WO2004071401A2 - Inhibiteur de l'histone desacetylase - Google Patents

Inhibiteur de l'histone desacetylase Download PDF

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WO2004071401A2
WO2004071401A2 PCT/JP2004/001437 JP2004001437W WO2004071401A2 WO 2004071401 A2 WO2004071401 A2 WO 2004071401A2 JP 2004001437 W JP2004001437 W JP 2004001437W WO 2004071401 A2 WO2004071401 A2 WO 2004071401A2
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compound
preparation
mhz
nmr
manner similar
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WO2004071401A3 (fr
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Yasuharu Urano
Mitsuru Hosaka
Kazunori Kamijo
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Fujisawa Pharmaceutical Co., Ltd.
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Publication of WO2004071401A2 publication Critical patent/WO2004071401A2/fr
Publication of WO2004071401A3 publication Critical patent/WO2004071401A3/fr

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Definitions

  • the present invention relates to a compound, which is useful as a medicament, and to a pharmaceutical composition comprising the same.
  • HDAC Histone deacetylase
  • WO 01/38322 discloses an inhibitor of histone deacetylase represented by the following formula:
  • Cy is cycloalkyl, aryl, heteroaryl or heterocyclyl , each of which is optionally substituted;
  • L 1 is -(CH 2 ) m -W-, wherein m is an integer of 0 to 4, and W is selected from the group consisting of -C(0)NH-, -S(0) 2 NH-, etc. ;
  • Ar is optionally substituted arylene which is optionally fused to an aryl, heteroaryl ring, etc.
  • Y 1 is a chemical bond or a straight- or branched-chain saturated alkylene, wherein said alkylene is optionally substituted; and Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl and -O-M, wherein M is H or a pharmaceutically acceptable cation.
  • WO 0222577 discloses the following hydroxamate compound as a deacetylase inhibitor:
  • Ri is H, halo, or a straight chain Ci-C ⁇ alkyl
  • R 2 is selected from H, Ci-Cio alkyl, C-C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl , C 4 -C 9 heterocycloalkylalkyl , cycloalkylalkyl , aryl, heteroaryl, etc.
  • R5 is selected from H, Ci-C ⁇ alkyl, etc.
  • n, ni, n 2 and n 3 are the same or different and independently selected from 0-6 , when ni is 1-6 , each carbon atom can be optionally and independently substituted with R 3 and/or R;
  • X and Y are the same or different and independently selected from H, halo, C ⁇ C 4 alkyl, etc. ; or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a novel compound, which is useful as a medicament, and to a pharmaceutical composition comprising the same.
  • the present invention relates to a compound, which has a potent inhibitory effect on the activity of histone deacetylase.
  • a histone deacetylase inhibitor such as compound of the formula (I) (hereinafter also referred to as compound [I] ) , has a potent immunosuppressive effect and potent antitumor effect. Therefore, a histone deacetylase inhibitor such as compound [I] is useful as an active ingredient of an immunosuppressant and an antitumor agent, and useful as a therapeutic or prophylactic agent for diseases such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections, tumors, etc.
  • diseases such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections, tumors, etc.
  • one object of the present invention is to provide a compound, which has biological activities for treating or preventing the diseases as stated above.
  • Another object of the present invention is to provide a pharmaceutical composition containing the compound [I] as an active ingredient.
  • a further object of the present invention is to provide use of the histone deacetylase inhibitors, such as the compound [I], for treating or preventing the diseases as stated above.
  • a yet further object of the present invention is to provide a commercial package comprising the pharmaceutical composition containing the compound [I] and a written matter associated therewith, the written matter stating that the pharmaceutical composition may or should be used for treating or preventing the diseases as stated above.
  • the present invention provides [1] a compound of the formula (I) :
  • R 1 is lower alkyl optionally substituted with one or more suitable substituent (s) ; aryl optionally substituted with one or more suitable substituent (s) ; or fused ring, R 2 is acylamino or optionally protected hydroxy, L 1 is lower alkenylene, and R 3 is hydroxyamino, or a salt thereof;
  • R 1 is lower alkyl optionally substituted with aryl (lower) alkoxyaryl ; aryl optionally substituted with the group (s) selected from lower alkoxy, halogen, aryl, aryl (lower) alkoxy and mono- or di-substituted amino; or fused ring, and R 2 is acylamino selected from lower alkylcarbonylamino, lower alkylsulfonylamino and arylcarbonylamino; or hydroxy optionally protected with lower alkyl , or a salt thereof, etc.
  • the compound [I] or a salt thereof can be prepared by the process as illustrated in the following reaction schemes.
  • R 1 and R 3 are each as defined above,
  • R 4 is lower alkyl (e.g., methyl, ethyl, etc.) or aryl (e.g., phenyl , etc . ) ,
  • R 5 is lower alkyl (e.g., methyl, ethyl, etc.) , aryl (e.g., phenyl, etc . ) ,
  • R 6 is hydroxy protecting group (e.g., methyl, etc.),
  • X is halogen (e.g., iodine, etc.) , methanesulfonyloxy, p- toluenesulfonyloxy, etc. , and
  • R a is hydroxy protecting group (e.g., tetrahydropyranyl , etc.) .
  • R a is hydroxy protecting group (e.g., tetrahydropyranyl , etc.) .
  • the compounds [II-l] , [II-2] , [II-3] and [II-4] are also encompassed in the scope of the compound [II] .
  • each of the starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations in the present specification or in a manner similar thereto.
  • the compounds (A-l) , (A-2) , (A-3) , (A-4) , (A-5) , (A-6) and (A-7) can be obtained by the procedures as illustrated in Preparations 1 , 2 , 3, 4, 5, 6 and 7, respectively;
  • the compounds (B-l) , (B-2) , (B-3) and (B-4) can be obtained by the procedures as illustrated in
  • the compounds (C-l) , (C-2) , (C-3) and (C-4) can be obtained by the procedures as illustrated in Preparations 14, 15, 16 and 17, respectively;
  • the compounds (D-l) , (D-2) , (D-3) and (D-4) can be obtained by the procedures as illustrated in Preparations 34, 35, 36 and 37, respectively;
  • the compounds (E-l) , (E-2) , (E-3) and (E-4) can be obtained by the procedures as illustrated in Preparations 79, 80, 81 and 82, respectively;
  • the compounds (F-1) and (F-2) can be obtained by the procedures as illustrated in Preparations 84 and 85, respectively.
  • the compound [II-l] can be obtained by the procedure as illustrated in Preparation 8, 13 or 18, and the compounds [II-2] , [II-3] and [II-4] can be obtained by the procedures as illustrated in Preparations 38, 83 and 86, respectively.
  • the compound [I] of the present invention can be obtained from compound [II] according to the following process.
  • R 1 , R 2 , R 3 , L 1 and R a are as defined above.
  • the Compound [I] is obtained by deprotecting the hydroxy group of the Compound [II] .
  • the reaction may be carried out in the presence of acid, for example, hydrogen chloride solution (e.g. , hydrogen chloride in solvent such as methanol, dioxane, ethyl acetate, diethyl ether, etc.), acetic acid, p-toluenesulfonic acid, boric acid, etc.
  • acid for example, hydrogen chloride solution (e.g. , hydrogen chloride in solvent such as methanol, dioxane, ethyl acetate, diethyl ether, etc.), acetic acid, p-toluenesulfonic acid, boric acid, etc.
  • one or more suitable solven (s) for the deprotection is (are) used.
  • solvent includes methanol, ethanol, ethyl acetate, dioxane, diethyl ether, acetic acid, etc.
  • the temperature of the reaction is not critical and the reaction is usually carried out under from cooling to heating. This process is exemplified by Example 1, etc.
  • the compound [I] has stereoisomers , such isomers are also encompassed in the present invention.
  • the compound [I] may form a salt, which is also encompassed in the present invention.
  • the salt when a basic group such as an amino group is present in a molecule, the salt is exemplified by an acid addition salt (e.g., salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,, etc., salt with an organic acid such as methanesulfonic acid, fumaric acid, maleic acid, mandelic acid, citric acid, salicylic acid, etc.)
  • an acidic group such as carboxyl group
  • the salt when an acidic group such as carboxyl group is present, the salt is exemplified by a basic salt (e.g. , salt with a metal such as sodium, potassium, calcium, magnesium, aluminum, etc. , salt with an amino acid such as lysine, etc. ) , etc.
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • lower used in the description is intended to mean 1 to 6 carbon atoms, unless otherwise indicated.
  • Suitable example of “one or more” means the number of 1 to 6, preferably 1 to 3.
  • Suitable examples of the “lower alkyl” include straight or branched one having 1 to 6 carbon atom(s) , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, etc.
  • Suitable lower alkyl for the "lower alkyl optionally substituted with one or more suitable substituent (s) " for R 1 includes methyl, etc.
  • Suitable examples of the "lower alkoxy" include straight or branched one having 1 to 6 carbon atom(s) , such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert- butoxy, pentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy, etc.
  • Suitable examples of the "aryl” include a Ce-Cie aryl such as phenyl, naphthyl, anthryl, pyrenyl, phenanthryl, azulenyl, etc.
  • Suitable examples of the “aryl” for the “aryl optionally substituted with one or more suitable substituent (s) " for R 1 include phenyl, etc.
  • fused ring examples include a 5- or 6- membered fused ring, each of which may contain one or more heteroatom selected from a sulfur atom, an oxygen atom and a nitrogen atom besides carbon atoms and one or more carbon atom(s) is/are optionally replaced with oxo group (s).
  • Suitable examples of the "fused ring” include indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl , imidazopyridyl (e.g., imidazo [4 ,5-c]pyridyl, etc.), tetrahydroimidazopyridyl (e.g., 4,5,6, 7-tetrahydro [4 , 5-c] pyridyl , etc.), 7-azabicyclo [2.2.
  • imidazopyridyl e.g., imidazo [4 ,5-c]pyridyl, etc.
  • tetrahydroimidazopyridyl e.g., 4,5,6, 7-tetrahydro [4 , 5-c] pyridyl , etc.
  • R 1 Suitable examples of the "fused ring" for R 1 include 1,3- benzodioxol-5-yl , etc.
  • acyl for the “acylamino”
  • alkanoyl e.g., formyl, lower alkyl-carbonyl (e.g., acetyl, propanoyl, butanoyl, 2-meth lpropanoyl , pentanoyl, pivaloyl, 2,2- dimethylpropanoyl , hexanoyl, etc .
  • alkoxycarbonyl e.g., lower alkoxycarbonyl (e.g., methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , isopropoxycarbonyl , butoxycarbonyl , t-butoxycarbonyl , pentyloxycarbonyl, etc.
  • lower alkyl-carbonylox lower alkylcarbonyl (e.g., acetyloxyacetyl, ethylcarbonyloxyacetyl , etc.); arylcarbonyl [e.g., C 6 - ⁇ o arylcarbonyl (e.g., benzoyl, toluoyl, naphthoyl , fluorenylcarbonyl , etc.
  • arylalkanoyl e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl , phenylpropanoyl , phenylbutanoyl , phenylisobutanoyl , phenylpentanoyl , phenylhexanoyl , etc.), naphthyl (lower) alkanoyl (e.g., naphthylacetyl , naphthylpropanoyl, naphthylbutanoyl , etc.), etc.
  • phenyl (lower) alkanoyl e.g., phenylacetyl , phenylpropanoyl , phenylbutanoyl , phenylisobutanoyl , phenylpentanoyl , phenylhexanoyl , etc.
  • arylalkenoyl e.g., aryl (C 3 -C 6 ) alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl , phenylmethacryloyl , phenylpentenoyl , phenylhexenoyl , etc. ) , etc.
  • naphthylalkenoyl e.g., naphthyl (C 3 -Ce) alkenoyl (e.g., naphthylpropenoyl , naphthylbutenoyl , naphthylmethacryloyl , naphth lpentenoyl , naphthylhexenoyl , etc.
  • arylalkoxycarbonyl e.g., aryl (lower) alkoxycarbonyl such as phenyl (lower) alkoxycarbonyl (e.g., benzyloxycarbonyl , etc.), fluorenyl (lower) alkoxycarbonyl (e.g.
  • aryloxycarbonyl e.g., phenoxycarbonyl , naphthyloxycarbonyl , etc .
  • aryloxyalkanoyl e.g., aryloxy (lower) alkanoyl (e.g., phenoxyacetyl , phenoxypropionyl , etc. ) , etc.
  • heterocyclic acyl e.g., heterocycliccarbonyl , etc.
  • heterocyclic alkanoyl e.g., heterocyclic (lower) alkanoyl (e.g., heterocyclic acetyl, heterocyclic propanoyl, heterocyclic butanoyl, heterocyclic pentanoyl, heterocyclic hexanoyl, etc.), etc.
  • heterocyclic alkenoyl e.g., heterocyclic (lower) alkenoyl
  • heterocyclic propenoyl e.g., heterocyclic butenoyl, heterocyclic pentenoyl, heterocyclic hexenoyl, etc.
  • carbamoyl e.g., alkylcarbamoyl [e.g., lower alkylcarbamoyl (e.g., methylcarbamoyl , ethylcarbamoyl , etc.
  • alkoxycarbamoyl e.g., lower alkoxycarbamoyl (e.g., methoxycarbamoyl , ethoxycarbamoyl , etc.)], etc.
  • arylcarbamoyl e.g., C 6 - ⁇ o arylcarbamoyl (e.g., phenylcarbamoyl , naphthylcarbamoyl , etc. ) , etc.
  • arylthiocarbamoyl e.g., C 6 - ⁇ o arylthiocarbamoyl (e.g., phenylthiocarbamoyl , naphthylthiocarbamoyl , etc. ) , etc.
  • alkylsulfonyl e.g., lower alkylsulfonyl (e.g., methylsulfonyl , ethylsulfonyl , etc.
  • alkoxysulfonyl e.g., lower alkoxysulfonyl (e.g., methoxysulfonyl , ethoxysulfonyl, etc. ) ] , etc. ; arylsulfonyl (e.g., phenylsulfonyl , etc.); arylglyoxyloyl [e.g., C 6 - 10 arylglyoxyloyl (e.g., phenylglyoxyloyl , naphthylglyoxyloyl , etc. ) , etc. ] ; heterocyclicglyoxyloyl , etc.
  • Each of the acyl is optionally substituted by one or more suitable substituent (s) .
  • Suitable examples of hydroxy protective group for the "optionally protected hydroxy" for R 2 include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.); lower alkoxy (lower) alkyl (e.g., methoxymethyl , etc.); lower alkoxy (lower) alkoxy (lower) alkyl (e.g., 2- me hoxyethoxymethy1 , etc.
  • lower alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.
  • lower alkoxy (lower) alkyl e.g., methoxymethyl , etc.
  • aryl (lower) alkyl in which the aryl portion is optionally substituted with one or more suitable substituent (s) (e.g., benzyl (Bn) , p-methoxybenzyl , 2,3-dimethoxybenzyl, etc.); aryl (lower) alkoxy (lower) alkyl in which the aryl portion is optionally substituted with one or more suitable substituent (s) (e.g., benzyloxymethyl, p-methoxybenzyloxymethyl , etc.); lower alkylthio (lower) alkyl (e.g., methylthiomethyl , ethylthiomethyl, propylthiomethyl , isopropylthiomethyl , butylthiomethyl , isobutylthiomethyl, hexylthiomethyl , etc.); heterocyclic group (e.g., tetrahydropyranyl , etc.); trisubsti
  • Suitable examples of the "lower alkenylene” include a straight or branched alkenylene having 1 to 6 carbon atom(s) , such as vinylene, 1-methylvinylene , 2-methylvinylene , 1- propenylene, 2-propenylene, 2-methyl-l-propenylene, 2-methyl-2- propenylene, 1-butenylene , 2-butenylene, 3-butenylene, 1- pentenylene, 2-pentenylene, 3-pentenylene , 4-pentenylene, 1- hexenylene, 2-hexenylene , 3-hexenylene , 4-hexenylene , 5- hexenylene, etc.
  • Suitable examples of the "lower alkenylene” for L 1 include vinylene, etc.
  • R 1 for the compound [I] include lower alkyl optionally substituted with aryl (lower) alkoxyaryl (e.g., 4-benzyloxyphenyl , etc.), of which the preferred are methyl, (4-benzyloxyphenyl)methyl, etc.; aryl optionally substituted with the group (s) selected from lower alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), halogen (e.g., chloro, bromo, iodo, etc.), aryl (e.g., phenyl, naphthyl, etc.), aryl (lower) alkoxy (e.g., benzyloxy, naphthylmethyloxy, etc.) and mono- or di-substituted amino (e.g.
  • aryl (lower) alkoxyaryl e.g., 4-benzyloxyphenyl , etc.
  • the preferred are methyl, (4-benzy
  • acylamino for R 2 include lower alkyl-carbonylamino (e.g. , acetylamino, ethylcarbonylamino , propylcarbonylamino, etc.), lower alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.), arylcarbonylamino (e.g., phenylcarbonylamino , naphthylcarbonylamino, etc.), etc., of which the preferred are acetylamino, methylsulfonylamino, phenylcarbonylamino, etc.
  • lower alkyl-carbonylamino e.g. , acetylamino, ethylcarbonylamino , propylcarbonylamino, etc.
  • Suitable examples of "optionally protected hydroxy” include hydroxy, lower alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), of which the preferred are hydroxy, methoxy, etc.
  • Boc t-butyloxycarbonyl
  • HOBT 1- hydroxybenzotriazole
  • WSCD l-ethyl-3- (3 '-dimethylaminopropyl) - carbodiimide
  • DMF R,R-dimethylformamide
  • aq. aqueous solution
  • Test 1 Determination of histone deacetylase inhibitory activity The partial purification of human histone deacetylase, the preparation of [ 3 H] acetyl histones, and the assay for histone deacetylase activity were performed as follows basically according to the method as proposed by Yoshida et al .
  • the human histone deacetylase was partially purified from human T cell leukemia Jurkat cells.
  • Jurkat cells (5 x 10 8 cells) were suspended in 40 mL of the HDA buffer consisting of 15 mM potassium phosphate (pH 7.5), 5% glycerol and 0.2 mM EDTA. After homogenization, nuclei were collected by centrifugation (35,000 x g, 10 min) and homogenized in 20 mL of the same buffer supplemented with 1 M (NH 4 ) 2 S0.
  • the viscous homogenate was sonicated and clarified by centrifugation (35,000 x g, 10 min) , and the deacetylase was precipitated by raising the concentration of (NH 4 ) 2 S0 4 to 3.5 M.
  • the precipitated protein was dissolved in 10 mL of the HDA buffer and dialyzed against 4 liters of the same buffer.
  • the dialyzate was then loaded onto a DEAE-cellulose (Whatman DE52) column (25 x 85 mm) equilibrated with the same buffer and eluted with 300 mL of a linear gradient (0-0.6 M) of NaCl.
  • a single peak of histone deacetylase activity appeared between 0.3 and 0.4 M NaCl.
  • the washed cells were suspended in 15 mL of ice-cold lysis buffer (pH 6.5, 10 mM Tris-HCl, 50 mM sodium bisulfite, 1% Triton X-100, 10 mM MgCl 2 , 8.6% sucrose). After Dounce homogenization (30 stroke) , the nuclei were collected by centrifugation at 1000 rpm for 10 min, washed 3 times with 15 mL of the lysis buffer, and once with 15 mL of ice-cooled washing buffer (pH 7.4, 10 mM Tris-HCl, 13 mM EDTA) successively.
  • ice-cold lysis buffer pH 6.5, 10 mM Tris-HCl, 50 mM sodium bisulfite, 1% Triton X-100, 10 mM MgCl 2 , 8.6% sucrose.
  • the pellet was suspended in 6 mL of ice-cooled water using a mixer, and 68 ⁇ l of H 2 S0 4 was added to the suspension to give a concentration of 0.4 N. After incubation at 4°C for 1 hr, the suspension was centrifuged for 5 min at 15,000 rpm, and the supernatant was taken and mixed with 60 mL of acetone. After overnight incubation at -20 °C, the coagulated material was collected by microcentrifugation, air-dried, and stored at -80°C. Assay for histone deacetylase activity
  • Test 2 Determination of T-cell growth inhibitor activity The T lymphocyte blastogenesis test was performed in microtiter plates with each well containing 1.5 x 10 5 splenic cells of Lewis rats in 0.1 mL RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) , 50 mM 2-mercaptoethanol , penicilln (100 units/mL) and streptomycin (100 ⁇ g/mL) , to which
  • FBS fetal bovine serum
  • penicilln 100 units/mL
  • streptomycin 100 ⁇ g/mL
  • Concanavalin A (1 ⁇ g/mL) was added. The cells were incubated at 37 °C in a humidified atmosphere of 5% C0 2 for 72 hrs. After the culture period, suppressive activities of the test compounds in T lymphocyte blastogenesis were quantified by AlamarBlue (trademark) Assay. The test samples were dissolved in DMSO and further diluted with RPMI-1640 medium and added to the culture. The activities of the test compounds were expressed as IC 50 . The results of those tests are shown in the Table 1.
  • Table 1 HDAC inhibitory activity and T-cell growth inhibitory activity of the compound of the present invention
  • Test 1 Test 2:
  • the pharmaceutical composition of the present invention comprising histone deacetylase inhibitor such as the compound [I] is useful as a therapeutic or prophylactic agent for diseases caused by abnormal gene expression, such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL) , protozoal infection, etc. Further, it is useful as an antitumor agent or immunosuppressant, which prevents an organ transplant rejection and autoimmune diseases as exemplified below.
  • Rejection reactions by transplantation of organs or tissues e.g., heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, intervertebral disc, trachea, myoblast, cartilage, etc.
  • organs or tissues e.g., heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, intervertebral disc, trachea, myoblast, cartilage, etc.
  • graft-versus-host reactions following bone marrow transplantation e.g., rheumatoid arthritis, systemic lupus erythematosus , Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, etc.
  • infections caused by pathogenic microorganisms e.g., Aspergillus fumigatus, Fusarium oxysporum, Trich
  • Inflamatory or hyperproliferative skin diseases or cutaneous manifestations of immunologically-mediated diseases e.g., psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, erythema, dermal eosinophilia, lupus erythematosus , acne , alopecia areata, etc.
  • immunologically-mediated diseases e.g., psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa,
  • autoimmune diseases of eye e.g., keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis , herpetic keratitis , conical keratitis , corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopath , Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye) , phlyctenule, iridocyclitis , sarcoidosis, endocrine ophthalmopathy, etc.); reversible obstructive airway diseases [e.g., asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma) , particularly chronic or inveter
  • intestinal inflammations/allergies e.g., coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, etc.
  • food-related allergic diseases with symptomatic manifestation remote from the gastrointestinal tract e.g., migrain, rhinitis, eczema, etc.
  • renal diseases e.g., intestitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, etc.
  • nervous diseases e.g., multiple myositis, Guillain-Barre syndrome, Meniere's disease, multiple neuritis, solitary neuritis, cerebral infarction, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) , radiculopathy, etc.
  • cerebral ischemic diseases e.g., head injury, hemorrhage in brain (e.g.
  • endocrine diseases e.g., hyperthyroidism, Basedow's disease, etc.
  • hematic diseases e.g.
  • pure red cell aplasia aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, etc.
  • bone diseases e.g., osteoporosis, etc.
  • respiratory diseases e.g., sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, etc.
  • skin diseases e.g., dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma, etc.
  • circulatory diseases e.g., arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis , etc.
  • collagen diseases e.g. , scleroderma, Wegener's granuloma,
  • Sj ⁇ gren's syndrome , etc. adiposis; eosinophilic fasciitis; periodontal diseases (e.g., damage to gingiva, periodontium, alveolar bone or substantia ossea dentis, etc.) ; nephrotic syndrome (e.g., glomerulonephritis , etc.); male pattern alopecia, alopecia senile; muscular dystrophy; pyoderma and Sezary syndrome; chromosome abnormality-associated diseases (e.g., Down's syndrome, etc. ) ;
  • Addison's disease; active oxygen-mediated diseases ⁇ e.g., organ injury [e.g., ischemic circulation disorders of organs (e.g. , heart, liver, kidney, digestive tract, etc.) associated with preservation and transplantation, etc.], ischemic diseases (e.g., thrombosis, cardial infarction, etc.), intestinal diseases (e.g., endotoxin shock, pseudomembranous colitis, drug- or radiation-induced colitis, etc.), renal diseases (e.g., ischemic acute renal insufficiency, chronic renal failure, etc.), pulmonary diseases [e.g., toxicosis caused by pulmonary oxygen or drugs (e.g., paracort, bleomycin, etc.), lung cancer, pulmonary emphysema, etc.], ocular diseases (e.g., cataracta, iron-storage disease (siderosis bulbi) , retinitis, pigmentosa, senile plaques, vitreous scar
  • the pharmaceutical composition of the present invention is useful for the therapy and prophylaxis of liver diseases [e.g., immunogenic diseases (e.g., chronic autoimmune liver diseases such as autoimmune hepatic diseases, primary biliary cirrhosis, sclerosing cholangitis, etc.), partial liver resection, acute liver necrosis (e.g., necrosis caused by toxins, viral hepatitis, shock or anoxia, etc.) , hepatitis B, non-A non-B hepatitis, hepatocirrhosis, hepatic failure (e.g., fulminant hepatitis, late-onset hepatitis and "acute-on-chronic" liver failure (acute liver failure on chronic liver diseases), etc.), etc . ] .
  • immunogenic diseases e.g., chronic autoimmune liver diseases such as autoimmune hepatic diseases, primary biliary cirrhosis, sclerosing cholangit
  • the pharmaceutical composition of the present invention can be used in the form of pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which contains the histone deacetylase inhibitor, such as the compound [I] , as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral administrations.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, ointments, liniments, eye drops, lotion, gel, cream, and any other form suitable for use.
  • the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in a solid, semisolid, or liquid form. Additionally, auxiliary, stabilizing, thickening, solubilizing ' and coloring agents and perfumes may be used in combination with the carrier.
  • the composition is preferably applied by intravenous, intramuscular, topical or oral administration, or by a vascular stent impregnated with the compound [I] .
  • the dosage of therapeutically effective amount of the histone deacetylase inhibitor, such as the compound [I] varies depending upon the age and condition of each individual patient to be treated, when an individual patient is to be treated, in the case of intravenous administration, a daily dose of 0.01-10 mg of the histone deacetylase inhibitor, such as the compound [I] , per kg weight of human being, in the case of intramuscular administration, a daily dose of 0.1-10 mg of the histone deacetylase inhibitor, such as the compound of the formula [I] , per kg body weight of human being, and in the case of oral administration, a daily dose of 0.5-50 mg of the histone deacetylase inhibitor, such as the compound [I] , per kg body weight of human being, is generally given for treatment.
  • the compound [I] or a salt thereof can be also combined together with other immunosuppressive substances, such as repamycin, mycophenolic acid, cyclosporin A, tacrolimus and brequinar sodium.
  • Example 7 Compound E7 (1.31 g) was obtained from Compound (46) in a manner similar to Example 1.
  • Example 11 Compound Ell (651.6 mg) was obtained from Compound (68) in a manner similar to Example 1.
  • Tables 2-1 to 2-13) and Table 3 (including Tables 3-1 and 3-2) .
  • a compound having a potent inhibitory effect on the activity of histone deacetylase and a pharmaceutical composition containing said compound as an active ingredient can be provided.
  • the compound is useful as an active ingredient of an immunosuppressant and an antitumor agent, and useful as a therapeutic or prophylactic agent for diseases such as inflammatory disorders, diabetes, diabetic complications, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, autoimmune diseases, protozoal infections , ' tumors , etc.

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Abstract

L'invention concerne un composé de la formule suivante (I), dans laquelle R1 représente alkyle inférieur éventuellement substitué par au moins un substituant approprié ; aryle éventuellement substitué par au moins un substituant approprié ; ou un cycle condensé, R2 représente acylamino ou hydroxy éventuellement protégé, L1 représente alcénylène inférieur, et R3 représente hydroxyamino, ou un sel de celui-ci. Ledit composé peut servir d'inhibiteur de l'histone désacétylase.
PCT/JP2004/001437 2003-02-11 2004-02-10 Inhibiteur de l'histone desacetylase WO2004071401A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
JP2013173743A (ja) * 2005-11-24 2013-09-05 Dompe Pha R Ma Spa （ｒ）−アリールアルキルアミノ誘導体類と、それらを含有する薬剤組成物
JP2015504056A (ja) * 2011-12-29 2015-02-05 ファーマサイクリックス，インク． ヒストンデアセチラーゼ８の阻害剤としての珪皮酸ヒドロキシアミド
US9435813B2 (en) 2010-05-11 2016-09-06 The General Hospital Corporation Biomarkers of hemorrhagic shock

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038322A1 (fr) * 1999-11-23 2001-05-31 Methylgene, Inc. Inhibiteurs de l'histone deacetylase
WO2002022577A2 (fr) * 2000-09-01 2002-03-21 Novartis Ag Inhibiteurs de desacetylase
WO2003087066A1 (fr) * 2002-04-11 2003-10-23 Sk Chemicals, Co., Ltd. Derives d'acide hydroxamique $g(a),$g(b)-insatures et leur utilisation comme inhibiteurs de l'histone desacetylase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038322A1 (fr) * 1999-11-23 2001-05-31 Methylgene, Inc. Inhibiteurs de l'histone deacetylase
WO2002022577A2 (fr) * 2000-09-01 2002-03-21 Novartis Ag Inhibiteurs de desacetylase
WO2003087066A1 (fr) * 2002-04-11 2003-10-23 Sk Chemicals, Co., Ltd. Derives d'acide hydroxamique $g(a),$g(b)-insatures et leur utilisation comme inhibiteurs de l'histone desacetylase

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7741494B2 (en) 2005-07-14 2010-06-22 Takeda San Diego, Inc. Histone deacetylase inhibitors
JP2013173743A (ja) * 2005-11-24 2013-09-05 Dompe Pha R Ma Spa （ｒ）−アリールアルキルアミノ誘導体類と、それらを含有する薬剤組成物
US9435813B2 (en) 2010-05-11 2016-09-06 The General Hospital Corporation Biomarkers of hemorrhagic shock
JP2015504056A (ja) * 2011-12-29 2015-02-05 ファーマサイクリックス，インク． ヒストンデアセチラーゼ８の阻害剤としての珪皮酸ヒドロキシアミド

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