WO2014148574A1 - Il-2産生抑制 - Google Patents
Il-2産生抑制 Download PDFInfo
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- WO2014148574A1 WO2014148574A1 PCT/JP2014/057597 JP2014057597W WO2014148574A1 WO 2014148574 A1 WO2014148574 A1 WO 2014148574A1 JP 2014057597 W JP2014057597 W JP 2014057597W WO 2014148574 A1 WO2014148574 A1 WO 2014148574A1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
- C07K16/246—IL-2
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
- G01N33/6869—Interleukin
Definitions
- the present invention relates to an IL-2 production inhibitor or a preventive or therapeutic agent for diseases involving IL-2.
- IL-2 (interleukin-2) is a kind of cytokine, is mainly produced by activated T cells, and acts on cells such as T cells, B cells, and macrophages.
- IL-2 is T cell proliferation and activation, B cell proliferation and enhancement of antibody production, monocyte / macrophage activation, natural killer cell (NK cell) proliferation / activation, lymphokine activated killer cell Inducing action such as.
- the T cell antigen receptor T Cell Receptor, TCR
- TCR T cell antigen receptor
- the T cell produces IL-2 by receiving antigen presentation from an antigen presenting cell such as a macrophage. .
- TCR present on the surface of T cells exists in a complex with a molecule called CD4.
- Phospholipase C (PLC) ⁇ is involved in the release of calcium ions from the endoplasmic reticulum, causing calmodulin and calcineurin activation in a calcium-dependent manner.
- Calcineurin dephosphorylates the transcription factor NF-AT and moves it into the nucleus. Thereafter, NF-AT binds to the IL-2 promoter and IL-2 mRNA production is enhanced.
- the immunosuppressants tacrolimus (FK506) and cyclosporin A suppress IL-2 production in T cells. These drugs bind to intracellular cyclophilin and FK506 binding protein (FKBP), and the drug-protein complex binds to calcineurin. As already mentioned, calcineurin is an important molecule in the transcriptional regulation of IL-2, and this mechanism suppresses calcineurin-dependent dephosphorylation of transcription factor NF-AT, resulting in an immunosuppressive action. These drugs are mainly used for the purpose of suppressing rejection after organ transplantation. Tacrolimus and the like are also used for the treatment of atopic dermatitis.
- Non-Patent Documents 1 and 2 It has been reported that cytokines such as IL-2 are deeply involved in bronchial asthma and the like.
- Non-patent Document 3 cytokine balance is involved in the onset of rheumatoid arthritis, and in particular, Th1-type cytokines such as IL-2 are known to play a promoting role in the onset of arthritis.
- IL-2 production includes AIDS, cancer, skin diseases (psoriasis, atopic dermatitis, urticaria), visceral diseases (lupus nephritis), ophthalmic diseases (allergic conjunctivitis, stye, chalazion, spring catarrh, Uveitis, cancer), autoimmune diseases (polymyositis, Hashimoto's disease, Behcet's disease, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, hay fever, scleroderma), gastrointestinal diseases, inflammatory diseases (Gout, psoriatic arthritis, rheumatoid arthritis), central diseases (multiple sclerosis), respiratory diseases (asthma, chronic obstructive pulmonary disease), fibromyalgia, myasthenia gravis, sarcoidosis, rhinitis, nasal catarrh, etc. It is also known to be involved in other diseases
- Patent Document 1 Japanese Patent No. 4296345 (Patent Document 1), Japanese Patent No. 5061134 (Patent Document 2), and Japanese Patent No. 4360292 (Patent Document 3), some 2-phenylbenzothiazoline derivatives are specifically disclosed, They act as kappa opioid receptor agonists and have been shown to be useful as therapeutic agents for pain, pruritus and the like, and as pain threshold lowering inhibitors.
- the ( ⁇ )-O, O′-diacetyl-L-tartrate salt of ⁇ 5-methoxyphenyl] benzothiazoline is the product of European Journal of Pharmacology (2010), 647 (1-3), 62-67 (Non-patent Document 4).
- Non-Patent Document 5 European ⁇ RTIgt; Journal ⁇ / RTI> of ⁇ RTIgt; Pharmacology (2011), ⁇ / RTI> 671 (1-3), 53-60 (Non-Patent Document 5), which have been shown to have antinociceptive, antipruritic, and weak sedative effects.
- FK506, cyclosporine, and steroidal anti-inflammatory drugs also have IL-2 production inhibitory action.
- these drugs are used for various treatments, there are problems such as the occurrence of strong side effects due to long-term administration, and no safe and effective drug has been found. Therefore, a safe drug that has a potent IL-2 production inhibitory action and is safe is desired.
- Patent No. 4296345 Japanese Patent No. 5061134 Japanese Patent No. 4360292
- An object of the present invention is to find a compound that suppresses IL-2 production, and to provide an IL-2 production inhibitor containing the compound as an active ingredient or a preventive or therapeutic agent for a disease involving IL-2.
- A represents a lower alkylene group
- R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted with a halogen atom
- R 2 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group
- R 3 and R 4 are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with a hydroxy group, a lower alkyl group substituted with a lower alkoxy group, or a lower alkoxy group substituted with a lower alkoxy group.
- a lower alkyl group substituted with or a lower alkyl group substituted with an acetoxy group] Or a pharmaceutically acceptable salt thereof suppresses IL-2 production, and contains the present compound as an active ingredient
- the present invention was completed by finding an IL-2 production inhibitor or a preventive or therapeutic agent for a disease involving IL-2.
- the present invention relates to the following.
- A represents a lower alkylene group
- R 1 represents a halogen atom
- R 2 represents a lower alkoxy group
- R 3 represents a lower alkyl group
- R 4 represents a lower alkyl group substituted with a hydroxyl group, a lower alkyl group substituted with a lower alkoxy group, a lower alkyl group substituted with a lower alkoxy group
- a compound showing a lower alkyl group substituted with an alkyl group or an acetoxy group The IL-2 production inhibitor according to (1) above.
- A represents a trimethylene group or 1-methyltrimethylene group
- R 1 represents a chlorine atom
- R 2 represents a methoxy group
- R 3 represents an isopropyl group
- R 4 represents a 2-hydroxyethyl group, a 2-methoxyethyl group, a 2-ethoxyethyl group, a 2- (methoxymethoxy) ethyl group or a 2-acetoxyethyl group.
- the IL-2 production inhibitor according to (1) or (2).
- the compound represented by the general formula (I) is (+)-3-acetyl-6-chloro-2- [2- (3- (N- (2-ethoxyethyl) -N-isopropylamino). (Propoxy) -5-methoxyphenyl] benzothiazoline, ( ⁇ ) -3-acetyl-6-chloro-2- [2- (3- (N- (2-ethoxyethyl) -N-isopropylamino) propoxy) -5 -Methoxyphenyl] benzothiazoline, (+)-3-acetyl-6-chloro-2- [2- (3- (N- (2-hydroxyethyl) -N-isopropylamino) propoxy) -5-methoxyphenyl] Benzothiazoline or (+)-3-acetyl-6-chloro-2- [2- (3- (N-isopropyl-N- (2-methoxyethyl) amino) propoxy) -5-meth
- IL-2 production inhibitor according to any one of (1) to (5), wherein the IL-2 production inhibitor is a preventive or therapeutic agent for a disease involving IL-2.
- the present invention also relates to the following.
- a pharmaceutical composition for preventing or treating a disease involving IL-2 comprising a therapeutically effective amount of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof and an excipient. .
- composition for inhibiting IL-2 production comprising a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
- a method for inhibiting IL-2 production comprising administering a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
- an IL-2 production inhibitor or a prophylactic or therapeutic agent for a disease involving IL-2 comprising the present compound as an active ingredient in the present invention.
- Halogen atom means a fluorine, chlorine, bromine or iodine atom.
- the “lower alkyl group” refers to a linear or branched alkyl group having 1 to 8 carbon atoms, preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, isopropyl group, isobutyl group, sec-butyl group, Examples thereof include a tert-butyl group and an isopentyl group.
- the “lower alkoxy group” refers to a group in which a hydrogen atom of a hydroxyl group is substituted with the above lower alkyl group. Specific examples include methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentoxy group, n-hexyloxy group, n-heptyloxy group, n-octyloxy group, isopropoxy group, isobutoxy group, sec -Butoxy group, tert-butoxy group, isopentyloxy group and the like.
- the “lower alkylene group” refers to a linear or branched alkylene group having 1 to 8 carbon atoms, and a linear or branched alkylene group having 1 to 6 carbon atoms is preferable. Specific examples include methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, heptamethylene group, octamethylene group, methylmethylene group, ethylmethylene group, 1-methylethylene group, 1-methyltrimethyl group. And methylene.
- the lower alkyl group substituted with a halogen atom refers to the above lower alkyl group substituted with one or more halogen atoms. Specific examples include a trifluoromethyl group and a trichloromethyl group.
- lower alkyl group substituted with a lower alkoxy group refers to the above lower alkyl group substituted with one or more lower alkoxy groups. Specific examples include 2-methoxyethyl group, 2-ethoxyethyl group, 3-methoxypropyl group, 3-ethoxypropyl group and the like.
- the lower alkyl group substituted with a lower alkoxy group substituted with a lower alkoxy group refers to the above lower alkyl group having one lower alkoxy group substituted with one lower alkoxy group as a substituent. Specific examples include 2- (methoxymethoxy) ethyl group and 3- (methoxymethoxy) propyl group.
- lower alkyl group substituted with an acetoxy group refers to the above lower alkyl group substituted with one or more acetoxy groups. Specific examples include 2-acetoxyethyl group and 3-acetoxypropyl group.
- a plurality of substituents refers to a number of substituents that is not less than 2 and not more than the number that can be substituted at a substitution site. Each substituent may be the same or different, and the number of substituents is preferably 2 or 3.
- a hydrogen atom and a halogen atom are also included in the concept of “substituent”.
- the pharmaceutically acceptable salt in the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, such as a salt with an inorganic acid, a salt with an organic acid, a quaternary ammonium salt, a salt with a halogen ion, etc. Is mentioned.
- a pharmaceutically acceptable salt such as a salt with an inorganic acid, a salt with an organic acid, a quaternary ammonium salt, a salt with a halogen ion, etc.
- the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- Salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, diacetyltartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid , Hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid And salts with lauryl, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid and the like.
- Examples of quaternary ammonium salts include salts with methyl bromide, methyl iodide and the like.
- Examples of salts with halogen ions include salts with chloride ions, bromide ions, iodide ions and the like.
- the pharmaceutically acceptable salt in the present invention is preferably hydrochloride and O, O'-diacetyl tartrate, particularly preferably (-)-O, O'-diacetyl-L-tartrate.
- the present compound in the present invention can be in the form of a hydrate or a solvate.
- the crystalline polymorph is also included in the scope of the present invention.
- (A) As a preferable example in this compound, in the compound represented by the general formula (I), a compound in which each group is a group shown below or a pharmaceutically acceptable salt thereof can be mentioned.
- (A1) A represents a lower alkylene group; and / or (a2) R 1 represents a halogen atom; and / or (a3) R 2 represents a lower alkoxy group; and / or (a4) R 3 represents a lower alkyl group; and / or (a5) R 4 is a lower alkyl group substituted with a hydroxyl group, a lower alkyl group substituted with a lower alkoxy group, a lower alkoxy group substituted with a lower alkoxy group And a lower alkyl group substituted with an acetoxy group.
- a compound comprising one or more combinations selected from the above (a1), (a2), (a3), (a4) and (a5), or a pharmacy thereof
- a salt that is acceptable is given.
- a compound comprising all combinations of the above (a1), (a2), (a3), (a4) and (a5) or a pharmaceutically acceptable salt thereof is particularly preferred. Take as an example.
- (B) As a more preferable example in this compound, the compound or its pharmaceutically acceptable salt in which each group is a group shown below in the compound represented by the general formula (I).
- (B1) A represents a trimethylene group or 1-methyltrimethylene group; and / or (b2) R 1 represents a chlorine atom; and / or (b3) R 2 represents a methoxy group; Or (b4) R 3 represents an isopropyl group; and / or (b5) R 4 represents a 2-hydroxyethyl group, 2-methoxy group ethyl group, 2-ethoxy group ethyl group, 2- (methoxymethoxy) ethyl group Or 2-acetoxyethyl group.
- a compound comprising one or more combinations selected from the above (b1), (b2), (b3), (b4) and (b5), or a pharmacy thereof
- a salt that is acceptable is given.
- the selected condition can be combined with the condition (a).
- a compound consisting of all combinations of the above (b1), (b2), (b3), (b4) and (b5) or a pharmaceutically acceptable salt thereof is particularly preferred. Take as an example.
- the present compound in the present invention can be produced, isolated and purified according to ordinary methods in the field of synthetic organic chemistry, and can also be synthesized, for example, by the method described in Japanese Patent No. 4296345 or Japanese Patent No. 5061134. .
- geometrical isomers, tautomers, optical isomers, enantiomers, or diastereoisomers of the present compound in the present invention can also be produced and isolated according to ordinary methods such as column chromatography and HPLC. Can be purified.
- the IL-2 production inhibitor in the present invention is an inhibitor that suppresses IL-2 production mainly by activated T cells.
- the IL-2 production inhibitor can be used for prevention or treatment of various disease groups caused by T cell overactivation and T cell proliferation by inhibiting IL-2 production.
- the disease involving IL-2 in the present invention is a disease caused by IL-2 production, enhanced IL-2 receptor expression, etc., and is known as common sense in the art.
- Diseases involving IL-2 include, for example, AIDS, cancer, skin diseases (psoriasis, atopic dermatitis, urticaria), visceral diseases (lupus nephritis), ophthalmic diseases (allergic conjunctivitis, stye, chalazion, Spring catarrh, uveitis, cancer), autoimmune diseases (polymyositis, Hashimoto's disease, Behcet's disease, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, hay fever, scleroderma), gastrointestinal diseases, Inflammatory diseases (gout, psoriatic arthritis, rheumatoid arthritis), central diseases (multiple sclerosis), respiratory diseases (asthma, chronic obstructive
- the IL-2 production inhibitor of the present invention or a prophylactic or therapeutic agent for diseases involving IL-2 can be administered either orally or parenterally, and no special technique is required for their formulation, and they are widely used. Can be formulated using a technique. Examples of the dosage form include tablets, capsules, granules, powders, injections, eye drops, ointments and the like.
- excipients When used as oral preparations such as tablets, capsules, granules, powders, etc., excipients, lubricants, binders, disintegrants, coating agents, film agents, stabilizers, flavoring agents, etc., as necessary Can be prepared.
- Excipients include lactose, mannitol, crystalline cellulose, starch, vegetable oil, light anhydrous silicic acid, calcium carbonate, calcium hydrogen phosphate, etc.
- Lubricants include stearic acid, magnesium stearate, talc, etc.
- binder examples include starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone
- disintegrant examples include carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, low-substituted hydroxypropylmethylcellulose
- coating agent examples include hydroxypropyl methylcellulose, macrogol, and silicone resin.
- the coating agent examples include gelatin peel. And the like, as the stabilizer, ethyl parahydroxybenzoate, benzyl alcohol, and examples of the flavoring agents, sweeteners, acidulants, such as perfumes.
- isotonic agents for parenteral preparations such as injections and eye drops, isotonic agents, buffering agents, surfactants, stabilizers, preservatives and the like can be added as necessary.
- isotonic agent include sodium chloride and concentrated glycerin
- examples of the buffering agent include sodium phosphate, sodium acetate, boric acid, borax, citric acid, and the like.
- examples include oxyethylene sorbitan monooleate, polyoxyl stearate, and polyoxyethylene hydrogenated castor oil.
- Stabilizers include sodium citrate and sodium edetate.
- Preservatives include benzalkonium chloride and parabens. And other preservatives.
- the pH of the eye drop may be within the range acceptable for ophthalmic preparations, preferably in the range of pH 4-8, more preferably in the range of pH 5-7.
- an ointment it can be prepared using a widely used base, and examples of the base include white petrolatum and liquid paraffin.
- the dosage of this compound and its pharmaceutically acceptable salt depends on the dosage form, the severity of symptoms of the subject (human or animal, etc.) to be administered, age, weight, route of administration, judgment of the doctor, etc. It can be changed as appropriate.
- the daily dose is usually within the range of 0.1 to 5000 mg, preferably within the range of 1 to 1000 mg, and can be administered once or in several divided doses.
- the daily dose is usually in the range of 0.01 to 500 ⁇ g, preferably in the range of 0.05 to 100 ⁇ g, and can be administered once or several times a day.
- the concentration of the present compound in the eye drop is not particularly limited, but an eye drop having a concentration in the range of 0.00001 to 3 w / v%, preferably in the range of 0.0001 to 1 w / v% may be instilled. it can.
- the concentration of the eye drop may be calculated based on any weight of the free form of this compound and its salt.
- the daily dose is usually within the range of 0.0001 to 50 mg, preferably within the range of 0.0003 to 20 mg, and can be administered once or divided into several times.
- the IL-2 production inhibitor of the present invention and the preventive or therapeutic agent for diseases involving IL-2 are nonsteroidal anti-inflammatory agents such as indomethacin, ibuprofen, diclofenac, and aspirin; steroids such as dexamethasone, betamethasone, prednisolone, and triamcinolone Anti-inflammatory agents; immunosuppressive agents such as tacrolimus, cyclosporine, sirolimus; diphenhydramine, chlorpheniramine, triprolidine, promethazine, alimemazine, hydroxyzine, cyproheptadine, fexofenadine, olopatadine, epinastine, loratadine, cetirizine, bepotastine, mequitazine, etc.
- nonsteroidal anti-inflammatory agents such as indomethacin, ibuprofen, diclofenac, and aspirin
- steroids such as dexamethasone, betamet
- Anti-histamines such as bucillamine, salazosulfapyridine, methotrexate; infliximab, adalimumab, tocilizumab It can be used in combination with such.
- the desired formulation can be prepared by appropriately changing the type and amount of the present compound and additives.
- Test Compound Solution An appropriate amount of Test Compound 2 was weighed and dissolved in dimethyl sulfoxide (DMSO), and then prepared to a final concentration using a culture solution.
- DMSO dimethyl sulfoxide
- Lipofectamine 2000 was used for 1 ⁇ g of plasmid, mixed with Plasmid in Opti-MEM, and added to the cells after 20 minutes.
- A-2187 (Sigma) or DMSO, which is a transcriptional activator of IL-2 was added to Jurkat cells into which IL-2 Gene Promoter Reporter Vector had been introduced to a final concentration of 0.3 ⁇ M, It seed
- Compound 2 was added to a final concentration of 0.3 ⁇ M, 1 ⁇ M, and 10 ⁇ M, respectively, and cultured in a 37 ° C.
- test compound solution Preparation of test compound solution and test method for test compounds 3, 4, 5 and comparative compound asimadoline and U-50488, a test compound solution was prepared in the same manner as IL-2 production inhibitory action (1), and IL-2 transcription was suppressed. Activity was measured.
- Results and discussion Table 2 shows the results. Compounds 3, 4 and 5 suppressed the transcriptional activation of IL-2, and the rate of inhibition was greater than that of asimadoline and U-50488, which are also kappa opioid receptor agonists. From the above results, it was suggested that the present compound in the present invention suppresses IL-2 transcription activation and is useful as an IL-2 production inhibitor or a preventive or therapeutic agent for diseases involving IL-2.
- the present invention is useful as an IL-2 production inhibitor or a preventive or therapeutic agent for diseases involving IL-2.
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Abstract
Description
Aは低級アルキレン基を示し、;
R1は水素原子、ハロゲン原子、低級アルキル基又はハロゲン原子で置換された低級アルキル基を示し、;
R2は水素原子、ハロゲン原子、低級アルキル基又は低級アルコキシ基を示し、;
R3及びR4は同一又は異なって、水素原子、低級アルキル基、ヒドロキシ基で置換基された低級アルキル基、低級アルコキシ基で置換された低級アルキル基、低級アルコキシ基で置換された低級アルコキシ基で置換された低級アルキル基又はアセトキシ基で置換された低級アルキル基を示す]
で表される化合物又はその薬学的に許容される塩(以下、これらを総称して「本化合物」ともいう)が、IL-2産生を抑制することを見出し、そして本化合物を有効成分として含有するIL-2産生抑制剤又はIL-2が関与する疾患の予防若しくは治療剤を見出し、本発明を完成させた。
Aは低級アルキレン基を示し;
R1は水素原子、ハロゲン原子、低級アルキル基又はハロゲン原子で置換された低級アルキル基を示し;
R2は水素原子、ハロゲン原子、低級アルキル基又は低級アルコキシ基を示し;そして
R3及びR4は同一又は異なって、水素原子、低級アルキル基、ヒドロキシル基で置換基された低級アルキル基、低級アルコキシ基で置換された低級アルキル基、低級アルコキシ基で置換された低級アルコキシ基で置換された低級アルキル基又はアセトキシ基で置換された低級アルキル基を示す]
で表される化合物又はその薬学的に許容される塩を有効成分として含有する、IL-2産生抑制剤。
式中、
Aが低級アルキレン基を示し;
R1がハロゲン原子を示し;
R2が低級アルコキシ基を示し;
R3が低級アルキル基を示し;そして
R4がヒドロキシル基で置換基された低級アルキル基、低級アルコキシ基で置換された低級アルキル基、低級アルコキシ基で置換された低級アルコキシ基で置換された低級アルキル基又はアセトキシ基で置換された低級アルキル基を示す化合物である、
前記(1)に記載のIL-2産生抑制剤。
式中、
Aがトリメチレン基又は1-メチルトリメチレン基を示し;
R1が塩素原子を示し;
R2がメトキシ基を示し;
R3がイソプロピル基を示し;そして
R4が2-ヒドロキシエチル基、2-メトキシエチル基、2-エトキシエチル基、2-(メトキシメトキシ)エチル基又は2-アセトキシエチル基を示す化合物である、
前記(1)又は(2)に記載のIL-2産生抑制剤。
(a1)Aが低級アルキレン基を示し、;及び/又は
(a2)R1がハロゲン原子を示し、;及び/又は
(a3)R2が低級アルコキシ基を示し、;及び/又は
(a4)R3が低級アルキル基を示し、;及び/又は
(a5)R4がヒドロキシル基で置換基された低級アルキル基、低級アルコキシ基で置換された低級アルキル基、低級アルコキシ基で置換された低級アルコキシ基で置換された低級アルキル基又はアセトキシ基で置換された低級アルキル基を示す。
(b1)Aがトリメチレン基又は1-メチルトリメチレン基を示し、;及び/又は
(b2)R1が塩素原子を示し、;及び/又は
(b3)R2がメトキシ基を示し、;及び/又は
(b4)R3がイソプロピル基を示し、;及び/又は
(b5)R4が2-ヒドロキシエチル基、2-メトキシ基エチル基、2-エトキシ基エチル基、2-(メトキシメトキシ)エチル基又は2-アセトキシエチル基を示す。
3-アセチル-6-クロロ-2-[2-(3-(N-(2-ヒドロキシエチル)-N-イソプロピルアミノ)プロポキシ)-5-メトキシフェニル]ベンゾチアゾリン、
3-アセチル-6-クロロ-2-[2-(3-(N-イソプロピル-N-(2-メトキシエチル)アミノ)プロポキシ)-5-メトキシフェニル]ベンゾチアゾリン、
3-アセチル-6-クロロ-2-[2-(3-(N-(2-エトキシエチル)-N-イソプロピルアミノ)プロポキシ)-5-メトキシフェニル]ベンゾチアゾリン、
3-アセチル-6-クロロ-2-[2-(3-(N-イソプロピル-N-(2-(メトキシメトキシ)エチル)アミノ)プロポキシ)-5-メトキシフェニル]ベンゾチアゾリン、
2-[2-(3-(N-(2-アセトキシエチル)-N-イソプロピルアミノ)プロポキシ)-5-メトキシフェニル]-3-アセチル-6-クロロベンゾチアゾリン、
3-アセチル-6-クロロ-2-[2-(3-(N-(2-ヒドロキシエチル)-N-イソプロピルアミノ)-1-メチルプロポキシ)-5-メトキシフェニル]ベンゾチアゾリン、
3-アセチル-6-クロロ-2-[2-(3-(N-イソプロピル-N-(2-メトキシエチル)アミノ)-1-メチルプロポキシ)-5-メトキシフェニル]ベンゾチアゾリン、
3-アセチル-6-クロロ-2-[2-(3-(N-(2-エトキシエチル)-N-イソプロピルアミノ)-1-メチルプロポキシ)-5-メトキシフェニル]ベンゾチアゾリン、
3-アセチル-6-クロロ-2-[2-(3-(N-イソプロピル-N-(2-(メトキシメトキシ)エチル)アミノ)-1-メチルプロポキシ)-5-メトキシフェニル]ベンゾチアゾリン、
2-[2-(3-(N-(2-アセトキシエチル)-N-イソプロピルアミノ)-1-メチルプロポキシ)-5-メトキシフェニル]-3-アセチル-6-クロロベンゾチアゾリン、又はそれらの薬学的に許容される塩が挙げられる。
式(II):
式(III):
式(IV):
式(V):
式(VI):
(+)-3-アセチル-6-クロロ-2-[2-(3-(N-(2-エトキシエチル)-N-イソプロピルアミノ)プロポキシ)-5-メトキシフェニル]ベンゾチアゾリン(化合物1)の合成
(+)-3-アセチル-6-クロロ-2-[2-(3-クロロプロポキシ)-5-メトキシフェニル]ベンゾチアゾリン(特許5061134号に記載の参考化合物14-1、5.0g、12mmol)の無水N,N-ジメチルホルムアミド(25mL)溶液に、N-(2-エトキシエチル)イソプロピルアミン(特許5061134号に記載の参考化合物20-1、2.4g、18mmol)の無水N,N-ジメチルホルムアミド(10mL)溶液、炭酸カリウム(3.4g、25mmol)及びヨウ化ナトリウム(3.7g、25mmol)を加え、60℃で終夜撹拌した。反応液に水(200mL)を加え、酢酸エチル(120mL)で抽出した。有機層を水(200mL)、飽和塩化アンモニウム水溶液(200mL)、飽和食塩水(200mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去した後、残渣をシリカゲルカラムクロマトグラフィーで精製することにより、標記化合物4.6gを得た。(収率75%)
1H-NMR(400MHz,CDCl3)δ1.02(d,J=6.6Hz,6H),1.17-1.21(m,3H),1.90-1.97(m,2H),2.14(brs,3H),2.60-2.74(m,4H),2.93-3.00(m,1H),3.44-3.51(m,4H),3.66(s,3H),4.04-4.13(m,2H),6.58-6.60(m,1H),6.75-6.85(m,3H),7.00-7.04(m,1H),7.08(dd,J=2.2,8.5Hz,1H),8.16(brs,1H)
[α]D 20 +513.0(c=1.00,メタノール)
(+)-3-アセチル-6-クロロ-2-[2-(3-(N-(2-エトキシエチル)-N-イソプロピルアミノ)プロポキシ)-5-メトキシフェニル]ベンゾチアゾリン (-)-O,O’-ジアセチル-L-酒石酸塩(化合物2)の合成
(+)-3-アセチル-6-クロロ-2-[2-(3-(N-(2-エトキシエチル)-N-イソプロピルアミノ)プロポキシ)-5-メトキシフェニル]ベンゾチアゾリン(化合物1、7.69g、15.2mmol)に(-)-O,O’-ジアセチル-L-酒石酸(3.56g、15.2mmol)及び酢酸エチル47.5mLを加えて、室温で1時間撹拌した。減圧下で溶媒を留去して得られる残渣を酢酸エチル及びメチルtert-ブチルエーテルを用いて固化させることにより、標記化合物8.95gを得た。(収率79%)
1H-NMR(500MHz,DMSO-d6,70℃)1.08-1.10(m,9H),1.93-2.00(m,2H),2.05(s,6H),2.18(brs,3H),2.85-2.95(m,4H),3.20-3.28(m,1H),3.46(q,J=7.2Hz,2H),3.50-3.54(m,2H),3.60(s,3H),4.05-4.15(m,2H),5.37(s,2H),6.49(d,J=3.1Hz,1H),6.87(dd,J=3.1,8.8Hz,1H),6.97-7.05(m,2H),7.18(dd,J=2.4,8.8Hz,1H),7.31(d,J=2.4Hz,1H),7.97(brs,1H)
[α]D 20 +314.2(c=1.00,メタノール)
本発明における本化合物を配合した製剤の具体例を以下に示す。
錠剤(100mg中)
本化合物 1mg
乳糖 68.4mg
トウモロコシデンプン 20mg
カルボキシメチルセルロースカルシウム 6mg
ヒドロキシプロピルセルロース 4mg
ステアリン酸マグネシウム 0.6mg
カプセル剤(150mg中)
本化合物 5mg
乳糖 145mg
被験化合物2を適量秤量し、ジメチルスルオキサイド(DMSO)に溶解後、培養液を用いて最終濃度になるように調製した。
Luciferase Assayは常法に従って行った(荒谷ら、Mol.Cell.Biol. 21(14): 4460-4469(2001))。すなわち、ATCCより購入したヒト白血病患者より樹立されたJurkat細胞(TIB-152クローン)を常法に従って培養し実験に用いた。Jurkat細胞を2.5×105個になるようにプレートに播種し、Affymetrix/Panomicsより購入した0.5 μgの IL-2 Gene Promoter Reporter Vector、プロメガより購入した5ngのベクターpRL-TKを遺伝子導入試薬であるLipofectamine 2000(Invitrogene)のプロトコールに従ってトランスフェクションした。すなわち、1μgのplasmid に対し、2μlのLipofectamine 2000を使用し、Opti-MEM 中でPlasmidと混ぜ20分後に細胞に添加した。
20分間の反応後、IL-2 Gene Promoter Reporter Vectorを導入したJurkat細胞に、最終濃度が0.3μMとなるようにIL-2の転写活性化剤であるA23187(Sigma)もしくはDMSOを添加し、2.5×105個になるように24穴プレートに播種した。それぞれ最終濃度が0.3μM、1μM、10μMとなるように化合物2を添加し、37℃インキュベーター(設定:37℃、5%CO2/95%空気)で培養した。24時間後細胞を回収し、Passive Lysis Buffer(Promega)に溶解し、Luciferase活性は市販のLuc 活性測定キット(Promega)のDual-Luciferase Reporter Assayを用い、ルミノメーター(BertholdのCentro XS3 LB-960)を用いて測定した。
各実験は3例数で行い、Dual Lusiferase法により補正した。Luc活性値は、測定値をコントロールの値(pRL-TK 活性)で割り、DMSOを添加した時の値を1とした。さらに、下記式に従い、IL-2転写活性化の抑制率を算出した。
抑制率=(1-被験化合物のA23187の刺激ありのLuc活性値/DMSOのA23187の刺激ありのLuc活性値)×100(%)
表1中に結果を示す。Luc値は平均(例数3)を示す。その結果、A23187の刺激によって、IL-2の転写活性化は有意に亢進した。その亢進に対し、化合物2は統計学的に有意な抑制作用を示した。以上の結果から、本発明における本化合物はIL-2転写活性化を抑制し、IL-2産生抑制剤又はIL-2が関与する疾患の予防若しくは治療剤として有用であることが示唆された。
被験化合物3、4、5及び比較化合物アシマドリン、U-50488について、IL-2産生抑制作用(1)と同様に、被験化合物溶液を調製し、IL-2転写抑制活性を測定した。
表2中に結果を示す。化合物3、4及び5は、IL-2の転写活性化を抑制し、それらの抑制率は、同じくκオピオイド受容体アゴニストであるアシマドリン及びU-50488の抑制率より大きかった。以上の結果から、本発明における本化合物はIL-2転写活性化を抑制し、IL-2産生抑制剤又はIL-2が関与する疾患の予防若しくは治療剤として有用であることが示唆された。
Claims (15)
- 一般式(I)で表される化合物が、
式中、
Aが低級アルキレン基を示し;
R1がハロゲン原子を示し;
R2が低級アルコキシ基を示し;
R3が低級アルキル基を示し;そして
R4がヒドロキシル基で置換基された低級アルキル基、低級アルコキシ基で置換された低級アルキル基、低級アルコキシ基で置換された低級アルコキシ基で置換された低級アルキル基又はアセトキシ基で置換された低級アルキル基を示す化合物である、
請求項1に記載のIL-2産生抑制剤。 - 一般式(I)で表される化合物が、
式中、
Aがトリメチレン基又は1-メチルトリメチレン基を示し;
R1が塩素原子を示し;
R2がメトキシ基を示し;
R3がイソプロピル基を示し;そして
R4が2-ヒドロキシエチル基、2-メトキシエチル基、2-エトキシエチル基、2-(メトキシメトキシ)エチル基又は2-アセトキシエチル基を示す化合物である、
請求項1又は2に記載のIL-2産生抑制剤。 - 一般式(I)で表される化合物が、(+)-3-アセチル-6-クロロ-2-[2-(3-(N-(2-エトキシエチル)-N-イソプロピルアミノ)プロポキシ)-5-メトキシフェニル]ベンゾチアゾリン、(±)-3-アセチル-6-クロロ-2-[2-(3-(N-(2-エトキシエチル)-N-イソプロピルアミノ)プロポキシ)-5-メトキシフェニル]ベンゾチアゾリン、(+)-3-アセチル-6-クロロ-2-[2-(3-(N-(2-ヒドロキシエチル)-N-イソプロピルアミノ)プロポキシ)-5-メトキシフェニル]ベンゾチアゾリン又は(+)-3-アセチル-6-クロロ-2-[2-(3-(N-イソプロピル-N-(2-メトキシエチル)アミノ)プロポキシ)-5-メトキシフェニル]ベンゾチアゾリンである、請求項1~3のいずれか1項に記載のIL-2産生抑制剤。
- 一般式(I)で表される化合物の薬学的に許容される塩が、(-)-O,O’-ジアセチル-L-酒石酸塩又は塩酸塩である、請求項1~4のいずれか1項に記載のIL-2産生抑制剤。
- IL-2産生抑制剤が、IL-2が関与する疾患の予防若しくは治療剤である、請求項1~5のいずれか1項に記載のIL-2産生抑制剤。
- IL-2が関与する疾患の予防若しくは治療における使用のための、請求項1に記載の一般式(I)で表わされる化合物又はその薬学的に許容される塩。
- IL-2が関与する疾患の予防若しくは治療用の医薬の製造のための、請求項1に記載の一般式(I)で表わされる化合物又はその薬学的に許容される塩の使用。
- 治療有効量の請求項1に記載の一般式(I)で表わされる化合物又はその薬学的に許容される塩及び賦形剤を含む、IL-2が関与する疾患の予防若しくは治療のための医薬組成物。
- IL-2が関与する疾患の予防若しくは治療のための方法であって、請求項1に記載の一般式(I)で表わされる化合物又はその薬学的に許容される塩の有効量を投与することを含む方法。
- IL-2産生の抑制における使用のための、請求項1に記載の一般式(I)で表わされる化合物又はその薬学的に許容される塩。
- 請求項1に記載の一般式(I)で表わされる化合物又はその薬学的に許容される塩を含む、IL-2産生の抑制のための組成物。
- IL-2産生の抑制のための、請求項1に記載の一般式(I)で表わされる化合物又はその薬学的に許容される塩の使用。
- IL-2産生の抑制のための組成物の製造のための、請求項1に記載の一般式(I)で表わされる化合物又はその薬学的に許容される塩の使用。
- IL-2産生の抑制のための方法であって、請求項1に記載の一般式(I)で表わされる化合物又はその薬学的に許容される塩を投与することを含む方法。
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GB1518757.8A GB2528413B (en) | 2013-03-22 | 2014-03-19 | Inhibition of IL-2 production |
CA2907921A CA2907921C (en) | 2013-03-22 | 2014-03-19 | Inhibition of il-2 production |
US14/778,925 US9650351B2 (en) | 2013-03-22 | 2014-03-19 | Inhibition of IL-2 production |
US15/584,773 US20170231966A1 (en) | 2013-03-22 | 2017-05-02 | Inhibition of il-2 production |
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US15/584,773 Continuation US20170231966A1 (en) | 2013-03-22 | 2017-05-02 | Inhibition of il-2 production |
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JP (1) | JP6275517B2 (ja) |
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WO (1) | WO2014148574A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2018230713A1 (ja) | 2017-06-16 | 2018-12-20 | 学校法人同志社 | カスパーゼ阻害活性を有する化合物、これらの化合物を含む、角膜内皮の症状、障害または疾患を治療または予防するための医薬およびその応用 |
US11433090B2 (en) | 2017-06-16 | 2022-09-06 | The Doshisha | mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof |
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- 2014-03-19 US US14/778,925 patent/US9650351B2/en active Active
- 2014-03-19 GB GB1518757.8A patent/GB2528413B/en active Active
- 2014-03-19 JP JP2014057047A patent/JP6275517B2/ja not_active Expired - Fee Related
- 2014-03-19 WO PCT/JP2014/057597 patent/WO2014148574A1/ja active Application Filing
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2017
- 2017-05-02 US US15/584,773 patent/US20170231966A1/en not_active Abandoned
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018230713A1 (ja) | 2017-06-16 | 2018-12-20 | 学校法人同志社 | カスパーゼ阻害活性を有する化合物、これらの化合物を含む、角膜内皮の症状、障害または疾患を治療または予防するための医薬およびその応用 |
US11433090B2 (en) | 2017-06-16 | 2022-09-06 | The Doshisha | mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof |
Also Published As
Publication number | Publication date |
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CA2907921A1 (en) | 2014-09-25 |
JP2014208611A (ja) | 2014-11-06 |
JP6275517B2 (ja) | 2018-02-07 |
US20160046591A1 (en) | 2016-02-18 |
GB201518757D0 (en) | 2015-12-09 |
US9650351B2 (en) | 2017-05-16 |
CA2907921C (en) | 2021-09-07 |
GB2528413B (en) | 2018-05-23 |
US20170231966A1 (en) | 2017-08-17 |
GB2528413A (en) | 2016-01-20 |
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