JP2009084274A - New 1,3,3-trimethyl-7-phenyl-3,4-dihydro-1h-quinoxalin-2-one derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To carry out a research for synthesizing new 1,3,3-trimethyl-7-phenyl-3,4-dihydro-1H-quinoxalin-2-one derivatives and to find pharmacological actions thereof. <P>SOLUTION: Compounds expressed by general formula (1) or salts thereof are useful as glucocorticoid receptor modulators. Particularly, they are useful as therapeutic agents for diseases against which glucocorticoid receptor agonists such as steroids are effective, e.g., inflammatory bone and joint diseases and inflammatory eye diseases (anterior or posterior eye inflammatory diseases). <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention relates to novel 1,3,3-trimethyl-7-phenyl-3,4-dihydro-1H-quinoxalin-2-one derivatives or salts thereof useful as pharmaceuticals and pharmaceutical compositions containing them. The derivative or a salt thereof has a binding activity to a glucocorticoid receptor and is useful as a non-steroidal glucocorticoid receptor modulator. That is, it is useful as a glucocorticoid receptor agonist and / or a glucocorticoid receptor antagonist, and is particularly effective for diseases in which glucocorticoid receptor agonists such as steroids are effective, such as inflammatory bone and joint diseases, It is useful as a therapeutic agent for ocular inflammatory diseases (anterior or posterior ocular inflammatory diseases).

  The glucocorticoid receptor is a 94 kDa ligand-activated intracellular transcriptional regulator belonging to the nuclear receptor superfamily. This receptor regulates the metabolism of carbohydrates, proteins, fats, etc., suppresses immune and inflammatory responses, activates the central nervous system, regulates cardiovascular functions, and regulates basic and stress-related homeostasis. I am a mediator. Diseases involving glucocorticoid action include diabetes, obesity and other metabolic disorders, arthritis, enteritis, inflammatory diseases such as chronic obstructive pulmonary disease, autoimmune diseases such as collagen disease, asthma, atopic dermatitis, allergies Allergic diseases such as rhinitis and allergic conjunctivitis, central nervous system diseases such as psychosis, Alzheimer, drug use disorders, hypertension, hypercalcemia, hyperinsulinemia, cardiovascular diseases such as hyperlipidemia, nerves -Homeostasis-related diseases, glaucoma and the like that cause abnormal balance between immunity and endocrine are known (Non-patent Document 1).

  Therefore, a compound having binding activity to the glucocorticoid receptor is considered useful as a therapeutic agent for these diseases.

  Examples of the compound having binding activity to the glucocorticoid receptor include in vivo glucocorticoid receptor agonists such as cortisol and corticosterone, dexamethasone, prednisone, prednisone and other synthetic glucocorticoid receptor agonists such as RU486, and the like. Non-selective glucocorticoid receptor antagonists are known (Patent Document 1).

On the other hand, there is no known document that specifically discloses a compound having a 1,3,3-trimethyl-7-phenyl-3,4-dihydro-1H-quinoxalin-2-one structure. There is also no known use as a glucocorticoid receptor modulator, ie as a glucocorticoid receptor agonist and / or glucocorticoid receptor antagonist.
General Clinical, 54 (7), 1951-2076 (2005) JP 2002-193955 A

Synthetic studies of novel 1,3,3-trimethyl-7-phenyl-3,4-dihydro-1H-quinoxalin-2-one derivatives or their salts and finding pharmacological actions of their derivatives or their salts are very interesting issues It is.

  The present inventors have conducted synthetic studies on 1,3,3-trimethyl-7-phenyl-3,4-dihydro-1H-quinoxalin-2-one derivatives having a new chemical structure or salts thereof, and found many new compounds. Was successfully created.

  Furthermore, as a result of studying the pharmacological action of the derivative or salt thereof, the present inventor has found that the derivative or salt thereof has binding activity to a glucocorticoid receptor (hereinafter referred to as “GR”), It was found useful and the present invention was completed.

That is, 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 comprising the present compound. A preferred invention of the compound of the present invention for use in medicine relates to a glucocorticoid receptor modulator (glucocorticoid receptor agonist and / or glucocorticoid receptor antagonist), and glucocorticoid action (glucocorticoid receptor agonist action and / or Or a glucocorticoid receptor antagonistic action), which is an invention relating to a prophylactic and / or therapeutic agent for a disease, particularly a disease in which a glucocorticoid receptor agonist such as a steroid is effective, such as an inflammatory bone / joint disease The invention relates to a preventive and / or therapeutic agent for ocular inflammatory diseases (anterior or posterior ocular inflammatory diseases).

[R ¹ represents the following general formula (2a), (3a), (4a) or (5a);

R ² represents a lower alkyl group;
R ³ represents a hydrogen atom, a lower alkyl group that may have a substituent, a lower cycloalkyl group that may have a substituent, an aryl group that may have a substituent, or a complex that may have a substituent. A cyclic group, an aralkyl group which may have a substituent or a heterocyclic lower alkyl group which may have a substituent;
R ^{4 and} R ⁵ are the same or different and are a hydrogen atom, a lower alkyl group that may have a substituent, an aralkyl group that may have a substituent, or a heterocyclic lower alkyl group that may have a substituent. R ⁴ and R ⁵ may together form a nitrogen-containing 5- or 6-membered ring which may have a substituent;
A represents a lower alkylene group;
R ⁶ , R ⁷ , R ⁸ or R ⁹ represents a halogen atom, an optionally substituted lower alkyl group, a hydroxy group, an optionally substituted lower alkoxy group or a nitro group;
m, n, p or q represents 0, 1 or 2,
When m, n, p or q represents 2, each R ⁶ , R ⁷ , R ⁸ or R ⁹ may be the same or different. same as below. ]

The present invention provides a 1,3,3-trimethyl-7-phenyl-3,4-dihydro-1H-quinoxalin-2-one derivative or a salt thereof useful as a medicine. The compound of the present invention has excellent glucocorticoid receptor binding activity and is useful as a non-steroidal glucocorticoid receptor modulator. That is, it is useful as a glucocorticoid receptor agonist and / or glucocorticoid receptor antagonist, and particularly a disease in which a glucocorticoid receptor agonist such as steroids is effective, such as inflammatory bone / joint disease, ocular inflammatory It was confirmed that it is useful as a therapeutic agent for diseases (anterior or posterior eye inflammatory diseases).

  Definitions of terms (atoms, groups, etc.) used in this specification will be described in detail below.

“Halogen atom” refers to a fluorine, chlorine, bromine or iodine atom.

The “lower alkyl group” refers to a linear or branched alkyl group having 1 to 8, preferably 1 to 6, and particularly preferably 1 to 4 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl group and the like. .

The “lower cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl groups.

The “aryl group” is a residue obtained by removing one hydrogen atom from a monocyclic aromatic hydrocarbon having 6 to 14 carbon atoms or a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon. Show. Specific examples include phenyl, naphthyl, anthryl, phenanthryl group and the like.

The “heterocyclic group” is a saturated or unsaturated monocyclic heterocycle having 1 or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring (preferably 1 or 2 A saturated or unsaturated monocyclic heterocyclic 5- or 6-membered ring having 3 to 5 carbon atoms, or a bicyclic or tricyclic fused polycyclic heterocyclic ring (preferably 1 Or a residue obtained by removing one hydrogen atom from a bicyclic or tricyclic fused polycyclic heterocyclic ring having 7 to 13 carbon atoms and having 2 heteroatoms in the ring.

Specific examples of “saturated monocyclic heterocycle” include pyrrolidine, pyrazolidine, imidazolidine, triazolidine, piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine, homopiperidine, homopiperazine ring having a nitrogen atom in the ring. Tetrahydrofuran, tetrahydropyran ring, etc. having an oxygen atom in the ring, tetrahydrothiophene, tetrahydrothiopyran ring, etc. having a sulfur atom in the ring, oxazolidine, isoxazolidine, morpholine ring having a nitrogen atom and an oxygen atom in the ring And the like include thiazolidine, isothiazolidine, thiomorpholine ring having a nitrogen atom and a sulfur atom in the ring.

In addition, 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. Benzofuran, dihydroisobenzofuran, chroman, isochroman, dihydrobenzothiophene, dihydroisobenzothiophene, thiochroman, isothiochroman, dihydrobenzoxazole, dihydrobenzoisoxazole, dihydrobenzoxazine, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydrobenzothia Bicyclic or tricyclic condensation such as gin, xanthene, 4a-carbazole and perimidine ring Polycyclic heterocyclic ring may be formed.

Specific examples of “unsaturated monocyclic heterocycle” include dihydropyrrole, pyrrole, dihydropyrazole, pyrazole, dihydroimidazole, imidazole, dihydrotriazole, triazole, tetrahydropyridine, dihydropyridine, pyridine, tetrahydro having a nitrogen atom in the ring. Pyridazine, dihydropyridazine, pyridazine, tetrahydropyrimidine, dihydropyrimidine, pyrimidine, tetrahydropyrazine, dihydropyrazine, pyrazine ring, etc. are dihydrofurans, furans, dihydropyrans, pyran rings, etc. having an oxygen atom in the ring. Dihydrothiophene, thiophene, dihydrothiopyran, thiopyran ring, etc. contained in the dihydrooxazole, oxazole, dihydroisoxa having a nitrogen atom and an oxygen atom in the ring Lumpur, 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.

In addition, 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, β-carboline, phenanthridine, acridine, phen Ntororin, phenazine, phenothiazine, may form a 2 fused polycyclic heterocyclic cyclic or tricyclic, such as phenoxazine ring.

Of the aforementioned “heterocyclic groups”, a 5-membered or 6-membered saturated or unsaturated monocyclic heterocyclic ring containing one or more nitrogen atoms is referred to as a “nitrogen-containing 5- or 6-membered ring”.

The “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, n-heptyloxy, n-octyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy group Etc.

The “lower alkylamino group” refers to a group in which one or both hydrogen atoms of an amino group are substituted with a lower alkyl group. Specific examples include methylamino, ethylamino, propylamino, dimethylamino, diethylamino, ethyl (methyl) amino group, and the like.

The “aralkyl group” refers to a group in which one or more hydrogen atoms of a lower alkyl group are substituted with an aryl group. Specific examples include benzyl, phenethyl, naphthylmethyl groups and the like.

The “heterocyclic lower alkyl group” refers to a group in which one or more hydrogen atoms of the lower alkyl group are substituted with a heterocyclic group. Specific examples include furanylmethyl, thiophenylmethyl, pyrrolylmethyl, pyridylmethyl and the like.

The “lower alkylene group” refers to a linear or branched alkylene group having 1 to 8, preferably 1 to 6, and particularly preferably 1 to 4 carbon atoms. Specific examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, methylmethylene, ethylmethylene groups and the like.

The "optionally substituted lower alkyl group" or "optionally substituted lower alkoxy group" may have one or more substituents selected from the following alpha ¹ group A preferable “lower alkyl group” or “lower alkoxy group” is shown.

[Α ¹ group]
A halogen atom, a hydroxy group, a lower alkoxy group, an amino group, a lower alkylamino group, a nitro group and a cyano group;

“Optionally substituted lower cycloalkyl group”, “optionally substituted aryl group”, “optionally substituted heterocyclic group” and “optionally substituted” The “good nitrogen-containing 5- or 6-membered cyclic group” means “lower cycloalkyl group”, “aryl group”, “heterocyclic group” which may have one or more substituents selected from the following β ¹ group And “nitrogen-containing 5- or 6-membered cyclic group”.

[Β ¹ group]
A halogen atom, a lower alkyl group, a lower alkyl group substituted with a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkoxy group substituted with a halogen atom, an amino group, a lower alkylamino group, a nitro group and a cyano group;

The “aralkyl group optionally having substituent (s)” or “heterocyclic lower alkyl group optionally having substituent (s)” means one or more of those lower alkyl moieties selected from the above α ¹ group “Aralkyl group” or “heterocyclic lower alkyl group” which may have one or more substituents selected from the above β ¹ group, and / or their aryl moiety or heterocyclic moiety. Indicates.

The “plural groups” as used in the present invention may be the same or different, and each group represents two or more groups at the substitution site, and the number of substitutions or less. The number is preferably two. Further, a hydrogen atom and a halogen atom are also included in the concept of “group”.

The “glucocorticoid receptor modulator” as used in the present invention refers to a substance that expresses a pharmaceutical action by binding to a glucocorticoid receptor. For example, a glucocorticoid receptor agonist, a glucocorticoid receptor antagonist, etc. are mentioned.

The term “glucocorticoid receptor agonist” as used in the present invention refers to a substance that exhibits a full agonist action or a partial agonist action by binding to a glucocorticoid receptor.

The “therapeutic agent” as used in the present invention means a drug used for preventing and / or treating a disease.

The pharmaceutical use of the “glucocorticoid receptor agonist” of the present invention is not particularly limited as long as it is a disease treatable with a glucocorticoid receptor agonist. It is usually applicable to all diseases that can be treated with steroids.

For example, chronic adrenocortical dysfunction (primary, secondary, pituitary, iatrogenic), acute adrenocortical dysfunction (adrenal crisis), adrenal genital syndrome, subacute thyroiditis, thyroid poisoning [thyroid (addictive) ) Crisis], malignant ocular protrusion associated with thyroid disease, ACTH deficiency, idiopathic hypoglycemia, and other endocrine diseases; lupus erythematosus (systemic and chronic discoid), systemic vasculitis (aortitis syndrome, nodular) (Including periarteritis, polyarteritis, vegena granulomatosis), polymyositis (dermatomyositis), collagen diseases such as scleroderma; renal diseases such as nephrosis and nephrotic syndrome; heart diseases such as congestive heart failure; Allergic diseases such as bronchial asthma, asthmatic bronchitis (including childhood asthmatic bronchitis), allergies / addictions (including drug eruptions and poisoning eruptions) caused by drugs and other chemicals, purpura (platelets) Blood disorders such as hypoplastic and non-thrombocytopenic), aplastic anemia, leukemia (including acute leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, cutaneous leukemia), hemolytic anemia, granulocytopenia Gastrointestinal diseases such as ulcerative colitis, localized enteritis, improvement of general condition of severe debilitating diseases (including terminal cancer and sprue); fulminant hepatitis, cholestatic acute hepatitis, chronic hepatitis, cirrhosis, etc. Liver diseases; pulmonary diseases such as sarcoidosis, diffuse interstitial pneumonia (including pulmonary fibrosis and radiation pneumonitis); severe infections severe infections; pulmonary tuberculosis, tuberculous meningitis, tuberculous pleurisy, tuberculous peritonitis, Tuberculous diseases such as tuberculous cystitis; encephalomyelitis (including encephalitis and myelitis), peripheral neuritis (including Guillain-Barre syndrome), myotonia, myasthenia gravis, multiple sclerosis (visual) Syringomyelia), chorea, facial nerve palsy, spine Neurological diseases such as myelogenous retinitis; malignant lymphoma (lymphosarcoma, reticulosarcoma, Hodgkin's disease, cutaneous reticulosis, mycosis fungoides) and similar diseases (related diseases), eosinophilic granuloma, breast cancer Malignant tumors such as recurrent metastasis; Gastrointestinal symptoms (nausea / vomiting) associated with administration of antineoplastic agents (cisplatin, etc.); Adrenalectomy, surgical invasion to patients with cortical dysfunction, post-invasive lung edema, organ / tissue transplantation, Snake venom / insect poison (including severe insect bites), surgical diseases such as fever of unknown cause; obstetrics and gynecological diseases such as prevention of adhesion after oviduct plastic surgery; urological diseases such as prostate cancer, penile induration; eczema・ Dermatitis group (acute eczema, subacute eczema, chronic eczema, contact dermatitis, monetary eczema, self-sensitizing dermatitis, atopic dermatitis, breast / infant / pediatric eczema, Vidar lichen, other neurodermatitis , Seborrheic dermatitis, progressive palmokeratosis, other finger skin , Genital or anal eczema, eczema / dermatitis in the auricle and ear canal, eczema / dermatitis around the nasal vestibule and nasal wing), urticaria (including childhood stroflus, hives-like lichen, fixed urticaria), urticaria Psoriasis and psoriasis (psoriasis vulgaris (severe cases), psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, limbic limb dermatitis, pustular impetigo, Reiter syndrome), palmoplantar pustulosis , Lichen planus, adult edematous sclerosis, erythema (polymorphic exudative erythema, erythema nodosum), anaphylactoid purpura (simple type, Shaneline type, Henoch type), Weber Christian disease, mucocutaneous eye syndrome (Opening erosive dermatosis, Stevens-Johnson disease, cutaneous stomatitis, Fuchs syndrome, Behcet's disease, Lippschitz acute genital ulcer), Raynaud's disease, alopecia areata, pemphigus group (pemphigus vulgaris, lobular pemphigus, S near-Usher syndrome, proliferative pemphigus), During zoster dermatitis (including pemphigus vulgaris, gestational herpes zoster), congenital epidermolysis bullosa, herpes zoster, erythroderma (including Hebra erythema) Dermatological diseases such as facial disseminated miliary lupus, allergic vasculitis and the like (including acute acne-like lichenoid eruption), ulcerative chronic pyoderma, neonatal sclerema; acute and chronic otitis media; Exudative otitis media / tubal stenosis, Meniere's disease and Meniere's syndrome, acute sensorineural hearing loss, vasomotor (neurological) rhinitis, allergic rhinitis, hay fever (hay fever), progressive gangrenous rhinitis, laryngitis / larynx Edema, postoperative therapy in otolaryngology, olfactory disturbance, otolaryngology diseases such as acute / chronic (recurrent) salivary glanditis; oral surgery diseases such as refractory stomatitis and glossitis; rheumatic fever (rheumatic heart) (Including flames), rheumatic Examples include polymyalgia, rheumatic diseases such as ankylosing spondylitis (rheumatic spondylitis), and the following inflammatory diseases.

The “inflammatory disease” as used in the present invention is not particularly limited as long as it is a disease accompanied by inflammation.

Examples include inflammatory bone / joint diseases, ocular inflammatory diseases, asthma, bronchitis, rhinitis, dermatitis, inflammatory bowel disease, etc., preferably inflammatory bone / joint diseases and / or ocular inflammatory Disease.

Here, the “inflammatory bone / joint disease” is not particularly limited as long as it is a disease accompanied by inflammation in the joint part. For example, rheumatoid arthritis, juvenile rheumatoid arthritis (including Still's disease), degenerative joint Disease, osteoporosis, spondyloarthritis and the like, preferably rheumatoid arthritis and / or osteoarthritis.

Further, the “eye inflammatory disease” is not particularly limited as long as it is a disease accompanied by inflammation in the eye. For example, if it is an anterior eye inflammatory disease, keratitis, keratoconjunctivitis, conjunctivitis, blepharitis, Examples include dry eye syndrome, allergic conjunctivitis, anterior uveitis, post-operative inflammation of the anterior eye, inflammation due to ocular tissue transplant rejection, preferably dry eye syndrome or allergic conjunctivitis It is done.

  For posterior eye inflammatory diseases, age-related macular degeneration, diabetic retinopathy, diabetic macular edema, neovascular macular disease, idiopathic macular membrane, proliferative vitreoretinopathy, retinitis pigmentosa, retina center Venous occlusion, central retinal artery occlusion, retinal vein occlusion, retinal artery occlusion, retinal inflammation or degeneration caused by retinal detachment or trauma (including posterior ocular surgery), retina Inflammation, uveitis, scleritis, optic neuritis, etc., preferably age-related macular degeneration, diabetic retinopathy, diabetic macular edema, neovascular macular disease, idiopathic macular membrane, proliferative vitreoretinopathy Inflammation caused by retinitis pigmentosa, central retinal vein occlusion, central retinal artery occlusion, branch retinal vein occlusion, branch retinal artery occlusion, retinal detachment or trauma (including posterior eye surgery) Retinal diseases such as aging, degeneration, and retinitis, particularly preferably age-related macular degeneration, diabetic network Disease, diabetes macular edema.

The “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, Glucoheptonic 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, trifluoromethane Salts with organic acids such as sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid, quaternary ammonium salts with methyl bromide, methyl iodide, bromine Salts with halogen ions such as ions, chlorine ions, iodine ions, lithium, sodium, potassium, etc. Salt with Lucari metal, salt with alkaline earth metal such as calcium and magnesium, metal salt with iron and zinc, salt with ammonia, triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2 -Salts with organic amines such as ethanediamine and the like.

When geometrical isomers and / or optical isomers are present in the compound of the present invention, these isomers are also included in the scope of the present invention.

When proton tautomerism exists in the compound of the present invention, those tautomers (keto form, enol form) are also included in the present invention.

When hydrates and / or solvates are present in the compound of the present invention, these hydrates and / or solvates are also included in the scope of the present invention.

When the compound of the present invention has a crystal polymorph and a crystal polymorph group (crystal polymorph system), those crystal polymorphs and crystal polymorph groups (crystal polymorph system) are also included in the present invention. Here, the crystal polymorph group (crystal polymorph system) means various crystal forms depending on conditions and states (including the formulated state in this state) such as production, crystallization, and storage of these crystals. It means the crystal form and the whole process at each stage when changing.

(A) As an example of this invention compound, the compound or its salt whose group is the group shown below in the compound or its salt shown by General formula (1) is mentioned.

(A1) R ¹ represents the following general formula (2a), (3a), (4a) or (5a); and / or

(A2) R ² represents a lower alkyl group; and / or
(A3) R ³ has a hydrogen atom, a lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. An optionally substituted heterocyclic group, an optionally substituted aralkyl group or an optionally substituted heterocyclic lower alkyl group; and / or
(A4) R ⁴ or R ⁵ are the same or different and are a hydrogen atom, a lower alkyl group which may have a substituent, an aralkyl group which may have a substituent, or a heterocyclic ring which may have a substituent Represents a lower alkyl group, R ⁴ and R ⁵ may be taken together to form an optionally substituted nitrogen-containing five- or six-membered ring; and / or
(A5) A represents a lower alkylene group; and / or
(A6) R ⁶ , R ⁷ , R ⁸ or R ⁹ represents a halogen atom, a lower alkyl group which may have a substituent, a hydroxy group, a lower alkoxy group which may have a substituent or a nitro group. And / or
(A7) m, n, p or q represents 0, 1 or 2;
When m, n, p or q represents 2, each R ⁶ , R ⁷ , R ⁸ or R ⁹ may be the same or different.

That is, in the compound represented by the general formula (1) or a salt thereof, each combination selected from the above (A1), (A2), (A3), (A4), (A5), (A6) and (A7) Or a salt thereof.

(B) As a preferable example in this invention compound, the compound or its salt in which each group is group shown below in the compound or its salt shown by General formula (1) is mentioned.

(B1) R ¹ represents the following general formula (2a), (3a), (4a) or (5a); and / or

(B3) R ² represents a lower alkyl group; and / or (B4) R ³ represents a hydrogen atom, a lower alkyl group that may have a substituent, a lower cycloalkyl group that may have a substituent, or a substituent. An aryl group that may have a substituent, a heterocyclic group that may have a substituent, an aralkyl group that may have a substituent, or a heterocyclic lower alkyl group that may have a substituent; and / Or (B5) R ⁴ or R ⁵ is the same or different and is a hydrogen atom, a lower alkyl group that may have a substituent, an aralkyl group that may have a substituent, or a heterocycle that may have a substituent. R ⁴ represents a lower alkyl group, and R ⁴ and R ⁵ may be combined to form an optionally substituted nitrogen-containing five- or six-membered ring; and / or (B6) A is a lower alkylene And / or (B7) R ⁶ is a halogen atom, a lower alkyl group, a hydroxy group, And / or (B8) R ⁷ represents a halogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group; and / or (B9) R ⁸ represents a halogen atom, lower group; An alkyl group, a hydroxy group or a lower alkoxy group;
(B10) R ⁹ represents a halogen atom or a lower alkyl group; and / or (B11) m, n or p represents 1 or 2,
When m, n or p represents 2, each R ⁶ , R ⁷ and R ⁸ may be the same or different; and / or (B12) q represents 0 or 1.

That is, in the compound represented by the general formula (1), the above (B1), (B2), (B3), (B4), (B5), (B6), (B7), (B8), (B9), A compound or a salt thereof comprising one or more combinations selected from (B10), (B11) and (B12).

The compounds satisfying the combination of the conditions (B) and the conditions (A) or salts thereof are also within the scope of the compounds of the present invention.

(C) As a more preferable example in this invention compound, the compound or its salt in which each group is group shown below in the compound or its salt shown by General formula (1) is mentioned.

(C1) R ¹ represents the following general formula (2b-1), (2b-2), (2b-3), (3b-1), (3b-2) or (5b-1); and / or

(C2) R ² represents a lower alkyl group; and / or (C3) R ³ represents a heterocyclic group, an aralkyl group or a heterocyclic lower alkyl group which may have a lower alkyl group or a lower alkylamino group as a substituent. And / or (C4) R ⁴ or R ⁵ is the same or different and represents a lower alkyl group, and R ⁴ and R ⁵ together may form a nitrogen-containing six-membered ring; and / Or (C5) A represents a lower alkylene group.

That is, in the compound represented by the general formula (1), a compound consisting of one or more combinations selected from the above (C1), (C2), (C3), (C4) and (C5) or a salt thereof .

In addition, the compound or its salt that satisfies the combination of the condition (C) and the condition (A) and / or (B) is also within the scope of the present invention.

(D) Particularly preferred specific examples of the compound of the present invention include the following compounds or salts thereof.

7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-ethylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-diethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3- Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N-methyl-N- [2- (piperidin-1-yl) ethyl] aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl)- 1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N- (pyridin-3-ylmethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxy-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N-ethyl-N- (2-diethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3- Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N, N-bis (2-dimethylaminopropyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3- Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 , 3-Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methyl-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl- 3,4-Dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenylaminomethyl) -1,3 3-Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-diethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenylaminomethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-isopropylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxy-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxy-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (2-methyl-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methyl-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-ethylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 , 3-Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 , 3-Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N- (pyridin-3-ylmethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxy Methyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 , 3-Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N, N-bis (3-dimethylaminopropyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 3-Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-isopropylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 , 3-Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

8- (5-Bromothiophen-2-ylcarbonyloxymethyl) -7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -1,3 , 3-Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (4-methylbenzoyloxymethyl) -1,3,3-trimethyl- 3,4-Dihydro-1H-quinoxalin-2-one.

7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (4-methylbenzoyloxymethyl) -1,3,3-trimethyl- 3,4-Dihydro-1H-quinoxalin-2-one.

7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (4-methylbenzoyloxymethyl) -1,3,3-trimethyl- 3,4-Dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (4-methoxybenzoyloxymethyl) -1,3,3-trimethyl- 3,4-Dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-ethylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl- 3,4-Dihydro-1H-quinoxalin-2-one.

7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl- 3,4-Dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N- (pyridin-3-ylmethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1, 3,3-Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl- 3,4-Dihydro-1H-quinoxalin-2-one.

7- [4- [N, N-bis (3-dimethylaminopropyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3 , 4-Dihydro-1H-quinoxalin-2-one.

7- [4- [N- (2-dimethylaminoethyl) -N-isopropylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl- 3,4-Dihydro-1H-quinoxalin-2-one.

7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenylaminomethyl) -1,3 3-Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenylaminomethyl) -1,3 3-Trimethyl-3,4-dihydro-1H-quinoxalin-2-one.

The compound of the present invention can be produced by the following method. In addition, each specific manufacturing method is demonstrated in detail by the below-mentioned Example "Section Example". Moreover, these illustrations are for understanding the present invention better and are not intended to limit the scope of the present invention. In addition, Hal shown in the following synthetic pathway shows a halogen atom.

The compound (I) of the present invention can be synthesized according to Synthesis Route 1. That is, the compound (II) and 1,1′-carbonyldiimidazole (hereinafter referred to as CDI) in the presence of 4-dimethylaminopyridine (hereinafter referred to as “DMAP”), dichloromethane, tetrahydrofuran (hereinafter referred to as “THF”). In an organic solvent such as Obtainable.

The compound (I)-(a) of the present invention (a compound in which R ¹ is (3a) in the general formula (1)) can also be synthesized according to the synthesis route 2. That is, after reacting compound (II)-(a) (compound in which R ¹ is (3a)) and the corresponding amine according to the method of synthesis route 1, the reaction mixture is dissolved in an organic solvent such as DMF or dichloromethane. Compound (I)-(d) can be obtained by treatment at 0 ° C. to 50 ° C. for 5 minutes to 24 hours in the presence of a base such as piperidine.

The compound (II) can be synthesized according to Synthesis Route 3. That is, the compound (IV) is treated in an organic solvent such as diethyl ether or THF in the presence of a reducing agent such as lithium aluminum hydride at −30 ° C. to room temperature for 1 to 24 hours. can get. The resulting compound (IV) and methyl iodide were converted to 0 in the presence of a base such as cesium carbonate, potassium carbonate, sodium hydride in an organic solvent such as N, N-dimethylformamide (hereinafter referred to as DMF), THF or ethanol. The compound (V) is obtained by reacting at 1 to 48 ° C. for 1 to 48 hours. Further, the resulting compound (V) and methanesulfonyl chloride are reacted in an organic solvent such as dichloromethane or THF in the presence of a base such as triethylamine or DIEA at 0 ° C. to room temperature for 30 minutes to 12 hours. ) Is obtained. The resulting compound (VI) and the corresponding phenols or amines in an organic solvent such as DMF, THF, ethanol, etc. in the presence of a base such as cesium carbonate, potassium carbonate, sodium hydride at 0 ° C. to 100 ° C. for 1 hour To 48 hours to give compound (VII). (Also, the compound (V) and the corresponding phenols are mixed with phosphine such as triphenylphosphine and tributylphosphine in diethyl benzene, THF and the like, diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1 ′-(azo Compound (VII) can also be obtained by reacting at room temperature for 1 to 2 days in the presence of Mitsunobu reagent such as dicarbonyl) dipiperidine. Furthermore, compound (VII) and the corresponding boronic acid or its ester (VIII ) In a solvent such as DMF, 1,4-dioxane, ethanol, toluene, water, and a base such as cesium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium phosphate, and bis (triphenylphosphine) palladium (II) dichloride, tetrakis Catalysts such as (triphenylphosphine) palladium (0) The reaction is carried out at 50 to 120 ° C. for 1 to 48 hours to obtain compound (IX). The compound (IX) obtained is treated in an organic solvent such as 1,4-dioxane or dichloromethane in the presence of an acid such as hydrogen chloride or trifluoroacetic acid at 0 to 50 ° C. for 1 to 24 hours to give a compound (II) can be obtained.

The compound (II) can be synthesized according to Synthesis Route 4. That is, a boronic acid corresponding to compound (IV) or an ester thereof (VIII) in a solvent such as DMF, 1,4-dioxane, ethanol, toluene, water, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, etc. By reacting the base with a catalyst such as bis (triphenylphosphine) palladium dichloride (II) or tetrakis (triphenylphosphine) palladium (0) at 50 to 120 ° C. for 1 to 48 hours, the compound ( X) is obtained. Further, the resulting compound (X) is reacted with methanesulfonyl chloride in an organic solvent such as dichloromethane or THF in the presence of a base such as triethylamine or DIEA at 0 ° C. to room temperature for 30 minutes to 12 hours to give compound (XI ) Is obtained. The resulting compound (XI) and the corresponding phenols, carboxylic acids or amines in an organic solvent such as DMF, THF or ethanol in the presence of a base such as potassium carbonate or sodium hydride at 0 to 100 ° C. for 1 hour To 48 hours to give compound (XII). (Also, the phenol or carboxylic acid corresponding to the compound (X) is mixed with a phosphine such as triphenylphosphine or tributylphosphine, diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1 ′ in an organic solvent such as benzene or THF. -Compound (XII) can also be obtained by reacting at room temperature for 1 to 2 days in the presence of Mitsunobu reagent such as-(azodicarbonyl) dipiperidine.) Compound (XII) obtained and methyl iodide are converted to DMF, Compound (XIII) is obtained by reacting in an organic solvent such as THF and ethanol in the presence of a base such as cesium carbonate, potassium carbonate and sodium hydride at 0 to 100 ° C. for 1 to 48 hours. Further, the obtained compound (XIII) is treated in an organic solvent such as 1,4-dioxane and dichloromethane in the presence of an acid such as hydrogen chloride and trifluoroacetic acid at 0 to 50 ° C. for 1 to 24 hours. Compound (II) can be obtained.

The compound (III) can be synthesized according to the synthesis route 5. That is, compound (XIV) is treated in an organic solvent such as methanol, ethanol and DMF in the presence of a reducing agent such as tin chloride (II) and iron chloride (II) at 50 to 120 ° C. for 1 to 12 hours. Thus, compound (XV) is obtained. The resulting compound (XV) is reacted with an acetylating agent such as acetyl chloride or acetic anhydride in an organic solvent such as dichloromethane or THF at 0 to 50 ° C. for 1 to 12 hours in the presence of a base such as triethylamine or DIEA. Thus, compound (XVI) is obtained. Compound (XVII) is obtained by reacting the obtained compound (XVI) and nitric acid in a solvent such as water in the presence of an acid such as sulfuric acid at −20 ° C. to room temperature for 30 minutes to 12 hours. The resulting compound (XVII) is treated in an organic solvent such as methanol in the presence of an acid such as boron trifluoride diethyl ether complex at 50 ° C. under reflux for 1 to 12 hours to obtain compound (XVIII). It is done. The compound (XX) is obtained by reacting the resulting compound (XVIII) with the corresponding halide (XIX) in the presence of a base such as cesium carbonate or potassium carbonate at 50 to 120 ° C. for 1 to 120 hours. . The resulting compound (XX) is treated in an organic solvent such as methanol, ethanol and DMF in the presence of a reducing agent such as tin (II) chloride and iron (II) chloride at 50 to 120 ° C. for 1 to 12 hours. Thus, compound (III) can be obtained.

The compound (II)-(a) can be synthesized according to the synthesis route 6. That is, compound (IX)-(a) (compound (IX) in which R ¹ is (3a)) and 9-fluorenylmethoxycarbonyl chloride in a solvent such as 1,4-dioxane, water, hydrogen carbonate Compound (XXI) is obtained by reacting at 0 to 50 ° C. for 1 to 24 hours in the presence of a base such as sodium. The compound (XXI) obtained is treated in an organic solvent such as 1,4-dioxane or dichloromethane in the presence of an acid such as hydrogen chloride or trifluoroacetic acid at 0 ° C. to 50 ° C. for 1 to 24 hours. (II)-(a) can be obtained.

In order to find the usefulness of the compound of the present invention as a pharmaceutical, GR reception by polarized fluorescence using a glucocorticoid receptor (hereinafter referred to as “GR”) competition assay kit (manufactured by Invitrogen, Cat No. P2816) A body competition assay was conducted to examine the binding activity of the compounds of the present invention to GR. As a result, the compound of the present invention showed an excellent GR bond rate of 80% or more with respect to GR.

    Next, in order to evaluate the possibility of the compound of the present invention as a GR agonist, the IL-6 production inhibitory action in a human corneal epithelial cell line after stimulation with Lipopolysaccharide (hereinafter referred to as “LPS”) was examined. As a result, the compound of the present invention showed an excellent IL-6 production inhibitory action, that is, an action as a GR agonist. Therefore, the compound of the present invention is useful as a therapeutic agent for diseases in which GR agonists such as steroids are effective, particularly inflammatory diseases (bone / joint diseases, inflammatory eye diseases, etc.).

  Furthermore, in order to find out the possibility of the compound of the present invention as a therapeutic agent for inflammatory diseases of the anterior segment of the eye, the inhibitory effect of the compound of the present invention on the enhancement of vascular permeability was investigated on a mouse allergic conjunctivitis model. As a result, the compound of the present invention showed an excellent vascular permeability enhancement inhibitory effect. Therefore, the compound of the present invention is useful as a therapeutic agent for anterior ocular inflammatory diseases, particularly for allergic eye diseases such as allergic conjunctivitis.

  Moreover, in order to find out the possibility as a therapeutic agent for the posterior ocular inflammatory disease of the compound of the present invention, the choroidal neovascularization inhibitory effect of the compound of the present invention on the rat choroidal neovascularization model was examined. As a result, the compound of the present invention showed an excellent choroidal neovascularization inhibitory action. Therefore, the compound of the present invention is useful as a therapeutic agent for posterior ocular inflammatory diseases, particularly as a therapeutic agent for retinal diseases such as age-related macular degeneration, diabetic retinopathy, and diabetic macular edema.

  From the above pharmacological tests, the compounds of the present invention are useful as pharmaceutical compositions, GR modulators, and GR agonists. It is particularly useful as a therapeutic agent for inflammatory diseases (bone / joint diseases, inflammatory eye diseases, etc.), and more specifically, useful as a therapeutic agent for inflammatory diseases of the anterior eye segment and / or posterior eye segment. confirmed.

Details of this will be described in detail in the “Pharmacological Test Section” below.

The compound of the present invention can be administered orally or parenterally. Examples of dosage forms include tablets, capsules, granules, powders, injections, eye drops, suppositories, transdermal absorption preparations, ointments, aerosols (including inhalants), etc., and these are general-purpose technologies. Can be formulated.

  For example, oral preparations such as tablets, capsules, granules, powders are lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, calcium hydrogen phosphate and other excipients, stearic acid, magnesium stearate , Lubricants such as talc, binders such as starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, calcium citrate, hydroxypropylmethylcellulose, macrogol, Coating agents such as silicone resins, stabilizers such as ethyl paraoxybenzoate and benzyl alcohol, and flavoring agents such as sweeteners, acidulants and fragrances can be prepared using necessary amounts as necessary. it can.

  In addition, parenterals such as injections and eye drops are made of isotonic agents such as sodium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, potassium chloride, sorbitol, mannitol, sodium phosphate, sodium hydrogen phosphate, sodium acetate. Buffering agents such as citric acid, glacial acetic acid, trometamol, surfactants such as polysorbate 80, polyoxy40 stearate, polyoxyethylene hydrogenated castor oil 60, stabilizers such as sodium citrate and sodium edetate, benzal chloride PH adjustment of preservatives such as luconium, paraben, benzotonium chloride, paraoxybenzoate, sodium benzoate, chlorobutanol, hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate Agent, benzyl alcohol, etc. If necessary the soothing agent or the like, using the required amount can be prepared.

The dose of the compound of the present invention can be appropriately selected and used depending on the type of disease, symptoms, age, dosage form and the like. For example, an oral preparation can be administered usually in an amount of 0.01 to 1000 mg, preferably 1 to 100 mg per day, once or in several divided doses. In addition, the eye drops are usually administered in a concentration of 0.0001% to 10% (w / v), preferably 0.01% to 5% (w / v) in one or several divided doses. it can.

The production examples, formulation examples and pharmacological test results of the compounds of the present invention are shown below. In addition, these illustrations are for understanding this invention better, and do not limit the scope of the present invention.

[Production example]
Reference example 1
7-Bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound 1)

Methyl 5-amino-2-bromobenzoate (Reference compound 1- (1))
Methyl 2-bromo-5-nitrobenzoate (25.3 g, 97.3 mmol) was dissolved in anhydrous methanol (500 mL), tin (II) chloride (93.3 g, 487 mmol) was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool, ethyl acetate (500 mL) and water (100 mL) were added, neutralized with 4N aqueous sodium hydroxide solution, and filtered through celite. The filtrate was concentrated under reduced pressure, ethyl acetate (200 mL) was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution (200 mL, twice), water (200 mL) and saturated brine (200 mL). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title reference compound (21.0 g) as a yellow oil. (Yield 94%)

Methyl 5-acetylamino-2-bromobenzoate (Reference compound 1- (2))

Methyl 5-amino-2-bromobenzoate (reference compound 1- (1), 21.0 g, 91.2 mmol) was dissolved in anhydrous dichloromethane (450 mL), and triethylamine (19.0 mL, 137 mmol) and Acetyl chloride (13.0 mL, 182 mmol) was added dropwise in that order over 30 minutes, and the mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was washed successively with water (200 mL, twice), saturated aqueous sodium hydrogen carbonate solution (200 mL, twice) and saturated brine (200 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was collected by filtration with hexane-ethyl acetate (20: 1) to give the titled reference compound (24.2 g) as a pale yellow solid. (Yield 98%)

Methyl 3-acetylamino-6-bromo-2-nitrobenzoate (reference compound 1- (3))

After adding methyl 5-acetylamino-2-bromobenzoate (reference compound 1- (2), 18.5 g, 68.1 mmol) little by little to concentrated sulfuric acid (150 mL) at 0 ° C., concentrated nitric acid (150 mL) Was added dropwise over 1 hour. After stirring for 30 minutes, the reaction solution was added to ice water (1 L) and extracted with ethyl acetate (500 mL, twice). The organic layer was washed successively with water (1 L, twice), saturated aqueous sodium hydrogen carbonate solution (1 L) and saturated brine (1 L), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (13.4 g) as a yellow solid. (Yield 62%)

Methyl 3-amino-6-bromo-2-nitrobenzoate (reference compound 1- (4))

Methyl 3-acetylamino-6-bromo-2-nitrobenzoate (reference compound 1- (3), 13.4 g, 42.2 mmol) was dissolved in methanol (240 mL), and boron trifluoride diethyl ether complex (24 0.0 mL, 190 mmol) was added, and the mixture was heated to reflux for 2.5 hours. The reaction solution was neutralized with sodium hydrogen carbonate (48 g), and then concentrated under reduced pressure. Ethyl acetate (500 mL) and water (700 mL) were added to the reaction solution for partitioning, and the ethyl acetate layer was washed successively with water (700 mL) and saturated brine (700 mL), dried over anhydrous magnesium sulfate, and then the solvent under reduced pressure. Was distilled off to obtain the title reference compound (11.6 g) as an orange solid. (Yield 100%)

Methyl 6-bromo-3-[(2-ethoxycarbonyl) propan-2-yl] amino-2-nitrobenzoate (Reference compound 1- (5))

Methyl 3-amino-6-bromo-2-nitrobenzoate (reference compound 1- (4), 11.6 g, 42.0 mmol), ethyl 2-bromoisobutyrate (60.4 mL, 412 mmol), potassium iodide (7 A mixture of .76 g, 46.2 mmol) and cesium carbonate (56.1 g, 172 mmol) was stirred at 85 ° C. for 4 days. After allowing to cool, ethyl acetate (500 mL) and water (500 mL) were added to the reaction solution for partitioning, and the aqueous layer was extracted with ethyl acetate (300 mL). The organic layers were combined, washed successively with water (1 L, 2 times) and saturated brine (1 L), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (5.08 g) as an orange oil. (Yield 31%)

7-Bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound 1)

Methyl 6-bromo-3-[(2-ethoxycarbonyl) propan-2-yl] amino-2-nitrobenzoate (reference compound 1- (5), 105 mg, 0.26 mmol) in absolute ethanol (4.5 mL) Into the solution, tin (II) chloride (247 mg, 1.30 mmol) was added and heated to reflux for 5 hours. After allowing to cool, ethyl acetate (25 mL) was added to the reaction mixture, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and filtered through celite. After partitioning the filtrate, the aqueous layer was extracted with ethyl acetate (10 mL, twice), and the combined organic layers were washed successively with water (50 mL, twice) and saturated brine (50 mL), and anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (56.3 mg) as a pale yellow solid. (Yield 70%)

Reference example 2
7-Bromo-8-hydroxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 2-1)

Under a nitrogen atmosphere, lithium aluminum hydride (38.5 mg, 1.01 mmol) was suspended in anhydrous tetrahydrofuran (0.5 mL). At 0 ° C., anhydrous tetrahydrofuran (1.5 mL) of 7-bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound 1, 101 mg, 0.323 mmol) ) The solution was added dropwise and stirred at the same temperature for 1 hour. Ethyl acetate (10 mL), water (10 mL) and 1N hydrochloric acid (2 mL) were sequentially added to the reaction solution and partitioned. The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (67.4 mg) as an orange amorphous. (Yield 74%)

Hereinafter, Reference Compound 2-2 was obtained using Reference Compound 6-6 according to the production method of Reference Compound 2-1.

Reference example 3
7-Bromo-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 3)

7-Bromo-8-hydroxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 2-1, 62.7 mg, 0.220 mmol), methyl iodide (68. A mixture of 6 μL, 1.10 mmol) and cesium carbonate (180 mg, 0.552 mmol) was suspended in anhydrous N, N-dimethylformamide (1 mL) and stirred at room temperature for 2.5 hours. The reaction mixture was partitioned by adding ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (45.5 mg) as an orange amorphous. (Yield 69%)

Reference example 4
7-Bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 4)

7-Bromo-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 3, 37.5 mg, 0.125 mmol) was added to anhydrous dichloromethane (1 mL). After dissolution, triethylamine (20.9 μL, 0.150 mmol) and methanesulfonyl chloride (10.7 μL, 0.138 mmol) were added sequentially. The reaction was stirred at room temperature overnight. The reaction mixture was partitioned by adding ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (28.7 mg) as an orange amorphous. (Yield 72%)

Reference Example 5
7-Bromo-8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 5-1)

7-bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 4, 801 mg, 2.52 mmol), 5-fluoro-2-methylphenol A mixture of (330 μL, 3.02 mmol) and potassium carbonate (524 mg, 3.79 mmol) was suspended in anhydrous N, N-dimethylformamide (10 mL) and stirred at 80 ° C. overnight. After cooling, ethyl acetate (80 mL) and water (50 mL) were added and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (945 mg) as a colorless solid. (Yield 92%)
Reference compound 5-1 can also be synthesized by the following method.

7-bromo-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference compound 3, 805 mg, 2.69 mmol), 5-fluoro-2-methylphenol (382 μL, 3.50 mmol) and tri-n-butylphosphine (874 μL, 3.50 mmol) were dissolved in anhydrous tetrahydrofuran (25 mL) and 1,1 ′-(azodicarbonyl) dipiperidine (883 mg, 3.50 mmol). ) And stirred at room temperature for 1 hour. Further 5-fluoro-2-methylphenol (382 μL, 3.50 mmol), tri-n-butylphosphine (874 μL, 3.50 mmol) and 1,1 ′-(azodicarbonyl) dipiperidine (890 mg, 3.53 mmol) were added. Added and stirred for 20 minutes. Hexane (15 mL) was added to the reaction solution, and insoluble material was removed by filtration. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (0.90 g) as a colorless solid. (Yield 82%)

参考例６
８−（５−フルオロ−２−メチルフェノキシメチル）−７−［２−メトキシ−４−（２−ニトロベンゾイルオキシ）フェニル］−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物６−１）

アルゴン雰囲気下、７−ブロモ−８−（５−フルオロ−２−メチルフェノキシメチル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物５−１、２．３２ｇ、５．７０ｍｍｏl）、２−メトキシ−４−メトキシメトキシフェニルボロン酸（参考化合物１０、２．４３ｇ、１１．５ｍｍｏl）、炭酸セシウム（９．４６ｇ、２９．０ｍｍｏl）および二塩化ビス（トリフェニルホスフィン）パラジウム（ＩＩ）（４１５ｍｇ、０．５９１ｍｍｏl）の混合物を無水Ｎ，Ｎ−ジメチルホルムアミド（２５ｍL）に懸濁し、８０℃で５時間攪拌した。放冷後、酢酸エチル（１５０ｍL）および水（１５０ｍL）を加えて分配した。有機層を飽和食塩水（１５０ｍL）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記参考化合物（２．７３ｇ）を無色固体として得た。（収率９７％）

Hereinafter, reference compounds 5-2, 5-6 were obtained according to the production method of reference compound 5-1, using compounds selected from reference compounds 2-2, 3, 4 and commercially available compounds.

Reference Example 6
8- (5-Fluoro-2-methylphenoxymethyl) -7- [2-methoxy-4- (2-nitrobenzoyloxy) phenyl] -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline -2-one (Reference compound 6-1)

Under an argon atmosphere, 7-bromo-8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 5-1, 2.32 g, 5.70 mmol), 2-methoxy-4-methoxymethoxyphenylboronic acid (reference compound 10, 2.43 g, 11.5 mmol), cesium carbonate (9.46 g, 29.0 mmol) and bis (2 dichloride) A mixture of triphenylphosphine) palladium (II) (415 mg, 0.591 mmol) was suspended in anhydrous N, N-dimethylformamide (25 mL) and stirred at 80 ° C. for 5 hours. After allowing to cool, ethyl acetate (150 mL) and water (150 mL) were added and partitioned. The organic layer was washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (2.73 g) as a colorless solid. (Yield 97%)

参考例７
７−（２−メトキシ−４−メトキシメトキシフェニル）−８−(５−メチルチオフェン−２−イルカルボニルオキシメチル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物７）

７−（２−メトキシ−４−メトキシメトキシフェニル）−８−（５−メチルチオフェンカルボニルオキシメチル）−３，３−ジメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物５−６、１．５８ｇ、３．１８ｍｍｏｌ）、よう化メチル（４００μL、６．４３ｍｍｏｌ）および炭酸セシウム（２．２４ｇ、６．８７ｍｍｏｌ）の混合物を無水Ｎ，Ｎ−ジメチルホルムアミド（３０ｍL）に懸濁し、室温で２時間攪拌した。酢酸エチル（１５０ｍL）を加え希釈した。水（１５０ｍL）および飽和食塩水（１５０ｍL）で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記参考化合物（１．３８ｇ）を淡黄色アモルファスとして得た。（収率８５％）

Hereinafter, using compounds selected from Reference Compounds 1, 5-2 to 5-5, and 10 and commercially available compounds, Reference Compounds 6-2 to 6-6 are obtained according to the production method of Reference Compound 6-1. It was.

Reference Example 7
7- (2-Methoxy-4-methoxymethoxyphenyl) -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxaline-2- ON (Reference compound 7)

7- (2-methoxy-4-methoxymethoxyphenyl) -8- (5-methylthiophenecarbonyloxymethyl) -3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 5- 6, 1.58 g, 3.18 mmol), methyl iodide (400 μL, 6.43 mmol) and cesium carbonate (2.24 g, 6.87 mmol) in suspension in anhydrous N, N-dimethylformamide (30 mL), Stir at room temperature for 2 hours. Ethyl acetate (150 mL) was added for dilution. The extract was washed successively with water (150 mL) and saturated brine (150 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.38 g) as a pale yellow amorphous product. (Yield 85%)

Reference Example 8
8- (5-Fluoro-2-methylphenoxymethyl) -7- (4-hydroxy-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference) Compound 8-1)

8- (5-Fluoro-2-methylphenoxymethyl) -7- (2-methoxy-4-methoxymethoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one ( Reference compound 6-1, 2.73 g, 5.52 mmol) was dissolved in a mixed solution of 1,4-dioxane (25 mL) and methanol (5 mL), and 4N hydrogen chloride / 1,4-dioxane solution (7.0 mL) was dissolved. , 28 mmol). The reaction solution was stirred at room temperature for 1 hour, and diluted by adding ethyl acetate (130 mL). The extract was washed successively with aqueous sodium hydrogen carbonate solution (130 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.41 g) as a pale yellow solid. (Yield 97%)

参考例９
２−ブロモ−５−メトキシメトキシアニソール（参考化合物９）

４−ブロモ−３−メトキシフェノール（５００ｍｇ、２．４６ｍｍｏｌ）、クロロジメチルエーテル（２８１μL、３．７０ｍｍｏｌ）および炭酸カリウム（８５０ｍｇ、６．１５ｍｍｏｌ）の混合物を無水Ｎ，Ｎ−ジメチルホルムアミド（８ｍL）に懸濁し、５０℃で１時間攪拌した。放冷後、酢酸エチル（１５０ｍL）を加えて希釈した。水（１５０ｍＬ）および飽和食塩水（５０ｍL）で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記参考化合物（４２１ｍｇ）を無色油状物して得た。（収率６９％）

Reference compounds 6-2, 6-3, 6-5, 7 and 11 were used below to obtain reference compounds 8-2 to 8-6 according to the production method of compound 8-1.

Reference Example 9
2-Bromo-5-methoxymethoxyanisole (Reference compound 9)

A mixture of 4-bromo-3-methoxyphenol (500 mg, 2.46 mmol), chlorodimethyl ether (281 μL, 3.70 mmol) and potassium carbonate (850 mg, 6.15 mmol) was suspended in anhydrous N, N-dimethylformamide (8 mL). It became cloudy and stirred at 50 ° C. for 1 hour. After cooling, ethyl acetate (150 mL) was added for dilution. The extract was washed successively with water (150 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (421 mg) as a colorless oil. (Yield 69%)

Reference Example 10
2-methoxy-4-methoxymethoxyphenylboronic acid (reference compound 10)

2-Bromo-5-methoxymethoxyanisole (reference compound 9, 7.94 g, 32.1 mmol), bis (neopentyl glycolate) diboron (10.9 g, 48.3 mmol), potassium acetate (6.30 g, 64.64 g). 2 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane complex (1: 1) (2.10 g, 2.57 mmol) were suspended in dimethyl sulfoxide (90 mL). , And stirred at 80 ° C. for 6 hours. After allowing to cool, ethyl acetate (500 mL) and water (500 mL) were added to the reaction solution and partitioned. The aqueous layer was extracted with ethyl acetate (200 mL, twice), the organic layers were combined, washed with saturated brine (400 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the obtained solid was collected by filtration with hexane to give the titled reference compound (1.94 g) as a colorless solid. (Yield 28%)

Reference Example 11
8- [N- (9-fluorenylmethoxycarbonyl) -N- (2-methoxyphenyl) aminomethyl] -7- (2-methoxy-4-methoxymethoxyphenyl) -1,3,3-trimethyl-3 , 4-Dihydro-1H-quinoxalin-2-one (Reference Compound 11)
7- (2-methoxy-4-methoxymethoxyphenyl) -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference compound 6) -4, 104 mg, 0.212 mmol) and sodium bicarbonate (22.0 mg, 0.262 mmol) were dissolved in a mixed solution of 1,4-dioxane (1.5 mL) and water (1 mL), and 9-fluorinated chloride was dissolved. Nylmethoxycarbonyl (60.3 mg, 0.233 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and diluted with ethyl acetate (50 mL). The extract was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (149 mg) as a colorless amorphous. (Yield 99%)

[Example]
Example 1
7- [4- [N- (2-Dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3- Trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound 1-1)

8- (5-Fluoro-2-methylphenoxymethyl) -7- (4-hydroxy-2-methoxyphenyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (reference) Compound 8-1 (400 mg, 0.888 mmol), 1,1′-carbonyldiimidazole (723 mg, 4.46 mmol) and 4-dimethylaminopyridine (12.5 mg, 0.102 mmol) were mixed in anhydrous tetrahydrofuran (8 ml). And stirred at room temperature for 1 hour. The reaction solution was heated to 60 ° C., N, N, N′-trimethylethylenediamine (600 μL, 4.62 mmol) was added, stirred for 3 hours, and purified by silica gel column chromatography (hexane-ethyl acetate). The title compound (402 mg) was obtained as a colorless amorphous. (Yield 78%)

実施例２
７−［４−［N−（２−ジメチルアミノエチル）−N−メチルアミノカルボニルオキシ］−２−メトキシフェニル］−８−（２−メトキシフェニルアミノメチル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（化合物２）
８−［N−（９−フルオレニルメトキシカルボニル）−N−（２−メトキシフェニル）アミノメチル］−７−（４−ヒドロキシ−２−メトキシフェニル）−１，３，３−トリメチル−３，４−ジヒドロ−１Ｈ−キノキサリン−２−オン（参考化合物８−６、３０．０ｍｇ、０．０４４８ｍｍｏｌ）、１，１’−カルボニルジイミダゾール（３６．３ｍｇ、０．２２４ｍｍｏｌ）および４−ジメチルアミノピリジン（０．５５ｍｇ、０．００４４８ｍｍｏｌ）の混合物を無水テトラヒドロフラン（０．５ｍｌ）に溶解し、室温で３０分攪拌した。反応液を６０℃に加温し、Ｎ,Ｎ,N’−トリメチルエチレンジアミン（２３．０ｍｇ、０．２２４ｍｍｏｌ）を加え、１．５時間撹拌した。反応液をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製した。得られた無色アモルファスをＮ，Ｎ−ジメチルホルムアミド（１．０ｍＬ）に溶解し、ピペリジン（５０μＬ）を加え、室温で２０分間攪拌した後、酢酸エチル（１０ｍL）で希釈した。水（１０ｍL）及び飽和食塩水（１０ｍL）で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン−酢酸エチル）で精製することにより標記化合物（１８．６ｍｇ）を無色アモルファスとして得た。（収率７２％）

Hereinafter, using a compound selected from Reference Compounds 8-1 to 8-5 and a commercially available compound, Compounds 1-2 to 1-14 were obtained according to the production method of Compound 1-1.

Example 2
7- [4- [N- (2-Dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3 , 4-Dihydro-1H-quinoxalin-2-one (compound 2)
8- [N- (9-fluorenylmethoxycarbonyl) -N- (2-methoxyphenyl) aminomethyl] -7- (4-hydroxy-2-methoxyphenyl) -1,3,3-trimethyl-3, 4-dihydro-1H-quinoxalin-2-one (reference compound 8-6, 30.0 mg, 0.0448 mmol), 1,1′-carbonyldiimidazole (36.3 mg, 0.224 mmol) and 4-dimethylaminopyridine (0.55 mg, 0.00448 mmol) was dissolved in anhydrous tetrahydrofuran (0.5 ml) and stirred at room temperature for 30 minutes. The reaction solution was heated to 60 ° C., N, N, N′-trimethylethylenediamine (23.0 mg, 0.224 mmol) was added, and the mixture was stirred for 1.5 hours. The reaction solution was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained colorless amorphous was dissolved in N, N-dimethylformamide (1.0 mL), piperidine (50 μL) was added, and the mixture was stirred at room temperature for 20 minutes, and then diluted with ethyl acetate (10 mL). The extract was washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the title compound (18.6 mg) as a colorless amorphous product. (Yield 72%)

[Formulation example]
Examples of general preparations containing the compound of the present invention are shown below.

1) Tablet (in 150mg)
1 mg of the present compound
Lactose 100mg
Corn starch 40mg
Carboxymethylcellulose calcium 4.5mg
Hydroxypropylcellulose 4mg
Magnesium stearate 0.5mg

The tablet of the above formulation can be coated with 3 mg of a coating agent (for example, a commonly used coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the intended tablet. Moreover, a desired tablet can also be obtained by changing suitably the compound of this invention, the kind of additive, and / or the quantity of an additive.

2) Capsule (in 150mg)
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 compound of the present invention, the type of additive and / or the amount of additive.

3) 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 compound of the present invention, the type of additive and / or the amount of the additive.

[Pharmacological test]
1. GR binding activity evaluation test In order to evaluate the binding activity of the compound of the present invention to GR, a GR receptor competition assay by polarized fluorescence was performed. The assay was performed using a GR competition assay kit (Invitrogen, Cat No. P2816) according to the protocol attached to this kit. The specific method is described below.

(Reagent preparation)
GR screening buffer: 10 mM potassium phosphate (pH 7.4), 20 mM sodium molybdate (Na ₂ MoO ₄ ), 0.1 mM ethylenediaminetetraacetic acid (EDTA), 5 mM dithiothreitol (DTT), 0.1 mM stabilizing peptide and 2% A buffer of dimethyl sulfoxide was prepared.

4 × GS1 solution: Fluormone ^™ GS1, which is a fluorescent glucocorticoid ligand, was diluted with a GR screening buffer to prepare a 4 nM solution.

  4 × GR solution: Recombinant human GR was diluted with GR screening buffer to prepare a 16 nM solution.

(Preparation of test compound solution)
After the test compound was dissolved in dimethyl sulfoxide, this solution was diluted with a GR screening buffer to prepare a 20 μM test compound solution.

(Test method and measurement method)
1) A test compound solution was injected into a 384-well plate at 10 μL per well, and then 4 × GS1 solution and 4 × GR solution were added at 5 μL per well.

2) Incubate in the dark at room temperature for 2-4 hours.

3) Using a multi-mode plate reader Analyst ^™ HT (manufactured by LJL Biosystems), measure the fluorescence polarization of each well using a well containing GR screening buffer instead of the test compound solution and 4 × GS1 solution as a blank. did.

4) A GR screening buffer was used in place of the test compound solution, and the other operations were the same as in 1-3) described above, and the result was used as a negative control.

5) Using 2 mM dexamethasone instead of the test compound solution, the same procedure as in 1) to 3) above was performed, and the result was used as a positive control.

(Calculation of GR coupling rate)
The GR bond rate (%) was calculated by the following formula.

GR binding rate (%) = 100 × {1− (fluorescence polarization of test compound solution−fluorescence polarization of positive control solution) / (fluorescence polarization of negative control solution−fluorescence polarization of positive control solution)}

(Test results and discussion)
As test compounds, compound 1-1, compound 1-2, compound 1-3, compound 1-4, compound 1-5, compound 1-6, compound 1-7, compound 1-8, compound 1-9, compound When 1-10, Compound 1-11, Compound 1-12, and Compound 1-13 were used, all of these compounds exhibited a GR bond rate of 80% or more.

2. Evaluation Test of GR Agonist Activity In order to evaluate the action of the compound of the present invention as a GR agonist, the IL-6 production inhibitory action in human corneal epithelial cell lines after LPS stimulation was examined. The measurement of IL-6 production in the sample was performed using the HTRF method (Boehringer-Ingelheim, Cat No. 62IL6PEB) according to the attached protocol. The specific method is described below.

(Reagent preparation)
LPS preparation solution: LPS was dissolved in PBS (−), and this solution was diluted with a culture solution to prepare a 1 μg / mL LPS solution.

(Preparation of test compound solution and dexamethasone (hereinafter referred to as `` DEX '') solution)
After the test compound was dissolved in dimethyl sulfoxide, this solution was diluted with a culture solution to prepare a 100 μM test compound solution. In addition, DEX was dissolved in the same manner to prepare a 100 μM DEX solution, and the inhibition rate of IL-6 production by DEX was measured and used to calculate Efficiency (% DEX).

(Used cells and culture method)
Cells used: Human corneal epithelial cell line (HCE-T) (RIKEN)
Culture method:
1) HCE-T grown to a subconfluent state was washed with PBS (-), and the cells were detached by trypsin-EDTA treatment.

2) Add SHEM medium (supplemented hormone epithelial medium: 15% FBS, 5μg / mL insulin, 0.1μg / mL choleratoxin, 10ng / mL human EGF, 40μg / mL gentamicin-containing DMEM / Ham's F12) to inactivate trypsin did.

3) The above suspension was recovered, and a cell sediment after centrifugation at 1000 rpm for 5 minutes was obtained.

4) The cell sediment was suspended in a SHEM medium, seeded in a culture flask, and cultured in a CO ₂ incubator (temperature: 37 ° C., CO ₂ concentration: 5%). By this method, cells that had been subcultured were used for the test.

(Test method and measurement method)
1) The subcultured HCE-T was collected and cells were seeded in a 96-well flat bottom culture plate at 2.0 × 10 ⁴ cells / 0.1 mL / well.

2) After overnight culture, the medium was removed, and 10% FBS-DMEM / Ham's F12 medium was added at 80 μL / well.

3) 10 μL / well of each test compound solution was added.

4) 10 μL / well of LPS solution was added.

        5) A negative control was prepared by adding 10% FBS-DMEM / Ham's F12 medium instead of each test compound solution and LPS solution.

        6) 10% L / well of 10% FBS-DMEM / Ham's F12 medium containing 1% DMSO instead of each test compound solution was used as a positive control.

7) After 4 hours of culture, the supernatant was collected, and the amount of IL-6 released in the supernatant was measured using HTRF human IL-6 Kit.

8) The IL-6 production inhibition rate was calculated according to the following formula.

(Calculation of IL-6 production inhibition rate)
IL-6 production inhibition rate (%) was calculated by the following formula.

IL-6 production suppression rate (%) = 100X {1− (IL-6 production amount of each sample−IL-6 production average value of negative control group) / (IL-6 production average value of positive control group−) IL-6 production average value of negative control group)} (%)

Further, IL-6 production inhibition rate (Efficacy (% DEX)) was calculated when the DEX treatment group was taken as 100.

表Ｉに示したとおり本発明化合物は優れたIL-6産生抑制作用を示した。よって、前記１．GR結合活性評価試験の結果と併せ、本発明化合物はGRアゴニストとして有用であり、ステロイド類等のGRアゴニストが有用とされる疾患、特に炎症性疾患（骨・関節疾患、炎症性眼疾患等）の治療剤として有用であることが確認された。 Efficacy (% DEX) = 100X {(average IL-6 production suppression rate of each sample) / (average DEX treatment group IL-6 production suppression rate)} (%)

(Test results and discussion)
As test compounds, compound 1-1, compound 1-2, compound 1-3, compound 1-4, compound 1-5, compound 1-6, compound 1-7, compound 1-8, compound 1-9, compound Table I shows the IL-6 production inhibition rate (% DEX) when 1-10, Compound 1-11, Compound 1-12 and Compound 1-15 are used.

As shown in Table I, the compound of the present invention showed an excellent IL-6 production inhibitory action. Therefore, the above 1. Together with the results of the GR binding activity evaluation test, the compounds of the present invention are useful as GR agonists, and diseases in which GR agonists such as steroids are useful, particularly inflammatory diseases (bone / joint diseases, inflammatory eye diseases, etc.) It was confirmed to be useful as a therapeutic agent.

3. Inhibitory Effect of Increased Vascular Permeability in Allergic Conjunctivitis Model In order to evaluate the antiallergic action of the compound of the present invention, the effect of the compound of the present invention on the increase in vascular permeability was examined against the allergic conjunctivitis model of mice. This effect can be calculated from the amount of dye leakage in the base administration group (control group) and the amount of dye leakage in the test compound administration group.

(Preparation of test compound suspension)
0.5% polysorbate 80 / physiological saline was added to the test compound to prepare a 1% (W / V) test compound suspension.

(Method for producing and evaluating allergic conjunctivitis model)
1) Aluminum hydroxide gel-adsorbed ovalbumin (20 μg / mL) was dissolved in physiological saline, and 500 μL each was injected intraperitoneally into a 6-week-old male BALB / c mouse for active sensitization.

2) On the 6th day of sensitization, 500 μL each of aluminum hydroxide gel-adsorbed ovalbumin (20 μg / mL) was injected again for additional sensitization.

3) On the 11th, 12th, 13th, 14th and 15th day from the first sensitization, 2 μL / eye of a 50% glycerol solution containing 15% (W / V) ovalbumin was used in the right eye of each mouse. Instilled into the skin to induce allergic conjunctivitis.

4) At 3 hours, 1 hour and 15 minutes before ophthalmic ophthalmic ophthalmic administration on the 15th day of sensitization (total 3 times), the test compound suspension was instilled into the right eye of the mouse at 2 μL / eye each. Administered. In the base administration group (control group), 0.5% polysorbate 80 / physiological saline was used instead of the test compound suspension.

5) Immediately before the instillation of ovalbumin on the 15th day of sensitization, 0.1% Evans Blue solution was injected from the tail vein of the mouse. The pigment was extracted with Next, the absorbance of the extracted dye is measured, the amount of the leaked dye is calculated from the obtained absorbance, and the inhibition rate of the increase in vascular permeability of the test compound administration group with respect to the increase in vascular permeability associated with allergic conjunctivitis is calculated using Formula 1. did.

表ＩＩに示したとおり、本化合物は優れた血管透過性亢進阻害作用を示した。よって、本化合物は前眼部炎症性疾患の治療剤、特にアレルギー性結膜炎等のアレルギー性眼疾患の治療剤として有用であることが確認された。
(Calculation formula 1)
Inhibition rate of increased vascular permeability (%) = (1-Ax / Ao) x 100 in the test compound administration group
Ao: Dye leakage in the base administration group (control group)
Ax: Dye leakage in the test compound administration group

(Test results and discussion)
Table II shows the inhibition rate of increase in vascular permeability when Compound 1-1, Compound 1-2, Compound 1-3, Compound 1-5, and Compound 1-6 were used as test compounds.

As shown in Table II, this compound showed an excellent vascular permeability enhancement inhibitory action. Therefore, it was confirmed that this compound is useful as a therapeutic agent for anterior ocular inflammatory diseases, particularly for allergic eye diseases such as allergic conjunctivitis.

4). Evaluation test of choroidal neovascularization inhibitory effect As one of the general methods for evaluating the choroidal neovascularization inhibitory effect of drugs, a neovascularization test using a rat choroidal neovascularization model is known, and the test method is Graefe's Arch. Cli. Exp. Ophthalmol., 235,313-319 (1997). Therefore, in accordance with the method described in the above-mentioned literature, a neovascular expression test of the compound of the present invention is performed, and the ratio of the neovascular expression rate of the compound administration group to the neovascular expression rate of the base administration group (control group) is calculated. Thus, the choroidal neovascularization inhibitory effect of the compound of the present invention can be evaluated using it as an index.

(Preparation of test compound suspension)
In the case of ophthalmic administration, the test compound was suspended in 0.5% polysorbate 80 / physiological saline to prepare a 1% (W / V) test compound suspension. In the case of subconjunctival administration, the test compound was suspended in 0.5% hydrogenated castor oil / saline solution to prepare a 20 mg / mL test compound suspension.

(Laser-induced rat choroidal neovascularization model)
1) Rats (Brown Norway male rats, 7-8 weeks old) were intramuscularly administered with a 7: 1 mixture (1 mL / kg) of 5% ketamine hydrochloride injection and 2% xylazine hydrochloride injection and general anesthesia.

2) Tropicamide / phenylephrine hydrochloride ophthalmic solution (trade name: Midrin P) was instilled to give mydriasis, and then the Bruch membrane of the rat was photocoagulated using a krypton laser photocoagulator.

Laser irradiation was performed in a scattered manner at 8 locations per eye, avoiding the thick retinal blood vessels in the back of the fundus and focusing on the deep retina. The photocoagulation conditions were a spot size of 100 μm, an output of 100 mM, and a coagulation time of 0.1 seconds.

3) After photocoagulation, fundus photography was performed to confirm the photocoagulation (laser irradiation) site.

(Test method and measurement method)
1) In the case of ophthalmic administration, the test compound suspension was instilled 4 times a day from the laser irradiation day (1st day) to the 8th day. In the case of subconjunctival administration, 50 μL was injected once immediately after laser irradiation.

2) Use 0.5% polysorbate 80 / saline solution or 0.5% hydrogenated castor oil / saline solution as the base administration group (control group) instead of the test compound suspension, and otherwise use the same method as 1). A test was conducted and the result was used as a control.

(Evaluation methods)
1) On day 7 of photocoagulation, 0.1 mL of a 10% fluorescein aqueous solution was injected from the tail vein of the rat, and fluorescence fundus imaging was performed.

2) Next, when the fluorescence fundus angiography showed no fluorescence leakage spot, the spot where fluorescence leakage was observed was positive, and there were two photocoagulation sites where some fluorescence leakage was observed. Judgment was positive.

3) The neovascularization rate was calculated according to Formula 1. According to the calculation formula 2 from the neovascularization rate of each administration group, the ratio of the neovascularization rate of the test compound administration group to the base administration group was calculated.

表ＩＩＩに示したとおり、本化合物は基剤と比較して、優れた新生血管抑制作用を示した。よって、後眼部炎症性疾患治療剤、特に加齢黄斑変性、糖尿病網膜症、糖尿病黄斑浮腫等の網膜疾患の治療剤として有用であることが確認された。 (Calculation formula 1)
New blood vessel expression rate (%) = (number of positive photocoagulation sites / total number of photocoagulation sites) x 100
(Calculation formula 2)
Neovascular inhibition rate of test compound administration group (%) = (1-Ax / Ao) x 100
Ao: Neovascularization rate in the vehicle administration group (control group)
Ax: Neovascularization rate of test compound administration group

(Test results and discussion)
Table III shows the inhibition rates when Compound 1-1, Compound 1-2, Compound 1-3, and Compound 1-4 were used as test compounds.

As shown in Table III, this compound showed an excellent neovascular inhibitory action as compared with the base. Therefore, it was confirmed that it is useful as a therapeutic agent for posterior ocular inflammatory diseases, particularly retinal diseases such as age-related macular degeneration, diabetic retinopathy, and diabetic macular edema.

Claims (12)

A compound represented by the following general formula (1) or a salt thereof.

[R ¹ represents the following general formula (2a), (3a), (4a) or (5a);

R ² represents a lower alkyl group;
R ³ represents a hydrogen atom, a lower alkyl group that may have a substituent, a lower cycloalkyl group that may have a substituent, an aryl group that may have a substituent, or a complex that may have a substituent. A cyclic group, an aralkyl group which may have a substituent or a heterocyclic lower alkyl group which may have a substituent;
R ^{4 and} R ⁵ are the same or different and are a hydrogen atom, a lower alkyl group that may have a substituent, an aralkyl group that may have a substituent, or a heterocyclic lower alkyl group that may have a substituent. R ⁴ and R ⁵ may together form a nitrogen-containing 5- or 6-membered ring which may have a substituent;
A represents a lower alkylene group;
R ⁶ , R ⁷ , R ⁸ or R ⁹ represents a halogen atom, an optionally substituted lower alkyl group, a hydroxy group, an optionally substituted lower alkoxy group or a nitro group;
m, n, p or q represents 0, 1 or 2,
When m, n, p or q represents 2, each R ⁶ , R ⁷ , R ⁸ or R ⁹ may be the same or different. ]
In general formula (1),
R ¹ represents the following general formula (2a), (3a), (4a) or (5a);

R ² represents a lower alkyl group;
R ³ represents a hydrogen atom, a lower alkyl group that may have a substituent, a lower cycloalkyl group that may have a substituent, an aryl group that may have a substituent, or a complex that may have a substituent. A cyclic group, an aralkyl group which may have a substituent or a heterocyclic lower alkyl group which may have a substituent;
R ^{4 and} R ⁵ are the same or different and are a hydrogen atom, a lower alkyl group that may have a substituent, an aralkyl group that may have a substituent, or a heterocyclic lower alkyl group that may have a substituent. R ⁴ and R ⁵ may together form a nitrogen-containing 5- or 6-membered ring which may have a substituent;
A represents a lower alkylene group;
R ⁶ represents a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group or a nitro group;
R ⁷ represents a halogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group;
R ⁸ represents a halogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy group;
R ⁹ represents a halogen atom or a lower alkyl group;
m, n or p represents 1 or 2,
when m, n or p represents 2, each R ⁶ , R ⁷ and R ⁸ may be the same or different;
The compound or a salt thereof according to claim 1, wherein q represents 0 or 1.
In general formula (1),
R ¹ represents the following general formula (2b-1), (2b-2), (2b-3), (3b-1), (3b-2) or (5b-1);

R ² represents a methyl group;
R ³ represents a lower alkyl group, a lower alkyl group optionally having a lower alkylamino group as a substituent, an aralkyl group or a heterocyclic lower alkyl group;
R ⁴ or R ⁵ may be the same or different and each represents a lower alkyl group, and R ⁴ and R ⁵ may be combined to form a nitrogen-containing six-membered ring;
The compound or a salt thereof according to claim 1, wherein A represents a lower alkylene group.
7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-ethylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-diethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3- Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N-methyl-N- [2- (piperidin-1-yl) ethyl] aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl)- 1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N- (pyridin-3-ylmethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxy-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N-ethyl-N- (2-diethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3- Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N, N-bis (2-dimethylaminopropyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3- Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 , 3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methyl-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl- 3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenylaminomethyl) -1,3 3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-isopropylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxy-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxy-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (2-methyl-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methyl-5-nitrophenoxymethyl) -1,3,3 -Trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-ethylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 , 3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 , 3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N- (pyridin-3-ylmethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxy Methyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 , 3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N, N-bis (3-dimethylaminopropyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-isopropylaminocarbonyloxy] -2-methoxyphenyl] -8- (5-methylthiophen-2-ylcarbonyloxymethyl) -1,3 , 3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
8- (5-Bromothiophen-2-ylcarbonyloxymethyl) -7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -1,3 , 3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (4-methylbenzoyloxymethyl) -1,3,3-trimethyl- 3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (4-methylbenzoyloxymethyl) -1,3,3-trimethyl- 3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (4-methylbenzoyloxymethyl) -1,3,3-trimethyl- 3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (4-methoxybenzoyloxymethyl) -1,3,3-trimethyl- 3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-ethylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl- 3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl- 3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N- (pyridin-3-ylmethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1, 3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl- 3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N, N-bis (3-dimethylaminopropyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl-3 , 4-dihydro-1H-quinoxalin-2-one,
7- [4- [N- (2-dimethylaminoethyl) -N-isopropylaminocarbonyloxy] -2-methoxyphenyl] -8- (2-methoxyphenylaminomethyl) -1,3,3-trimethyl- 3,4-dihydro-1H-quinoxalin-2-one,
7- [4- [N-benzyl-N- (2-dimethylaminoethyl) aminocarbonyloxy] -2-methoxyphenyl] -8- (5-fluoro-2-methylphenylaminomethyl) -1,3 3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one, and 7- [4- [N- (3-dimethylaminopropyl) -N-methylaminocarbonyloxy] -2-methoxyphenyl]- A compound selected from the group consisting of 8- (5-fluoro-2-methylphenylaminomethyl) -1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one or a salt thereof.
A pharmaceutical composition comprising at least one of the compound according to claim 1 or a salt thereof.
A glucocorticoid receptor modulator comprising the compound according to claim 1 or a salt thereof.
The glucocorticoid receptor modulator according to claim 6, wherein the glucocorticoid receptor modulator is a glucocorticoid receptor agonist.
An inflammatory disease therapeutic agent comprising at least one of the glucocorticoid receptor modulators according to claim 7 as an active ingredient.
A therapeutic agent for bone and joint diseases comprising at least one of the glucocorticoid receptor modulators according to claim 7 as an active ingredient.
The therapeutic agent for ocular inflammatory diseases containing at least one of the glucocorticoid receptor modulators according to claim 7 as an active ingredient.
The therapeutic agent for ocular inflammatory disease according to claim 10, wherein the ocular inflammatory disease is an anterior ocular inflammatory disease.
The therapeutic agent for ocular inflammatory disease according to claim 10, wherein the ocular inflammatory disease is a posterior ocular inflammatory disease.