WO2010024227A1 - ウレイド基、アミノカルボニル基及び置換基を有してもよい二環式基を置換基として有する新規ピロール誘導体 - Google Patents
ウレイド基、アミノカルボニル基及び置換基を有してもよい二環式基を置換基として有する新規ピロール誘導体 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to a novel pyrrole derivative or a salt thereof having a ureido group, an aminocarbonyl group and a bicyclic group which may have a substituent, which are useful as a medicament, as a substituent.
- the derivative or a salt thereof has an interleukin-6 (hereinafter referred to as “IL-6”) production inhibitory activity, and a prophylactic and / or therapeutic agent for diseases associated with IL-6, particularly ocular inflammatory diseases Useful as.
- IL-6 interleukin-6
- IL-6 is a cytokine found as a B cell differentiation inducing factor, such as antibody production system, induction of biosynthesis of acute phase protein in liver, promotion of hematopoietic stem cell proliferation based on synergistic action with interleukin-3, etc. Has a variety of physiological activities.
- IL-6 production can be controlled, it becomes possible to prevent and / or treat diseases in which IL-6 is involved.
- diseases associated with IL-6 include polyclonal B cell abnormal diseases (intra-atrial myxoma, Castleman syndrome, rheumatoid arthritis, cervical cancer, acquired immune deficiency syndrome, alcoholic cirrhosis, etc.), lymphoid tumors (Multiple myeloma, Rennert T lymphoma, etc.), mesangial proliferative nephritis, renal cell carcinoma, psoriasis and the like are known (Non-patent Document 1).
- Non-patent Documents 2, 3, and 4 More recently, the relationship between IL-6 and ocular inflammatory diseases such as age-related macular degeneration, diabetic retinopathy, and diabetic macular edema has been known (Non-patent Documents 2, 3, and 4).
- Patent Document 1 discloses that a benzimidazole derivative having an EP4 agonistic action inhibits IL-6 production, and anti-IL-6 receptor.
- Non-patent document 5 describes MRA as an antibody.
- Patent Document 6 discloses a pyrrole derivative having an aminocarbonyl group as a substituent as a therapeutic agent for immune / allergic diseases.
- Patent Document 2 discloses a pyrrole derivative having an aminocarbonyl group as a substituent as a therapeutic agent for immune / allergic diseases.
- pyrrole derivatives having both a ureido group and an aminocarbonyl group as substituents are not known, and pyrrole derivatives having a bicyclic group in addition to those substituents are completely unknown compounds. Of course, its use is not known.
- the present inventors have conducted research on the synthesis of a novel pyrrole derivative or a salt thereof having a ureido group, an aminocarbonyl group, and a bicyclic group which may have a substituent as a substituent, and have created many new compounds. Successful.
- the present inventors have found that the derivatives or salts thereof have an IL-6 production inhibitory activity and completed the present invention.
- the present invention relates to a compound represented by the following general formula (1) or a salt thereof (hereinafter referred to as “the present compound”) and a pharmaceutical composition containing at least one of the present compounds as an active ingredient.
- a preferred invention for its pharmaceutical use is an IL-6 production inhibitor containing at least one compound of the present invention as an active ingredient, or a disease associated with IL-6 containing at least one compound of the present invention as an active ingredient
- the present invention relates to a preventive and / or therapeutic agent for ocular inflammatory diseases containing at least one of the compounds of the present invention as an active ingredient.
- the invention of the pharmaceutical composition includes age-related macular degeneration, retinopathy of prematurity, polypoidal choroidal vasculopathy, retinal vein occlusion, diabetic retina containing at least one of the compounds of the present invention as an active ingredient.
- Diabetic macular edema, keratitis, conjunctivitis or uveitis particularly preferably age-related macular degeneration, diabetic retinopathy or diabetes containing at least one compound of the present invention as an active ingredient
- the present invention relates to a preventive and / or therapeutic agent for macular edema.
- R 1 represents a halogen atom, a hydrogen atom, a lower alkyl group which may have a substituent, a formyl group or a lower alkylcarbonyl group which may have a substituent
- R 2 represents a bicyclic hydrocarbon group which may have a substituent or a bicyclic heterocyclic group which may have a substituent
- R 3 represents a hydrogen atom, a lower alkyl group which may have a substituent, an aryl group or an acyl group which may have a substituent. same as below.
- the present invention provides a novel pyrrole derivative or a salt thereof having a ureido group, an aminocarbonyl group and a bicyclic group which may have a substituent as a substituent.
- the compound of the present invention has an excellent IL-6 production inhibitory activity and is an IL-6 production inhibitor, a preventive and / or therapeutic agent for diseases associated with IL-6, and a prophylactic and / or therapeutic agent for ocular inflammatory diseases Useful as an agent.
- a preventive and / or therapeutic agent for age-related macular degeneration retinopathy of prematurity, polypoidal choroidal vasculopathy, retinal vein occlusion, diabetic retinopathy, diabetic macular edema, keratitis, conjunctivitis or uveitis Useful as.
- Halogen atom refers to a fluorine, chlorine, bromine or iodine atom.
- “Lower alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl groups and the like.
- “Lower alkenyl group” refers to a straight or branched alkenyl group having 2 to 6 carbon atoms. Specific examples include vinyl, propenyl, butenyl, pentenyl, hexenyl, ethylpropenyl, methylbutenyl groups and the like.
- “Lower cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl groups and the like.
- Aryl group means a residue obtained by removing one hydrogen atom from a monocyclic aromatic hydrocarbon group having 6 to 14 carbon atoms or a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon Indicates. Specific examples include phenyl, naphthyl, anthryl, phenanthryl group and the like.
- lower alkoxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkyl group. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy group and the like.
- “Lower cycloalkyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower cycloalkyl group. Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy groups and the like.
- Aryloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with an aryl group. Specific examples include phenoxy, naphthoxy, anthryloxy, phenanthryloxy groups and the like.
- “Lower alkylcarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkyl group. Specific examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, isopentylcarbonyl group. Etc.
- “Acyl group” refers to —C (O) —R t .
- Rt represents a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, an aryl group or a heterocyclic group.
- Heterocycle means a saturated or unsaturated monocyclic heterocycle having one or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring, or a bicyclic or tricyclic fused ring Indicates a polycyclic heterocycle.
- saturated monocyclic heterocycles include pyrrolidine, pyrazolidine, imidazolidine, triazolidine, piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine, homopiperidine, homopiperazine ring having a nitrogen atom in the ring, oxygen, Tetrahydrofuran, tetrahydropyran ring, etc. having an atom in the ring, tetrahydrothiophene, tetrahydrothiopyran ring, etc. having a sulfur atom in the ring, oxazolidine, isoxazolidine, morpholine ring, etc. having a nitrogen atom and an oxygen atom in the ring And thiazolidine, isothiazolidine, and thiomorpholine rings having nitrogen and sulfur atoms in the ring.
- these saturated monocyclic heterocycles are condensed with a benzene ring or the like to form dihydroindole, dihydroindazole, dihydrobenzimidazole, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydrocinnoline, tetrahydrophthalazine, tetrahydroquinazoline, tetrahydroquinoxaline, dihydroquinone.
- the unsaturated monocyclic heterocycle include dihydropyrrole, pyrrole, dihydropyrazole, pyrazole, dihydroimidazole, imidazole, dihydrotriazole, triazole, tetrahydropyridine, dihydropyridine, pyridine, tetrahydropyridazine having a nitrogen atom in the ring, Dihydropyridazine, pyridazine, tetrahydropyrimidine, dihydropyrimidine, pyrimidine, tetrahydropyrazine, dihydropyrazine, pyrazine, triazine ring, etc., dihydrofuran, furan, dihydropyran, pyran ring, etc.
- dihydrooxazole having an oxygen atom in the ring ring a sulfur atom Dihydrothiophene, thiophene, dihydrothiopyran, thiopyran ring, etc. in the dihydrooxazole, oxazole, dihydro having nitrogen and oxygen atoms in the ring Sookisazoru, isoxazole, dihydro-oxazine, oxazine rings and the like, dihydrothiazole having a nitrogen atom and a sulfur atom in the ring, thiazole, dihydro-isothiazole, isothiazole, dihydrothiazine, thiazine ring, and the like.
- these unsaturated monocyclic heterocycles are condensed with a benzene ring or the like to form indole, indazole, benzimidazole, benzotriazole, dihydroquinoline, quinoline, dihydroisoquinoline, isoquinoline, phenanthridine, dihydrocinnoline, cinnoline, Dihydrophthalazine, phthalazine, dihydroquinazoline, quinazoline, dihydroquinoxaline, quinoxaline, benzofuran, isobenzofuran, chromene, isochromene, benzothiophene, isobenzothiophene, thiochromene, isothiochromene, benzoxazole, benzoisoxazole, benzoxazine, benzothiazole, benzo Isothiazole, benzothiazine, phenoxanthine, carbazole, ⁇ -carboline,
- pyrrolidine, piperidine, piperazine, morpholine, dihydroindole, pyrrole, pyridine, pyrazine, furan, thiophene, pyran, isoxazole or thiazole ring are preferable, and pyrrolidine, piperidine, piperazine, morpholine, A pyridine, pyrazine or thiophene ring is preferred.
- Heterocyclic group means a residue obtained by removing one hydrogen atom from a heterocyclic ring.
- Heterocyclic oxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a heterocyclic group.
- Nonrogen-containing heterocycle refers to a ring containing one or more nitrogen atoms in the heterocycle. Specific examples include pyrrolidine, piperidine, piperazine, homopiperazine, morpholine, pyrrole, pyridine ring and the like.
- Bicyclic hydrocarbon group refers to a residue obtained by removing one hydrogen atom from a bicyclic hydrocarbon formed of 8 to 10 carbon atoms. Specific examples include a naphthalene ring group, a dihydronaphthalene ring group, a tetrahydronaphthalene ring group, an octatetrahydronaphthalene ring group, an indene ring group, an indane ring group, and an azulene ring group.
- Bicyclic heterocyclic group means a hydrogen atom removed from a bicyclic hydrocarbon formed of one or more selected from a nitrogen atom, an oxygen atom and a sulfur atom and from 5 to 9 carbon atoms. Residues. Specific examples include indole ring group, dihydroindole ring group, indazole ring group, benzimidazole ring group, quinoline ring group, dihydroquinoline ring group, tetrahydroquinoline ring group, isoquinoline ring group, phthalazine ring group, quinazoline ring group, quinoxaline ring.
- the “lower alkyl group optionally having substituent (s)” and / or the “lower alkylcarbonyl group optionally having substituent (s)” are halogen atom, lower cycloalkyl group, aryl group, heterocyclic group, hydroxy group , A lower alkoxy group, a lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a nitro group, a cyano group and one or more substituents selected from the group consisting of —NR u R v “Lower alkyl group” and / or “lower alkylcarbonyl group” are shown.
- Aryl group optionally having substituent (s) “Bicyclic hydrocarbon group optionally having substituent (s)” and / or “Bicyclic heterocyclic group optionally having substituent (s)” , Halogen atom, lower alkyl group, lower cycloalkyl group, aryl group, heterocyclic group, hydroxy group, lower alkoxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, carbonyl group (oxo group), nitro
- substituents selected from the group consisting of a group, a cyano group, and —NR u R v which may have a “aryl group that may have a substituent”, “may have a substituent A “good bicyclic hydrocarbon group” and / or “an optionally substituted bicyclic heterocyclic group”.
- R u and R v are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group or a heterocyclic group, and R u and R v together form a nitrogen-containing group.
- a heterocycle may be formed.
- plural substituents refers to the maximum number that can be substituted, which may be the same or different, and the number is 2 and / or 3 Is particularly preferable.
- group includes “atom”, “group”, “ring” and the like defined above.
- IL-6 production inhibitor refers to a compound that exhibits a pharmaceutical action by inhibiting the production of IL-6.
- “Ocular inflammatory disease” as used herein refers to age-related macular degeneration, retinopathy of prematurity, polypoidal choroidal vasculopathy, retinal vein occlusion, diabetic retinopathy, diabetic macular edema, keratitis, conjunctivitis, uveitis, etc. However, preferably, age-related macular degeneration, diabetic retinopathy or diabetic macular edema is used.
- the “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or the like.
- Salt with organic acid quaternary ammonium salt with methyl bromide, methyl iodide, bromine ion, chloride ion
- the compound of the present invention may be in the form of a hydrate or a solvate.
- crystal polymorphism system When the compound of the present invention has crystal polymorphism and / or crystal polymorphism group (crystal polymorphism system), those crystal polymorphism and / or crystal polymorphism group (crystal polymorphism system) are also included in the present invention.
- the crystal polymorph group means a crystal form depending on conditions and / or states (including the formulated state in this state) such as production, crystallization, and storage of the crystals. Means the individual crystal form and / or the whole process at each stage when.
- R 1 represents a halogen atom, a hydrogen atom, an optionally substituted lower alkyl group, a formyl group or an optionally substituted lower alkylcarbonyl group; and / or (a2) R 2 Represents a bicyclic hydrocarbon group which may have a substituent or a bicyclic heterocyclic group which may have a substituent; and / or (a3) R 3 has a hydrogen atom or a substituent.
- the lower alkyl group which may be substituted, the aryl group which may have a substituent, or the acyl group is shown.
- R 1 represents a halogen atom or a hydrogen atom
- R 2 represents a bicyclic hydrocarbon group which may have a substituent or a bicyclic hetero ring which may have a substituent.
- R 3 represents a hydrogen atom.
- a compound or a salt thereof comprising one or more combinations selected from the above (b1), (b2) and / or (b3) can be mentioned. Further, the selected condition can be combined with the condition (a).
- Preferred examples of the bicyclic hydrocarbon group in the compound of the present invention include a case of showing a naphthalene ring group or a tetrahydronaphthalene ring group. Further, the selected condition can be combined with the condition (a) and / or (b).
- Examples of preferable bicyclic heterocyclic group in the compound of the present invention include indole ring group, benzofuran ring group, dihydrobenzofuran ring group, benzodioxole ring group, dihydrobenzodioxin ring group, benzothiophene ring group, benzo Examples include an oxazine ring group, a benzothiazole ring group, or a benzothiazine ring group. Further, the selected condition can be combined with the condition (a) and / or (b).
- the compound of the present invention can be produced by the following method.
- each specific manufacturing method is demonstrated in detail by the below-mentioned Example [section of a manufacturing example].
- Hal used in the following synthesis route represents a halogen atom.
- the method for producing the compound of the present invention can be roughly divided into the following methods, and the method can be appropriately selected according to the type of the substituent.
- the compound (I) of the present invention can be produced according to synthesis route 1. That is, compound (II) and trichloroacetyl isocyanate are -80 ° C. to room temperature in an organic solvent such as tetrahydrofuran (hereinafter referred to as “THF”), N, N-dimethylformamide (hereinafter referred to as “DMF”) or the like. After reacting for 1 to 3 hours, an ammonia-methanol solution is further added, and the reaction is continued from 0 ° C. to room temperature for 1 to 72 hours to obtain the compound (I) of the present invention.
- THF tetrahydrofuran
- DMF N, N-dimethylformamide
- Compound (II)-(a) can be produced according to Synthesis route 2-1. That is, compound (III) is treated in an organic solvent such as methylene chloride and THF in the presence of a halogenating agent such as phenyltrimethylammonium tribromide and N-bromosuccinimide at 0 to 60 ° C. for 1 to 24 hours. Thus, compound (IV) can be obtained. The resulting compound (IV) and malonamamidine (V) are reacted in an organic solvent such as ethanol or DMF in the presence of a base such as sodium ethoxide or potassium carbonate at 0 to 80 ° C. for 1 to 48 hours. II)-(a) can be obtained.
- Compound (II)-(b) can be produced according to Synthesis route 2-2. That is, the compound (II)-(c) and an alkyl halide or aryl halide (VI) in an organic solvent such as THF or DMF in the presence of a base such as sodium hydroxide or sodium hydride at 0 ° C. to 100 ° C. Compound (II)-(b) can be obtained by reacting for 1 to 24 hours.
- the compound (I)-(a) of the present invention can be produced according to the synthesis route 3. That is, the compound (I)-(b) of the present invention is heated at room temperature to 80 ° C. in an organic solvent such as methylene chloride and DMF in the presence of a halogenating agent such as N-chlorosuccinimide and N-bromosuccinimide.
- a halogenating agent such as N-chlorosuccinimide and N-bromosuccinimide.
- the compound (I)-(a) of the present invention can be obtained by treating for 24 hours.
- the compound of the present invention produced by the above synthetic route can be made into the above-mentioned salt, hydrate or solvate form using a widely used technique.
- the compound of the present invention has excellent IL-6 production inhibitory activity. Therefore, the compound of the present invention is useful as an IL-6 inhibitor. Further, as described above, since IL-6 is involved in the expression of various diseases, the compound of the present invention having IL-6 inhibitory activity is used as a preventive and / or therapeutic agent for diseases in which IL-6 is involved. Useful.
- preventive and / or therapeutic agents for ocular inflammatory diseases in particular, age-related macular degeneration, retinopathy of prematurity, polypoidal choroidal vasculopathy, retinal vein occlusion, diabetic retinopathy, diabetic macular edema, It is useful as a preventive and / or therapeutic agent for keratitis, conjunctivitis, and uveitis.
- the compound of the present invention can be administered orally or parenterally.
- dosage forms include oral administration, topical ocular administration (instillation administration, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, subtenon administration, etc.), intravenous administration, transdermal administration, etc.
- a pharmaceutically acceptable additive can be appropriately selected and used, and can be formulated into a dosage form suitable for the dosage form.
- Examples of the dosage form include tablets, capsules, granules, powders, and the like in the case of oral preparations, and examples of parenteral preparations include injections, eye drops, eye ointments, and insertion agents.
- excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose; carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium Disintegrating agents such as hydroxypropyl cellulose, ethyl cellulose, gum arabic, starch, partially pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol; stearic acid Lubricants such as magnesium, calcium stearate, talc, hydrous silicon dioxide, hydrogenated oil; refined white sugar, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcell Over scan, ethylcellulose, coating agents such as polyvinyl pyrrolidone; citric acid, aspartame, ascorbic acid, selected and used as necessary flavoring agent such as menthol, etc. can be formulated.
- excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, suc
- Injections are appropriately selected as needed, such as isotonic agents such as sodium chloride; buffering agents such as sodium phosphate; surfactants such as polyoxyethylene sorbitan monooleate; thickeners such as methylcellulose. Can be used and formulated.
- isotonic agents such as sodium chloride
- buffering agents such as sodium phosphate
- surfactants such as polyoxyethylene sorbitan monooleate
- thickeners such as methylcellulose.
- Eye drops include isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surface activity such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil Agents: Stabilizers such as sodium citrate and sodium edetate; preservatives such as benzalkonium chloride and paraben can be appropriately selected and used as necessary, and the pH is ophthalmic. As long as it is within the range acceptable for pharmaceutical preparations, there is no particular problem, and a pH range of 4 to 8 is desirable.
- Ophthalmic ointment can be formulated using a widely used base such as white petrolatum or liquid paraffin.
- the intercalator can be formulated using biodegradable polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid, etc., if necessary, excipients, binders, stable An agent, a pH adjuster, and the like can be appropriately selected and used as necessary.
- biodegradable polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid, etc., if necessary, excipients, binders, stable
- An agent, a pH adjuster, and the like can be appropriately selected and used as necessary.
- the intraocular implant preparation can be formulated using a biodegradable polymer such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, hydroxypropyl cellulose, etc. , Binders, stabilizers, pH adjusters and the like can be appropriately selected and used as necessary.
- a biodegradable polymer such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, hydroxypropyl cellulose, etc.
- Binders, stabilizers, pH adjusters and the like can be appropriately selected and used as necessary.
- the dose of the compound of the present invention can be appropriately selected according to the dosage form, patient symptoms, age, body weight and the like.
- 0.01 to 5000 mg, preferably 0.1 to 2500 mg, particularly preferably 0.5 to 1000 mg can be administered in 1 to several times per day.
- 0.00001 to 2000 mg, preferably 0.0001 to 1500 mg, particularly preferably 0.001 to 500 mg can be administered in 1 to several times per day.
- 0.00001 to 10% (w / v), preferably 0.0001 to 5% (w / v), particularly preferably 0.001 to 1% is applied once to several times a day. can do.
- one containing 0.0001 to 2000 mg can be applied.
- an insertion agent or a preparation for intraocular implant one containing 0.0001 to 2000 mg can be inserted or implanted.
- Reference Example 1-1 2-Amino-5- (2-naphthyl) pyrrole-3-carboxamide (Reference compound 1-1) Under ice cooling, sodium ethoxide (2.7 g, 40 mmol) was added to a suspension of malonamamidine hydrochloride (5.5 g, 40 mmol) in dehydrated ethanol (130 mL), and the mixture was stirred for 20 minutes. Further 2-bromoacetylnaphthalene (5.0 g, 20 mmol) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title reference compound (1.5 g) as a black solid (yield 30%).
- N-dimethylformamide 40 mL was added malonamamidine hydrochloride (1.5 g, 11 mmol) and potassium carbonate (1.5 g, 11 mmol), and the mixture was stirred at 60 ° C. overnight. After allowing to cool, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL ⁇ 2). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title reference compound (0.33 g) as a green-black solid (yield 23%).
- Reference compounds 1-3 to 20 were obtained using commercially available compounds and reference compounds 3-1 and 6-1 according to the production method of reference compound 1-1 or 1-2.
- Reference example 2 5'-Chloro-2 '-(2-methyl-2-propenyloxy) acetophenone (Reference compound 2-1) 5'-chloro-2'-hydroxyacetophenone (0.86 g, 5.0 mmol), potassium carbonate (1.4 g, 10 mmol) and 3-bromo-2-methylpropene (0.56 mL, 5.5 mmol) in anhydrous N , N-dimethylformamide (20 mL) suspension was stirred at 60 ° C. for 4 hours. After allowing to cool, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL).
- Reference example 3 7-acetyl-5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran (reference compound 3-1)
- 5-chloro-2- (2-methyl-2-propenyloxy) acetophenone Reference compound 2-1, 6.6 g, 29 mmol
- aluminum chloride 6.0 g, 45 mmol
- Reference example 4 3′-Bromo-2 ′-(2-bromoethoxy) -5′-chloroacetophenone (Reference Compound 4-1) 3′-bromo-5′-chloro-2′-hydroxyacetophenone (2.4 g, 10 mmol), potassium carbonate (2.8 g, 20 mmol) and 1,2-dibromoethane (3.5 mL, 41 mmol) in anhydrous N, A suspension of N-dimethylformamide (30 mL) was stirred at 50 ° C. overnight. After allowing to cool, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL).
- Reference Example 5 2- [3-Bromo-2- (2-bromoethoxy) -5-chlorophenyl] -2,5,5-trimethyl-1,3-dioxane (Reference compound 5-1) 3′-bromo-2 ′-(2-bromoethoxy) -5′-chloroacetophenone (Reference compound 4-1, 4.4 g, 10 mmol), neopentyl glycol (1.2 g, 12 mmol) and p-toluenesulfonic acid A solution of monohydrate (0.22 g, 1.2 mmol) in anhydrous toluene (50 mL) was stirred overnight with heating under reflux.
- Reference Example 6 7-acetyl-5-chloro-2,3-dihydrobenzofuran (reference compound 6-1) Of 2- [3-bromo-2- (2-bromoethoxy) -5-chlorophenyl] -2,5,5-trimethyl-1,3-dioxane (reference compounds 5-1, 2.8 g, 6.3 mmol)
- an anhydrous tetrahydrofuran (30 mL) solution an n-butyllithium-hexane solution (1.6 M, 4.7 mL, 7.6 mmol) was added dropwise at ⁇ 70 ° C. over 5 minutes, and the mixture was stirred for 1.5 hours.
- the mixture was further stirred for 1 hour under ice cooling and overnight at room temperature.
- the reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL).
- the organic layer was washed with saturated aqueous ammonium chloride solution (50 mL), saturated aqueous sodium hydrogen carbonate (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate.
- the solvent was distilled off under reduced pressure, and tetrahydrofuran (30 mL), methanol (5 mL) and 1N hydrochloric acid (30 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 5 hours.
- the reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was collected by filtration with hexane (10 mL) to obtain the title reference compound (0.31 g) as a pale yellow solid (yield 25%).
- Example 1 2-Aminocarbonylamino-5- (2-naphthyl) pyrrole-3-carboxamide (Compound 1-1) To a solution of 2-amino-5- (2-naphthyl) pyrrole-3-carboxamide (Reference compound 1-1, 1.0 g, 4.0 mmol) in anhydrous tetrahydrofuran (20 mL) at ⁇ 30 ° C., trichloroacetyl isocyanate (470 ⁇ L) was added. 4.0 mmol) was added dropwise over 5 minutes and stirred for 1.5 hours. Further, 2.0 M ammonia-methanol solution (20 mL, 40 mmol) was added, and the mixture was stirred at room temperature for 3 days.
- a tablet of the above formulation can be coated with 3 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the intended tablet.
- a coating agent for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.
- a desired tablet can also be obtained by changing suitably the kind and / or quantity of this invention compound and an additive.
- Capsule (in 150mg) The compound of the present invention 5mg Lactose 135mg Carboxymethylcellulose calcium 4.5mg Hydroxypropylcellulose 4mg Magnesium stearate 1.5mg Desired capsules can be obtained by appropriately changing the type and / or amount of the compound of the present invention and additives.
- Eye drops (in 100ml) Compound of the present invention 100mg Sodium chloride 900mg Polysorbate 80 500mg Sodium hydroxide appropriate amount Hydrochloric acid appropriate amount Sterilized purified water appropriate amount Desired eye drops can be obtained by appropriately changing the type and / or amount of the compound of the present invention and additives.
- IL-6 Production Inhibitory Activity Measurement Test The inhibitory effect on TNF ⁇ -induced IL-6 production from human normal skin fibroblast-derived CCD-1059Sk cells (ATCC No. CRL-2072) was evaluated. The amount of IL-6 was measured by a homogeneous time-resolved fluorescence method using HTRF TM Human IL-6 kit (manufactured by Sysbio International, catalog number 62IL6PEB). The specific test method is described below.
- test compound solution After dissolving the test compound in dimethyl sulfoxide, this solution was added to a D-MEM medium (hereinafter referred to as “medium”) containing 0.1% inactivated fetal bovine serum, 0.1 mM MEM non-essential amino acid solution, 100 U / mL penicillin and 100 ⁇ g / mL streptomycin. And a 40 ⁇ M test compound solution was prepared.
- medium D-MEM medium
- test compound was added to each well.
- IL-6 production inhibition rate (%) was calculated by the following formula.
- IL-6 production inhibition rate (%) 100 ⁇ ⁇ 1 ⁇ (IL-6 amount of test compound ⁇ background IL-6 amount) / (control IL-6 amount ⁇ background IL-6 amount) ⁇ (Evaluation results) As an example of the evaluation result, IL-6 production inhibition rate (%) of the test compound (compounds 1-1, 1-5, 1-6, 1-8, 1-12, 1-15 and 3-1) at 10 ⁇ M Are shown in Table I.
- the compounds of the present invention showed excellent IL-6 production inhibitory activity. Therefore, the compound of the present invention can be used as an IL-6 production inhibitor and is useful as a preventive and / or therapeutic agent for diseases associated with IL-6, ocular inflammatory diseases and the like.
- the present invention provides a novel pyrrole derivative or a salt thereof having, as a substituent, a ureido group, an aminocarbonyl group and a bicyclic group which may have a substituent.
- the compound of the present invention has an excellent IL-6 production inhibitory activity and is an IL-6 production inhibitor, a preventive and / or therapeutic agent for diseases associated with IL-6, and a prophylactic and / or therapeutic agent for ocular inflammatory diseases Useful as an agent.
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Abstract
Description
R2は置換基を有してもよい二環式炭化水素基又は置換基を有してもよい二環式複素環基を示し;
R3は水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよいアリール基又はアシル基を示す。以下、同じ。]
(a2)R2は置換基を有してもよい二環式炭化水素基又は置換基を有してもよい二環式複素環基を示し;及び/又は
(a3)R3は水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよいアリール基又はアシル基を示す。
(b2)R2が置換基を有してもよいニ環式炭化水素基又は置換基を有してもよいニ環式複素環基を示し;及び/又は
(b3)R3が水素原子を示す。
参考例1-1
2-アミノ-5-(2-ナフチル)ピロール-3-カルボキサミド(参考化合物1-1)
氷冷下、マロナムアミジン塩酸塩(5.5g、40mmol)の脱水エタノール(130mL)懸濁液にナトリウムエトキシド(2.7g、40mmol)を加え、20分間撹拌した。さらに2-ブロモアセチルナフタレン(5.0g、20mmol)を加え、室温で一晩撹拌した。反応液を減圧濃縮し、得られた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、標記参考化合物(1.5g)を黒色固体として得た(収率30%)。
2-アミノ-5-(7-メトキシベンゾフラン-2-イル)ピロール-3-カルボキサミド(参考化合物1-2)
2-アセチル-7-メトキシベンゾフラン(1.0g、5.3mmol)の無水テトラヒドロフラン(25mL)溶液にフェニルトリメチルアンモニウムトリブロミド(2.0g、5.3mmol)を加え、室温で4時間撹拌した。不溶物を濾去した後、濾液を減圧濃縮することにより、2-ブロモアセチル-7-メトキシベンゾフランを含む混合物を得た。この混合物の無水N,N-ジメチルホルムアミド(40mL)溶液にマロナムアミジン塩酸塩(1.5g、11mmol)及び炭酸カリウム(1.5g、11mmol)を加え、60℃で一晩撹拌した。放冷後、反応液を水(200mL)で希釈し、酢酸エチル(100mL×2回)で抽出した。有機層を飽和食塩水(100mL)で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた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、標記参考化合物(0.33g)を緑黒色固体として得た(収率23%)。
5’-クロロ-2’-(2-メチル-2-プロペニルオキシ)アセトフェノン(参考化合物2-1)
5'-クロロ-2'-ヒドロキシアセトフェノン(0.86g、5.0mmol)、炭酸カリウム(1.4g、10mmol)及び3-ブロモ-2-メチルプロペン(0.56mL、5.5mmol)の無水N,N-ジメチルホルムアミド(20mL)懸濁液を60℃で4時間撹拌した。放冷後、反応液を水(100mL)で希釈し、酢酸エチル(100mL)で抽出した。有機層を飽和塩化アンモニウム水溶液(50mL)及び飽和食塩水(50mL)で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去することにより、標記参考化合物(1.1g)を橙色油状物として得た(収率96%)。
7-アセチル-5-クロロ-2,2-ジメチル-2,3-ジヒドロベンゾフラン(参考化合物3-1)
5-クロロ-2-(2-メチル-2-プロペニルオキシ)アセトフェノン(参考化合物2-1、6.6g、29mmol)の無水ジクロロメタン(200mL)溶液に、-70℃で塩化アルミニウム(6.0g、45mmol)を加え、1時間撹拌した。ゆっくりと-40℃まで昇温し、さらに1時間撹拌した。反応液に水(200mL)を加え、クロロホルム(100mL)で抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、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、標記参考化合物(1.1g)を無色固体として得た(収率17%)。
3’-ブロモ-2’-(2-ブロモエトキシ)-5’-クロロアセトフェノン(参考化合物4-1)
3'-ブロモ-5'-クロロ-2'-ヒドロキシアセトフェノン(2.4g、10mmol)、炭酸カリウム(2.8g、20mmol)及び1,2-ジブロモエタン(3.5mL、41mmol)の無水N,N-ジメチルホルムアミド(30mL)懸濁液を50℃で一晩撹拌した。放冷後、反応液を水(100mL)で希釈し、酢酸エチル(100mL)で抽出した。有機層を飽和塩化アンモニウム水溶液(50mL×2回)及び飽和食塩水(50mL)で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去することにより、標記参考化合物(4.4g)を橙色油状物として得た(定量的)。
2-[3-ブロモ-2-(2-ブロモエトキシ)-5-クロロフェニル]-2,5,5-トリメチル-1,3-ジオキサン(参考化合物5-1)
3'-ブロモ-2'-(2-ブロモエトキシ)-5'-クロロアセトフェノン(参考化合物4-1、4.4g、10mmol)、ネオペンチルグリコール(1.2g、12mmol)及びp-トルエンスルホン酸1水和物(0.22g、1.2mmol)の無水トルエン(50mL)溶液を加熱還流下で一晩撹拌した。放冷後、反応液に酢酸エチル(50mL)及び飽和重曹水(100mL)を加え、分配した。有機層を飽和食塩水(50mL)で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、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、標記参考化合物(2.8g)を薄黄色油状物として得た(収率63%)。
7-アセチル-5-クロロ-2,3-ジヒドロベンゾフラン(参考化合物6-1)
2-[3-ブロモ-2-(2-ブロモエトキシ)-5-クロロフェニル]-2,5,5-トリメチル-1,3-ジオキサン(参考化合物5-1、2.8g、6.3mmol)の無水テトラヒドロフラン(30mL)溶液に、-70℃でn-ブチルリチウム-へキサン溶液(1.6M、4.7mL、7.6mmol)を5分間で滴下し、1.5時間撹拌した。さらに氷冷下で1時間、室温で一晩撹拌した。反応液を水(50mL)で希釈し、酢酸エチル(50mL)で抽出した。有機層を飽和塩化アンモニウム水溶液(50mL)、飽和重曹水(50mL)及び飽和食塩水(50mL)で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣にテトラヒドロフラン(30mL)、メタノール(5mL)及び1N塩酸(30mL)を加え、室温で5時間撹拌した。反応液を水(50mL)で希釈し、酢酸エチル(50mL)で抽出した。有機層を飽和重曹水(50mL)及び飽和食塩水(50mL)で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた固体をヘキサン(10mL)で濾取することにより、標記参考化合物(0.31g)を黄白色固体として得た(収率25%)。
2-アミノカルボニルアミノ-5-(2-ナフチル)ピロール-3-カルボキサミド(化合物1-1)
2-アミノ-5-(2-ナフチル)ピロール-3-カルボキサミド(参考化合物1-1、1.0g、4.0mmol)の無水テトラヒドロフラン(20mL)溶液に、-30℃でイソシアン酸トリクロロアセチル(470μL、4.0mmol)を5分間で滴下し、1.5時間撹拌した。さらに2.0Mアンモニア-メタノール溶液(20mL、40mmol)を加え、室温で3日間撹拌した。析出した固体を濾取し、ジエチルエーテル-エタノール(3:1)混合溶媒(20mL)で洗浄した。固体を40℃減圧下で乾燥することにより、標記化合物(0.67g)を灰白色固体として得た(収率58%)。
2-アミノカルボニルアミノ-4-クロロ-5-(2-ナフチル)ピロール-3-カルボキサミド(化合物2-1)
2-アミノカルボニルアミノ-5-(2-ナフチル)ピロール-3-カルボキサミド(化合物1-1、92mg、0.31mmol)及びN-クロロこはく酸イミド(46mg、0.34mmol)の無水N,N-ジメチルホルムアミド(2mL)溶液を60℃で2時間撹拌した。放冷後、水(10mL)を加えて析出した固体を濾取し、水(10mL)及びアセトン(10mL)で洗浄した。固体を50℃減圧下で乾燥することにより、標記化合物(46mg)を薄褐色固体として得た(収率45%)。
2-アミノカルボニルアミノ-5-(2,3-ジヒドロベンゾフラン-7-イル)ピロール-3-カルボキサミド(化合物3-1)
2-アミノカルボニルアミノ-5-(5-ブロモ-2,3-ジヒドロベンゾフラン-7-イル)ピロール-3-カルボキサミド(化合物1-7、45mg、0.12mmol)のメタノール-無水N,N-ジメチルホルムアミド(2:1)懸濁液(1.5mL)に10%パラジウム炭素(0.01g)を加え、水素雰囲気下室温で一晩撹拌した。不溶物を濾去後、濾液を減圧濃縮し、残渣に水(5mL)を加えた。析出した固体を濾取し、水(5mL)で洗浄した。固体を40℃減圧下で乾燥することにより、標記化合物(21mg)を桃色固体として得た(収率60%)。
本発明化合物の代表的な製剤例を以下に示す。
本発明化合物 1mg
乳糖 100mg
トウモロコシデンプン 40mg
カルボキシメチルセルロースカルシウム 4.5mg
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 0.5mg
上記処方の錠剤にコーティング剤(例えば、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコーン樹脂等の通常のコーティング剤)3mgを用いてコーティングを施し、目的とする錠剤を得ることができる。また、本発明化合物並びに添加物の種類及び/又は量を適宜変更することで、所望の錠剤を得ることもできる。
本発明化合物 5mg
乳糖 135mg
カルボキシメチルセルロースカルシウム 4.5mg
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 1.5mg
本発明化合物並びに添加剤の種類及び/又は量を適宜変更することで、所望のカプセル剤を得ることができる。
本発明化合物 100mg
塩化ナトリウム 900mg
ポリソルベート80 500mg
水酸化ナトリウム 適量
塩酸 適量
滅菌精製水 適量
本発明化合物及び添加物の種類及び/又は量を適宜変更することで、所望の点眼剤を得ることができる。
1.IL-6産生阻害活性測定試験
ヒト正常皮膚線維芽細胞由来CCD-1059Sk細胞(ATCC番号CRL-2072)からのTNFα誘発IL-6産生に対する阻害効果を評価した。IL-6量は、HTRFTM Human IL-6キット(シスバイオ・インターナショナル社製、カタログ番号62IL6PEB)を使用し、ホモジニアス時間分解蛍光法にて測定した。以下にその具体的な試験方法を記載する。
被験化合物をジメチルスルホキシドに溶解した後、この溶液を0.1%非働化ウシ胎児血清、0.1mM MEM非必須アミノ酸溶液、100U/mLペニシリン及び100μg/mLストレプトマイシンを含むD-MEM培地(以下、「培地」とする)で希釈して40μM被験化合物溶液を調製した。
1)3×105cells/mLに調整したCCD-1059Sk細胞を384ウェルプレートへ10μLずつ播種して3×103cells/wellとした。
IL-6産生阻害率(%)は以下の式により算出した。
(評価結果)
評価結果の一例として、被験化合物(化合物1-1、1-5、1-6、1-8、1-12、1-15及び3-1)の10μMにおけるIL-6産生阻害率(%)を表Iに示す。
Claims (14)
- 一般式(1)において、
R1がハロゲン原子又は水素原子を示し;
R2が置換基を有してもよいニ環式炭化水素基又は置換基を有してもよいニ環式複素環基を示し;
R3が水素原子を示す請求項1記載の化合物又はその塩。 - 一般式(1)において、
R2が置換基を有してもよいニ環式炭化水素基である場合、該ニ環式炭化水素基がナフタレン環基又はテトラヒドロナフタレン環基である請求項2記載の化合物又はその塩。 - 一般式(1)において、
R2が置換基を有してもよいニ環式複素環基である場合、該ニ環式複素環基がインドール環基、ベンゾフラン環基、ジヒドロベンゾフラン環基、ベンゾジオキソール環基、ジヒドロベンゾジオキシン環基、ベンゾチオフェン環基、ベンゾオキサジン環基、ベンゾチアゾール環基又はベンゾチアジン環基である請求項2記載の化合物又はその塩。 - ・2-アミノカルボニルアミノ-5-(2-ナフチル)ピロール-3-カルボキサミド、
・2-アミノカルボニルアミノ-5-(ベンゾフラン-2-イル)ピロール-3-カルボキサミド、
・2-アミノカルボニルアミノ-5-(ベンゾチオフェン-5-イル)ピロール-3-カルボキサミド、
・2-アミノカルボニルアミノ-5-(ベンゾフラン-5-イル)ピロール-3-カルボキサミド、
・2-アミノカルボニルアミノ-5-(2,3-ジヒドロ-1,4-ベンゾジオキシン-5-イル)ピロール-3-カルボキサミド、
・2-アミノカルボニルアミノ-5-(3-メチルベンゾチオフェン-2-イル)ピロール-3-カルボキサミド、及び
・2-アミノカルボニルアミノ-5-(2,3-ジヒドロベンゾフラン-7-イル)ピロール-3-カルボキサミドから選択される化合物又はその塩。 - 請求項1~4のいずれか1記載の化合物又はその塩の少なくとも一つを含有する医薬組成物。
- 請求項1~4のいずれか1記載の化合物又はその塩の少なくとも一つを有効成分とするIL-6産生阻害剤。
- 請求項1~4のいずれか1記載の化合物又はその塩の少なくとも一つを有効成分とするIL-6が関与するとされる疾患の予防又は治療剤。
- 請求項1~4のいずれか1記載の化合物又はその塩を有効成分とする眼炎症性疾患の予防又は治療剤。
- 眼炎症性疾患が加齢黄斑変性、糖尿病網膜症、糖尿病黄斑浮腫、角膜炎、結膜炎又はブドウ膜炎である請求項9記載の予防又は治療剤。
- 患者に請求項1~4のいずれか1記載の化合物又はその塩の薬理上有効な量を投与することからなる眼炎症性疾患の予防又は治療方法。
- 眼炎症性疾患が加齢黄斑変性、糖尿病網膜症、糖尿病黄斑浮腫、角膜炎、結膜炎又はブドウ膜炎である請求項11記載の予防又は治療方法。
- 眼炎症性疾患を予防又は治療剤するための、請求項1~4のいずれか1記載の化合物又はその塩。
- 眼炎症性疾患が加齢黄斑変性、糖尿病網膜症、糖尿病黄斑浮腫、角膜炎、結膜炎又はブドウ膜炎である請求項13記載の化合物又はその塩。
Priority Applications (5)
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CA2733648A CA2733648A1 (en) | 2008-08-25 | 2009-08-25 | Novel pyrrole derivative having, as substituents, ureide group, aminocarbonyl group and bicyclic group which may have substituent |
CN2009801331193A CN102131774A (zh) | 2008-08-25 | 2009-08-25 | 含有脲基、氨基羰基及可以具有取代基的二环式基团作为取代基的新型吡咯衍生物 |
RU2011111267/04A RU2500669C2 (ru) | 2008-08-25 | 2009-08-25 | Новое производное пиррола, имеющее в качестве заместителей уреидогруппу, аминокарбонильную группу и бициклическую группу, у которых могут быть заместители |
EP09809878A EP2319831A4 (en) | 2008-08-25 | 2009-08-25 | NOVEL PYRROLE DERIVATIVE WITH A UREID GROUP, AN AMINOCARBONYL GROUP AND A BIZYCLIC GROUP EQUIPPED WITH A SUBSTITUENT AS SUBSTITUENTS |
US12/737,807 US8088817B2 (en) | 2008-08-25 | 2009-08-25 | Pyrrole derivative having, as substituents, ureido group, aminocarbonly group and bicyclic group which may have substituent |
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EP (1) | EP2319831A4 (ja) |
JP (1) | JP5492496B2 (ja) |
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CN (1) | CN102131774A (ja) |
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WO2017151409A1 (en) | 2016-02-29 | 2017-09-08 | University Of Florida Research Foundation, Incorporated | Chemotherapeutic methods |
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EP2319831A4 (en) | 2012-10-24 |
CA2733648A1 (en) | 2010-03-04 |
JP5492496B2 (ja) | 2014-05-14 |
RU2500669C2 (ru) | 2013-12-10 |
JP2010077120A (ja) | 2010-04-08 |
RU2011111267A (ru) | 2012-09-27 |
US20110136794A1 (en) | 2011-06-09 |
CN102131774A (zh) | 2011-07-20 |
EP2319831A1 (en) | 2011-05-11 |
KR20110044767A (ko) | 2011-04-29 |
US8088817B2 (en) | 2012-01-03 |
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