WO2005037837A1 - 置換2−アミノ−[1,2,4]トリアゾロ[1,5−a]ピリミジン誘導体及びその用途 - Google Patents
置換2−アミノ−[1,2,4]トリアゾロ[1,5−a]ピリミジン誘導体及びその用途 Download PDFInfo
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- WO2005037837A1 WO2005037837A1 PCT/JP2004/015245 JP2004015245W WO2005037837A1 WO 2005037837 A1 WO2005037837 A1 WO 2005037837A1 JP 2004015245 W JP2004015245 W JP 2004015245W WO 2005037837 A1 WO2005037837 A1 WO 2005037837A1
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Definitions
- the present invention relates to an immunosuppressant or an immune tolerance inducer.
- the present invention is used as an immunosuppressant for the treatment or prevention of autoimmune diseases, allergic diseases, diseases associated with tissue inflammation, rejection of organ transplantation or bone marrow transplantation, or graft-versus-host reaction.
- a substituted 2-amino- [1,2,4] triazolo [1,5-a] pyrimidine derivative is also contains substituted 2-amino- [1,2,4] triazolo [1,5-a] pyrimidine derivatives that can be used to engraft transplanted patients or transplanted bone marrow in transplant patients as immune tolerance inducers Pharmaceutical.
- immunosuppressive agents such as steroids, cyclosporin A, tacrolimus, mycophenol moftyl, mizoribine, and deoxyspagarin are used for transplant rejection, autoimmune diseases, allergic diseases, and various autoimmune diseases. It is used for treatment and prevention of diseases.
- steroids that have been used as anti-inflammatory agents for a long time have been known to act on macrophages and lymphocytes to exert an immunosuppressive effect when administered in large amounts.
- Cyclosporine A and tacrolimus exert an immunosuppressive effect by suppressing the production of cytoforce, a regulator of lymphocytes.
- Cyclosporin A has been administered to patients with renal transplantation, liver transplantation, bone marrow transplantation, suppression of heart transplant rejection, Behcet's disease, psoriasis, aplastic anemia, and nephrotic syndrome.
- Tacrolimus has been administered as a more potent inhibitor of cytoforce in production for renal transplantation, liver transplantation, bone marrow transplantation, inhibition of heart transplant rejection, atopic dermatitis, and myasthenia gravis.
- Mofethyl mycophenolate and mizoribine exert an immunosuppressive action by antagonizing nucleic acid metabolism of lymphocytes. Mofethyl mycophenolate suppresses renal transplant rejection Mizoribine has been used for suppressing renal transplant rejection, nephrotic syndrome, lupus nephritis, and rheumatoid arthritis.
- Deoxyspagarin exerts an immunosuppressive effect by inhibiting antibody production and lymphocyte function, and is used for treating rejection after renal transplantation.
- Immunosuppressants are also effective against autoimmune diseases other than the above-mentioned indication diseases.
- cyclosporin II is not only an indication disease but also atopic dermatosis, autoimmune hepatitis, Crohn's disease, ulcer, etc. It has been reported that it is effective for diseases such as ulcerative colitis, myasthenia gravis, multiple sclerosis, rheumatoid arthritis, and insulin-dependent diabetes.
- a self-harmful immune phenomenon occurs through presentation of an antigen that causes a disease state.
- an autoimmune disease a self-antigen or a foreign antigen similar to a self-antigen is presented to immunocompetent cells by ⁇ cells, one of the antigen-presenting cells, and an immune response to the self-antigen is elicited. It is thought that destruction of tissue has occurred! / Puru (Non-Patent Document 1).
- Non-Patent Document 2 In rheumatism, which is an inflammatory disease, accumulation of ⁇ cells, which are antigen-presenting cells, has been observed at the joint lesion site in patients, suggesting that antigen presentation is involved in the onset and exacerbation.
- Non-Patent Document 3 discloses the histocompatibility complex (gene histocompatibility complex) in T cell activation and tissue injury at the lesion site, even in autoimmune diseases and inflammatory diseases, through the histocompatibility complex (gene histocompatibility complex) (Non-Patent Document 3).
- Non-Patent Document 4 Non-Patent Document 4
- Non-Patent Document 5 describes the synthesis of N-alkenyl-substituted 2-amino-7-phenyl [1,2,4] triazolo [1,5-a] pyrimidine. Was also used for N-alkyl-substituted 2-amino-7-phenyl [1,2,4] triazolo [1,5-a] pyrimidine derivatives Drugs are also described!
- Patent Document 1 discloses 2-amino-7-phenyl [1,2,4] triazolo [1,5 ⁇ ] pyrimidine substituted with an alkyl group which may be substituted with an amino group which may be substituted. Derivatives are described.
- Non-patent document 1 Ludovic et al., "Current Opinion in Immunology,” Vol. 13, 2001, o57 Sada Ludewig, B. et ai., Current Opinion in Immunology, vol. Id, p 657 (2001))
- Non-Patent Document 2 Thomas et al., Journal of Leukocytes Biology, Vol. 66, p286 (1999)
- Non-Patent Document 3 Immunology Illustrated (5th Edition), Roitt, I. et al., Translated by Tomio Tada, Nankodo (2000), 128-131 and 355-358
- Non-patent Document 4 Ralph et al., "Procedin's Dobs of the National Academy of Sciences,” Vol. 99, p. 351 (Ralph, MS et al., Proceedings of the National Academy of Sciences, vol. 99). , 351 (2002))
- Non-Patent Document 5 Allen, C.F.H. et al., J. Org.Chem., 24, p796—801 (1959)
- Patent Document 1 International Publication No. 02Z20495 pamphlet
- autoimmune diseases In autoimmune diseases, allergic diseases, tissue inflammatory diseases, and rejection reactions of organ transplantation or bone marrow transplantation, the presentation of antigens that cause disease states by antigen presenting cells is involved, and the expression of antigen presenting molecules is suppressed. It is thought that inhibition or modification of antigen presentation by antigen-presenting cells can suppress abnormal or excessive immune response.
- compounds having such an action are known at present.
- Antigen presentation is a specific function of the immune system, and substances that specifically inhibit antigen presentation and Z-modifying effects have an effect on other than the immune system, ie, have side effects such as those observed with currently known immunosuppressants. Probably not. [0016] In addition, suppression of maturation of antigen-presenting dendritic cells may increase immature dendritic cells and induce immunological tolerance, but compounds having such an effect are currently unknown. Not in.
- the present inventors have found that the compound can be used as an immunological tolerance inducer because it suppresses the expression of an antigen presenting conjugate molecule involved in antigen presentation, and thus completed the present invention.
- the present inventors have found that the compound has cell growth inhibitory activity against lymphoma cell line cells, and thus can be used as an anti-malignant tumor agent, thus completing the present invention.
- the present invention provides:
- Ar represents a phenyl group which may have a substituent or a 5- to 6-membered aromatic heterocyclic group containing one hetero atom and having a substituent.
- R is a halogeno group, a cyano group, a nitro group, a hydroxyl group, a (C1-C6) alkoxyl group, a benzyl group And a 5- to 6-membered aromatic heterocyclic group containing one heteroatom, which may be substituted with a substituent selected from the group consisting of C 1 -C 6 ) Alkyl groups, (C2-C7) alkoxycarbol groups which may be substituted with substituents, having the same or different 13 substituents, may be substituted by (C1 -C13 )
- the present invention relates to a medicament comprising a substituted 2-amino [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient
- the present invention relates to an antigen presentation inhibitor comprising the above-mentioned substituted 2-amino- [1,2,4] triazolo [1,5-a] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Further, the present invention relates to an immunosuppressant or an immunological tolerance inducer comprising the above substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. .
- the present invention provides a transplant rejection reaction or a graft-versus-host reaction containing the above substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention relates to an agent for treating or preventing a disease.
- the present invention provides a therapeutic or preventive agent for an autoimmune disease comprising the above-mentioned substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- a therapeutic or preventive agent for an autoimmune disease comprising the above-mentioned substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides a method for treating rheumatoid arthritis, multiple sclerosis, and systemic use comprising the above-mentioned substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention relates to a therapeutic or prophylactic agent for scleroderma, mixed connective tissue disease, ankylosing spondylitis, or chronic thyroiditis.
- the present invention provides a therapeutic or therapeutic agent for an allergic disease containing the above substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- a therapeutic or therapeutic agent for an allergic disease containing the above substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention relates to an atopic dermatosis, pollinosis, contact, and the like comprising the above substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It relates to the treatment or prevention of irritability, asthma, psoriasis, or anaphylaxis.
- the present invention provides a therapeutic or prophylactic agent for an inflammatory disease comprising the above substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- Agent for an inflammatory disease comprising the above substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention relates to Behcet's disease, polyarteritis, sarcode, comprising the above-mentioned substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention relates to a therapeutic or prophylactic agent for monocis, glomerulonephritis, nephrotic syndrome, intractable vasculitis, or Xgener syndrome.
- the present invention relates to a cell growth inhibitor comprising the above substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Furthermore, the present invention relates to an antineoplastic agent comprising the above-mentioned substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Further, the present invention provides a compound represented by the general formula (III):
- A is a halogeno group, a hydroxyl group, a (C1-C6) alkyl group, a cyano group, a nitro group, a (C1-C6) alkoxyl group, a benzyloxy group, an amino group, a (C1-C7) acylamino group and A substituent group containing one heteroatom, which may be substituted with the same or different 13 groups selected from the substituent groups (A) which also form a methylenedioxy group (A) ( A) may be substituted with the same or different 1 to 3 substituents selected from 5) 6-membered aromatic heterocyclic group,
- W represents a halogeno group, a hydroxyl group, a (C1-C6) alkoxyl group, a phenyl group, and a 5- to 6-membered aromatic heterocyclic group containing one heteroatom.
- a substituent group consisting of a phenyl group, a methoxyphenyl group and a 5- to 6-membered aromatic heterocyclic group containing one heteroatom, which may be substituted with one selected substituent; C2-C7) alkoxycarbyl group;
- Z—CO— ⁇ Z is (C1-C6) alkyl, halogeno, hydroxyl, oxo, trifluoromethyl, cyano, nitro, (C1-C6) alkoxyl, benzyloxy, (C1-C6) Substituent group consisting of alkylsulfur group, (C1-C6) alkoxycarbol group, amino group, di (C1-C6) alkylamino group, (C1-C7) acylamino group and methylenedioxy group (B) Same or different aromatic hydrocarbon groups optionally having one to three substituents selected from one to fourteen hetero atoms independently selected from N, O and S Substituted with the same or different 1 to 3 substituents selected from the substituent group (B) and containing an atom! /, Or! /, A 5- to 6-membered saturated or unsaturated heterocyclic group A cyclic acyl group represented by ⁇ ;
- the present invention relates to a substituted 2-amino- [1,2,4] triazolo [1,5-a] pyrimidine derivative represented by the formula: or a pharmaceutically acceptable salt thereof.
- the present invention provides a method for producing a substituted 2-amino- [1,2,4] triazolo [1,5-a] pyrimidine derivative comprising 3-benzenesulfol-N- (7-thiophene-2-yl [1,2 4] triazolo [1,5a] pyrimidine-2yl) propionamide, 3 benzenesulfol-N- [7- (4-methoxyphenyl) [1,2,4] triazolo [1,5a] Pyrimidine 2yl] propionamide, (S) —2— (tert tertbutoxycarbol) amino-N— (7-thiophene 2-yl [1,2,4] triazolo [1,5a] pyrimidine 2yl ) Butyramide, (S) -2 amino-N- (7-thiophene 2-yl)
- the substituted 2-amino- [1,2,4] triazolo [1,5-a] pyrimidin-2-ylperrea derivative represented by the general formula (I) of the present invention, or a pharmaceutically acceptable salt thereof Has an inhibitory effect on antigen presentation and lymphocyte function, and is useful as a medicament for treating or preventing autoimmune disease, transplant rejection, graft-versus-host reaction, allergic disease or inflammatory disease. It also suppresses the expression of costimulatory molecules involved in antigen presentation and is useful as a drug for inducing immune tolerance.
- the medicament of the present invention is a compound of the above general formula (I) wherein Ar represents a phenyl group which may have a substituent or one heteroatom and has a substituent.
- Ar represents a phenyl group which may have a substituent or one heteroatom and has a substituent.
- R is a halogeno group, a cyano group, a nitro group, a hydroxyl group, a (C1-C6) alkoxyl group, a benzyloxy group, a phenyl group, and a 5- to 6-membered aromatic heterocyclic group containing one heteroatom.
- (C1-C6) alkyl groups which may be substituted with a substituent selected from the group consisting of the following substituents, (C2-C7) alkoxycarbol groups which may be substituted with a substituent, (C13-C13) aliphatic acryl group, amino acid group which may be protected at the N-terminus, or the same or different 113 substituents, each having one to three different substituents 2- or 3-amino [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative represented by the following formula: Salt as the active ingredient.
- the substituent for Ar in the general formula (I) is preferably a halogeno group, a hydroxyl group, a (C1-1C6) alkyl group, a cyano group, a nitro group, a (C1-1C6) alkoxyl group, a benzyloxy group, an amino group, (C11-C7) acylamino group and methylenedioxy group
- the substituents of the (C1-C6) alkyl group include a halogeno group, a cyano group, a nitro group, a hydroxyl group, a (C1-C6) alkoxyl group, a benzyloxy group, and a phenol.
- R of the general formula (I) a substituent containing a (C2-C7) alkoxycarbyl group, preferably a phenyl group, a methoxyphenyl group and one hetero atom, Substituent group power of 6-membered aromatic heterocyclic group One selected substituent and the like.
- R of the general formula (I) as a substituent of the (C1-C13) aliphatic acyl group, preferably a halogeno group, a hydroxyl group, an oxo group, a (C1-C6) alkoxyl group, a (C1-C7) Acyl group, (C1-C7) acyloxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, OH group, (CI-C6) alkylsulfur group, benzylsulfur group, arylsulfur group, (C1-1C6) alkylsulfol group, arylsulfol group, (C1-1C6) Alkoxycarbol group, amino group, (C1-1C6) alkylamino group, di (C1-1C6) alkylamino group, (C1-1C7) acylamino group, (C1-1C6) alkoxycarbolamino group, benzyl
- the N-terminal may be protected, and the amino acid group may be an ⁇ -amino acid group in which the N-terminal may be protected.
- [ ⁇ ] represents a hydrogen atom, a methyl group, an ethyl group, a propyl group or an isopropyl group
- Q represents a hydrogen atom, a (C1 to C7) acyl group or a (C1 to C6) alkoxycarbol group.
- a 3- to 7-membered cyclic acyl group which may have the same or different 13 substituent (s) in R of the general formula (I) is preferably ⁇ -CO — ⁇ is an aromatic hydrocarbon group which may have a substituent or may have a substituent, and may be one to fourteen hetero atoms independently selected from N, O and S Represents a 5- to 6-membered saturated or unsaturated heterocyclic group containing an atom, and the substituent is preferably a (C1-C6) alkyl group, a halogeno group, a hydroxyl group, an oxo group, Trifluoromethyl group, cyano group, nitro group, (C1-1C6) alkoxyl group, benzyloxy group, (C1-1C6) alkylsulfur group, (C1-1C6) alkoxycarbol group, amino group , Di (C1-1C6) alkylamino group, (C1-1C7) acylamino group, and methyl
- the 5- to 6-membered aromatic heterocyclic group containing one hetero atom is preferably N, O and A 5- to 6-membered aromatic heterocyclic group containing one heteroatom independently selected from S, specifically furan-2-yl, furan-3-yl, thiophene2 —Yl group, thiophen-3-yl group, pyridine-2-yl group, pyridine-3-yl group or pyridine-4-yl group, preferably thiophen-2-yl group, thiophen-3-yl And a pyridine-3-yl group or a pyridine-4-yl group, more preferably a thiophen-2-yl group or a thiophen-3-yl group.
- the halogeno group is a fluoro group, a chloro group, a bromo group or an odo group, preferably a fluoro group or a chloro group, and more preferably a fluoro group.
- the (C1-C6) alkyl group means a linear, branched or cyclic alkyl group having 116 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a isopropyl group, and a butyl group.
- the (C1-C6) alkoxyl group is a group in which the (C1-C6) alkyl group is bonded to an oxygen atom, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group.
- a (C1-C12) alkyl group which may contain an unsaturated double bond may be a straight-chain, branched-chain or cyclic alkyl group having 1-12 carbon atoms, for example, a methyl group, an ethyl group Group, propyl group, isopropyl group, butyl group, isobutyl group, tertbutyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group 1,2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl
- (C1 -C7) acyl group refers to an (C1 -C13) acyl group having 117 carbon atoms in the (C1 -C13) acyl group of the compound represented by the general formula (I).
- Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanol, cyclopropylcarbol, cyclopentylcarbol.
- a cyclohexanecarbon group and the like can be mentioned.
- the (C1-1C7) acyloxy group is a group in which the (C1-1C7) acyl group is bonded to an oxygen atom, for example, a formyloxy group, an acetoxy group, a propionyloxy group, a ptyryloxy group, Examples include an isoptyryloxy group, a valeryloxy group, an isovaleryloxy group, a vivaloyloxy group, a hexanoyloxy group, a cyclopropylcarboxy group, a cyclopentylcarboxy group or a cyclohexanecarboxy group.
- it is an acetoxy group, a propionyloxy group or a bivaloyloxy group, and more preferably an acetoxy group.
- the (C1-1C7) acylamino group is a group in which the (C1-1C7) acyl group is bonded to a nitrogen atom, for example, a formylamino group, an acetylamino group, a propioamino group, a butyrylamino group. , Isobutyrylamino group, valerylamino group, isovalerylamino group, bivaloylamino group, hexanoylamino group, cyclopropylcarbolamino group, cyclopentylcarbolamino group or cyclohexanecarbolamino group.
- Preferred is an acetylamino, propio-amino, or vivaloylamino group, and more preferred is an acetylamino group.
- the (C1-C6) alkylsulfur group is a group in which the (C1-C6) alkyl group is bonded to a sulfur atom, for example, a methylsulfur group, an ethylsulfur group , Propylsulfur, isopropylsulfur, butylsulfuryl, isobutylsulfur, tert-butylsulfur, pentylsulfuryl, isopentylsulfur, 2 —Methylbutylsulfur group, neopentylsulfur group, 1-ethylpropylsulfur group, hexylsulfur group, 4-methylpentylsulfur group, 3methylpentylsulfur group 1,2-methylpentylsulfur group, 1-methylpentylsulfur group, 3,3-dimethylbutylsulfur 1,2-dimethylbutylsulfur, 1,1 di
- the arylsulfanyl group is preferably a group in which an aromatic hydrocarbon group having 6 to 10 carbon atoms is bonded to a sulfur atom, such as a phenylsulfanyl group and a toluene-2-ylsulfanyl group.
- a sulfur atom such as a phenylsulfanyl group and a toluene-2-ylsulfanyl group.
- It is an ethylsulfur group or a toluene-4-ylsulfur group, more preferably a pheny
- the (C1-1C6) alkylsulfol group is a group in which the (C1-1C6) alkyl group is bonded to a sulfol group, such as a methylsulfol group, an ethylsulfol group, Propyl sulfol group, isopropyl sulfol group, butyl sulfol group, isobutyl sulfol group, tert-butyl sulfol group, pentyl sulfol group, isopentyl sulfol group, 2-methylbutyl sulfol group , Neopentyl sulfonyl group, 1 ethynolepropinolesnorenolinole group, hexinolesnolehoninole group, 4-methinolepentinolesnolehonyl group, 3 methylp
- methylsulfoninole ethinolesnolehoninole, propinolesnolehoninole, isopropinolesnolehoninole, A butylsulfol group, an isobutylsulfol group or a tert-butylsulfol group, more preferably a methylsulfol group or an ethylsulfol group.
- the arylsulfol group is preferably a group in which an aromatic hydrocarbon group having 6 to 10 carbon atoms is bonded to a sulfol group, for example, a phenylsulfol group, toluene 2 ino.
- it is a polysulfole group, a toluene-3-ylsulfol group or a toluene-4-ylsulfol group, more preferably a polysulfol group.
- the (C1-C6) alkylamino group is a group in which one of the (C1-C6) alkyl groups is bonded to a nitrogen atom, for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group.
- the di (C1-1C6) alkylamino group is a group in which two identical groups of the above-mentioned (C1-1C6) alkyl group are bonded to a nitrogen atom, such as a dimethylamino group, a getylamino group, Dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, dipentylamino group, dihexylamino group, bis- (3,3-dimethylbutyl) amino group, dicyclopropylamino group, dicyclopentylamino group Or a dicyclohexylamino group.
- a nitrogen atom such as a dimethylamino group, a getylamino group, Dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, dipentylamino group, dihexylamino group, bis
- the (C2-C7) alkoxycarbolamino group is a group in which the (C2-C7) alkoxycarbonyl group is bonded to a nitrogen atom, for example, a methoxycarbolamino group, an ethoxycarbo group.
- methoxycarbamino ethoxycarbamino
- propoxycarbamino isopropoxycarbamino
- butoxycarbamino isobutoxycarbamino or tert-butoxycarbamino
- the compound represented by the general formula (I) in the medicament of the present invention has N, O, and S forces in the substituent at R containing 1 to 4 hetero atoms which are independently selected.
- Preferred as the membered heterocyclic group are, for example, tetrahydrofuran-2-yl, tetrahydropyran-2-yl, tetrahydropyran-4-yl, [1,3] dioxolan-2-yl, and [1,3] dioxane 2-yl group, pyrrolidine 1-yl group, piperidine-1-yl group, piperidine 4-yl group, azepanyl 1-yl group, morpholine 4-yl group, thiomorpholine 4-yl group, oxazolidin 3-yl group, isoxazolidin Saturated heterocyclic groups such as 2-yl group, thiazolidine 3-yl group, imidazolidin-1-yl group, piperazine 1-yl group, or dihydrofur
- the above-mentioned heterocyclic group in the substituent of the (C1-C13) aliphatic acyl group may be a tetrahydrofuran-2-yl group, a tetrahydropyran-4-yl group, a furan-2-yl group.
- a thiophene group, a thiophene-2-yl group or a pyridine-3-yl group is particularly preferred.
- R is a cyclic acyl group in which Z is —CO—
- the heterocyclic group in Z is a furan-2-yl group, a furan-3-yl group, a dihydropyran 2 —Yl group, thiophen-2-yl group, thiophen-3-yl group, pyrroyl-2-yl group, pyridine-2-yl group, pyridin-3-yl group, pyridine-4-yl group, pyrimidine
- Unsaturated heterocyclic groups such as 4-yl group or pyrazine-2-yl group are more preferable, and furan-2-yl group, dihydropyran-2-yl group, thiophen-2-yl group, and pyrroyl-2-yl group are preferred.
- Groups or pyridine 3-yl groups are particularly preferred.
- Ar include, for example, a phenyl group, a 3-fluorophenyl group, a 3-chlorophenol group, —Hydroxyphenyl group, 3-Cyanophenyl group, 3-Trophenyl group, 3-Methylphenyl group, 3-Ethylphenyl group, 3-Propylphenyl group, 3-Isopropylphenyl group 3-, 3-butylphenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-isopropoxyphenyl, 3-isobutoxyphenyl, 3-aminophenyl, 3- Acetylaminophenyl group, 3-propylaminophenyl group, 4-fluorophenyl group, 4-chlorophenol group, 4-hydroxyphenyl group, 4-cyanophenol group, 4 —-Trophenyl group, 4 Methylphenyl group, 4 —
- R are preferably a methyl group, an ethyl group, a tert-butoxycarbol group, an acetyl group, a benzoyl group, Chloro-2-methoxybenzoyl group, furan-2-ylcarbol group, 3 (phenylsulfol) propiol group, (S) -2-aminopropiol group, (S) -2-aminobutylyl group , (S) -2-amino-3-methylbutyryl group, (S) -2- (tert-butoxycarbol) aminopropiol group, (S) -2- (tert-butoxycarbol) aminobutyryl group or (S) — 2 -— (tert-butoxycarbol) amino-3-methylbutyryl group, more preferably 3- (phenylsulfol) propiol group, (S) -2 amino
- substituted 2-amino- [1,2,4] triazolo [1,5-a] pyrimidine derivative represented by the general formula (I) in the medicament of the present invention include: A compound derived by combining the above specific examples of Ar and R corresponds to the compound.
- isomers exist in these In each case, each isomer and a mixture thereof are also included in the present invention. That is, in the case of optical isomers, the present invention includes a racemate, each optical isomer, and a mixture of any ratio thereof.
- Such optical isomers are prepared by a conventional production method, that is, synthesis using an optically active starting material, or optical resolution or separation of the synthesized compound.
- salts of the [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative in the medicament of the present invention are adjusted by a conventional salt-forming operation, and include, for example, sodium salt, potassium salt, Alkali metal salts such as lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; other metal salts such as aluminum salts, iron salts and zinc salts; ammonium salts, etc .; morpholine salts, ethylenediamine salts Organic amine salts such as, guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, proforce salt, diethanolamine salt, piperazine salt, tetramethylammonium salt; Hydrohalides such as hydrochloride, hydrobromide and hydroiodide; inorganic salts such as nitrate, perchlorate, sulfate and phosphate; methanesulfonate and trifluoromethan
- the drug of the present invention is produced by an oxidation reaction, a reduction reaction, a hydrolysis reaction, etc., for example, with an enzyme or gastric acid.
- Prodrugs include, for example, acylated, alkylated and phosphorylated forms of the active compound which can be produced by ordinary organic reactions.
- the present invention also includes a solvate such as a hydrate of the substituted 2-amino- [1,2,4] triazolo [1,5-a] pyrimidine derivative or a pharmaceutically acceptable salt thereof. Included.
- the present invention further includes an immunosuppressant comprising the substituted 2-amino- [1,2,4] triazolo [1,5-a] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It is.
- the present invention relates to a lymphocyte proliferation inhibitor comprising the substituted 2-amino- [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient, Also includes differentiation / maturation inhibitors, immune tolerance inducers, and therapeutic or preventive agents for transplant rejection or graft-versus-host disease, autoimmune disease therapeutic or preventive agents, allergic disease therapeutic or preventive agents. It also includes therapeutic or prophylactic agents for inflammatory diseases and antineoplastic agents.
- the antigen-presenting inhibitor of the present invention can be used for treating or preventing acute rejection in transplantation, graft-versus-host disease, chronic rejection, or inducing immune tolerance.
- Transplantable organs can be any organs such as bone marrow, kidney, liver, heart and spleen.
- the relationship between donor hosts can be any case, such as xenotransplantation, allogeneic transplantation, and blood-incompatible transplantation.
- organ transplants such as bone marrow transplantation, peripheral blood stem cell transplantation, and umbilical cord blood stem cell transplantation used in cancer treatment, autoimmune disease treatment, gene therapy, regenerative medicine, etc.
- the therapeutic or prophylactic agent for an autoimmune disease include rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, discoid lupus erythematosus, siedalen syndrome, Crohn's disease, ulcer disease, and ulcer disease. Ulcerative colitis, idiopathic thrombocytopenia, aplastic anemia, autoimmune hepatitis, insulin-dependent diabetes, myasthenia gravis, polymyositis, scleroderma, mixed connective tissue disease, ankylosing spondylitis, Or a therapeutic or prophylactic agent for chronic thyroiditis.
- therapeutic or prophylactic agent for an allergic disease include a therapeutic or prophylactic agent for atopic dermatosis, hay fever, contact hypersensitivity, asthma, psoriasis, or anaphylaxis.
- therapeutic or prophylactic agent for an inflammatory disease include a therapeutic or prophylactic agent for Behcet's disease, polyarteritis, sarcoidosis, glomerulonephritis, nephrotic syndrome, intractable vasculitis, or pegenna syndrome. Is mentioned.
- antineoplastic agent include therapeutic agents for malignant tumors such as lymphoma, leukemia, brain tumor, lung cancer, spleen cancer, stomach cancer, and colorectal cancer.
- the medicament of the present invention can be administered as it is, or can be administered as a pharmaceutical composition mixed with a pharmaceutically acceptable carrier.
- the dosage form of the pharmaceutical composition may be any. These formulations may also contain other therapeutically valuable components.
- the proportion of the active ingredient of the present invention in the preparation is about 100% by weight, preferably about 10 to 90%, based on the whole preparation.
- the medicament of the present invention may be administered by any administration method such as oral, injection, rectal administration, intraportal administration, perfusion of an organ, and local administration to an organ.
- the dosage of the medicament of the present invention varies depending on the administration method, indication, patient condition, age, body weight, etc., but the usual dosage is 0.05 Olmg-5OOmg / kg, preferably 0.05 mg-50mgZkg per day. It may be administered once or in several divided doses. Administration can be daily or daily, but administration can be repeated for several days with a few months. If necessary, other administration methods, dosages and administration schedules can be used.
- the [1,2,4] triazolo [1,5 ⁇ ] pyrimidine derivative represented by the general formula (I) according to the present invention when R is an alkyl group, is represented by the following reaction formula C, for example.
- R is an alkoxycarbyl group, an aliphatic acyl group, an amino acid group or a cyclic acyl group, for example, it can be obtained by the method represented by the following reaction formula A or reaction formula B.
- Ar has the same meaning as described above.
- the compound in the reaction may form a salt. Examples thereof include those similar to the salts of the [1,2,4] triazolo [1,5-a] pyrimidine derivative (hereinafter, compound (1)) represented by the above general formula (I).
- the ECO may be substituted with a substituent (C2-C7) alkoxycarbol group, and may have the same or different 113 substituents ( C13-C13) an aliphatic acyl group, an amino acid group which may be protected at the N-terminus, or a 3- to 7-membered cyclic acyl group having the same or different 13 substituents; L represents a residue of a certain group, and L represents a leaving group.
- Examples of the leaving group include a halogeno group, a 4-trophenoxy group, a pentafluorophenoxy group, a pyridine-2-ylsulfur group, an imidazole-1-yl group, and an alkoxycarbonyloxy group. is there.
- the compound (a) is reacted with the compound (b) to obtain a compound ( ⁇ ).
- This reaction is generally performed in the absence or presence of a base, preferably in the presence of a base.
- the base include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, lithium hydride and hydrogen hydride.
- Alkali metal hydrides such as sodium hydroxide and potassium hydride
- alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium methoxide, sodium methoxide, sodium ethoxide
- Alkali metal alkoxides such as potassium tert-butoxide, alkyl metals such as butyllithium and tertbutylmagnesium chloride, lithium diisopropylamide (LDA), lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, etc.
- LDA lithium diisopropylamide
- LDA lithium bis (trimethylsilyl) amide
- sodium bis (trimethylsilyl) amide etc.
- Metal amides triethylami , Toribuchiruamin, diisopropyl E chill ⁇ Min, N-methylmorpholine, pyridine, 4 -(N, N-Dimethylamino) pyridine, N, N-Dimethyla-line, N, N-Diethyla-line, 1,5-Diazabicyclo [4.3.0] Non-5-ene, 1,4-Diazabicyclo [2.
- Organic amines such as 2.2] octane (DABCO) and 1,8-diazabicyclo [5.4.0] -7-indene (DBU) are preferred, and alkali metal hydrides and metal amides are preferred.
- organic amines more preferably sodium hydride, lithium bis (trimethylsilyl) amide, diisopropylethylamine or pyridine.
- the amount of the base to be used is 0.5-5 molar equivalents, preferably 112 molar equivalents, relative to compound (a).
- the amount of compound (b) to be used is 0.5-5 molar equivalents, preferably 112 molar equivalents, relative to compound (a).
- a catalytic amount of a reaction catalyst such as 4 (N, N-dimethylamino) pyridine may be added.
- This reaction is carried out in the absence or presence of a solvent, and is preferably carried out in the presence of a solvent.
- the solvent is not particularly limited as long as the reaction proceeds. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, petroleum ether, aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, etc., ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, acetonitrile, propio-tolyl, etc.
- Amides such as -tolyls, dimethylformamide, dimethylacetamide, and hexamethylphosphoric acid triamide; ureas such as 1,3-dimethylimidazolidin-2-one; and a mixed solvent of the above solvents.
- Hydrocarbons, ethers or A Rea acids more preferably methylene chloride and tetrahydrofuran, or 1, 3-dimethyl-imidazolidin-2-one.
- the reaction temperature is usually -80-150 ° C, preferably 10-50 ° C.
- the reaction time is usually 10 minutes to 48 hours.
- the reaction is preferably performed by protecting with a protecting group used in a usual reaction.
- a commercially available product may be used as it is, or may be produced according to a known method or a method analogous thereto.
- the compound when L of the compound (b) is a fluorine atom, the compound is a compound wherein L is a hydroxyl group. It is also possible to derive from objects.
- the fluorinating reagent to be used include Futsudani Nannare, TFFH (tetramethylfluoroformamidinium nexaf luoropho sphate), DAST ((dimethylamino) sulfur trifluoride), etc., and preferably TFFH.
- the fluorination reaction is carried out in the absence or presence of a base, preferably 0.5 to 5 molar equivalents, preferably 112 molar equivalents, based on the compound in which is a hydroxyl group.
- the reaction is carried out in the presence of a base such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethyl.
- a base such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethyl.
- the fluorination reaction is carried out in the absence or presence of a solvent, preferably in the presence of a solvent.
- the solvent is not particularly limited as long as the reaction proceeds. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, petroleum ether, aromatic hydrocarbons such as benzene, toluene and xylene, and chlorides.
- Halogenated hydrocarbons such as methylene, chloroform, 1,2-dichloroethane, etc., ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, acetonitrile, propio-tolyl, etc.
- Amides such as -tolyls, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; ureas such as 1,3-dimethylimidazolidine 2-one; and mixed solvents of the above solvents.
- the reaction temperature is usually -80-150 ° C, preferably 10-50 ° C.
- the reaction time is usually 10 minutes to 12 hours.
- a commercially available product may be used as it is, or may be produced according to a known method or a method analogous thereto.
- the conjugate obtained by the fluorination reaction may be isolated according to a conventional method, but without isolation. The reaction solution may be used for the next reaction.
- the reaction conditions with the compound (a) are as follows: in the presence of 12 equivalents of alkali metal hydrides or metal amides, tetrahydrofuran or 1,3- It is particularly preferable to perform the reaction in dimethylimidazolidin-2-one at a reaction temperature of -10 to 50 ° C.
- the compound when L of the compound (b) is a chlorine atom, the compound can be derived from a compound in which L is a hydroxyl group.
- the chlorinating reagent to be used include, for example, Shii-Dani-Oxalil, Shii-Dani-Oxalil, and Shii-Dani-Oxalil.
- the chlorination reaction is carried out under the same conditions as the above-mentioned fluorination reaction, and preferable reaction conditions are also the same.
- the compound (c) is converted to an acid anhydride (d) with a dehydrating condensing agent, and then reacted with the compound (a) to obtain a substituted 2-amino- [1,2,4] triazolo [1,5-a].
- a method for producing the pyrimidine derivative ( ⁇ ) will be described.
- the dehydrating condensing agent that can be used include dicyclohexyl carbodiimide, diisopropyl carbodiimide, 1-dimethylaminopropyl 3-ethyl carbodiimide and the like, and preferably diisopropyl carbodiimide.
- the dose is 0.3-0.8 molar equivalent, preferably 0.5 molar equivalent, relative to compound (c).
- the dehydration condensation reaction is carried out in the absence or presence of a solvent, and is preferably carried out in the presence of a solvent.
- the solvent is not particularly limited as long as the reaction proceeds. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, petroleum ether, aromatic hydrocarbons such as benzene, toluene and xylene, and chlorides.
- Halogenated hydrocarbons such as methylene, chloroform, 1,2-dichloroethane, etc.
- ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, acetonitrile, propio-tolyl, etc.
- ureas such as 1,3-dimethylimidazolidin-2-one, or a mixed solvent of the above-mentioned solvents, preferably halogenated hydrocarbons, ethers or ureas, more preferably Shiojiri Methylene, tetrahydrofuran or 1,3 dimethylimi Dazolidine 2 on.
- the reaction temperature is usually -20 to 100 ° C, preferably -10 to 50 ° C.
- the reaction time is usually several minutes to 12 hours.
- a commercially available product may be used as it is, or may be prepared according to a known method or a method analogous thereto.
- the acid anhydride (d) obtained by the dehydration condensation reaction may be isolated according to a conventional method, but may be used in the next reaction without isolation as a reaction solution.
- the amount of acid anhydride (d) used is 0.5-4 based on compound (a). 2.0 molar equivalents, preferably 1.0-3.0 molar equivalents.
- This reaction is carried out in the absence or presence of a solvent, preferably in the presence of a solvent.
- the solvent the solvent represented by the above reaction formula A can be used.
- the reaction temperature is usually between room temperature and 150 ° C, preferably 80-120 ° C.
- the reaction time is usually 11 to 12 hours. This reaction is performed when compound (a) or compound (c) has a reactive group such as a hydroxyl group or an amino group, and is protected by a protecting group.
- D represents an optionally substituted (CI-C6) alkyl group
- L ′ represents a leaving group
- Y may optionally have a substituent (C1 C6) represents an alkyl group.
- Examples of the leaving group include a chloro group, a bromo group, an odo group, a methanesulfonoxy group, and a p-toluenesulfonyl group.
- Compound (e) is reacted with compound ( ⁇ ') obtained also in Reaction Formula A or B to obtain compound (f), and then the compound ( ⁇ '') is obtained by a dealkoxycarbonylation reaction.
- the first-step reaction is usually performed in the presence of a base, and examples of the base include alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, and carbonate.
- Alkali metal bicarbonates such as potassium hydrogen, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide
- Metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, alkyl metals such as butyllithium, tert-butylmagnesium chloride, lithium disopropylamide (LDA), lithium bis (trimethylsilyl) Amide, sodium bis (trimethylsilyl) a
- Metal amides such as amides, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaline, N, N-dimethylaline, 1,5 —Diazabicyclo [4.3
- the amount of the base to be used is 0.5-5 molar equivalents, preferably 1-2 molar equivalents, relative to compound ( ⁇ ′).
- the amount of compound (e) to be used is 0.5-5 molar equivalents, preferably 1-2 molar equivalents, relative to compound ( ⁇ ′).
- This reaction is carried out in the absence or presence of a solvent, and is preferably carried out in the presence of a solvent.
- the solvent is not particularly limited as long as the reaction proceeds. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, petroleum ether, aromatic hydrocarbons such as benzene, toluene and xylene, and chlorides.
- Halogenated hydrocarbons such as methylene, chloroform, 1,2-dichloroethane, etc., ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, acetonitrile, propio-tolyl, etc.
- Amides such as -tolyls, dimethylformamide, dimethylacetamide, and hexamethylphosphoric acid triamide; ureas such as 1,3 dimethylimidazolidine 2-one; and mixed solvents of the above solvents.
- Ri is preferably tetrahydrofuran, dimethylformamide or 1, 3-dimethyl-imidazolidin-2-one.
- the reaction temperature is usually 80-150 ° C, preferably 0-80 ° C.
- the reaction time is usually from 10 minutes to 48 hours.
- the reaction of the first step is preferably performed by protecting with a protecting group.
- a commercially available product may be used as it is, or may be prepared according to a known method or a method analogous thereto.
- the reaction in the second stage is carried out under the conditions of a general dealkoxycarbonylation reaction.
- Y is preferably, for example, a tert-butyl group or a benzyl group.
- the reaction is carried out with an acid such as trifluoroacetic acid or hydrochloric acid. This is carried out by a reduction reaction.
- the compound (a) used in the above reaction formula A or B can be prepared by a known method for producing a [1,2,4] triazolo [1,5-a] pyrimidine derivative, for example, as described in JP-A-04-099775. No. 4,444,774, Reiter et al., Tetrahedron, Pergamon 'Journals, Vol. 43, No. 11, pp. 2497-2504, 1987 (Reiter, et al., Tetrahedron, vol. 43, 24 97-2504). (1987)), etc., according to the method described in the following reaction formula D.
- R ' represents a (C1-C6) alkyl group.
- the acetophenone derivative (k) is condensed with a formamide dimethyl acetal compound to obtain a compound (m).
- the amount of the formamide dimethyl acetal conjugate to be used is 0.5-5 molar equivalents, preferably 113 molar equivalents, relative to compound (k).
- This reaction is performed in the absence or presence of a solvent.
- the solvent is not particularly limited as long as the reaction proceeds. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, petroleum ether, aromatic hydrocarbons such as benzene, toluene and xylene, and chlorides.
- Halogenated hydrocarbons such as methylene, chloroform, 1,2-dichloroethane, etc., ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, or mixed solvents of the above solvents, etc. And aromatic hydrocarbons such as benzene, toluene and xylene.
- the reaction temperature is usually 80-200 ° C, preferably 110-150 ° C.
- the reaction time is usually 6-48 hours.
- the compound (m) is condensed with 3,5-diamino-1,2,4 triazole to obtain a compound (a).
- This reaction is generally carried out in the absence or presence of an acid, preferably in the presence of an acid.
- the acid include mineral acids such as hydrochloric acid and sulfuric acid, carboxylic acids such as acetic acid, trifluoroacetic acid and benzoic acid, and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid.
- Examples include acids, Lewis acids such as boron trifluoride, titanium tetrachloride, tin tetrachloride, etc., and preferred are sulfonic acids.
- the amount of the acid to be used is 0.1 molar equivalent or a large excess with respect to compound (m), preferably 0.2 molar equivalent. One molar equivalent.
- the amount of 3,5-diamino-1,2,4-triazole to be used is 0.5-10 molar equivalents, preferably 114 molar equivalents, relative to compound (m).
- This reaction is carried out in the presence of a solvent, and the solvent is not particularly limited as long as the reaction proceeds.
- the solvent is not particularly limited as long as the reaction proceeds. Examples thereof include hexane, heptane, lignin, aliphatic hydrocarbons such as petroleum ether, and benzene.
- the substituent of Ar and R in the compound represented by the general formula (I) may be determined by a known method or a method analogous thereto, for example, an esterification reaction, an amidation reaction, or a hydrolysis reaction. It can also be produced by conversion by reactions such as decomposition reaction, oxidation reaction, reduction reaction, alkylation reaction, and deprotection reaction in a conventional manner.
- the product can be converted into a salt when it is obtained in a free form, or into a free form when the product is obtained as a salt, according to a conventional method.
- the protecting group may be a known group (for example, Greene, TW et al., "PROTECTIVE GRO UPS IN ORGANIC SYNTHESIS” Edition, the method described in WILEY'INTERSCIENCE (USA)).
- amino-protecting group examples include (C1-C7) acyl, benzoyl, (C2-C7) alkoxycarbol, benzyloxycarbol, and phthaloyl. It is.
- hydroxyl-protecting group examples include (C1-C6) alkyl, benzyl, (C1-C7) acyl, benzoyl, and alkyl-substituted silyl groups.
- Each product in each of the above production methods can be isolated and purified by known separation means, for example, distillation, concentration under reduced pressure, solvent extraction, crystallization, chromatography and the like.
- W represents a halogeno group, a hydroxyl group, a (C1-C6) alkoxyl group, a phenyl group, and a 5- to 6-membered aromatic heterocyclic group containing one heteroatom.
- a substituent group consisting of a phenyl group, a methoxyphenyl group and a 5- to 6-membered aromatic heterocyclic group containing one heteroatom, which may be substituted with one selected substituent; C2-C7) alkoxycarbyl group;
- Z—CO— ⁇ Z is (C1-C6) alkyl, halogeno, hydroxyl, oxo, trifluoromethyl, cyano, nitro, (C1-C6) alkoxyl, benzyloxy, (C1-C6) Substituent group consisting of alkylsulfur group, (C1-C6) alkoxycarbol group, amino group, di (C1-C6) alkylamino group, (C1-C7) acylamino group and methylenedioxy group (B) Contains the same or different aromatic hydrocarbon group optionally having 13 substituents selected from the group, or contains 114 heteroatoms independently selected from N, O and S Substituted with the same or different 1 to 3 substituents selected from the substituent group (B)! /, Or! /, Representing a 5- to 6-membered saturated or unsaturated heterocyclic group ⁇
- Preferred conjugates of the substituted 2-amino- [1,2,4] triazolo [1,5-a] pyrimidine derivatives of the present invention include: 3 benzenesulfol-N- (7-thiophene2- 1- [1,2,4] triazolo [1,5-a] pyrimidine-2 yl) propionamide, 3 benzenesulfol-N- [7- (4-methoxyphenyl)-[1,2,4 ] Triazolo [1,5-a] pyrimidine 2yl] propionamide, (S) -2- (tert-butoxycarbol) amino-N- (7-thiophene-2-yl [1,2,4] triazolo [ 1,5—a] pyrimidine 2yl) butyramide, (S) —2amino-N— (7-thiophene-2-yl [1,2,4] triazolo [1,5—a] pyrimidine 2yl) butyramide Or (S)
- Test Example 1 Action on MHC class I expression of T1 cells (human lymphoma cell line 174xCEM.)
- RPMI 1640 medium Iwaki Glass
- FBS 10% bovine serum
- the cells were cultured in an incubator containing 5% carbon dioxide at 37 ° C for 3 days. After culturing, the cells were stained with a fluoroisothiocyanate-labeled mouse anti-human MHC class I monoclonal antibody (antibody produced by cell line W6Z32 (ATCC No. CRL1991)).
- the average fluorescence intensity (hereinafter referred to as MFI) of the stained cells was measured using flow cytometry FACScan (BD), and this was defined as the expression level of MHC class I molecules. Based on the following formula (1), the test compound concentration (EC value) that suppresses the expression level of MHC class I molecules by 20% was calculated and is shown in Table 1.
- Test Example 2 Effect of human peripheral blood-derived dendritic cells on MHC class I molecule expression
- Mononuclear cells were separated from human peripheral blood using specific gravity centrifugation, and CD14-positive cells were collected from peripheral blood mononuclear cells using mouse anti-human CD14 antibody-conjugated micropore beads and a magnetic cell separation system (Miltenyi Biotec). Was isolated.
- the isolated CD14-positive cells were suspended in RPMI 1640 medium containing 10% FBS, and seeded on a 6-well plate to form 1. OxlO 6 cells in a 37 ° C incubator containing 5% carbon dioxide. For 20 minutes. After the culture, non-adherent cells that had no adherence and floated in the solution were removed.
- GM-CSF human recombinant granulocyte colony stimulating factor
- IL 4 human recombinant interleukin 4
- FBS FBS
- RPMI 1640 was cultured in a 37 ° C incubator containing 2 mL / Delka syrup and 5% carbon dioxide.
- CD14-positive cells are cultured in the presence of GM-CSF, IL-4, CD14-positive cells are transformed into non-adherent immature dendritic cells. After culturing for 7 days, immature ⁇ cells were obtained by collecting non-adherent cells.
- TNF- ⁇ human recombinant tumor necrosis factor ⁇
- RPMI 1640 containing 10% FBS containing the test compound
- the number of highly expressed cells Z The ratio of the total number of cells was measured.
- the reduction rate of the number of cells expressing high levels of MHC class I molecules was calculated from the following formula (2), and the concentration (EC value) of the test compound showing a 50% reduction was determined. The results are shown in Table 2.
- Eexp (Number of cells with high expression of MHC class I molecule in cultured cells with test compound) / ( Total cell count)
- Cexp (number of MHC class I molecule highly expressing cells in cultured cells without test compound) / (total number of cells)
- the compounds of the present invention have been shown to suppress the expression of MHC class I molecules in human peripheral blood-derived ⁇ cells.
- Test Example 3 Effect on the ability of human dendritic cells to induce allogeneic T cell proliferation
- the cells are collected on a glass filter using a cell harvester (Skatron instrument), dried, added with a scintillator ACS-II (Amersham pharmacia biotech), and used with a liquid scintillation counter.
- the radioactivity of [ 3 H] -thymidine incorporated into cells was measured.
- the formula (3) below the inhibition rate of DNA synthesis in lymphocytes is calculated, and the concentration (IC value) of the test compound that exhibits 50% inhibition is calculated. Table 3 shows the results.
- the compounds of the present invention were shown to suppress the ability of ⁇ cells to induce lymphocyte proliferation.
- Test Example 4 Cytotoxic effect on T1 cells (human lymphoma cell line 174xCEM.)
- the compound of the present invention has a cytotoxic effect on Tl cells and has an anti-cell proliferation inhibitory activity.
- Example 3 By heating to reflux in xylene in the presence of N, N-dimethylformamide getyl acetal in the same manner as in Example 001, 3-dimethylamino-1-phenylprobenone (yield 41%) was obtained.
- the title compound (63% yield) was obtained by reacting with 3,5-diamino-1,2,4-triazole in the presence of medium 10 camphorsulfonic acid.
- Example 005 The compound of Example 005 (69.4 mg, 0.22 mmol) was dissolved in N, N-dimethylformamide (1.6 mL), and sodium hydride (60% paraffin solution, 17.6 mg, 0.44 mmol) and Then, methyl iodide (27.4 / zL, 0.44 mmol) was added and stirred at room temperature for 1 hour. After dilution with methylene chloride (5 mL), the mixture was washed with 0.4 M hydrochloric acid and distilled water. The organic layer was concentrated under reduced pressure, hexane was added to the residue, and the residue was washed by suspension to obtain a light brown powder (59. Omg).
- Example 035 (23) -2-Methyl-1- (7-thiophen-2-yl [1,2,4] triazolo [1,5-a] pyrimidine-2-ylcarbamoyl) propyl tert-butyl rubamate Synthesis of ester (Example of Reaction Formula A)
- N- (tert-butoxycarbol) -L-parin (21.7 mg, 0.10 mmol) and TFFH (25.Omg, 0.1 mmol) are dissolved in tetrahydrofuran (1 mL), and N, N-diisopropylpropylethylamine ( 34.8 / zL, 0.20 mmol) was added and stirred at room temperature for 1 hour to prepare acid fluoride.
- Example 040 Synthesis of ((S) -2 amino-3-methyl-N— (7-thiophen-2-yl [1,2,4] triazolo [1,5—a] pyrimidine-2-yl) butylamide
- Example 054 Synthesis of 3 benzenesulfol-N- [7- (3-methoxyphenyl)-[1,2,4] triazolo [1,5-a] pyrimidin-2-yl] propionamide (Example of reaction formula B)
- Example 001-060 synthesized by using the methods described in the above-mentioned production methods and Examples and methods obvious to those skilled in the art are shown in the Table. See Figure 6. These were manufactured using the corresponding raw materials and reagents.
- the compound having an amino group in the structural formula can be obtained by using a raw material in which an amino group is protected by a tert-butoxycarbonyl group and deprotecting by the method described in Example 040 or Example 044. Was.
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Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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EP04792462A EP1674454A4 (en) | 2003-10-17 | 2004-10-15 | SUBSTITUTED 2-AMINO-1,2,4-TRIAZOLO 1,5-A-PYRIMIDINE DERIVATIVE AND THE USE THEREOF |
CA002542290A CA2542290A1 (en) | 2003-10-17 | 2004-10-15 | Substituted 2-amino-[1,2,4]triazolo[1,5-a]pyrimidine derivative and use thereof |
US10/575,527 US20070129383A1 (en) | 2003-10-17 | 2004-10-15 | Substituted 2-amino-[1,2,4]triazolo[1,5-a]pyrimidine derivative and use thereof |
JP2005514793A JPWO2005037837A1 (ja) | 2003-10-17 | 2004-10-15 | 置換2−アミノ−[1,2,4]トリアゾロ[1,5−a]ピリミジン誘導体及びその用途 |
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JP2003-357143 | 2003-10-17 | ||
JP2003357143 | 2003-10-17 |
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WO2005037837A1 true WO2005037837A1 (ja) | 2005-04-28 |
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US (1) | US20070129383A1 (ja) |
EP (1) | EP1674454A4 (ja) |
JP (1) | JPWO2005037837A1 (ja) |
CA (1) | CA2542290A1 (ja) |
WO (1) | WO2005037837A1 (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005075435A1 (en) * | 2004-01-30 | 2005-08-18 | Vertex Pharmaceuticals Incorporated | Modulators of atp-binding cassette transporters |
WO2009005046A1 (ja) * | 2007-07-02 | 2009-01-08 | Asahi Kasei Kuraray Medical Co., Ltd. | ミゾリビンを含有する潰瘍性大腸炎治療薬 |
WO2009128520A1 (ja) * | 2008-04-18 | 2009-10-22 | 塩野義製薬株式会社 | P13k阻害活性を有する複素環化合物 |
US7977322B2 (en) | 2004-08-20 | 2011-07-12 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011105394A1 (ja) * | 2010-02-23 | 2011-09-01 | 日本化薬株式会社 | 制御性樹状細胞の作製方法 |
WO2014081878A2 (en) | 2012-11-21 | 2014-05-30 | Stategics, Inc. | Substituted triazolo-pyrimidine compounds for modulating cell proliferation, differentiation and survival |
US11827640B2 (en) | 2020-10-23 | 2023-11-28 | Ildong Pharmaceutical Co., Ltd. | Substituted pyrazolo[1,5-a]pyrimidines as CFTR modulators |
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JPH07309872A (ja) * | 1994-03-24 | 1995-11-28 | Otsuka Pharmaceut Factory Inc | 縮環ピリミジン誘導体及び鎮痛剤 |
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JP2004323458A (ja) * | 2003-04-28 | 2004-11-18 | Nippon Kayaku Co Ltd | [1,2,4]トリアゾロ[1,5−a]ピリミジン−2−イルアミン誘導体,その製造法及びその用途 |
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JP2001302667A (ja) * | 2000-04-28 | 2001-10-31 | Bayer Ag | イミダゾピリミジン誘導体およびトリアゾロピリミジン誘導体 |
EP1317433A2 (en) * | 2000-09-06 | 2003-06-11 | Chiron Corporation | Inhibitors of glycogen synthase kinase 3 |
-
2004
- 2004-10-15 US US10/575,527 patent/US20070129383A1/en not_active Abandoned
- 2004-10-15 CA CA002542290A patent/CA2542290A1/en not_active Abandoned
- 2004-10-15 WO PCT/JP2004/015245 patent/WO2005037837A1/ja active Application Filing
- 2004-10-15 JP JP2005514793A patent/JPWO2005037837A1/ja active Pending
- 2004-10-15 EP EP04792462A patent/EP1674454A4/en not_active Withdrawn
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JPS56110620A (en) * | 1980-02-08 | 1981-09-01 | Mochida Pharmaceut Co Ltd | Inhibitor against metastasis of cancer |
JPH05148267A (ja) * | 1991-02-22 | 1993-06-15 | Egyt Gyogyszervegyeszeti Gyar | 5−(置換アミノ)−1,2,4−トリアゾロ[1,5−aピリミジン誘導体および製薬上許容され得るその酸付加塩、それらの製造法、並びにそれらを活性成分として含んでなる製剤組成物 |
JPH07309872A (ja) * | 1994-03-24 | 1995-11-28 | Otsuka Pharmaceut Factory Inc | 縮環ピリミジン誘導体及び鎮痛剤 |
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JP2004323458A (ja) * | 2003-04-28 | 2004-11-18 | Nippon Kayaku Co Ltd | [1,2,4]トリアゾロ[1,5−a]ピリミジン−2−イルアミン誘導体,その製造法及びその用途 |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005075435A1 (en) * | 2004-01-30 | 2005-08-18 | Vertex Pharmaceuticals Incorporated | Modulators of atp-binding cassette transporters |
JP2007519740A (ja) * | 2004-01-30 | 2007-07-19 | バーテックス ファーマシューティカルズ インコーポレイテッド | Atp結合カセットトランスポーターのモジュレーター |
US8759335B2 (en) | 2004-01-30 | 2014-06-24 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
US7977322B2 (en) | 2004-08-20 | 2011-07-12 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
WO2009005046A1 (ja) * | 2007-07-02 | 2009-01-08 | Asahi Kasei Kuraray Medical Co., Ltd. | ミゾリビンを含有する潰瘍性大腸炎治療薬 |
CN101687899B (zh) * | 2007-07-02 | 2012-11-28 | 旭化成医疗株式会社 | 含有咪唑立宾的溃疡性结肠炎治疗药 |
JP5697070B2 (ja) * | 2007-07-02 | 2015-04-08 | 旭化成メディカル株式会社 | ミゾリビンを含有する潰瘍性大腸炎治療薬 |
WO2009128520A1 (ja) * | 2008-04-18 | 2009-10-22 | 塩野義製薬株式会社 | P13k阻害活性を有する複素環化合物 |
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Publication number | Publication date |
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JPWO2005037837A1 (ja) | 2006-12-28 |
EP1674454A4 (en) | 2006-12-27 |
CA2542290A1 (en) | 2005-04-28 |
EP1674454A1 (en) | 2006-06-28 |
US20070129383A1 (en) | 2007-06-07 |
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