WO2003070691A1 - Derive de n-hydroxycarboxamide - Google Patents

Derive de n-hydroxycarboxamide Download PDF

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Publication number
WO2003070691A1
WO2003070691A1 PCT/JP2003/001681 JP0301681W WO03070691A1 WO 2003070691 A1 WO2003070691 A1 WO 2003070691A1 JP 0301681 W JP0301681 W JP 0301681W WO 03070691 A1 WO03070691 A1 WO 03070691A1
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methyl
branched
hydroxyamino
benzyl
amino
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PCT/JP2003/001681
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English (en)
Japanese (ja)
Inventor
Shinichi Uesato
Yasuo Nagaoka
Takao Yamori
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Osaka Industrial Promotion Organization
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Priority to JP2003569600A priority Critical patent/JPWO2003070691A1/ja
Priority to AU2003211362A priority patent/AU2003211362A1/en
Publication of WO2003070691A1 publication Critical patent/WO2003070691A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/08—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D215/54—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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to a novel N-hydroxyxylcarboxamide derivative having histone deacetylase inhibitory activity.
  • HDAC histone deacetylase
  • DNA has a nucleosome-based chromatin structure in the nucleus of a eukaryote, and histones are proteins that constitute the nucleosome. It is thought that when a specific lysine residue of histone is acetylated, the positive charge of the histone is neutralized, the nucleosomal structure is relaxed, and DNA transcription is activated. The acetylation of specific lysine residues in histone molecules is turned over by histone acetylase (HAT) and deacetylase (HDAC). In recent years, the aforementioned drugs that inhibit HDAC have been reported to have cell cycle arrest, differentiation and apoptosis-inducing activity of tumor cells [Exp.
  • HDAC inhibitors that accumulate highly acetylated histones are expected to be new anticancer substances, and their application to the development of anticancer drugs is strongly desired.
  • trichostatin A As an HDAC inhibitor, trichostatin A (TS A) [J. Biol. Cem., 265, 17174-17179 (1990)], trapoxin [J. Antibiot., 43 (12), 1524-1534 (1990)], FK228 [Exp. Cell Res., 24] 1, 126-133 (1998)].
  • MS-275 Proc. Natl. Acad. Sci. USA, 96, 4592-4597 (1999)
  • SAHA Proc. Natl. Acad. Sci. USA, 95, 3003-3007 (1998)
  • Etc. are under development.
  • said FK228, MS-275 and SAHA are in clinical trials.
  • TSA and trapoxin which are natural substances, have problems in physical properties (stability, solubility, etc.) and safety. It is also reported that the synthetic substances SAHA and MS-275 have relatively weak HDAC inhibitory activity. Furthermore, since FK228 has a peptide structure, it may have problems with drug pharmacokinetics such as blood half-life and in vivo stability.
  • an object of the present invention is to provide a novel N-hydroxycarpoxamide derivative which is excellent in physical properties such as stability and solubility, and has a strong histone deacetylase (HDAC) inhibitory activity. It is.
  • the present inventors have focused on tranexamic acid, which is known as an analog of the L-lysine residue of ⁇ -N-acetytri histone serving as a substrate for HDAC. This compound is already used in medicines as a hemostatic agent, binds to the L-lysine binding site of plasminogen, prevents the binding of plasminogen to fibrin, and suppresses fibrinolytic activity. Is known for.
  • tumor cells such as breast cancer, lung cancer, and stomach cancer have an effect of inhibiting metastasis, angiogenesis, proliferation, and the like. Therefore, the present inventors have proposed a tranexa Development of a new HD AC incipient, using humic acid as a lead compound, was studied. As a result, they have found that the following novel N-hydroxycarboxamide derivatives and salts thereof have a strong HDAC inhibitory action, and have completed the present invention.
  • the compound of the present invention is an N-hydroxycarboxamide derivative represented by the following general formula (1), a tautomer or stereoisomer thereof, or a salt thereof.
  • [A] is cyclohexylene or other C 3 -C 8 cycloalk Killen, bicyclic or tricyclic C 5 -C 16 cycloalkylene, Fuenire down, naphthylene, anthrylene, Fouesnant Bok rylene or other single, Cyclic, bicyclic or tricyclic unsaturated 5- to 16-membered ring, biphenylene, or monocyclic, bicyclic or tricyclic saturated or unsaturated 5- to 16-membered heterocyclic ring It is.
  • the above [A] may be substituted with one or more substituents, and these substituents may be the same or different from each other, and the substituent may be a halogen, a straight-chain or a branched C. i C 6 alkyl, phenyl, benzyl, hydroxy, straight or branched C Ce alkoxy, phenoxy, benzyloxy, mercapto, straight or branched Ci Ce alkylthio, phenylthio, benzylthio, formyl, straight or branched -C 6 Arukanoiru, Benzoiru, benzyl Cal Poni Le force Rupokishiru, straight-chain or branched C Ce alkoxy force Ruponiru, Karupamoiru, Straight-chain or branched ⁇ ⁇ ( ⁇ alkyl rubamoyl, one NR 2 R 3 (R 2 and R 3 are the same or different from each other; hydrogen, straight-chain or branched Ci Ce alkyl,
  • [C] is cyclohexyl or other ⁇ 3 ⁇ (8 cycloalkyl Le, Adamanchiru or other bi- or tricyclic C 5 -C 16 cyclo alkyl, phenyl, naphthyl, anthryl, Fuenantoriru, or Or other monocyclic, bicyclic or tricyclic unsaturated 5- to 16-membered ring, biphenylyl, pyridyl, quinolyl, isoquinolyl, indolyl, or other monocyclic, bicyclic or tricyclic Is a saturated or unsaturated 5- to 16-membered heterocyclic ring.
  • the above [C] may be substituted with one or more substituents, and the substituents may be the same or different from each other, and the substituent may be a halogen, a straight chain or a branched C.
  • L 1 and L 2 are the same or different and are each straight or branched C 12 alkylene or absent;
  • R 1 is hydrogen, straight or branched Ci Ce alkyl, formyl, straight or branched ⁇ Ce alkanol, benzoyl, or benzylcaplonyl.
  • the compound of the present invention having the above-mentioned structure, is excellent in physical properties such as stability and solubility, and has a strong HDAC inhibitory activity.
  • [A], [B], [C], L 1 , L 2 and R 1 in the above formula (1) preferably satisfy the following conditions. That is,
  • [A] is an atomic group represented by a structural formula obtained by removing any two hydrogens from a molecule represented by any one of the following formulas (12) to (64).
  • [B] is an atomic group represented by any one of the above formulas (2) to (11).
  • [C] is a substituent represented by a structural formula obtained by removing any one hydrogen from a molecule represented by any one of the following formulas (65) to (117).
  • the above [C] may be substituted with one or more substituents.
  • the substituents are the same or different from each other, and the substituent is halogen, linear or branched C to ( 6 alkyl, phenyl, benzyl, hydroxy, linear or branched C to 6 alkoxy, Phenoxy
  • Sulfo straight chain or branched C ⁇ . 6 alkylsulfo, sulfino, straight-chain or branched C to (: 6- alkylsulfino, hydroxy-substituted straight-chain or branched Ci Ce alkyl, mono-di- or trihalogen-substituted straight-chain or branched ( ⁇ - 6 Alkyl, mono- or di- or trihalogen-substituted linear or branched C i Ce alkoxy, hydrazino carbonyl, amidino, nitro, cyano, isocyano, cyanate, isocyanato, thiocyanato, isothiocyanato, ditroso, Oxo, imino or thioxo.
  • R 1 is hydrogen, straight or branched Ci Ce alkyl, formyl, straight or branched Ci Ce alkanol, benzoyl, or benzylcaplonyl.
  • [A], [B], [C], L 1 L 2 and R 1 in the above formula (1) are 03
  • [A] is an atomic group represented by any one of the following formulas (1 18) to (120).
  • [B] is an atomic group represented by any one of the above formulas (2), (4) and (6).
  • [C] is any of the molecules represented by any one of the above formulas (65) to (68), (77), (7oosnn8), (92), (94) or (95). It is a substituent represented by the structural formula excluding one hydrogen.
  • R 2 and R 3 are the same or different from each other and are each hydrogen, methyl, ethyl, propyl, isopropyl or t-butoxy) It is Bonyl.
  • L 1 is (CH 2 ) n
  • L 2 is (CH 2 ) m (n and, m are the same or different and are each an integer from 0 to 3)
  • R 1 is hydrogen
  • [A], [B], [C], LL 2 and R 1 in the formula (1) satisfy the following conditions. That is,
  • [A] is an atomic group represented by the O OSMH formula of any of the above (1 18) to (1 20).
  • [B] is an atomic group represented by the formula (2), (4) or (6).
  • [C] is a substituent represented by any one of the following formulas (1 2 1) to (1 37).
  • L 1 is (CH 2 ) n
  • L 2 is (CH 2 ) m (n and m are the same or different and each is 0 or 1)
  • R 1 is hydrogen.
  • the N-hydroxycarboxamide derivative of the formula (1) is optimally selected from the group consisting of the following compounds.
  • the present invention provides a method for treating or preventing a disease associated with HDAC activity in a human or animal patient, or reducing the symptom thereof, wherein the N-hydroxycarpoxamide derivative of the present invention, a tautomer thereof, A method comprising administering to said patient an effective amount of at least one substance selected from the group consisting of: isomers and stereoisomers, and physiologically acceptable salts thereof.
  • the present invention provides, for the manufacture of a medicament, selected from the group consisting of the N-hydroxycarboxamide derivative of the present invention, its tautomers and stereoisomers, and physiologically acceptable salts thereof.
  • the use of at least one substance is provided.
  • the medicament is preferably a medicament for treating or preventing a disease associated with HDAC activity or reducing its symptoms.
  • the medicament of the present invention is at least one selected from the group consisting of the above-mentioned N-hydroxycarpoxamide derivatives of the present invention, tautomers and stereoisomers thereof, and physiologically acceptable salts thereof. It is a medicine containing one kind of substance as an active ingredient.
  • the medicament of the present invention preferably further comprises one or more pharmaceutically acceptable excipients.
  • the medicament of the present invention may be used for treating a disease related to cell proliferation, since the active ingredient has histone deacetylase (HDAC) inhibitory activity. It can be used for alleviation and prevention of disease.
  • HDAC histone deacetylase
  • the diseases related to the cell proliferation include brain tumor, head and face cancer, neuroblastoma, sinus cancer, pharyngeal cancer, esophagus cancer, lung cancer, stomach cancer, colon cancer, rectum cancer, liver cancer, biliary tract cancer, ⁇ cancer, and prostate.
  • Cancer bladder cancer, testicular cancer, breast cancer, uterine cancer, uterine fibroids, uterine facial cancer, ovarian cancer, acute leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, malignant lymphoma, erythrocytosis, eukaryoteemia, May be at least one disease selected from the group consisting of essential thrombocytosis, myeloma, osteosarcoma, choriocarcinoma, Hodgkin's disease, non-Hodgkin's disease, glioblastoma, astrocytoma and soft tissue sarcoma preferable.
  • the N-hydroxycarboxamide derivative or a salt thereof of the present invention has a strong cancer cell growth inhibitory activity
  • the medicament of the present invention is preferably used as an anticancer agent or an anticancer agent.
  • the medicament of the present invention is preferably used as an immunosuppressant or an effect enhancer for gene therapy.
  • the medicament of the present invention is preferably used for at least one use selected from treatment, reduction of symptoms and prevention of neurodegenerative diseases.
  • the above-mentioned neurodegenerative disease is preferably a disease caused by expansion of polyglutamic acid repeat sequence.
  • At least one disease selected from the group consisting of dentatoru bral-pal 1 idoluysian atrophy (DRPLA)> Machado-Joseph disease (SC A3) and spinocerebellar ataxia type 6 (SCA6) is particularly preferred.
  • the HDAC inhibitor of the present invention is selected from the group consisting of the N-hydroxycarpoxamide derivative of the present invention, its tautomers and stereoisomers, and physiologically acceptable salts thereof. It is an HD AC inhibitor containing at least one substance.
  • N-hydroxycarboxamide derivative or a salt thereof of the present invention can be produced, for example, by the following method A or method B.
  • novel compound of the present invention is not limited to these production methods, and may be used by other production methods.
  • Method A can be carried out using the following steps 1A to 4A.
  • step 1A the above compounds (1-1A-1) and (1-1A-2) are prepared by reacting the above compounds (1-1A-1) and (1-1A-2) in the presence of a base or in the presence of a base and a condensing agent. Condensation gives compound (1-1A). When the condensation is carried out in the presence of a base and a condensing agent as in the latter case, the reaction may be further carried out under conditions containing an additive.
  • [A] and [L 1 ] are as defined in the above formula (1).
  • C ′ is a monocyclic, bicyclic or tricyclic 5 to 16 of the above [C].
  • a membered aromatic ring which may or may not contain a heteroatom.
  • a membered aromatic ring which may or may not contain a heteroatom.
  • B ′ is a sulfonyl group or a sulfonyl group
  • X is a halogen or a hydroxyl group. That is, the above (1-1A-2) is aryl carboxylic acid halide, aryl carboxylic acid, aryl sulfonic acid halide or aryl sulfonic acid.
  • methyl 4- (aminomethyl) cyclohexanecarpoxylate hydrochloride or methyl 4- (aminomethyl) benzoate hydrochloride can be used.
  • the base for example, triethylamine, DMAP, DBU, DBN, and the like can be used.
  • the condensing agent include bis (2-oxo-13-oxazolidinyl) phosphinic acid chloride (BOP-C 1), dicyclohexylcarbodiimide (DCC), and 1-ethyl 3- (3-dimethyl)
  • BOP-C 1 bis (2-oxo-13-oxazolidinyl) phosphinic acid chloride
  • DCC dicyclohexylcarbodiimide
  • 1-ethyl 3- (3-dimethyl) For example, H0Bt, HONB, HOSu, or the like can be used as an additive.
  • the reaction solvent is not particularly limited as long as it is an aprotic solvent.
  • ethers such as getyl ether, tetrahydrofuran and dioxane, alkyl halides such as chloroform and methylene chloride, and amides such as DMF are used. be able to.
  • the reaction temperature and reaction time are not particularly limited, and can be appropriately selected depending on the compound to be reacted and the solvent.
  • the reaction temperature is, for example, ⁇ 20 to 100, preferably 0 to 30 ° C.
  • the reaction time is, for example, 10 minutes to 24 hours, preferably 30 minutes to 15 hours.
  • the above (1-1A-2) is generated by reacting aryl carboxylic acid with oxalic acid chloride
  • the above (111A-1) and a base can be added for condensation.
  • the same solvent as described above can be used.
  • the reaction temperature between aryl carboxylic acid and oxalic acid chloride is The temperature is, for example, minus 20 to 100, preferably 0 to 30 ° C.
  • the reaction time is, for example, 10 minutes to 12 hours, preferably 30 minutes to 1 hour.
  • the reaction temperature and reaction time of the condensation reaction are not particularly limited, and can be appropriately selected depending on the compound to be reacted and the solvent.
  • the reaction temperature is, for example, -20 to 100, preferably 0 to 30 ° C.
  • the reaction time is, for example, 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
  • step 2A the compound (1-1A) is dissolved in a solvent together with a base and hydrolyzed to obtain a carboxylic acid (112A).
  • a base for example, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide can be used.
  • the solvent for example, water or a mixed solvent of water and an organic solvent can be used.
  • the organic solvent for example, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, and alcohols such as methanol and ethanol can be used.
  • the reaction temperature and reaction time are not particularly limited, and can be appropriately selected depending on the compound to be reacted and the solvent.
  • the reaction temperature is, for example, ⁇ 20 to 100, preferably 0 to 30 ° C.
  • the reaction time is, for example, 10 minutes to 24 hours, preferably 30 minutes to 3 hours.
  • the crystals precipitated by acidifying the liquid are collected by filtration or extracted with an organic solvent to obtain carboxylic acid (112 A).
  • carboxylic acid (112 A) is reacted with 0-benzylhydroxylamine hydrochloride in the presence of a base and a condensing agent to obtain a compound represented by the general formula (113 A)
  • the hydroxybenzyl compound represented is obtained.
  • this step may be performed under conditions further including an additive.
  • triethylamine, DMAP, DBU, DBN and the like can be used as the base, and as the condensing agent, for example, BOP-Cl, DCC, WSC ⁇ HC1, and the like can be used.
  • the reaction solvent is not particularly limited as long as it is an aprotic solvent.
  • reaction temperature and reaction time are not particularly limited, and can be appropriately selected depending on the compound to be reacted and the solvent.
  • the reaction temperature is, for example, ⁇ 20 to 100 ° C., preferably 0 to 30 ° C.
  • the reaction time is, for example, 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
  • step 4A the hydroxybenzyl derivative (1-3A) is debenzylated by a hydrogenation reaction to obtain the final target compound (1_A).
  • This hydrogenation reaction can be carried out, for example, using a solvent such as methanol, ethanol, tetrahydrofuran, acetonitrile, ethyl acetate, acetic acid, and the like, and using a catalyst such as palladium, palladium hydroxide, palladium carbon, Raney nickel, and platinum. it can.
  • the reaction temperature, reaction pressure, and reaction time are not particularly limited, and can be appropriately selected depending on the compound to be reacted and the solvent.
  • the reaction temperature is, for example, -20 to 100: preferably 0 to 30 ° C.
  • the reaction pressure is, for example 1 0 5 ⁇ 1 0 7 P a, it is favored properly 1 0 5 to 10 6? & Dearu.
  • the reaction time is, for example, 1 to 36 hours, preferably 5 to 12 hours.
  • Step 4A-2 can be performed, for example, using an alcoholic solvent such as methanol, ethanol, or propanol and hydrochloric acid.
  • the reaction temperature at this time is particularly limited. Although not specified, it is, for example, 0 to 50 ° C, preferably 20 to 30 ° C. Although the reaction time is not particularly limited, it is, for example, 5 minutes to 5 hours, preferably 10 minutes to 1 hour.
  • Method B can be carried out using the following steps 1B to 4B.
  • Step IB the compound (1-1B-1) and (1-1B-2) are condensed with phosgene or triphosgene in the presence of a base to form the compound (1-1B-1). 1 B).
  • [A], [C], [L 1 ] and [L 2 ] are as defined in the above formula (1).
  • the compound (1-1B-1) for example, methyl 4- (aminomethyl) cyclohexanyl propyloxylate hydrochloride or methyl 4- (aminomethyl) benzoate hydrochloride, etc. can be used.
  • the compound (1-1B-2) for example, 1-adamantylamine is used.
  • the reaction solvent is not particularly limited as long as it is an aprotic solvent. Examples thereof include ethers such as getyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, and halogens such as chloroform and methylene chloride.
  • the reaction temperature and reaction time are not particularly limited, and can be appropriately selected depending on the compound to be reacted and the solvent.
  • the reaction temperature is, for example, 0 to 100 ° C, preferably 10 to 30 ° C.
  • the reaction time is, for example, 5 minutes to 3 hours, preferably 30 minutes to 1 hour.
  • the compound (111B) is dissolved in a solvent together with a base and hydrolyzed to obtain a carboxylic acid (112B).
  • a base for example, lithium hydroxide, sodium hydroxide, or an alkali metal hydroxide such as a hydroxide hydroxide can be used.
  • the solvent for example, water or a mixed solvent of water and an organic solvent can be used.
  • the organic solvent for example, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, and alcohols such as methanol and ethanol can be used.
  • the degree and the reaction time are not particularly limited, and can be appropriately selected depending on the compound to be reacted and the solvent.
  • the reaction temperature is, for example, ⁇ 20 to 100 ° C., preferably 0 to 30 ° C.
  • the reaction time is, for example, 10 minutes to 24 hours, preferably 30 minutes to 3 hours. Then, the crystals precipitated by acidifying the liquid after the reaction are collected by filtration or extracted with an organic solvent to obtain carboxylic acid (1-2B).
  • the carboxylic acid (1-2B) is reacted with ⁇ -benzylhydroxylamine hydrochloride in the presence of a base and a condensing agent to obtain a compound represented by the general formula (113B).
  • a base for example, triethylamine, DMAP, DBU, DBN and the like can be used, and as the condensing agent, for example, B0P-C1, DCC, WSC / HC1, and the like can be used.
  • the reaction solvent is not particularly limited as long as it is an aprotic solvent.
  • examples include ethers such as getyl ether, tetrahydrofuran and dioxane, nitriles such as acetonitrile, and halogenated compounds such as chloroform and methylene chloride. Amides such as alkyl and DMF can be used.
  • the reaction temperature and reaction time are not particularly limited, and can be appropriately selected depending on the compound to be reacted and the solvent.
  • the reaction temperature Is, for example, ⁇ 20 to 100 ° C., preferably 0 to 3 Ot.
  • the reaction time is, for example, 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
  • step 4B the hydroxybenzyl derivative (1-3B) is debenzylated by a hydrogenation reaction to obtain the final target compound (1-B).
  • This hydrogenation reaction is carried out, for example, using a solvent such as methanol, ethanol, tetrahydrofuran, acetonitrile, ethyl acetate, acetic acid, etc., and using a catalyst such as palladium, palladium hydroxide, palladium carbon, Raney nickel, platinum or the like. be able to.
  • the reaction temperature, reaction pressure, and reaction time are not particularly limited, and can be appropriately selected depending on the compound to be reacted and the solvent.
  • the reaction temperature is, for example, -20 to 100 ° C, preferably 0 to 30 ° C.
  • the reaction pressure is, for example, 1 0 5 ⁇ 1 0 7 P a, is favored properly a 1 0 5 ⁇ 1 0 6 P a.
  • the reaction time is, for example, 1 to 36 hours,
  • Boc can be eliminated in the same manner as described in Method A.
  • the compound represented by the above formula (1) or a salt thereof may be a tautomer or a stereoisomer.
  • isomers eg, geometric isomers and conformers
  • each of the separated isomers and mixtures is also included in the scope of the present invention.
  • the compound of the formula (1) or a salt thereof has an asymmetric carbon in its structure, an optically active substance and a racemic mixture thereof are also included in the scope of the present invention.
  • the salt of the compound represented by the formula (1) may be an acid addition salt or a base addition salt.
  • the acid forming the acid addition salt may be an inorganic acid or an organic acid.
  • the inorganic acid include, but are not limited to, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid.
  • the organic acid is not particularly limited, for example, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like are possible.
  • the base forming the base addition salt may be an inorganic base or an organic base.
  • the inorganic base is not particularly limited, but may be, for example, ammonium hydroxide, alkali metal hydroxide, alkaline earth metal hydroxide, carbonate, carbonate carbonate, and the like. More specifically, for example, , Sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like are possible.
  • the organic base is not particularly limited, for example, ethanolamine, triethylamine, tris (hydroxymethyl) aminomethane and the like are possible.
  • the administration form of the compound of the present invention is not particularly limited. Or parenterally.
  • the form for oral administration is not particularly limited, and may be ordinary or enteric-coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solvents, suspensions, syrups.
  • the form usually used by those skilled in the art can be selected, such as a liquid, a solid or liquid aerosol, and an emulsion.
  • the form for parenteral administration is not particularly limited, and a form commonly used by those skilled in the art, such as intravenous administration, intraperitoneal administration, subcutaneous administration, or intramuscular administration, can be selected.
  • the dose of the compound of the present invention per dose, the administration interval and the like are not particularly limited, and can be appropriately selected depending on the purpose. These include various factors, including the patient's age, weight, gender, medical condition, medical condition, route of administration, level of metabolic and excretory function of the patient, the dosage form used, the particular compound administered and its salts. Is selected by those skilled in the art in consideration of
  • the compounds of the invention are formulated with one or more pharmaceutically acceptable excipients prior to administration.
  • the additives are not particularly limited, but include, for example, inert substances such as carriers, diluents, flavors, sweeteners, lubricants, dissolving agents, suspending agents, binders, tablet disintegrants, and encapsulating materials. is there.
  • the active substance may be mixed with, for example, a diluent or enclosed in a carrier, which may be in the form of, for example, a capsule, sachet, paper or other container.
  • the carrier may also serve as a diluent, and may be a solid, a semi-solid, or a liquid acting as a vehicle.
  • the form of the preparation is, for example, tablet, pill, powder, lozenge, elixir, suspension, emulsion, solution, syrup, aerosol, ointment, soft * hard gelatin capsule, suppository, sterile injectable solution, and package sterilization Powder forms are possible.
  • Additives used in the preparation are not particularly limited, and for oral administration, for example, the following substances can be used.
  • the carrier include lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methylcellulose, and the like.
  • Disintegrators include, for example, corn flour, starch, methylcellulose, agar , Bentonite, xanthan gum, alginic acid, etc. are possible.
  • the binder include gelatin, natural sugar, beta-lactose, corn sweetener, natural and synthetic gums, arabic gum, tragacanth gum, sodium alginate, carboxymethylcellulose, polyethylene dalicol, wax and the like.
  • the lubricant include magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, salt, talc, and the like.
  • Mass spectrometry was performed using JEOL's Tandem MStation; 1MS-700, electron impact ionization (EI-MS), electron spray ionization (ESI-MS), or fast atom bombardment ionization (ESI-MS). FAB-MS). High-resolution mass spectrometry (HR-MS and HR-FABMS) was also performed using the above instruments.
  • Thin-layer chromatography uses pre-coated silica gel pre- (Merck Silica gel 60 F254 PLC Plate). Silica gel (Merck Silica gel 60) was used for all column chromatography separations. All chemicals were reagent grade and purchased from Wako Pure Chemical Industries, Ltd., Sigma-Aldorich. Co., Kanto Chemical Co., Ltd. and Tokyo Chemical Industry Co., Ltd.
  • Example 1 The following compounds of Examples 1 to 20 were synthesized by the following procedures. In Examples 1 to 5, 7 to 15 and 17 to 20, synthesis was performed according to the method A, and in Examples 6 and 16, synthesis was performed according to the method B.
  • Example 1 In Examples 1 to 5, 7 to 15 and 17 to 20, synthesis was performed according to the method A, and in Examples 6 and 16, synthesis was performed according to the method B.
  • Example 1 In Examples 1 to 5, 7 to 15 and 17 to 20, synthesis was performed according to the method A, and in Examples 6 and 16, synthesis was performed according to the method B.
  • Step 1A Methyl 4-( ⁇ [4- (dimethylamino) benzoyl] amino ⁇ methyl) cyclohexanecarboxylate
  • Step 2A 4-( ⁇ [4- (dimethylamino) benzoyl] amino ⁇ methyl) Methyl 4-( ⁇ [4- (dimethylamino) benzoyl] amino ⁇ methyl) cyclohexane obtained in step 1A
  • a 1 M aqueous solution of lithium hydroxide (5.5 mL) was added to a solution of carboxylate (0.5 g) in tetrahydrofuran (3.1 mL), and the mixture was stirred at room temperature for 12 hours.
  • a 1 M aqueous hydrochloric acid solution was added to the resulting aqueous solution to adjust the pH to 3. Crystals were precipitated, which were collected by filtration, dried, and colorless as 4-( ⁇ [4- (dimethylamino) benzoyl]).
  • Step 3A N-[(4 _ ⁇ [(benzyloxy) amino] aminopropyl] cyclohexyl) methyl] -4- (dimethylamino) benzamide
  • reaction solution was washed sequentially with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution, and the obtained solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 4A 4- (dimethylamino) -1-N — ( ⁇ 4-[(hydroxyamino) force]
  • N — [(4 -— [[(benzyloxy) amino] carbonyl) obtained in step 3A [Crohexyl) methyl] -14_ (dimethylamino) benzamide (0.15 g) in methanol (4.0 mL) was added with 10% Pd / C (13.0 mg), and the mixture was stirred at room temperature for 6 hours under a hydrogen stream. After filtering off Pd / C from The liquid was concentrated under reduced pressure. The residue obtained is purified by silica gel thin layer chromatography.
  • Step 1A Methyl 4 _ [(2-naphthoylamino) methyl] cyclohexanecarboxylate
  • Step 2A 4-[(2-Naphthoylamino) methyl] cyclohexanecarbonic acid)
  • Step 3A N — [(4 — ⁇ [(benzyloxy) amino] carbonyl ⁇ cyclohexyl) methyl] -12-naphthamide
  • Triethylamine was added to a suspension of 4-[(2-naphthoylamino) methyl] cyclohexanecarboxylic acid (2.00 g) and 0_benzylhydroxylamine hydrochloride (1.80 g) obtained in Step 2A in dichloromethane (31 mL). (3.55 mL) and bis (2-oxo-13-oxozolidinyl) phosphinic chloride (1.80 g) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was washed sequentially with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution. The obtained solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 4A N — ( ⁇ 4-[(hydroxyamino) carbonyl] cyclohexyl ⁇ methyl) -1-2-naphthamide)
  • Step 1A Methyl 4- ⁇ [([1,1,1-biphenyl] -14-ylcarbyl) amino] methyl ⁇ cyclohexanecarboxylate
  • Step 2A 4 — ⁇ [([1,1, —biphenyl] —4-ylcarponyl) ami] Methyl 4- ⁇ [([[1,1, -biphenyl] —] obtained in Step 1A
  • a solution of 4-ylcartrahydrofuran 15 mL was added a 1 M aqueous solution of lithium hydroxide (24 mL), and the mixture was stirred at room temperature for 12 hours.
  • An aqueous solution of hydrochloric acid was added to adjust the pH to 3. Crystals were precipitated, which were collected by filtration and dried to give 4_ ⁇ as colorless crystals.
  • Step 3A N — [(4-([(benzyloxy) amino] caprolyl) cyclohexyl) methyl] [1,2-biphenyl] —4couplic lipoxamide
  • Step 4A N — ( ⁇ 4 -— ((hydroxyamino) carbonyl) cyclohexyl ⁇ methyl) [1,1′-biphenyl] —4-potassium lipoxamide)
  • Step 1A Methyl 4- ⁇ [(phenylsulfonyl) amino] methyl ⁇ cyclohexanecarboxylate
  • Step 2A 4- ⁇ [(phenylsulfonyl) amino] methyl ⁇ cyclohexanecarboxylic acid
  • Step 3A N— (benzyloxy) _4-([(phenylsulfonyl) amino] methyl ⁇ cyclohexane lipoxamide)
  • Step 4A N-hydroxy-4- ⁇ [(phenylsulfonyl) amino] N- (benzyloxy) _4 — ⁇ [((phenylsulfonyl) amino] methyl ⁇ cyclohexanecarbo obtained in step 3A
  • oxamide 0.25 g
  • methanol 18 mL
  • 10% Pd / C 27 mg
  • the filtrate was concentrated under reduced pressure to give N-hydroxy-41-[[(phenylsulfonyl) amino] methyl] cyclohexane lipoxamide (0.19 g, yield 95%) as colorless crystals.
  • Step 1A Methyl 4- ⁇ [(2-naphthylsulfonyl) amino] methyl methyl 4- (aminomethyl) cyclohexanecarboxylate hydrochloride (2.0 g) and benzenesulfonyl chloride (2.18 g) in tetrahydro Triethylamine (2.7 mL) was added to a solution of frans (50 mL), and the mixture was stirred for 15 hours at room temperature. The reaction solution was concentrated, the residue was dissolved in chloroform, and the solution was diluted with 1 M aqueous hydrochloric acid and saturated sodium bicarbonate.
  • Step 2A 4- ⁇ [(2-naphthylsulfonyl) amino] methyl ⁇ cyclohexanecarboxylic acid
  • Step 4A N-Hydroxy_4 -— [[(2-Naphthylsulfonyl) amido) N-[(4 _ ⁇ [((benzyloxy) amino] carbonyl ⁇ cyclohexyl) methyl obtained in Step 3A ]
  • Step 1B Methyl 4-( ⁇ [(1_adamantylamino) carbonyl] amino ⁇ methyl) cyclohexanecarboxylate
  • Triphosgene (0.64 g) was dissolved in dichloromethane (40 ml), and to this solution was added an aqueous solution (75 mL) of 1.24 g of sodium carbonate, followed by vigorous stirring.
  • a solution of methyl 4- (aminomethyl) cyclohexanecarboxylate hydrochloride (1.0 g) in dichloromethane (75 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • To the obtained isocyanate mixed solution was added a solution of 11-Adamantanamine (1.7 g) in methanol (40 mL), and the mixture was stirred at room temperature for 30 minutes.
  • Step 2B 4-( ⁇ [(1--l] amino ⁇ methyl) cyclohexanecarboxylic acid)
  • Step 3B 4-( ⁇ [(1-adamantylamino) carbonyl] amino ⁇ methyl) -1-N— (benzyloxy) cyclocyclohexane lipoxamide)
  • a mixture of [(1-adamantylamino) proponyl] amino ⁇ methyl) cyclohexanecarboxylic acid (0.4 g) and O-benzylhydroxylamine hydrochloride (0.19 g) in dichloromethane (7 mL) was added triethylamine ( (0.7 mL) and bis (2-oxo-13-oxazolidinyl) phosphinic chloride (0.33 g) were added, and the mixture was stirred at room temperature for 15 hours.
  • Step 4B 4-( ⁇ [(1-adamantylamino) potassium) amino ⁇ me
  • the 4-( ⁇ [(1-adamantylamino) potassium) obtained in step 3B (Amino) methyl) -N- (benzyloxy) cyclohexanecarboxamide (0.17 g) in ethanol (11 mL) was added with 10% Pd / C (17 mg), and the mixture was stirred at room temperature for 12 hours under a stream of hydrogen. After filtering off Pd / C from the reaction solution, the filtrate was concentrated under reduced pressure to give 4-( ⁇ [(1-adamantylamino) carbonyl] amino ⁇ methyl) -1-N-hydroxyl as colorless crystals. Cyclohexanecarboxamide (0.11 g, yield 82%) was obtained.
  • Step 1A Methyl 4-[(1-naphthoylamino) methyl] cyclohexanecarboxylate
  • Step 2A 4-[(1-naphthoylamino) methyl] cyclohexane power Rubonic acid
  • Step 3A benzyl 4-[(1-naphthoylamino) methyl] cyclohexanecarboxylate
  • Step 4A N — ( ⁇ 4-[(hydroxyamino) caproluconyl] cyclohexyl ⁇ methyl) -11-naphthamide)
  • Step 1A Methyl 4-[(2_naphthoylamino) methyl] benzoate
  • Step 2A 4-[(2-Naphthoylamino) methyl] benzoic acid) Methyl 4-[(2-naphthoylamino) methyl] benzoate (2.80 g) obtained in Step 1A in tetrahydrofuran (19 mL) ) A 1 M aqueous solution of lithium hydroxide (19 mL) was added to the solution, and the mixture was stirred at room temperature for 6 hours. Reaction solution After distilling off tetrahydrofuran from the resulting solution, a 1 M aqueous hydrochloric acid solution was added to the obtained aqueous solution to adjust the pH to 3, and crystals were precipitated. This was collected by filtration and dried to give 41-[(2-naphthoylamino) methyl] benzoic acid (2.30 g, yield 86%) as colorless crystals.
  • Step 3 A -(4- ⁇ [(benzyloxy) amino] -caprolponyl ⁇ benzyl) -12-naphthamide
  • Triethylamine (2.8 mL) was added to a mixture of 4-[(2-naphthoylamino) methyl] benzoic acid (2.30 g) and dibenzylhydroxylamine hydrochloride (0.80 g) obtained in Step 2A in dichloromethane (25 niL).
  • bis (2-oxo-13-oxazolidinyl) phosphinic chloride (1.40 g) were added, and the mixture was stirred at room temperature for 15 hours.
  • the reaction solution was washed sequentially with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution.
  • the obtained solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This was recrystallized from methanol to give N- (4 _ ⁇ [(benzyloxy) amino] carbonyl ⁇ benzyl) -2-naphthamide (200 mg, yield 9.9%) as colorless crystals.
  • Step 4A N— ⁇ 4 -— [(hydroxyamino) potassium) benzyl ⁇ —2-naphthamide
  • Step 1A methyl 6-[(tert-butoxycarbonyl) amino] -12-naphthoyl ⁇ amino) methyl] benzoate
  • Step 2A 4-[( ⁇ 6-[(tert-butoxycarbonyl) amino] -2-naphthoyl ⁇ amino) methyl] benzoic acid)
  • Step 3A tert-butyl 6- ⁇ [(4 _ ⁇ [(benzyloxy) amino] power propyl] benzyl) amino] carbonyl ⁇ —2-naphthylcarbamate) [( ⁇ 6- [(tert-butoxycarbonyl) amino] — 2
  • Step 4A Step 1: tert-butyl 6-[( ⁇ 4-[(hydroxyamino) carbonyl] benzyl ⁇ amino) aminopropyl] —2_naphthylcarbamate) tert obtained in Step 3A —Butyl 6— ⁇ [(4_ ⁇ [(benzyloxy) amino] potanol ⁇ benzyl) amino] carbonyl ⁇ -1-naphthylcarbamate
  • Step 4A-2 6_amino-N— ⁇ 4 _ [(hydroxyamino) carbonyl] benzyl ⁇ —2-naphthamide hydrochloride
  • Step 1A Methyl 4-[(1-naphthoylamino) methyl] benzoate
  • Step 2A 4 _ [(1-naphthoylamino) methyl] benzoic acid) Methyl 4-[(1-naphthoylamino) methyl] benzoate (3.0 g) obtained in Step 1A in tetrahydrofuran (17 mL) After a 1 M aqueous solution of lithium hydroxide (27 mL) was added to the solution, the mixture was stirred at room temperature for 12 hours. After distilling off tetrahydrofuran from the reaction solution, a 1 M aqueous hydrochloric acid solution was added to the obtained aqueous solution to adjust the pH to 3, and crystals were precipitated. This is filtered and dried to obtain colorless crystals. Step 2A: 4-[(1-naphthoylamino) methyl] benzoic acid
  • Step 3A N— (4 _ ⁇ [(benzyloxy) amino] carbonyl ⁇ benzyl) -1 1-naphthamide)
  • Triethylamine (1.9 mL) was added to a mixture of 4-[(1-naphthoylamino) methyl] benzoic acid (1.0 g) obtained in Step 2A and dichloromethane (45 mL) of ⁇ ⁇ ⁇ ⁇ -benzylhydroxylamine hydrochloride (0.53 g). And bis (2-isoxo-1-oxazolidinyl) phosphinic chloride (0.88 g) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was washed sequentially with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution. The obtained solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 4A N— ⁇ 4-[(hydroxyamino) carbonyl] benzyl ⁇ _1—naphthamide
  • N- (4- ⁇ [(benzyloxy) amino] carbonyl ⁇ benzyl) _1-naphthamide (0.27 g) obtained in Step 3A in methanol (23 mL) was added 10% Pd / C ( 27 mg), and the mixture was stirred at room temperature for 12 hours under a hydrogen stream. After removing Pd / C from the reaction solution by filtration, the filtrate was concentrated under reduced pressure to give N- ⁇ 4-[(hydroxyamino) caprolucyl] benzylnaphthamide (0.12 g, yield 56%) as colorless crystals. I got
  • Step 1A Methyl 4- ⁇ [([1,1'-biphenyl] -4-ylcarbonyl) amino] methyl ⁇ benzoate
  • Triethylamine (17.2 mL) was added to a mixture of methyl 4- (aminomethyl) benzoate hydrochloride (5.00 g) and 4-biphenylcarbonyl chloride (4.70 g) in dichloromethane (130 mL), and the mixture was stirred at room temperature for 15 hours. .
  • the reaction solution was washed with a 1 M aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution in that order. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 2A 4-([[[1,1,1-biphenyl] -4-ylcarbonyl) amibenzoic acid) 1M lithium hydroxide was added to a solution of methyl 4- ⁇ [[[1,1'-biphenyl] -4-ylcarbonyl) amino] methyl ⁇ benzoate (6.80 g) in tetrahydrofuran (70 mL) obtained in Step 1A. After adding an aqueous solution (60 mL), the mixture was stirred at room temperature for 11 hours. After distilling off tetrahydrofuran from the reaction solution, a 1 M aqueous hydrochloric acid solution was added to the resulting aqueous solution to adjust the pH to 3, and crystals were precipitated. This was collected by filtration and dried to give 4- ⁇ [([1, -biphenyl] -4-ylcarbonyl) amino] methyl ⁇ benzoic acid (5.87 g, yield 85%) as colorless crystals.
  • Step 3A N- (benzyloxy) -14- ⁇ [([1,1'-biphenyl] -14-ylcarbonyl) amino] methyl ⁇ benzamide
  • Step 4A N— ⁇ 4-[(hydroxyamino) carbonyl] benzyl ⁇ [1,1′-biphenyl] _4_carpoxamide)
  • Step 1A Methyl 4-( ⁇ [(4'-Fluoro [1,2-biphenyl]-4-yl) carbonyl] amino ⁇ methyl) benzoate
  • This solution was washed sequentially with a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crystals. This was recrystallized with a mixed solution of formaldehyde and hexane, and methyl 4 _ ( ⁇ [(4'-fluoro [1,1'-biphenyl] -14-yl) carbonyl] amino ⁇ methyl) benzoate was obtained as an achromatic crystal. (3.60 g, yield 76%) was obtained.
  • Step 2A 4-( ⁇ [(4,1-Fluoro [ ⁇ , ⁇ -biphenyl] -14-yl) potrolponyl] amino ⁇ methyl) benzoic acid)
  • Step 3A N— (4- ⁇ [(benzyloxy) amino] potassium ⁇ benzyl) -14'-Fluoro [1,1,1-biphenyl] -14-potassium lipoxamide
  • Step 2A The obtained 4-( ⁇ [(4'-fluoro [1,1, -piphenyl] -14-yl) carbonyl] amino ⁇ methyl) benzoic acid (0.80 g) and benzylhydroxylamine hydrochloride (0.55 g) Triethylamine (2.6 mL) and bis (2-oxo-l_3-oxazolidinyl) phosphinic chloride (1.38 g) were added to a mixture of dimethylformamide (14 mL), and the mixture was stirred at room temperature for 7 hours.
  • N- (4- ⁇ [(benzyloxy) amino] carbonyl ⁇ benzyl) -4 'monofluoro [1,1,1-biphenyl]-4-carboxamide obtained in Step 3A (10 5 mg) 10% Pd / C (74 mg) was added to a methanol (30 mL) suspension, and the mixture was stirred at room temperature for 3 hours under a hydrogen stream. After removing Pd / C from the reaction solution by filtration, the filtrate was concentrated under reduced pressure to form colorless crystals.
  • Step 4A 4′-Fluoro-N— ⁇ 4-[(hydroxyamino) carbonyl] benzyl ⁇ [1, ⁇ -Biphenyl] -4 lipoxamide (54 mg, yield 68%) was obtained.
  • Step 1A Methyl 4 _ ⁇ [([1,1-piphenyl] -2-ylcarboxy) amino] methyl ⁇ benzoate
  • Step 2A 4-([[[1,1 ,,-biphenyl] -2-ylcarbonyl) amino] methyl ⁇ benzoic acid)
  • Step 3A N— (4 — ⁇ [(benzyloxy) amino] carbonyl ⁇ benzyl) [1,1, -biphenyl] -12-caprolepoxamide)
  • Step 4A N- ⁇ 4-[[hydroxyamino] carbonyl] benzyl] [1,1, -biphenyl] -12-caproloxamide
  • N- (4- ⁇ [(benzyloxy) amino] carbonyl ⁇ benzyl) [1,1-biphenyl] -12-force lipoxamide (0.50 g) obtained in Step 3A in methanol (39 mL)
  • Pd / C 143 mg
  • Triethylamine (2.7 mL) was added to a mixture of methyl 4- (aminomethyl) benzoate hydrochloride (2.00 g) and benzenesulfonyl chloride (1.70 g) in tetrahydrofuran (50 mL), and the mixture was stirred at room temperature for 15 hours.
  • the reaction solution was washed with a 1 M aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution in this order. .
  • the solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This was recrystallized from ethyl acetate to give methyl 4- ⁇ [(phenylsulfonyl) amino] methyl ⁇ benzoate (3.0 g, yield 99%) as colorless needles.
  • Step 3A N— (benzyloxy) -14 _ ⁇ [(phenylsulfonyl) amino] methyl ⁇ benzamide
  • Triethylamine was added to a mixture of 4- ⁇ [(phenylsulfonyl) amino] methyl ⁇ benzoic acid (1.00 g) and 0-benzylhydroxylamine hydrochloride (0.55 g) obtained in Step 2A in dichloromethane (7 mL). (0.5 mL) and bis (2-oxo-3-oxazolidinyl) phosphinic chloride (0.96 g) The mixture was stirred at room temperature for 15 hours. The reaction solution was washed sequentially with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution. The obtained solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This was recrystallized from ethyl acetate to obtain N- (benzyloxy) -4- ⁇ [(phenylsulfonyl) amino] methyl ⁇ benzamide (1.3 g, yield 39) as colorless crystals.
  • Step 1A Methyl 4- ⁇ [(2-naphthylsulfonyl) amino] methyl
  • Triethylamine (4.0 mL) was added to a mixture of methyl 4- (aminomethyl) benzoate hydrochloride (3.00 g) and 2-naphthalenesulfonyl chloride (3.28 g) in tetrahydrofuran (75 mL), and the mixture was added at room temperature for 15 hours. Stirred. The reaction solution was washed sequentially with a 1 M aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This was recrystallized from ethyl acetate to obtain methyl 4- ⁇ [(2-naphthylsulfonyl) amino] methyl ⁇ benzoate (4.36 g, yield 67%) as colorless needles.
  • Step 2A 4- ⁇ [(2-naphthylsulfonyl) amino] methyl ⁇ benzoic acid
  • Step 3A N— (benzyloxy) —4 _ ⁇ [(2_naphthylsulfonyl) amino] methyl ⁇ benzamide)
  • Step 2B 4-( ⁇ [(1-adamantylamino) carbonyl] amino ⁇ methyl) benzoic acid)
  • Step 3B 4-( ⁇ [(1-adamantylamino) potrolponyl] amino ⁇ methyl) -1-N- (benzyloxy) benzamide)
  • Step 2A - ⁇ [(1H-indole-3-ylcarbonyl) amino] methyl ⁇ benzoic acid
  • Step 4A N- ⁇ 4-[(hydroxyamino) carbonyl] benzyl ⁇ -1 ⁇ -indole-3-caproloxamide
  • Step 1A Methyl 6-[(phenylacetyl) amino] -2-naphthoate
  • Triethylamine (8.3 mL) was added to a mixture of methyl 6-amino-2-naphthoate (3.00 g) and dimethylacetamide (2.2 mL) in dimethylformamide (60 mL), and the mixture was stirred for 12 hours. Thereafter, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was dissolved in chloroform (200 ml), and the solution was washed sequentially with 1M hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was reprecipitated with a mixed solution of chloroform and hexane to give a colorless liquid W
  • IR (KBr) cur 1 3031, 1651, 1611, 1546, 1392, 1261, 925, 786.
  • Step 3A N- (benzyloxy) -6 _ [(phenylacetyl) amino] -2-naphthamide
  • Triethylamine was added to a mixture of 6-[(phenylacetyl) amino] -2-naphthoic acid (0.40 g) and 0-benzylhydroxylamine hydrochloride (250 mg) in dimethylformamide (7 mL) obtained in Step 2A. (0.73 mL) and bis (2- Sodium-3-oxazolidinyl) phosphinic chloride (400 mg) was added, and the mixture was stirred at room temperature for 17 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • WSCI (6.28 mL) was added to a solution of 2-quinolinecarboxylic acid (7.00 g) and HONB (7.32 g) in dimethylformamide (130 mL), and the mixture was stirred for 30 minutes.
  • the suspension obtained by this reaction was designated as A.
  • a suspension obtained by mixing triethylamine (5.58 mL) with a solution of methyl 4- (aminomethyl) benzoate hydrochloride (8.15 g) in dimethylformamide (129 mL) was referred to as B. did. After mixing the suspension A and the suspension B, the mixture was stirred at room temperature for 24 hours.
  • Step 2A 4 _ ⁇ [(2-quinolinylcarbonyl) amino] methyl ⁇ benzoic acid
  • Step 3A N- (4- ⁇ [(benzyloxy) amino] carbonyl ⁇ benzyl) -2-quinolinecarboxamide
  • H0NB 2.87 g
  • WSCI 2.48 g
  • Step 4A N- ⁇ 4-[(hydroxyamino) carbonyl] benzyl ⁇ -2-quinolinecarboxamide hydrochloride
  • HDAC s histone deacetylase
  • [H] Acetyl-labeled histone was obtained as a substrate for histone deacetylated Atsusei by the following method. That is, first, an RPMI-116 medium was prepared. This medium contains 10% FBS (fetal ov ine serum), penicillin (50 units / m1) and streptomycin (50 g / m1). Next, a 2 X 1 0 8 jars force Tsu preparative cells were mixed with [3 H] sodium butyrate sodium acetate and 5 M of the R PM I- 1 640 Medium 2 Om 1, 300 MB Q. The mixture was placed 7 5 cm 2 flasks in 5% C_ ⁇ 2 and 95% air atmosphere and incubated at 37 ° C 30 min.
  • FBS fetal ov ine serum
  • penicillin 50 units / m1
  • streptomycin 50 g / m1
  • a 2 X 1 0 8 jars force Tsu preparative cells were mixed with [3 H] sodium buty
  • the mixture was transferred to a centrifuge tube (50 ml), and the cells were collected by centrifugation at 100 rpm for 10 minutes, and washed once with phosphate buffered saline.
  • the washed cells lysis ice-cold buffer (1 OmM T ris-HC l , 5 OmM sodium bisulfite, 1% T riton X_ 1 00 , l OmM M g C 1 2, 8. 6% sucrose, p H6.5) It was suspended in 15 ml. After homogenization of Dounce (30 strokes), nuclei were collected by centrifugation at 1,000 rpm for 10 minutes, washed three times with 15 ml of the lysis buffer described above, and then iced.
  • the plate was washed once with 15 ml of a cold washing buffer (10 mM Tris_HCl, 13 mM EDTA, ⁇ H 7.4).
  • the pellet using a mixer was suspended in ice-cold water 6 m 1, the H 2 S 0 4 of 68m 1 To the suspension was added, so that the concentration of 0. 4 N (0. 2 M) I made it.
  • the suspension was centrifuged at 1500 rpm for 5 minutes, and the supernatant was collected and mixed with 6 Om1 of acetone. After overnight incubation at -20 ° C, the resulting aggregates were collected by microcentrifugation, air dried, and stored at -8 ° C.
  • HDAC s histone deacetylase
  • Jerkat cells (5 ⁇ 10 8 ) were suspended in 4 Om1 of HDA buffer.
  • This HDA buffer contains 15 mM potassium phosphate, 5% glycerin, and 0.211 £ 0.08 and has a pH of 7.5. You. After homogenization, nuclei were collected by centrifugation (3 5, 0 00 xg, 10 minutes) the other containing (NH 4) 2 S_ ⁇ 4 1M was homogenized in the same buffer 2 Om in l above. Its viscous homogenate to ultrasonic treatment to remove the turbidity by centrifugation, by increasing the concentration of (NH 4) 2 S_ ⁇ 4 3. 5 M, to precipitate de Asechiru enzyme.
  • the precipitated protein was dissolved in 10 ml of HDA buffer and dialyzed against 4 liters of the same buffer. Next, the dialysate was packed in a column (25 x 85 mm) of DE AE cell orifice (trade name: Whatman DE52) homogenized with the same buffer as above. Elution was performed by linearly increasing the concentration from 0 to 0.6 M. The liquid volume used for this elution was 300 ml. A single peak fraction of histone deacetylase activity eluted between 0.3 and 0.4 M NaCl.
  • the compounds of Examples 8, 9, 11, and 12 were assayed for histone deacetylase-inhibitory activity by the above-mentioned method. The same test was performed for SAHA as a control substance. In Table 1, IC 5. (Concentration of test substance that induces 50% enzyme inhibition: nM). Table 1: Histone deacetylase inhibitory activity Compound activity value (IC50-nM).
  • GI50 The concentration that suppresses proliferation by 50% compared to the absence of the test substance.
  • TGI The concentration that suppresses proliferation to the same cell number as Time Zero.
  • LC50 concentration that reduces cell number to 50% of Time Zero.
  • MG-MID Average value of logGI50 obtained for all tested strains.
  • A The chemical structure has novelty.
  • B MG-MID (average impeachment concentration) ⁇ -5.
  • Example 8 ⁇ -6.09 0.62 / 1.8CN
  • Example 3 ⁇ -5.44 1.2 / 1.78CN
  • Example 1 1 ⁇ -5.39 0.76 / 1.41
  • Example 9 ⁇ -5.57 ⁇ 1.21 / 2 • CN ⁇ , has a new structure.
  • Example 11 satisfies all the above criteria A to D, and the other compounds Also met most criteria. Therefore, these compounds are very promising as new anticancer agents.
  • the compound of this example showed an activity equal to or higher than that of SAHA in an HDAC s inhibition test using human T cell leukemia Jurkat cells (Jurkat cells).
  • Pharmacological Test Example 3 In vivo antitumor effect test with Xenograft The compound (subject) of the above example was subjected to an antitumor effect test on cultured human cancer cells according to the following procedure.
  • HT-29 colon cancer
  • 31 lines that can be transplanted into nude mice
  • HT-29 is one of the 39 strains described above.
  • An existing anticancer drug for nude mouse transplanted tumor fragment transplantation: less antitumor effect than the test in which cell suspension was transplanted was used.
  • Moderate sensitivity in the sensitivity tests of the following types (adriamycin / mitomycin c, cyclophosphamate, pinklistin, 5-fluorouracil, pinplastin, cisplatin, CPT-11, Pac1 itaxe1, etoposide) (2)
  • adriamycin / mitomycin c, cyclophosphamate, pinklistin, 5-fluorouracil, pinplastin, cisplatin, CPT-11, Pac1 itaxe1, etoposide (2)
  • the tumor is large enough to start administration of the subject 7 to 10 days after transplantation (50-150 mm 3 ), and was selected to satisfy the condition of small inter-individual variability.
  • Dose For each subject, the dose was as shown in Tables 3 to 7 below, and the volume was 0.1 ml per 10 g of mouse body weight.
  • Administration route Intravenous (i.v.) or intraperitoneal (i.p.) administration schedule: Administration schedule: Twice every four days (q4d X 2).
  • the size (major axis, minor axis) of the formed tumor and the body weight of the mouse were measured twice a week from the start of the administration (DayO).
  • the degree of tumor growth was determined by calculating the tumor growth rate (Relative Tumor Volume: RTV) and TZC% from the following formula, and judging according to the following evaluation criteria.
  • RTV Relative Tumor Volume: TZC%
  • T / C% RTV 14 treat ed / -RTV 14con t X 100
  • Test solution After the test sample was dissolved in DMSO, the same volume of cremophor was added, and further diluted with 8 volumes of physiological saline to prepare a 3.5 mgZml test solution.
  • Analyte solution After the analyte was dissolved in DMS ⁇ , the same volume of cremophor was added, and diluted with 8 volumes of physiological saline to prepare an lmg / ml analyte solution.
  • Test solution After the test sample was dissolved in DMS0, the same volume of cremophor was added, and further diluted with 8 volumes of physiological saline to prepare a test solution of 1.25 mg // ml. '
  • Test solution After the test sample was dissolved in DMS O, the same volume of cremophor was added, and further diluted with 8 volumes of physiological saline to prepare a 1 Omg / ml test solution.
  • Test solution After the test sample was dissolved in DMS O, the same volume of cremophor was added, and further diluted with 8 times volume of physiological saline to prepare a 5.2 SmgZml test solution.
  • the administration of the compounds of each Example shows a tumor growth inhibitory effect.
  • the compound of Example 11 was confirmed to have an excellent tumor suppressive effect.
  • the novel hydroxycarboxamide derivative of the present invention has a tumor-suppressing effect in vivo, indicating that it is useful as an anticancer agent or an anticancer agent.
  • the novel N-hydroxycarboxamide derivative of the present invention is excellent in physical properties such as stability and solubility, and has strong histone deacetylase (HDAC) inhibitory activity. Therefore, the N-hydroxycarboxamide derivative of the present invention is useful for treating diseases related to cell proliferation, reducing symptoms and It is useful for prevention and can be expected to exert a particularly high effect as an anticancer or anticancer agent. In addition, the N-hydroxycarboxamide derivative of the present invention can be expected to have an effect as an immunosuppressant or an effect enhancer for gene therapy, an effect on the treatment of neurodegenerative diseases, and a reduction and prevention of symptoms.
  • HDAC histone deacetylase

Abstract

L'invention concerne un nouveau dérivé de N-hydroxycarboxamide qui possède d'excellentes propriétés physiques, p. ex. stabilité et dissolution, et présente une puissante activité d'inhibition d'histone désacétylase (HDAC). Ce nouveau dérivé de N-hydroxycarboxamide, obtenu à l'aide d'acide tranexamique comme composé principal, et son sel présentent une puissante activité d'inhibition de HDAC. Ledit dérivé est utile pour traiter, soulager et prévenir des maladies associées à la prolifération cellulaire. Il est notamment susceptible d'être très efficace comme agent anticancéreux ou carcinostatique. De plus, il peut être efficace comme immunosuppresseur ou agent de potentialisation en thérapie génique pour traiter, soulager et prévenir des maladies neurodégénératives.
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