the general formula (10) or the general formula (12) (where R 13 represents a hydroxyl group), 2,4,5_trichlorophenol, pentachlorophenol or 412trophenol, etc. Phenols or N-hydroxy compounds such as N-hydroxysuccinimide and N-hydroxybenztriazole are condensed in the presence of dicyclohexylcarposimide to form an active ester, and then converted to an active ester form by the general formula (9) Alternatively, it can be obtained by reacting with a compound represented by the general formula (11).
また、 一般式 （10) または一般式 （12) (ただし、 R 13は水酸基をあら わす） で表される化合物を塩化ォキザリル、 塩化チォニル、 ォキシ塩化リンなど と反応させ、 酸塩化物に変換した後、 一般式 （9) または一般式 （1 1) で表さ れる化合物と縮合させることによって行うことができる。 また、 一般式（10) または一般式 （12) で表される化合物 （ただし R 13は水酸基を表す） と、 ク ロロ炭酸メチル、 クロ口炭酸ェチル、 クロ口炭酸ベンジル、 クロ口炭酸イソプチ ルまたはメタンスルホニルクロライド、 無水トリフルォロ酢酸などと反応させる ことによって混合酸無水物を得た後、 一般式 （9) または一般式 （1 1) で表さ れる化合物と縮合することによつても得られる。 さらにまた当該縮合反応は、 ジシクロへキシルカルポジイミド、 N , N ' —カルボニルジイミダゾール、 ジフ ェニルリン酸アジド、 シァノリン酸ジェチルなどのペプチド縮合試薬を用いて行 うこともできる。 In addition, a compound represented by the general formula (10) or (12) (where R 13 represents a hydroxyl group) was reacted with oxalyl chloride, thionyl chloride, phosphorus oxychloride, etc., and converted to an acid chloride. Thereafter, the reaction can be carried out by condensation with a compound represented by the general formula (9) or the general formula (11). In addition, a compound represented by the general formula (10) or (12) (wherein R 13 represents a hydroxyl group) and methyl chlorocarbonate, ethyl ethyl carbonate, benzyl carbonate, isobutyl carbonate or A mixed acid anhydride is obtained by reacting with methanesulfonyl chloride, trifluoroacetic anhydride, etc., and then represented by the general formula (9) or (11). Can also be obtained by condensation with the compound to be prepared. Furthermore, the condensation reaction can also be carried out using a peptide condensation reagent such as dicyclohexylcarposimide, N, N'-carbonyldiimidazole, diphenylphosphoric acid azide, or cytyl phosphate.
反応は、 通常一 2 0〜十 5 0 °Cで 0 . 5〜4 8時間反応させる。  The reaction is usually carried out at 120 to 150 ° C. for 0.5 to 48 hours.
用いられる溶媒としては例えば、ベンゼン、トルエンなどの芳香族炭化水素類、 テトラヒドロフラン、 ジォキサン、 ェチルエーテルなどのエーテル類、 ジクロロ メタン、 クロ口ホルムなどのハロゲン化炭化水素類、 N, N—ジメチルホルムァ ミドゃ D M I、 メタノール、 エタノール、 イソプロピルアルコールなどのアルコ ール類またはこれらの混合物が挙げられる。 有機塩基例えば、 トリェチルァミン またはピリジン、 4— (N, N—ジメチル） アミノビリジンなどを加えることに より、 反応速度を増大することもできる。  Examples of the solvent used include aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, dioxane and ethyl ether, halogenated hydrocarbons such as dichloromethane and chloroform, N, N-dimethylformamideア ル Alcohols such as DMI, methanol, ethanol, and isopropyl alcohol, or mixtures thereof. The reaction rate can also be increased by adding an organic base such as triethylamine or pyridine, 4- (N, N-dimethyl) aminoviridine or the like.
この反応は塩基の存在により反応が加速されることがある。 用いる塩基として はトリエチルァミンやピリジン、 4— N, N—ジメチルァミノピリジン、 N—メ チルモルホリンや N—メチルピぺリジンなどの有機塩基、ナトリウムメトキシド、 ナトリゥムエトキシドなどのアルコキシド塩基、炭酸力リゥム、炭酸ナトリゥム、 炭酸リチウムなどの無機塩基が挙げられる。  This reaction may be accelerated by the presence of a base. Examples of the base used include organic bases such as triethylamine and pyridine, 4-N, N-dimethylaminopyridine, N-methylmorpholine and N-methylpiperidine, and alkoxide bases such as sodium methoxide and sodium methoxide. And inorganic bases such as carbon dioxide, sodium carbonate and lithium carbonate.
このようにして縮合した化合物に保護基がある場合は、 その保護基の脱保護を 行う事により、 一般式 （1 ) であらわす化合物を合成する事ができる。 脱保護の 際には保護基によりそれぞれ適当な条件を用いる事ができるが、 例えば、 プロテ クティブ グループス イン オルガニック シンセシス（PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, TEHODORA W. GREENE and PETER G. M. WUTS、 JHON WILEY & S0NS、 INC. ) などに記載の方法を参照して脱保護する事ができる。  When the compound thus condensed has a protecting group, the compound represented by the general formula (1) can be synthesized by deprotecting the protecting group. In deprotection, appropriate conditions can be used depending on the protecting group. For example, Protective Groups in ORGANIC SYNTHESIS, TEHODORA W. , INC.) Etc. can be used for deprotection.
一般式 （1 ) で表される化合物は、 薬理的に許容される塩基と容易に塩を形成 しうる。 その塩基としては、 リチウム、 ナトリウム、 カリウム、 マグネシウム、 カルシウム、 アンモニゥムなどの無機塩基や、 メチルァミン、 ェチルァミン、 ベ ンジルアミンなどの有機塩基を挙げることができる。 これらの塩もまた分子体の 一般式 （1 ) の化合物と同様に本発明の有効成分化合物として用いることができ る。 一般式 （1) で表される化合物は、 反応混合物から通常の分離手段、 例えば抽 出法、 再結晶法、 カラムクロマトグラフィーなどの方法により単離精製すること ができる。 The compound represented by the general formula (1) can easily form a salt with a pharmacologically acceptable base. Examples of the base include inorganic bases such as lithium, sodium, potassium, magnesium, calcium, and ammonium, and organic bases such as methylamine, ethylamine, and benzylamine. These salts can also be used as the active ingredient compound of the present invention in the same manner as the molecular compound of the general formula (1). The compound represented by the general formula (1) can be isolated and purified from the reaction mixture by a usual separation means, for example, an extraction method, a recrystallization method, a column chromatography and the like.
本発明の一般式 （1) で表される化合物またはその塩は、 薬理学的に効果を示 す投与量において毒性を示さない。  The compound represented by the general formula (1) or a salt thereof of the present invention does not show toxicity at a pharmacologically effective dose.
以下に実施例を挙げて本発明を具体的に説明するが、 本発明はこれらによって 限定されるものではない。  Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.
[実施例 1 ]  [Example 1]
化合物番号 107の化合物の合成  Synthesis of Compound No. 107
(1 - 1) 3, 4—ビス （ベンジルォキシ） 安息香酸 （2. 67 g、 8. 0m mo 1 ) のジクロロメタン （50ml) 懸濁液に、 ォキザリルクロリド （0. 7 3m 1、 9. Ommo l) を加え、 さらに DMF—滴を加えた後 40°Cで 2時間 攪拌した。 溶媒を留去したのち、 1 Om 1のジクロロメタンを加え、 酸クロリド ジクロロメタン溶液を調製した。 1, 3—フエ二レンジァミン（0. 15 g、 1. 39mmo 1 ) のジクロロメタン （10m l) 懸濁液に、 ピリジン （1m l) を 加え、 氷冷下先に調製した酸クロリドのジクロロメタン溶液 （5m l) を滴下し た後、 室温で一晩反応させた。 水を加えた後クロ口ホルムで抽出した。 有機層を 飽和食塩水で洗浄後、 溶媒留去して得られた残さにメタノールおよびジイソプロ ピルエーテルを加え析出した固体を濾取、 乾燥することにより、 N， N ' —ビス 一 （3, 4_ビス （ベンジルォキシ） ベンゾィル） — 1， 3—フエ二レンジアミ ン （0. 81 g) を得た。  To a suspension of (1-1) 3,4-bis (benzyloxy) benzoic acid (2.67 g, 8.0 mmol) in dichloromethane (50 ml) was added oxalyl chloride (0.73 ml, 9. Ommol) was added, and DMF-droplets were added, followed by stirring at 40 ° C for 2 hours. After evaporating the solvent, 1 Om 1 of dichloromethane was added to prepare a dichloromethane solution of acid chloride. To a suspension of 1,3-phenylenediamine (0.15 g, 1.39 mmol 1) in dichloromethane (10 ml) was added pyridine (1 ml), and the resulting acid chloride in dichloromethane solution (1 ml) was added under ice cooling. After dropwise addition of 5 ml), the mixture was reacted at room temperature overnight. After adding water, the mixture was extracted with black form. The organic layer was washed with brine, the solvent was distilled off, methanol and diisopropyl ether were added to the residue, and the precipitated solid was collected by filtration and dried to give N, N'-bis- (3,4). _Bis (benzyloxy) benzoyl) -1,3-phenylenediamine (0.81 g) was obtained.
収率 78 %。 Yield 78%.
Ή-NMR (270 MHz, DMS0-d6) δ 5.08(4H, s) > 5.24(4Η s) , 7.14-7.54(29Η, m)、 8.19(1Η、 s；)、 10.33(2Η、 brs).  Ή-NMR (270 MHz, DMS0-d6) δ 5.08 (4H, s)> 5.24 (4 Ηs), 7.14-7.54 (29 Η, m), 8.19 (1 Η, s;), 10.33 (2 Η, brs).
(1 -2) Ν, Ν ' —ビス— （3, 4—ビス （ベンジルォキシ） ベンゾィル） ― 1, 3—フエ二レンジァミン （0. 74 g、 1. Ommo l) の THF (25m 1 ) 一メタノール （25m l) 懸濁液に、 窒素気流下 10% P d/C (50% we t、 0. 24g) を加え、 水素気流下、 室温で 2時間攪拌した。 窒素置換し た後触媒をろ過し、 濃縮してえられた残さにジイソプロピルエーテルを加えて析 出した固体を濾取することにより、 N, N ' —ビス一 （3， 4—ジヒドロキシべ ンゾィル） _ 1， 3—フエ二レンジァミン （0. 27 g) を得た。 (1 -2) Ν, Ν'—bis— (3,4-bis (benzyloxy) benzoyl) —1,3-phenylenediamine (0.74 g, 1. Ommol) in THF (25m 1) methanol (25 ml) 10% Pd / C (50% wet, 0.24 g) was added to the suspension under a nitrogen stream, and the mixture was stirred at room temperature for 2 hours under a hydrogen stream. Replace with nitrogen After filtration, the catalyst was filtered, concentrated, and diisopropyl ether was added to the obtained residue. The precipitated solid was collected by filtration to obtain N, N'-bis- (3,4-dihydroxybenzoyl) _1, 3-Fenylenediamine (0.27 g) was obtained.
収率 7 1 %。 Yield 71%.
融点 2 1 2— 9で （ d e c ) With melting point 2 1 2—9 (d e c)
Ή-NMR (270 MHz, DMSO- d6) δ 6,78(2H、 dd、 J=7.9、 7.9Hz), 6.99(2H、 dd、 J=1.3、 7.9Hz), 7.36(lH、ddd、J = 1.3、7.3、7.9Hz)、 7.46- 7.50 (4H、 m)、 8.14(1H、 d、 J=2.0Hz), 9.48(2H、 brs) 10.43(2H、 brs). 同様の方法にて、 以下の化合物を合成した。 以下に物性値を記す。  Ή-NMR (270 MHz, DMSO-d6) δ 6,78 (2H, dd, J = 7.9, 7.9Hz), 6.99 (2H, dd, J = 1.3, 7.9Hz), 7.36 (lH, ddd, J = 1.3, 7.3, 7.9Hz), 7.46- 7.50 (4H, m), 8.14 (1H, d, J = 2.0Hz), 9.48 (2H, brs) 10.43 (2H, brs). Compounds were synthesized. The physical properties are described below.
化合物番号 1 22の化合物 Compound No. 1 22 Compound
収率 60 %；融点 > 250 °C Yield 60%; melting point> 250 ° C
Ή-NMR (270 MHz, DMS0-d6) 6 6.97(4H、 s)、 7.21(1H、 dd、 J=7.6、 8.6Hz) , 7·39(2Η、 dd、 J=2.0、 8.6Hz)、 8.22(1H、 br s)、 9.90(2H、 brs). 化合物番号 1 1 5の化合物  NMR-NMR (270 MHz, DMS0-d6) 6 6.97 (4H, s), 7.21 (1H, dd, J = 7.6, 8.6Hz), 739 (2Η, dd, J = 2.0, 8.6Hz), 8.22 (1H, br s), 9.90 (2H, brs). Compound No. 1 15
収率 93 %；融点 230で （ d e c . ) Yield 93%; melting point 230 (d e c.)
Ή-NMR (270 MHz, DMSO- d6) 6 6.82 (2H、 d)、 7.20-7.44 (7H, m)、 8.24(1H、 s)、 9.95(2H、 brs).  Ή-NMR (270 MHz, DMSO-d6) 6 6.82 (2H, d), 7.20-7.44 (7H, m), 8.24 (1H, s), 9.95 (2H, brs).
[実施例 2 ] [Example 2]
化合物番号 1 04の化合物の合成法 Method for synthesizing compound No. 104
(2 - 1) 3， 4, 5—トリ （ベンジルォキシ） 安息香酸 （6. 66 g、 1 2mmo l ) の DM I ( 1 00 m 1 ) 溶液に C D I (2. 68 g、 16. 5 m mo 1 )を室温で加え、室温で 2. 5時間攪拌した。 m—フエ二レンジァミン（9. 7 g、 89. 8mmo I ) を加えた後氷冷しトリフルォロ酢酸 3. 4m 1を添 加したのち、 室温まで上げて一晩攪拌した。 反応液を水 （800m l ) にあけた のち固体を濾取、 温水で洗浄して、 N— (3—ァミノフエ二ル） _ 3， 4, 5 一トリベンジルォキシベンズアミドを得た。 (2 - 2) 4—ベンジルォキシ安息香酸 （0. 34 g、 1. 5mmo 1 ) のジク ロロメタン （1 0m l ) 懸濁液にォキザリルクロリド （ 0. 1 8m l ) を加えた 後 DMFを 1滴加えて 45でで 2時間攪拌した。 溶媒を留去したのち、 ジクロロ メタン （ 1 Om 1 ) に溶解した。氷冷下、 N— （3—ァミノフエニル） 一 3, 4, 5—トリベンジルォキシベンズアミド （0. 5 3 g、 1. Ommo 1 ) のピリジ ン（ 1 Om 1 ) —ジクロロメタン（7m l )溶液を滴下し、室温で一晩攪拌した。 水で希釈した後クロ口ホルムで抽出し、 有機層を水、 飽和食塩水で洗浄後乾燥、 溶媒留去して得られた残差をトルエンで 2回共沸脱ピリジンした後、 メタノール ージイソプロピルエーテルより結晶化して、 乾燥することにより N— (3— (4 一べンジルォキシベンゾィル） ァミノフエニル） 一 3， 4, 5—卜リベンジルォ キシベンズアミドを白色固体として得た。 これを THF 2 0mL-Me OH2 0 mLに溶解した後、 1 0 % P d/C (5 0 % we t) 0. 2 gを加え、 水素 気流下 2時間攪拌した。 触媒を濾別したのち溶媒を濃縮し、 得られた残さにメタ ノールおよびジイソプロピルエーテルを加え析出した固体を濾取、 乾燥すること により N— (3 - (4ーヒドロキシベンゾィル） ァミノフエ二ル） — 3， 4, 5 一トリヒドロキシベンズアミド 2 2 Omgを淡褐色固体として得た。 (2-1) 3,4,5-Tri (benzyloxy) benzoic acid (6.66 g, 12 mmol) in DMI (100 ml) solution with CDI (2.68 g, 16.5 mmol) 1) was added at room temperature, and the mixture was stirred at room temperature for 2.5 hours. After adding m-phenylenediamine (9.7 g, 89.8 mmoI), the mixture was cooled on ice, 3.4 ml of trifluoroacetic acid was added, and the mixture was warmed to room temperature and stirred overnight. After the reaction solution was poured into water (800 ml), the solid was collected by filtration and washed with warm water to obtain N- (3-aminophenyl) _3,4,5-tribenzyloxybenzamide. Oxalyl chloride (0.18 ml) was added to a suspension of (2--2) 4-benzyloxybenzoic acid (0.34 g, 1.5 mmol) in dichloromethane (10 ml), and then DMF was added. One drop was added and the mixture was stirred at 45 for 2 hours. After the solvent was distilled off, the residue was dissolved in dichloromethane (1 Om 1). N- (3-Aminophenyl) -1,3,4,5-tribenzyloxybenzamide (0.53 g, 1. Ommo 1) in pyridin (1 Om 1) -dichloromethane (7 ml) solution under ice-cooling Was added dropwise and stirred at room temperature overnight. After diluting with water and extracting with chloroform, the organic layer is washed with water and saturated saline, dried, and the solvent is distilled off.The residue obtained is azeotropically depyridine with toluene twice, and then methanol-diisopropyl. The crystals were crystallized from ether and dried to give N- (3- (4-benzyloxybenzoyl) aminophenyl) -1,4,5-tribenzyloxybenzamide as a white solid. This was dissolved in 20 mL of THF-20 mL-MeOH, then 0.2 g of 10% Pd / C (50% wet) was added, and the mixture was stirred under a hydrogen stream for 2 hours. After filtering off the catalyst, the solvent is concentrated, methanol and diisopropyl ether are added to the obtained residue, and the precipitated solid is collected by filtration and dried to give N- (3- (4-hydroxybenzoyl) aminophenyl. 2) Omg of 3,4,5-trihydroxybenzamide was obtained as a light brown solid.
融点 >2 5 0 Melting point> 2 5 0
Ή-NMR (270 MHz, DMS0-d6) δ 6.97(3H、 s)、 7.23-7.45 (6H, m) , 8.26(1H、 s), 9.0(1H、 br s)、 9.93(1H、 br s), 10.2(1H、 br s).  Ή-NMR (270 MHz, DMS0-d6) δ 6.97 (3H, s), 7.23-7.45 (6H, m), 8.26 (1H, s), 9.0 (1H, br s), 9.93 (1H, br s) , 10.2 (1H, br s).
AP C I -MS m/z = 3 8 1 同様にして以下の化合物を合成した。 以下に物性値を記す。 APCI-MS m / z = 381 The following compounds were synthesized in the same manner. The physical properties are described below.
化合物番号 5 0 2の化合物 Compound No. 502
収率 96 %；アモルファス状固体 96% yield; amorphous solid
Ή-NMR (270 MHz, DMS0-d6) δ 6.86(2H、 d)、 6.97(2Η、 s)、 7.24(1Η dd)、 7.39-7.44(2Η、 m)、 7.86(2Η、 d)、 8.23(1Η、 dd)、 9.1 (2Η、 br s)、 9·96(1Η、 s)、 10.4(1H、 br s). 化合物番号 569の化合物 Ή-NMR (270 MHz, DMS0-d6) δ 6.86 (2H, d), 6.97 (2Η, s), 7.24 (1Η dd), 7.39-7.44 (2Η, m), 7.86 (2Η, d), 8.23 ( 1Η, dd), 9.1 (2Η, br s), 996 (1Η, s), 10.4 (1H, br s). Compound No. 569
融点 1 24 (d e c. ) Melting point 1 24 (d e c.)
Ή-NMR (270 MHz, DMS0-d6) 6 3·88(3Η、 s)、 6·96(2Η、 s)、 7.25 - 7.31 (2Η、 m)、 7.61-7.64(2H, m) 7.68— 7.72 (1H、 m)、 8.16(lH、 ddd、 J=l.3、 1.6、 8.1Hz)、 8.22(1H、 d、 J=8.1Hz), 8.53(1H、 d、 J = 1.5Hz), 9.68(1H、 br s)、 10.3(1H、 br s).  Ή-NMR (270 MHz, DMS0-d6) 638.8 (3Η, s), 696 (2Η, s), 7.25-7.31 (2Η, m), 7.61-7.64 (2H, m) 7.68-7.72 (1H, m), 8.16 (lH, ddd, J = 1.3, 1.6, 8.1Hz), 8.22 (1H, d, J = 8.1Hz), 8.53 (1H, d, J = 1.5Hz), 9.68 ( 1H, br s), 10.3 (1H, br s).
[実施例 3 ] [Example 3]
テロメラーゼ阻害作用  Telomerase inhibitory action
化合物の評価  Compound evaluation
化合物の活性評価は、 U 937細胞を用レ 既知の TRAP法（Kimら、 Science 266:2011 (1994)、 および Nucleic Acid Res. 25: 2595-2597, 1997)) により行な レ I C 50値を算出し、 表一 8にまとめた。  The activity of the compound was evaluated using U937 cells by the known TRAP method (Kim et al., Science 266: 2011 (1994), and Nucleic Acid Res. 25: 2595-2597, 1997). It was calculated and summarized in Table 1-8.
【表 8】  [Table 8]
表— 8 Table 8
化合物番号； I C 50値 （マイクロ M) Compound number; IC50 value (micro M)
104 ; 8. 0  104; 8.0
107 ; 0. 67  107; 0.67
1 1 5 ; 0. 43  1 1 5; 0.43
122 ; 0. 47  122; 0.47
502 ; 5. 5  502; 5.5
589 ; 4. 1 産業上の利用可能性 本発明により、 テロメラーゼ阻害作用を有する化合物及びその薬理的に許容さ れる塩、 及びそれらを含有するテロメラーゼ阻害剤が提供される。 本発明に係る 化合物はテロメラーゼに関わる疾患の治療及び/又は改善に効果を示すため、 そ れら疾患の治療のための医薬組成物、 特に制癌剤として有用である。  589; 4.1 Industrial Applicability The present invention provides a compound having a telomerase inhibitory action, a pharmacologically acceptable salt thereof, and a telomerase inhibitor containing them. The compound according to the present invention is effective as a therapeutic composition and / or amelioration of telomerase-related diseases, and thus is useful as a pharmaceutical composition for treating such diseases, particularly as an anticancer agent.

Claims

請 求 の 範 囲 The scope of the claims
1. 一般式 （1) 1. General formula (1)
Figure imgf000028_0001
Figure imgf000028_0001
(式中、 Zは置換されているフエニル基、あるいは複素環基を表す。 R l、 R2、 R3、 R4、 R 7は水素原子あるいは OR 5基、アルコキシ基、ァシルォキシ基、 アミノ基、 炭素数 1〜5のアルキル基で置換されてもよいアミノ基、 ニトロ基、 力ルポキシル基、 炭素数 1〜5のアルコキシカルポニル基、 ハロゲン原子、 置換 されてもよいスルホ二ル基を （ただし、 R 1と R 2のいずれか一方は OR 5基を 表す)、 R 5は水素原子または水酸基の保護基を、 R 6は水素原子または炭素数 1 〜 5の置換されてもよいアルキル基またはベンジル基を表す。）で表される化合物 あるいはその薬理学的に許容される塩を含むテロメラ一ゼ阻害剤。 (In the formula, Z represents a substituted phenyl group or a heterocyclic group. R1, R2, R3, R4, and R7 represent a hydrogen atom or OR5 group, an alkoxy group, an acyloxy group, an amino group, a carbon number. An amino group, a nitro group, a propyloxyl group, an alkoxycarbonyl group having 1 to 5 carbon atoms, a halogen atom, and a sulfonyl group which may be substituted with 1 to 5 alkyl groups (R 1 And R 2 represents an OR5 group), R5 represents a hydrogen atom or a protecting group for a hydroxyl group, and R6 represents a hydrogen atom or an alkyl or benzyl group having 1 to 5 carbon atoms which may be substituted. A telomerase inhibitor comprising a compound represented by the following formula: or a pharmacologically acceptable salt thereof.
2. 一般式 （2) 2. General formula (2)
Figure imgf000028_0002
Figure imgf000028_0002
(式中、 R l、 R2、 R3、 R4、 R 5、 R6、 R 7は前記に同じ （ただし、 R 1と R 2のいずれか一方は〇R 5基を表す。） R8、 R9、 R 10、 R 1 1はそれ ぞれ独立して水素原子あるいは〇R 5基、 アルコキシ基、 ァシルォキシ基、 アミ ノ基、 炭素数 1〜5のアルキル基で置換されてもよいアミノ基、 ニトロ基、 カル ポキシル基、 炭素数 1〜 5のアルコキシカルボニル基、 ハロゲン原子、 置換され てもよいスルホ二ル基を表す （ただし、 R8、 R 9、 R I O, R 1 1は同時に水 素原子にならない。）） で表される請求項 1に記載の化合物又はその薬理学的に許 容される塩を含むテロメラーゼ阻害剤。 (Wherein, R 1, R 2, R 3, R 4, R 5, R 6, and R 7 are the same as described above (provided that one of R 1 and R 2 represents a ΔR 5 group). R 8, R 9, R 10, R 11 are each independently a hydrogen atom or a 〇R 5 group, an alkoxy group, an acyloxy group, an amino group, an amino group which may be substituted with an alkyl group having 1 to 5 carbon atoms, a nitro group, Cal Represents a poxyl group, an alkoxycarbonyl group having 1 to 5 carbon atoms, a halogen atom, or an optionally substituted sulfonyl group (however, R8, R9, RIO, and R11 are not hydrogen atoms at the same time)) A telomerase inhibitor comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof.
3. 一般式 （3) 3. General formula (3)
Figure imgf000029_0001
Figure imgf000029_0001
(式中、 R l、 R2、 R3、 R 5は前記に同じ （ただし、 1と尺2のぃずれか 一方は OR 5基を表す。）で表される請求項 2に記載の化合物又はその薬理学的に 許容される塩を含むテロメラーゼ阻害剤。  (Wherein, R 1, R 2, R 3, and R 5 are the same as described above (however, any one of 1 and 2 represents an OR 5 group). Telomerase inhibitors containing pharmacologically acceptable salts.
4. 一般式 （4) 4. General formula (4)
Figure imgf000029_0002
Figure imgf000029_0002
(式中、 R 5は前記に同じ。）で表される請求項 3に記載の化合物又はその薬理学 的に許容される塩を含むテロメラ一ゼ阻害剤。  4. A telomerase inhibitor comprising the compound according to claim 3, wherein R 5 is the same as defined above, or a pharmacologically acceptable salt thereof.
5. 請求項 1から請求項 4の何れか一項に記載の、 少なくともひとつのテロメ ラーゼ阻害剤を含む医薬品。  5. A medicament comprising at least one telomerase inhibitor according to any one of claims 1 to 4.
6. 請求項 1から請求項 4の何れか一項に記載の、 少なくともひとつのテロメ ラーゼ阻害剤を含む制癌剤。 6. An anticancer agent comprising at least one telomerase inhibitor according to any one of claims 1 to 4.
7. 一般式 （5) 7. General formula (5)
Figure imgf000030_0001
Figure imgf000030_0001
(式中、 Zは置換されているフエニル基、 あるいは複素環基を表す。 R3、 R4、 R7は、 それぞれ独立して水素原子あるいは OR 5基、 アルコキシ基、 ァシルォ キシ基、 アミノ基、 炭素数 1〜 5のアルキル基で置換されてもよいアミノ基、 二 トロ基、 カルボキシル基、 炭素数 1〜5のアルコキシカルポニル基、 ハロゲン原 子、置換されてもよいスルホニル基を、 R 5は水素原子または水酸基の保護基を、 R 6は水素原子または炭素数 1〜 5の置換されてもよいアルキル基またはべンジ ル基を、 R 12は水素原子あるいはアルコキシ基、 ァシルォキシ基、 アミノ基、 炭素数 1〜5のアルキル基で置換されてもよいアミノ基、 ニトロ基、 カルボキシ ル基、 炭素数 1〜 5のアルコキシカルポニル基、 ハロゲン原子、 置換されてもよ いスルホ二ル基を表す。） で表される化合物又はその薬理学的に許容される塩。  (In the formula, Z represents a substituted phenyl group or a heterocyclic group. R3, R4, and R7 are each independently a hydrogen atom or an OR5 group, an alkoxy group, an alkoxy group, an amino group, a carbon number. An amino group, a nitro group, a carboxyl group, an alkoxycarbonyl group having 1 to 5 carbon atoms, a halogen atom, an optionally substituted sulfonyl group, Or a protecting group for a hydroxyl group, R 6 is a hydrogen atom or an alkyl or benzyl group having 1 to 5 carbon atoms which may be substituted, and R 12 is a hydrogen atom or an alkoxy group, an acyloxy group, an amino group, a carbon number. It represents an amino group, a nitro group, a carboxyl group, an alkoxycarbonyl group having 1 to 5 carbon atoms, a halogen atom, and an optionally substituted sulfonyl group which may be substituted by 1 to 5 alkyl groups. In the compound or a pharmacologically acceptable salt thereof.
8. 一般式 （6) 8. General formula (6)
Figure imgf000030_0002
Figure imgf000030_0002
(式中、 R3、 R4、 R5、 R6、 R7、 R 12は前記に同じ。 R8、 R 9、 R 10、 R 1 1はそれぞれ独立して水素原子あるいは〇R 5基、 アルコキシ基、 ァ シルォキシ基、 アミノ基、 炭素数 1〜5のアルキル基で置換されてもよいアミノ 基、 ニトロ基、 カルボキシル基、 炭素数 1〜5のアルコキシカルボニル基、 ハロ ゲン原子、置換されてもよいスルホ二ル基を表す（ただし、 R 8、 R 9、 R 10、 R 1 1は同時に水素原子にならない））で表される請求項 7に記載の化合物又はそ の薬理学的に許容される塩。 (Wherein, R3, R4, R5, R6, R7, and R12 are the same as above. R8, R9, R10, and R11 are each independently a hydrogen atom or a 〇R5 group, an alkoxy group, an acyloxy group. Group, amino group, amino group which may be substituted with an alkyl group having 1 to 5 carbon atoms, nitro group, carboxyl group, alkoxycarbonyl group having 1 to 5 carbon atoms, halogen atom, sulfonyl which may be substituted Represents a group (provided that R 8, R 9, R 10, 8. The compound according to claim 7, wherein R 11 is not a hydrogen atom at the same time) or a pharmacologically acceptable salt thereof.
9. 一般式 （7) 9. General formula (7)
Figure imgf000031_0001
Figure imgf000031_0001
(式中、 R3、 R5、 R 12は前記に同じ。） で表される請求項 8に記載の化合物 又はその薬理学的に許容される塩。  (Wherein R3, R5, and R12 are the same as above.) Or a pharmacologically acceptable salt thereof.
10. 一般式 （ 8 )  10. General formula (8)
Figure imgf000031_0002
Figure imgf000031_0002
(式中、 R 5は前記に同じ。）で表される請求項 9に記載の化合物又はその薬理学 的に許容される塩。  (Wherein R 5 is the same as defined above), or a pharmacologically acceptable salt thereof, according to claim 9.
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