WO2004110454A1 - Composition de traitement ou de prevention de maladies necessitant l'administration d'un agoniste du recepteur a2a de l'adenosine - Google Patents

Composition de traitement ou de prevention de maladies necessitant l'administration d'un agoniste du recepteur a2a de l'adenosine Download PDF

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WO2004110454A1
WO2004110454A1 PCT/JP2004/008201 JP2004008201W WO2004110454A1 WO 2004110454 A1 WO2004110454 A1 WO 2004110454A1 JP 2004008201 W JP2004008201 W JP 2004008201W WO 2004110454 A1 WO2004110454 A1 WO 2004110454A1
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group
optionally substituted
substituted
disease
salt
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PCT/JP2004/008201
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English (en)
Japanese (ja)
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Fuminori Kato
Kazuhiro Yamamoto
Tetsuo Yoneda
Kumiko Azuma
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Ishihara Sangyo Kaisha, Ltd.
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Publication of WO2004110454A1 publication Critical patent/WO2004110454A1/fr

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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Definitions

  • Thread composition for treating or preventing diseases requiring administration of adenosine A2a receptor agonist
  • the present invention relates to a composition for treating or preventing a disease requiring administration of an adenosine A2a receptor agonist, and is useful as a medicament such as a wound healing promoter.
  • Adenosine receptor is a seven-transmembrane G protein-coupled receptor widely distributed in vivo, and it has been known that there are four subtypes of Al, A2a, A2b and A3 so far. I have. A1 and A3 are coupled to adenylate cyclase-inhibited Gi protein, and A2a and A2b are coupled to activated Gs protein, respectively, and play important roles in various physiological functions by regulating the concentration of cAMP, a second messenger It is considered. The A1 and A2a receptors have high affinity for adenosine, whereas the A2b and A3 receptors have low affinity, and their subtypes have different localization and distribution in tissues in vivo. I have.
  • Stimulation of adenosine A2a receptors by agonists is also associated with promotion of wound healing, sleep, hypothermia, hypotension, suppression of immune cell function, suppression of neutrophil function, tumor necrosis factor-H (TNF-a) and interleukin-1. It has been reported to induce various actions such as suppression of production of cytokins such as 2 (IL-2).
  • the condensed heterocyclic compound of the formula (I) described below is a compound described in WO02 / 40485 as an active ingredient of a preventive or therapeutic agent for diabetes.
  • these compounds have an adenosine A2a receptor agonist action.
  • Patent Document 1 International Publication WO02 / 40485
  • the present inventors have found that a specific fused heterocyclic compound or a salt thereof has an adenosine A2a agonist action, and have accomplished the present invention.
  • the present invention provides a compound represented by the formula (I)
  • A is a nitrogen atom or a CG group ⁇ G is CN, NO, SOR 3 group (R 3 is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, substitution which may be a cycloalkyl group, an optionally substituted cycloalkenyl group, a substituted by Moyoi Ariru group or an optionally substituted heterocyclic group), CO R 4 group (R 4 is , Hydrogen atom
  • R a and R b are each independently a hydrogen atom, a hydroxyl group, an alkoxy group, an optionally substituted alkyl group, a substituted Alkenyl group which may be substituted, alkynyl group which may be substituted, cycloalkyl group which may be substituted, cycloalkenyl group which may be substituted, aryl group which may be substituted or heterocyclic ring which may be substituted R a and R b together form a ring) or a CONR a R b group (where R a and R b are as defined above) ⁇ ;
  • R 1 and R 2 are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, An optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, a -B ⁇ R 5 group (B 1 is C ⁇ , COO, 0, ⁇ CO, OSO,
  • R 5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, Optionally substituted cycloalkenyl group, optionally substituted aryl group or substituted
  • An optionally substituted amino group or N CR 6 R 7 group (R 6 and R 7 are each independently a hydrogen atom, an optionally substituted alkyl group, An optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group. There is);
  • Y and Z are each independently a nitrogen atom or C - R 8 group ⁇ R 8 is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, ⁇ optionally substituted Norekiniru Group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted aryl group, optionally substituted heterocyclic group, —B 2 —R 9 group (B 2 is , CO ⁇ , 0, OCO, OSO, S, SO or SO, wherein R 9 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, A cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, an aryl group or a heterocyclic group which may be substituted), Group, a
  • X is a nitrogen atom or a CR 1Q group
  • R 1Q is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted A cycloalkyl group, an optionally substituted cycloalkenyl group, one B 2 —R 9 group (B 2 and R 9 are as defined above), an optionally substituted amino group, a cyano group or a nitro group ⁇ ;
  • Y is C one R 8 groups, if X is C one R 1Q group or Z is a C one R 8 groups, R 8 and R 1Q there have two R 8 are hetero atoms together such connexion A ring may be formed with or without the adenosine A2a receptor agonist containing, as an active ingredient, a fused heterocyclic compound represented by the formula (1) or a salt thereof. Composition.
  • the salt of the fused heterocyclic compound of the formula (I) may be a pharmaceutically acceptable salt, for example, a mineral acid salt such as hydrochloride, sulfate, nitrate, etc .; ⁇ _toluenesulfonate, propane Organic acid salts such as sulfonates and methanesulfonates; alkali metal salts such as potassium salts and sodium salts; alkaline earth metal salts such as calcium salts; triethanolamine salts; Organic amine salts such as ris (hydroxymethyl) aminomethane salt and the like can be mentioned. Some of these salts have water of crystallization.
  • a mineral acid salt such as hydrochloride, sulfate, nitrate, etc .
  • ⁇ _toluenesulfonate propane Organic acid salts such as sulfonates and methanesulfonates
  • alkali metal salts such as potassium salts and sodium salts
  • R 2 , R 3 The alkyl moiety of the alkyl group which may be substituted represented by R 1Q , Ra and R b generally has a carbon number of 119, for example, a methynole group, an ethyl group, a propyl group, a butyl group, a pentyl group Hexyl group, octyl group, nonyl group, decyl group, nonadecyl group and the like, and these also include those having linear or branched structural aliphatic isomers.
  • R 1 R 2 , R 3 The substituted or unsubstituted alkenyl moiety of the alkenyl group or the alkynyl moiety of the alkynyl group represented by R a or R b generally has 2 to 18 carbon atoms. They also include those having structural isomers of linear or branched fatty chains.
  • R 2 , R 3 , R 4 , R 5 , R 6 The cycloalkyl portion of the substituted or unsubstituted cycloalkyl group represented by R 1Q , R a and R b and the cycloalkenyl portion of the optionally substituted cycloalkenyl group generally have 3 to 10 carbon atoms.
  • Monocyclic groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopentenyl group and cyclohexenyl group, condensed polycyclic groups and crosslinked polycyclic groups. And the like.
  • the aryl group of the aryl group which may be substituted represented by R 5 , R 6 , R 7 , R 8 , R 9 , R a and R b may be a phenyl group or a condensed type such as a naphthyl group. And polycyclic groups.
  • the heterocyclic moiety of the optionally substituted heterocyclic group represented by R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R a and R b includes a pyrrolyl group, a pyrrolinyl group, a pyrrolidinyl Group, furanyl group, dihydrofuranyl group, tetrahydrofuranyl group, phenyl group, dihydrophenyl group, tetrahydrophenyl group, pyrazolyl group, pyrazolinyl group, pyrazolidinyl group, imidazolyl group, imidazolinyl group, imidazolidinyl group, oxazolyl group, oxazolinyl group Group, oxazolidinyl group, isoxazolyl group, isoxazolinyl group, isoxazolidinyl group, thiazolyl group, thi
  • R 2 , R 3 The secondary substituents of the substituted or unsubstituted, alkyl, substituted or alkenyl, substituted or unsubstituted or alkynyl groups represented by R 1Q , Ra and R b include: Halogen atom, hydroxyl group, mercapto group, substitutable alkoxy group, substitutable alkylthio group, substitutable alkenyloxy group, substitutable alkenylthio group, substitutable alkynyloxy group, substitutable alkynylthio group, substitutable cycloalkyl Group, substitutable cycloalkenyl group, substitutable cycloalkoxy group, substitutable cycloalkylthio group, substitutable cycloalkenyloxy group, substitutable cycloalkenylthio group, substitutable alkoxycarbonyl group, substitutable alkylcarbonyl group, substitutable Alkyl carboxy alkoxy, substituted alkenyloxycarbonyl,
  • R 2 , R 3 Secondary of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted aryl group and a substituted or unsubstituted heterocyclic group represented by R 1Q , R a and R b
  • substituent include a halogen atom, a hydroxyl group, a mercapto group, a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted alkoxy group, a substituted alkylthio group, a substituted alkenyloxy group, a substituted alkenyl group.
  • Examples of the substituted substituent of the substituted or unsubstituted amino group represented by R 8 and R 1Q include a hydroxyl group, a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted alkoxy group, Substituted alkenyloxy group, substituted alkynyloxy group, substituted cycloalkyl group, substituted cycloalkenyl group, substituted cycloalkoxy group, substituted cycloalkenyloxy group, substituted alkoxycarbonyl group, substituted alkylcal Bonyl group, substituted alkenyloxycarbonyl group, substituted alkenylcarbonyl group, substituted alkynyloxycarbonyl group, substituted alkynylcarbonyl group, substituted cycloalkoxycarbonyl group, substituted cycloalkylcarbonyl group, substituted cycloalkenyl group Xycarbonyl
  • the tertiary substituent of each substitutable group includes a halogen atom, a hydroxyl group, a mercapto group, a cyano group, a nitro group, a carboxy group, an amino group, an alkyl group, an alkenyl group, and an alkynyl group.
  • substitution groups may be the same or different. Further, when the secondary substituent is an amino group substituted by two tertiary substituents, the tertiary substituents may form a ring together with or without a hetero atom-containing force. Les ,.
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic moieties of these tertiary substituents further include a halogen atom, a hydroxyl group, a mercapto group, a cyano group, a nitro group, Carboxyl group, amino group, alkynole group, haloalkyl group, alkoxy group, haloalkoxy group, alkylthio group, noroanokelthio group, alkoxycarbonyl group, aminocarbonyl group, alkylaminocarboxy group, dialkylaminocarbonyl group, amino Quaternary groups such as sulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, anoalkylamino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino,
  • A is a CG group (G is as described above);
  • R 1 and R 2 are each independently a hydrogen atom, an optionally substituted alkyl group, a —B 1 —R 5 group (B 1 And R 5 are the same as described above) or an optionally substituted amino group
  • Y and Z are each independently a nitrogen atom or a CR 8 group (where R 8 is a hydrogen atom, And X is a nitrogen atom or a C_R 1Q group (R 1Q is a hydrogen atom or a halogen atom), or a —B 2 —R 9 group (B 2 and R 9 are as described above).
  • 0 is ⁇ CO R 4 group (R 4 is as described above), SO NR a R b group or CONR a R b group (R a and R b are as described above) (1 )) Or a salt thereof.
  • (3 1 and R 2 are each independently a condensation of (1) or (2) which is a B ⁇ R 5 group (B 1 and R 5 are as defined above) or an amino group which may be substituted.
  • R 1 and R 2 may have an amino group which may be substituted.A hydroxyl group, a substituted alkyl group, a substituted alkynyl group, a substituted alkoxy group, a substituted aryl group, a substituted aryloxy group or a substituted heterocyclic group
  • the fused heterocyclic compound of (1) which is an amino group which may be substituted with or a salt thereof.
  • the compound of the formula (I) or a salt thereof has an agonist action on adenosine A2a receptor, promotes wound healing, induces sleep, lowers body temperature, lowers blood pressure, suppresses immune cell function, and suppresses neutrophils. It has pharmacological effects such as suppression of function and suppression of production of cytokins such as TNF-, IL_2, IL_4, and interferon- ⁇ .
  • the compound of the formula (I) or a salt thereof is used for skin ulcer, leg ulcer, burn ulcer, frostbite ulcer, traumatic ulcer, pressure ulcer, venous ulcer, arterial ulcer, post-herpetic ulcer, radiation ulcer Wound healing promoter used for treatment or prevention of drug ulcer, diabetic ulcer, postoperative ulcer, etc .; Sleep inducer used for treatment or prevention of insomnia, psychiatric disease, etc .; Treatment of febrile illness Antipyretics used for the prevention or prevention of blood pressure; antihypertensives used for the treatment or prevention of hypertension; drugs for the treatment or prevention of diseases associated with abnormally enhanced immune cell function and / or production of cytodynamics; abnormal neutrophil function It is useful as an active ingredient such as a therapeutic or prophylactic agent for a disease associated with hypertension.
  • the above-mentioned diseases accompanied by abnormally enhanced immune cell function and / or cytodynamic production include autoimmune diseases, erythema nodosum leprosum, Behcet's disease, lupus erythematosus, aphthous ulcers, cancer and infectious diseases in infectious diseases.
  • Fluid quality Fluid quality, septic shock, adult respiratory distress syndrome, osteoarthritis, multiple sclerosis, Crohn's disease, inflammatory bowel disease, multiple organ failure, malaria, meningitis, hepatitis, acquired immunodeficiency syndrome, junction measles, Food allergy, anaphylactic shock, eosinophilia syndrome, asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, other allergic diseases, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, Hashimoto's thyroiditis, severe Examples include myasthenia, multiple sclerosis, other organ-specific autoimmune diseases, and rejection associated with organ transplantation.
  • Examples of the disease associated with abnormally enhanced neutrophil function include adult respiratory distress syndrome (
  • ARDS bronchitis, chronic bronchitis, chronic obstructive pneumonia, cystic fibrosis, asthma, emphysema, Tracheal diseases such as bronchiectasis, chronic sinusitis and rhinitis, male erectile dysfunction, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischemic reperfusion injury, rheumatoid arthritis, multiple sclerosis, psoriasis, Dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Helicobacter 'Heriobacter pylori' gastritis, non-Helicobacter 'H. pylori' gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract No.
  • a method for treating or preventing a disease requiring administration of an adenosine A2a receptor agonist comprising administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.
  • a method for treating or preventing a wound comprising administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.
  • a method for treating or preventing a sleep disorder which comprises administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.
  • a method for treating or preventing a febrile disease comprising administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.
  • a method for treating or preventing hypertension which comprises administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.
  • Treating or preventing a disease associated with abnormally enhanced immune cell function and / or cytodynamic production which comprises administering an effective amount of the compound of the formula (I) or a salt thereof to mammals including humans. how to.
  • a method for treating or preventing a disease associated with abnormally enhanced neutrophil function comprising administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.
  • the compound of the formula (I) or a salt thereof is generally used in the form of a general pharmaceutical preparation (for example, a method prescribed in the 14th revised Japanese Pharmacopoeia).
  • This pharmaceutical preparation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and lubricants.
  • Various forms of pharmaceutical preparations can be selected according to the purpose of treatment, such as tablets, pills, powders, powders, granules, capsules, suppositories, solutions, suspensions, emulsions, injections (solutions, suspensions).
  • Agents) sprays, aerosols, creams, ointments, lotions, transdermal agents (patches, matrices, tapes), gels and the like.
  • a wide variety of carriers known in the art can be widely used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and caic acid.
  • Excipients such as water, ethanol, propanol, single syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.IJ, dry starch, sodium alginate , Agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, disintegrants such as monoglyceride stearate, starch, lactose, sucrose, stearin, cocoa butter, hydrogenated oil, etc.
  • the tablet can be made into a tablet coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an S-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet.
  • a wide variety of carriers known in the art can be widely used as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, and the like. Examples thereof include a gum arabic powder, a tragacanth powder, a binder such as gelatin and ethanol, and a disintegrant such as laminaran agar.
  • excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, and the like.
  • examples thereof include a gum arabic powder, a tragacanth powder, a binder such as gelatin and ethanol, and a disintegrant such as laminaran agar.
  • conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. Can be.
  • the liquid preparation, emulsion and suspension are sterilized, and when formed into the form of these liquid preparations, emulsions and suspensions, which are preferably isotonic with blood and blood.
  • the diluent any one commonly used in this field can be used as a diluent, for example, water, aqueous solution of lactate, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid Esters and the like can be mentioned.
  • a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and ordinary solubilizers, buffers, and soothing agents are added. May be. Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent or the like and other pharmaceuticals may be incorporated into the pharmaceutical preparation, if necessary.
  • the amount of the compound of the formula (I) or a salt thereof to be contained in the composition of the present invention is not particularly limited and may be appropriately selected over a wide range. In a preferred embodiment, the content is preferably 5 to 50% by weight.
  • the administration method of the composition of the present invention is orally or parenterally administered according to a method depending on various formulation forms, patient age, sex and other conditions, degree of disease, etc., which are not particularly limited.
  • tablets, pills, solutions, suspensions, emulsions, granules, capsules and the like are mentioned as desirable embodiments.
  • Parenterally it can be administered in the form of topical administration, injection, transdermal, nasal, pulmonary, suppository, etc. In the case of injections, they are administered intravenously, alone or mixed with normal replenishers such as glucose and amino acids, and if necessary, intramuscularly, intradermally, subcutaneously, or intraperitoneally. This is a desirable mode.
  • composition of the present invention is used as a wound healing agent, it is desirable to administer the composition in the form of a topical administration agent.
  • a topically administered agent for example, a spray, an aerosol, a cream, an ointment, a lotion, a transdermal agent, a gel or the like, or a composition of the present invention contained in various kinds of wound dressings, To the skin and the like.
  • the affected area after administration can be protected with various wound dressings.
  • the dose of the composition of the present invention is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, and the like. Can be administered at a dose of about 0.05 to 50 mg per kg of body weight per day. In addition, it is a desirable embodiment that the active ingredient is contained in the dosage unit form in an amount of 110 mg.
  • composition of the present invention includes, for example, antiviral drugs, antibacterial drugs, antibiotics, antiparasitic drugs, antifungal drugs, antipruritics, analgesics, anti-inflammatory drugs, disinfectants, proteolytic enzymes, granulation and epidermis Formation promoter
  • At least one of various agents such as a wound covering agent, and may exhibit more excellent effects in treating or preventing a disease requiring administration of adenosine A2a receptor agonist.
  • the compound of the formula (I) or a salt thereof can be produced by a known method or a method analogous thereto, for example, a method described in WO02 / 40485.
  • Table 1 shows specific examples of the compound of the formula (I), but the compound of the formula (I) is not limited thereto.
  • a male ICR mouse (body weight: 22 soil, 2 g) was anesthetized with hexobarbital (90 mg / kg, intraperitoneal administration), and the skin of the shoulder and back was removed by a sharp punch with a diameter of 12 mm.
  • 30 ⁇ g / 20 ⁇ L of the test compound suspended in 1.5% CMC-Na was applied to the cut skin.
  • the test compound was applied once a day every day, and the wound area was measured 1, 3, 5, 7, 9 and 11 days later.
  • the wound area was measured with an image analyzer (Life Science Resources Vista, Version 3.0) after placing a transparent plastic sheet on the wound and tracing the wound boundary.
  • CT50 wound half-closure time
  • CT50 was calculated using Graph-Pad Prism (Graph Pad Software USA). The test was performed with 5 animals / group, and the difference between the mean values of the test substance administration group and the vehicle control group was tested by the Student's t test. The results are shown in Table 2. [Table 4] Table 2
  • a test compound suspended in 0.25% CMC_Na is orally administered to a male ICR mouse (body weight 22 ⁇ 2 g) at 150 mg / kg, and one hour later, 90 mg / kg of hexobarbital sodium is intraperitoneally administered. Then, the sleep time is measured using the recovery of the light reflection reaction as an index. The test is performed as 3 animals per group. Only evaluate the average sleep during sleep extension time rate calculated based on between group administered%? As ⁇ 10 13 ⁇ 4 & 110 1 1 solvent instead of the test compound. As a result, it is found that the compound of the present invention has a sleep-inducing effect.
  • a test compound suspended in 0.25% CMC_Na is orally administered to a male ICR mouse (body weight: 22 ⁇ 2 g) at 150 mg / kg, and rectal temperature is measured immediately thereafter (Thermolert, TH_5). Further, the body temperature is measured at 30, 60, 90 and 120 minutes later. If there is an average change of 5% or more compared to the body temperature before administration, it is considered that there is a significant change due to administration of the test compound.
  • the test is performed as 3 animals per group. As a result, it is found that the compound of the present invention has a body temperature lowering effect.
  • a test compound suspended in 0.25% CMC_Na was orally administered at 150 mg / kg, and immediately thereafter, blood pressure was increased by an indirect method. Measure (Blood-Pressure Indirect Sensors & Model B60, IITC USA). Further, blood pressure is measured at 1, 2 and 4 hours later. If the blood pressure changes by an average of 10% or more compared to the blood pressure before administration, it is considered that there is a significant change due to the administration of the test compound. The test is performed as 3 animals per group. As a result, it is found that the compound of the present invention has a blood pressure lowering effect.
  • Test Example 5 Inhibition of cytoforce-in production in human peripheral blood mononuclear cells (1) IL-2 production inhibitory action
  • Test Example 6 (Test for binding affinity to adenosine A2a receptor)
  • the [3 H] CGS 21680 and the test compound 10 mu Micromax adenosine A2a human recombinant receptor was expressed HEK-293 cell suspension Torichi ⁇ beam labeled 50nM added, the binding affinity to the adenosine A2a receptor
  • the binding inhibitory activity of [3H] CGS21680 as an index was measured using a liquid scintillation counter. The results are shown in Table 3 as the binding inhibition rate (%).
  • Test Example 7 (IL-2 production inhibitory action in mouse spleen cells)
  • the adenosine A2a receptor agonist action of the test compound was evaluated using the IL-2 production inhibitory activity induced by T cell receptor stimulation as an index. That is, the treatment of mouse spleen cells with anti-mouse CD3 antibody and human recombinant IL_2 (Genzym No. 2202) induced cytodynamic force-in production. A test compound was added to the cytoforce-in producing system, and its production was measured by the following method. Anti-mouse CD3 antibody prepared at 10-20 ⁇ g / ml with borate buffered saline (PH8.5) was dispensed into a 96-well cell culture plate at 50 ⁇ 1 / well and incubated at 4 ° C for 18 hours. Left for hours.
  • IL-2 adjusted to 10 ng / ml with RPMI solution containing 10% fetal calf serum (FCS) was dispensed at 50 ⁇ 1 / well.
  • FCS fetal calf serum
  • the test compound dilution was dispensed in 50 ⁇ l / well portions (final concentration: 10 ⁇ ), and 1 ⁇ 10 5 prepared from the spleen of Balb / c mouse (female, 7-10 weeks old). Seven cell suspensions / ml were dispensed at 100 ⁇ l / well. After culturing for 40-48 hours in an incubator (37 ° C, 5% CO2), the culture supernatant was collected and the amount of cytodynamic force produced was measured by ELISA.
  • the amount of IL-12 cytoplasm produced was measured by the following method. That is, IL-12 production
  • the amount was quantified by the following ELISA method.
  • rat anti-mouse IL-2 antibody (Pharmingin, Code No. 18161D) was diluted 1 / ig / ml with a carbonate buffer ( ⁇ 9.5) to form a 50 / well 96-well plate. (IWAKI, Code No. 3860-096), and coated at 4 ° C for 16 hours. Then the plate is 10. Blocking was performed at 37 ° C for 2 hours in phosphate buffered saline containing 7.2 g / oFCS (blocking buffer) (250 ⁇ l / well).
  • the plate is washed four times with PBS (washing buffer) containing 0.05% Tween20 (Nacalai Tester, Code No. 281-51), and the culture supernatant diluent is spread at 50 ⁇ l / well at room temperature. And incubated for 1 hour.
  • Recombinant mouse IL_2 (R & D Systems, Code No. 402—ML) was used to create a calibration curve.
  • the plate is washed four times using a washing buffer, and a biotin-labeled rat anti-mouse IL-12 antibody (Pharmingen, Code No. 18172D) is used as a secondary antibody in a blocking buffer containing 0.05% Tween 20 at 0.5 ⁇ l.
  • the solution diluted in gZml was added (50 ⁇ l 1-well), and incubated at room temperature for 1 hour. After washing the plate four times with the washing buffer, add streptavidin-labeled peroxidase (Prozyme, Code No. CJ30H001) diluted 800-fold with a blocking buffer containing 0.05% Tween20 (50 / il / well). The reaction was performed at room temperature for 15 minutes. The plate was was washed four times with a washing buffer, and 100 ⁇ l / well of a TNB substrate solution (Sigma, Code No. T-8665) was added for color development for 10-20 minutes. After stopping the reaction by adding 100 ⁇ l / well of 1 M sulfuric acid solution, the absorbance was measured (wavelength 450 nm) using a microplate reader (Spectramax, Wako Pure Chemical Industries, Ltd.).
  • T represents the average value of the test compound treated group
  • N represents the average value of the negative control group
  • P represents the average value of the positive control group.
  • Table 4 shows the inhibitory rates of production of each site force in this manner.

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Abstract

L'invention concerne une composition pour des traitements ou pour la prévention de maladies nécessitant l'administration d'un agoniste du récepteur A2a de l'adénosine. La composition contient en tant que principe actif soit un composé hétérocyclique fusionné représenté par la formule (I) dans laquelle A représente azote, C-G, etc. ; R1 et R2 représentent chacun indépendamment hydrogène, halogéno, alkyle facultativement substitué, aryle facultativement substitué, un groupe hétérocyclique facultativement substitué, etc. ; Y et Z représentent chacun indépendamment azote ou C-R8 et lorsque Y et Z représentent tous les deux C-R8, alors les deux R8 peuvent être identiques ou différents ; X représente azote ou C-R10 ; et lorsque Y représente C-R8 et soit X représente C-R10 soit Z représente C-R8, alors R8 et R10 ou les deux R8 peuvent être liés l'un à l'autre pour former un cycle contenant facultativement un ou plusieurs hétéroatomes, soit un sel du composé.
PCT/JP2004/008201 2003-06-13 2004-06-11 Composition de traitement ou de prevention de maladies necessitant l'administration d'un agoniste du recepteur a2a de l'adenosine WO2004110454A1 (fr)

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WO2009041663A1 (fr) * 2007-09-28 2009-04-02 Kyowa Hakko Kirin Co., Ltd. Agent destiné à la prévention et/ou au traitement de maladies cutanées
US7667036B2 (en) * 2004-08-13 2010-02-23 Teijin Pharma Limited Pyrazolo[1,5-a]pyrimidine derivatives
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
JP2011506501A (ja) * 2007-12-20 2011-03-03 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト 置換アザ二環式化合物およびそれらの使用
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor
US8314098B2 (en) 2008-12-26 2012-11-20 Ajinomoto Co., Inc. Pyrazolo-pyrimidine compounds
CN102791712A (zh) * 2010-03-05 2012-11-21 协和发酵麒麟株式会社 吡唑并嘧啶衍生物
US8343977B2 (en) 2009-12-30 2013-01-01 Arqule, Inc. Substituted triazolo-pyrimidine compounds
WO2013031931A1 (fr) 2011-09-02 2013-03-07 協和発酵キリン株式会社 Régulateur d'activité de récepteur de chimiokine
US8969363B2 (en) 2011-07-19 2015-03-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
CN111511745A (zh) * 2018-02-06 2020-08-07 江苏恒瑞医药股份有限公司 吡唑并[1,5-a][1,3,5]三嗪-2-胺类衍生物、其制备方法及其在医药上的应用
CN111825698A (zh) * 2019-07-30 2020-10-27 杭州阿诺生物医药科技有限公司 腺苷受体拮抗剂
WO2021018173A1 (fr) * 2019-07-30 2021-02-04 杭州阿诺生物医药科技有限公司 Antagoniste du récepteur de l'adénosine

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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
US7667036B2 (en) * 2004-08-13 2010-02-23 Teijin Pharma Limited Pyrazolo[1,5-a]pyrimidine derivatives
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor
WO2009041663A1 (fr) * 2007-09-28 2009-04-02 Kyowa Hakko Kirin Co., Ltd. Agent destiné à la prévention et/ou au traitement de maladies cutanées
JP5372763B2 (ja) * 2007-09-28 2013-12-18 協和発酵キリン株式会社 皮膚疾患の予防及び／または治療剤
US8729264B2 (en) 2007-09-28 2014-05-20 Kyowa Hakko Kirin Co., Ltd. Agent for prevention and/or treatment of skin diseases
JP2011506501A (ja) * 2007-12-20 2011-03-03 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト 置換アザ二環式化合物およびそれらの使用
US8314098B2 (en) 2008-12-26 2012-11-20 Ajinomoto Co., Inc. Pyrazolo-pyrimidine compounds
US8343977B2 (en) 2009-12-30 2013-01-01 Arqule, Inc. Substituted triazolo-pyrimidine compounds
CN102791712B (zh) * 2010-03-05 2015-07-01 协和发酵麒麟株式会社 吡唑并嘧啶衍生物
CN102791712A (zh) * 2010-03-05 2012-11-21 协和发酵麒麟株式会社 吡唑并嘧啶衍生物
US8815874B2 (en) 2010-03-05 2014-08-26 Kyowa Hakko Kirin Co., Ltd. Pyrazolopyrimidine derivative
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CN111511745A (zh) * 2018-02-06 2020-08-07 江苏恒瑞医药股份有限公司 吡唑并[1,5-a][1,3,5]三嗪-2-胺类衍生物、其制备方法及其在医药上的应用
CN111511745B (zh) * 2018-02-06 2022-05-27 江苏恒瑞医药股份有限公司 吡唑并[1，5-a][1，3，5]三嗪-2-胺类衍生物、其制备方法及其应用
CN112592354A (zh) * 2019-07-30 2021-04-02 杭州阿诺生物医药科技有限公司 一种异噁唑并嘧啶类杂环化合物的制备方法
CN112608330B (zh) * 2019-07-30 2021-09-28 杭州阿诺生物医药科技有限公司 A2a和/或a2b受体抑制剂
CN112500416A (zh) * 2019-07-30 2021-03-16 杭州阿诺生物医药科技有限公司 一种吡唑并三嗪类化合物中间体的制备方法
CN112574214A (zh) * 2019-07-30 2021-03-30 杭州阿诺生物医药科技有限公司 腺苷受体拮抗剂的制备方法
WO2021018172A1 (fr) * 2019-07-30 2021-02-04 杭州阿诺生物医药科技有限公司 Antagoniste du récepteur de l'adénosine
CN112608330A (zh) * 2019-07-30 2021-04-06 杭州阿诺生物医药科技有限公司 A2a和/或a2b受体抑制剂
CN112625050A (zh) * 2019-07-30 2021-04-09 杭州阿诺生物医药科技有限公司 一种a2a和/或a2b受体抑制剂的制备方法
WO2021018173A1 (fr) * 2019-07-30 2021-02-04 杭州阿诺生物医药科技有限公司 Antagoniste du récepteur de l'adénosine
CN112574214B (zh) * 2019-07-30 2021-09-28 杭州阿诺生物医药科技有限公司 腺苷受体拮抗剂的制备方法
CN112625050B (zh) * 2019-07-30 2021-10-01 杭州阿诺生物医药科技有限公司 一种a2a和/或a2b受体抑制剂的制备方法
CN111825698B (zh) * 2019-07-30 2021-10-15 杭州阿诺生物医药科技有限公司 腺苷受体拮抗剂
CN112500416B (zh) * 2019-07-30 2021-12-17 厦门宝太生物科技股份有限公司 一种吡唑并三嗪类化合物中间体的制备方法
CN112592354B (zh) * 2019-07-30 2022-05-27 厦门宝太生物科技股份有限公司 一种异噁唑并嘧啶类杂环化合物的制备方法
CN111825698A (zh) * 2019-07-30 2020-10-27 杭州阿诺生物医药科技有限公司 腺苷受体拮抗剂

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