WO2005037801A1 - Compose pyrimidine - Google Patents

Compose pyrimidine Download PDF

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Publication number
WO2005037801A1
WO2005037801A1 PCT/JP2004/015955 JP2004015955W WO2005037801A1 WO 2005037801 A1 WO2005037801 A1 WO 2005037801A1 JP 2004015955 W JP2004015955 W JP 2004015955W WO 2005037801 A1 WO2005037801 A1 WO 2005037801A1
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group
mes0
phnh
menhs0
pyrimidine
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PCT/JP2004/015955
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Japanese (ja)
Inventor
Hiroyuki Tsuruoka
Akihisa Matsuda
Yuichi Sugano
Toru Tatsuta
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Sankyo Company, Limited
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Publication of WO2005037801A1 publication Critical patent/WO2005037801A1/fr

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    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
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Definitions

  • the present invention relates to a pyrimidine derivative having an inhibitory action on mixed lymphocyte culture reaction (hereinafter abbreviated as MLR) or a pharmacologically acceptable salt thereof, and a medicament containing them as an active ingredient.
  • MLR mixed lymphocyte culture reaction
  • autologous lymphocyte cells on the recipient side react with non-autologous cells in the transplanted tissue to activate and proliferate lymphocyte cells. It is caused by eliminating attacks.
  • the rejection reactions were 1) recognition of non-self cells, 2) increased expression of costimulatory molecules on the surface of lymphocyte cells and production of proliferative cytokins, 3) activation and proliferation of lymphocytes, 4) proliferation It is a multi-step reaction consisting of steps such as attacking the graft with lymphocyte cells.
  • Recognition of non-self cells by lymphocytes is performed via major histocompatibility antigen (MHC).
  • Lymphocytes that recognize and activate non-self cells due to differences in MHC produce cytokins such as interleukin 2 (hereinafter abbreviated as IL-2), and various types of IL-2 Immune cells are activated to proliferate.
  • the activated lymphocyte is proliferated to activate various immune cells through co-stimulatory molecules expressed on the membrane surface.
  • Proliferative activated T cells, B cells, such as killer one T cell attack eliminate implanted lymphoid-tissue cells (IMMUN0BI0L0GY 3 rd edi t ion,
  • MLR is considered to be a simple evaluation system that reflects the activated proliferation reaction of autologous lymphocytes to non-autologous lymphocytes in this rejection reaction, and is one of the evaluation systems frequently used in the development of existing immunosuppressants. Has become one. Recently been found, some effective der Ru compounds in suppressing the rejection of transplants, in the present system has proved to exhibit a significant inhibitory effect (IMMUN0BI0L0GY 3 rd edi t ion, 505 ) 0 Thus, compounds that inhibit ML R suppresses rejection in such as bone marrow transplantation, organ transplantation, are expected as useful agents for maintaining the long-term engraftment of transplanted bone marrow and organs.
  • the experimental system for evaluating MLR is an experimental system that reflects cellular immunity such as lymphocyte cell proliferation and cell killing activity, and humoral immune functions such as antibody production. Is considered to be effective for the following diseases involving excessive cellular and humoral immune functions.
  • excessive cell-mediated immunity and humoral immunity can be caused by chronic arthritis, an inflammatory disease, multiple sclerosis, an organ-specific autoimmune disease, inflammatory bowel disease, diabetes, Primary biliary cirrhosis, chronic active hepatitis, pernicious anemia, Hashimoto's thyroiditis, atrophic gastritis, myasthenia gravis, psoriasis, and Sheddalen syndrome, non-organ-specific Rhinitis asthma-Asthma-Considered to be involved in the disease of atopic dermatitis [Immunol. Today, Vol. 16, 34-38, (1995), Science Vol. 260, 547-549 , (1993), Immunity, Vol.
  • MLR inhibitors are It is believed to show efficacy. From the above background, attempts have been made to find a compound having an excellent MLR inhibitory action. Disclosure of the invention
  • the present inventors conducted a sharp study on a derivative having an MLR inhibitory action.
  • the pyrimidine derivative of the present invention has an excellent MLR inhibitory action, low cytotoxicity and low bone marrow transplantation.
  • Inhibitors of rejection of transplants, etc. inhibitors of cancer cells by selective cell killing activity (eg, inhibitors of cancerous lymphocytes), or inflammatory diseases such as rheumatoid arthritis, organ-specific Autoimmune diseases (e.g., multiple sclerosis, inflammatory bowel disease, diabetes, glomerulonephritis, primary biliary cirrhosis, chronic active hepatitis, pernicious anemia, Hashimoto's thyroiditis, atrophic gastritis, myasthenia gravis, psoriasis Or non-organ-specific autoimmune diseases (eg, systemic lupus erythematosus) or allergic diseases (eg, rhinitis, asthma or atopic dermatitis)
  • R 1 represents a lower alkyl group
  • R 2 is an aryl group, a heterocyclic group, an arbitrary group selected from substituent group a, and an aryl group substituted with 1 to 5 substituents, or an arbitrary group selected from substituent group a.
  • A represents —NH— or an oxygen atom
  • R 3 is a hydrogen atom, a lower alkyl group, an aryl group, a heterocyclic group or one NHR 6 group (where R 6 is substituted with a lower alkyl group, a cycloalkyl group, a cycloalkyl group, and 1 to 3 independently substituted with any group selected from the group consisting of a killing group and a substituent group b, and independently selected from a cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, and a substituent group b.
  • R 4 is any selected from a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group, a lower alkyl group substituted with a cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, and a substituent group b Represents an arylsley group independently substituted by 1 to 5 groups or a heterocyclic group independently substituted by 1 to 3 groups selected from a substituent group b (where R 3 represents a hydrogen atom Excluding the case where R 4 represents a hydrogen atom.
  • R 5 is a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a heterocyclic group, a heterocyclic group independently substituted with 1 to 3 arbitrary groups selected from substituent group b, -NR 7 R 8 group or —OR 7 group (R 7 and R 8 are the same or different and each independently represents 1 to 5 groups selected from a hydrogen atom, a lower alkyl group, a cycloalkyl group, and a substituent group c. A substituted or unsubstituted lower alkyl group, aryl group, heterocyclic group, or an aryl group substituted with 1 to 5 substituents independently of an arbitrary group selected from substituent group b). — TY
  • T is an ⁇ or CH
  • Y is, 0, S, SO, S 0 2 or NZ (Z is any group selected from substituent group b) a ⁇ group represented by Except
  • Substituent group a is a lower alkylsulfonyl group, an aminosulfonyl group, a mono-lower alkylaminosulfonyl group, a mono-cycloalkylaminosulfonyl group, a mono- (hydroxy lower alkyl) aminosulfonyl group, a di-lower alkylaminosulfonyl group A mono- (carboxy lower alkyl) aminosulfonyl group, a nitrogen-containing saturated complex sulfonyl group and a mono-SO 3 H group,
  • Substituent group b includes a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, a carboxy group, an amino group, a mono-lower alkylamino group, Di-lower alkylamino group, aminosulfonyl group, hydroxy group, aryl group, aryloxy group, heterocyclic group, halogenoaryl group, halogenoaryloxy group, 1- (4-methylaminosulfonylphenyl) -ethylide A group consisting of 1- (4-methylsulfonylphenyl) -ethylidene-hydrazinocarbonyl group; Substituent group c represents an amino group, a mono-lower alkylamino group, a di-lower
  • a pyrimidine derivative or a pharmacologically acceptable salt thereof wherein R 2 is an aryl group independently substituted by 1 to 3 heterocyclic groups or an arbitrary group selected from substituent group a,
  • R 2 is selected from pyridyl group or (lower alkylsulfonyl group, aminosulfonyl group, mono-lower alkylaminosulfonyl group, monocycloalkylaminosulfonyl group, and mono- (carboxy lower alkyl) aminosulfonyl group)
  • a pyrimidine derivative or a pharmaceutically acceptable salt thereof which is a phenyl group substituted at the 4-position with an arbitrary group, (6) in any one selected from (1) to (3),
  • R 2 is a 4-pyridyl group, a 4-methylsulfonylphenyl group, a 4-ethylesulfonylphenyl group, a 4-aminosulfonylphenyl group, a 4-methylaminosulfonylphenyl group, a 4-ethylaminosulfonylphenyl group
  • R 2 is 4-pyridyl, 4-methylsulfonylphenyl, 4-aminosulfonylphenyl, 4-methylaminosulfonylphenyl, 4-cyclopropylaminosulfonylphenyl or 4-carboxymethylaminosulfonylphenyl
  • a pyrimidine derivative or a pharmaceutically acceptable salt thereof wherein R 2 is a 4-pyridyl group, a 4-methylsulfonylphenyl group or a 4-methylaminosulfonylphenyl group;
  • A is —NH—, a pyrimidine derivative or a pharmaceutically acceptable salt thereof,
  • R 3 is an aryl group, a heterocyclic group, a mono-aryl amino group, a mono-heterocyclic amino group, or any group in which the phenyl moiety is selected from (halogen atom, lower alkyl group and lower alkoxy group), independently 1 or A pyrimidine derivative or a pharmacologically acceptable salt thereof, which is a mono-phenylamino group which is two-shrunched, (11) In any one selected from (1) to (9),
  • R 3 is a 3-pyridyl group, a 1-indolinyl group, a phenylamino group, a 3-pyridylamino group or a phenyl moiety (a fluorine atom, a chlorine atom, a methyl group and a methoxy group);
  • a pyrimidine derivative which is a mono-phenylamino group substituted by 1 or 2 or a pharmacologically acceptable salt thereof,
  • R 3 is 3-pyridyl, 1-indolinyl, phenylamino, 3_pyri, lumino, 4-fluorophenylamino, 2-fluorophenylamino, 5-fluoro-2-methylphenyl
  • R 3 is a 3-pyridyl group, a 1-indolinyl group, a phenylamino group, a 3-pyridylamino group, a 2-fluorophenylamino group, a 5-fluoro-2-methylphenylamino group or a 2-methoxyphenylamino group;
  • a pyrimidine derivative or a pharmacologically acceptable salt thereof
  • R 4 is a hydrogen atom, a lower alkyl group, an aryl group, a heterocyclic group, an aralkyl group, or an aryl group independently substituted with 1 to 5 arbitrary groups selected from a substituent group b;
  • R 4 represents a hydrogen atom, a lower alkyl group, a phenyl group, a naphthyl group, an aromatic heterocyclic group, a condensed bicyclic heteroaryl group, a benzyl group or a (halogen atom, a lower alkyl group and Pyrimidine derivatives or pharmacologically acceptable salts thereof, which are phenyl groups independently substituted by 1 or 2 arbitrary groups selected from the group consisting of:
  • R 4 is hydrogen, phenyl, 1-naphthyl, 3-phenyl, 1,3-benzodioxolan-5-yl, 1,4-benzodioxane-6-yl, benzyl or benzyl Is a pyrimidine derivative or a pharmaceutically acceptable salt thereof, which is a phenyl group independently substituted by one or two arbitrary groups selected from (a fluorine atom, a chlorine atom, a methyl group and a methoxy group);
  • a pyrimidine derivative or a pharmacologically acceptable salt thereof wherein R 4 is a hydrogen atom, a phenyl group, a 3-phenyl group, a 4-fluorophenyl group, a 2-fluorophenyl group or a 2-methylphenyl group;
  • a pyrimidine derivative wherein R 4 is a hydrogen atom, a lower alkyl group, an aryl group, a heterocyclic group, or an aryl group independently substituted with 1 to 5 groups selected from a substituent group b, or a pharmacology thereof;
  • R 4 is a hydrogen atom, a lower alkyl group, an aryl group, a heterocyclic group, or an aryl group independently substituted with 1 to 5 groups selected from a substituent group b, or a pharmacology thereof;
  • R 4 is a hydrogen atom, a lower alkyl group, a phenyl group, a naphthyl group, an aromatic heterocyclic group, a condensed bicyclic heteroaryl group or any group selected from a (halogen atom, a lower alkyl group and a lower alkoxy group)
  • R 4 represents a hydrogen atom, a phenyl group, a 1-naphthyl group, a 3-phenyl group, a 1,3-benzodioxolan _ 5-yl group, a 1,4-benzodioxane-16-yl group, or a (fluorine atom, chlorine atom , A methyl group and a methoxy group), a pyrimidine derivative which is a phenyl group independently substituted with one or two phenyl groups, or a pharmaceutically acceptable salt thereof, (24)
  • R 4 is a hydrogen atom, a phenyl group, a 1-naphthyl group, a 3-phenyl group, a 1,3-benzodioxo-l
  • a pyrimidine derivative or a pharmacologically acceptable salt thereof which is a 1,4-benzodioxane-1-6-yl group, a 2-fluorophenyl group,
  • R 5 is a hydrogen atom, a halogen atom, a cycloalkyl group, a heterocyclic group, a heterocyclic group independently substituted with 1 to 3 arbitrary groups selected from substituent group b, — NR 7 R 8 group or R 7 groups (R 7 and R 8 are the same or different and are independently substituted with 1 to 5 hydrogen atoms, a lower alkyl group, a cycloanolenyl group, and any group selected from a substituent group c.
  • a pyrimidine derivative or a pharmacologically acceptable derivative thereof which is independently an aryl group substituted with 1 to 5 lower phenolic groups, aryl groups, heterocyclic groups or any group selected from substituent group b.
  • Acceptable salt
  • R 5 is a hydrogen atom, a heterocyclic group, a heterocyclic group substituted by one heterocyclic group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group or a lower alkyl moiety is a hydroxy group, a lower alkoxy group; Group, a hydroxy lower alkoxy group, a heterocyclic group, and 1 to 5 independently substituted with an arbitrary group selected from an aryl group substituted with 1 to 3 arbitrary groups selected from the substituent group b
  • R 5 is a hydrogen atom, 1-pyrazolyl group, 1-imidazolyl group, 1-azetidinyl group, 1-pyrrolidinyl group, 1- [4-1 (4-pyridyl)] pyrazolyl group, 1- [3- (4-pyridyl) ] Pyrazolyl group, 3- (4-pyridyl) 1-1-pyrrolyl group, (4-pyridyl) methylamino group, amino group, methylamino group, dimethylamino group, 2-hydroxyphenylamino group, 2-methoxyethylamino Group, 2- (2-hydroxyethoxy) Ethylamino, 2- (4-pyridyl) ethylamino, 3- (4-pyridyl) propylamino, 2- (4-pyridyl) -2-hydroxyethylamino, 2- (1,3-benzodiamino) Oxolane (1-1 ⁇ r) ethylethylamino, 3,
  • R 5 is a hydrogen atom, 1 one pyrazolyl group, 1 one imidazolyl group, 1 Azechijininore group, 1- [4- (4 one-pyridyl)] pyrazolyl group, 1 one [3 - (4-pyridyl)] Vila, glue J Les Group, 3- (4-pyridyl) -1-pyrrolyl group, (4-pyridyl) methylamino group, amino group, methylamino group, 2- (2-hydroxyethoxy) ethylamino group, 2- (4-pyridyl) ) Ethylamino, 3- (4-pyridyl) propylamino, 2- (4-pyridyl) -12-hydroxyethylamino, 2- (1,3-benzodioxolan-5-yl) Ethylamino, 3,4-dimethoxyphenethylamino, 2- (3,4-dimethyloxyphenyl) -1-hydroxyeth
  • R 5 is a hydrogen atom, 1-pyrazolyl group, 1-imidazolyl group, 1_ [4_ (4-pyridyl)] pyrazolyl group, 1_ [3- (4-pyridyl)] pyrazolyl group, 3- (4-pyridyl )-1-pyrrolyl, (4-pyridyl) methylamino, 2- (4-pyridyl) ethylamino, 3- (4-pyridyl) propylamino, 2- (4-pyridyl) -2-hydroxy Pyrimidine derivatives or pharmacology of a thiamino group, a 3,4-dimethoxyphenethylamino group, a 2- (3,4-dimethoxyphenyl) -1-2-hide-opening xyethylamino group or a 2_ (4-pyridyl) ethyloxy group Above acceptable salts,
  • R 5 is a hydrogen atom, a heterocyclic group, a heterocyclic group substituted by one heterocyclic group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group or a lower alkyl moiety is a hydroxy group, a lower alkyl group;
  • R 5 is a hydrogen atom, 1-pyrazolyl group, 1-imidazolyl group, 1- [1,2,3] -triazolyl group, 2- [1,2,3] _triazolyl group, 1- [1,2, 4] -triazolyl group, 4- [1,2,4] -triazolyl group, 1-azetidinyl group, 1-pyrrolidinyl group, 1- [4- (4-pyridyl)] pyrazolyl group, 1- [3— ( 4-pyridyl)] pyrazolyl, amino, methylamino, dimethylamino, 2-hydroxyethyldiamino, 2-methoxyethylamino, 2- (2-hydroxyethoxy) ethylamino or lower alkyl moiety Is selected from 3-pyridyl, 4-pyridyl, 1,3-ben, noxoxolan-15-yl, mono-methoxyphenyl, di-methoxyphenyl and aminosulf
  • R 5 is a hydrogen atom, 1-pyrazolyl group, 1-imidazolyl group, 1-azetidinyl group, 1-pyrrolidinyl group, 1- [4- (4-pyridyl)] pyrazolyl group, 1_ [3- (4-pyridyl) ] Pyrazolyl, amino, methylamino, dimethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2- (2-hydroxyethoxy) ethylamino, 2- (4-pyridyl A) pyrimidine derivative which is an ethylamino group, a 2- (1,3-benzodioxolan-5-yl) ethylamino group, a 3,4-dimethoxyphenethylamino group or a 4-aminosulfonylphenethylamino group, or a pharmacological agent thereof; Acceptable salts,
  • R 5 is a hydrogen atom, 1-pyrazolyl group, 1-imidazolyl group, 1-azetidinyl group, 11- [4- (4-pyridyl)] pyrazolyl group, amino group, methylamino group, 2- (2-hydroxyethoxy) ethylamino
  • a pyrimi derivative which is a 2-, 4- (4-pyridyl) ethylamino group, a 2- (1,3-benzodioxolan-5-yl) ethylamino group, a 3,4-dimethoxyphenethylamino group or a 4-aminosulfonylphenethylamino group Or a pharmacologically acceptable salt thereof,
  • R 1 is a methyl group
  • R 2 is a 4-pyridyl group, a 4-methylsulfonylphenyl group, a 4-aminosulfonylphenyl group, a 4-methylaminosulfonylphenyl group, a 4-cyclopropylaminosulfonyl phenyl group
  • An enyl group or a 4-hydroxyloxymethylaminosulfonylphenyl group, A is —NH—
  • R 3 is a 3-pyridyl group, 1-indolinyl group, phenylamino group, 3-pyridylamino group or phenyl moiety.
  • a mono-phenylamino group independently substituted by one or two groups selected from a fluorine atom, a chlorine atom, a methyl group and a methoxy group wherein R 4 is a hydrogen atom, a phenyl group or a 1-naphthyl group -1,3-Cenyl, 1,3-benzodioxolan-5-yl, 1,4-benzodioxane-6-yl, benzyl or (fluorine, chlorine, methyl Fine methoxy group) is any one or two substituted phenyl groups independently a group selected from, R 5 is a hydrogen atom, 1-pyrazolyl group, 1 _ imidazolyl group, 1-Azechijini group, 1- Pyrrolidinyl group, 1- [4- (4-pyridyl)] pyrazolyl group, 1- [3-'(4-pyridyl)] pyrazolyl group, 3- (4-pyridyl) -1
  • R 1 is a methyl group
  • R 2 is 4-pyridyl group, 4-methylsulfonylphenyl group, 4-aminosulfonylphenyl group, 4-methylaminosulfonylphenyl group, 4-cyclopropylaminosulfonylphenyl A or -NH-
  • R 3 is 3-pyridyl, 1-indolinyl, phenylamino, 3-pyridylamino, 4-fluorophenyla A amino group, a 2-fluorophenylamino group, a 5-fluoro-2-methylphenylamino group or a 2-methoxyphenylamino group
  • R 4 is a hydrogen atom, a phenyl group, a 3-phenyl group, a benzyl group, Fluorophenyl group, 2-fluorophenyl group or 2-methylphen
  • R 5 is a hydrogen atom, 1-pyrazolyl group, 1-imidazolyl group, 1-aze
  • R 1 is a methyl group
  • R 2 is a 4-pyridyl group, 4-methylsulfoelfenyl group or 4_methylaminosulfonylphenyl group
  • A is —NH—
  • R 3 is 3— Pyridyl group, 1-indolinyl group, phenylamino group, 3-pyridylamino group, 4-fluorophenylamino group, 2-fluorophenylamino group, 5-fluoro-2-methylphenylamino group or 2-methoxyphenylamino
  • R 4 is a hydrogen atom, a phenyl group, a 3-phenyl group, a 4-fluorophenyl group, a 2-fluorophenyl group or a 2-methylphenyl group
  • R 5 is a hydrogen atom, a 1-pyrazolyl group, —Imidazolyl group, 1-azetidinyl group, 1— [4- (4-pyridyl)] pyrazo
  • R 1 is a methyl group
  • R 2 is a 4-pyridyl group, a 4-methylsulfonylphenyl group or a 4-methylaminosulfonylphenyl group
  • A is —NH—
  • R 3 is a phenyl group.
  • a nilamino group, a 3-pyridylamino group, a 4-fluorophenylamino group or a 2-fluorophenylamino group wherein R 4 is a hydrogen atom, a phenyl group, a 3-phenyl group, a 4-fluorophenyl group, —Fluorophenyl group or 2-methylphenyl group, and R 5 is a hydrogen atom, 1-pyrazolyl group, 1-imidazolyl group, 1-azetidinyl group, 1- [4-(4_pyridyl)] pyrazolyl group, 1- [ 3- (4-pyridyl)] pyrazolyl group, 3- (4-pyridyl) -1-pyrrolyl group, (4-pyridyl) methylamino group, amino group, methylamino group, 2- (2-hydroxyethoxy) ethylamino group, 2 -(4-pyridyl) ethy
  • R 1 is a methyl group
  • R 2 is a 4-pyridyl group, 4-methylsulfonylphenyl group or 4-methylaminosulfonylphenyl group
  • A is —NH—
  • R 3 is phenyl
  • R 4 is a hydrogen atom, a phenyl group, a 3-phenyl group, a 4-fluorophenyl group, a 2-fluoro group, a nylamino group, a 3_pyridylamino group, a 4-fluorophenylamino group or a 2-fluorophenylamino group.
  • R 1 is a methyl group
  • R 2 is a heterocyclic group or an aryl group independently substituted by 1 to 3 groups selected from a substituent group a
  • A is 1 NH—
  • R 3 is an aryl group, a heterocyclic group, a monoarylamino group, a mono-heterocyclic amino group or a phenyl group
  • R 4 is a fluorine atom or a lower atom.
  • R 1 is a methyl group
  • R 2 is a pyridyl group or a (lower alkylsulfonyl group, an aminosulfonyl group, a mono-lower alkylaminosulfonyl group, a mono-cycloalkylaminosulfonyl group, and a mono- (carboxy lower alkyl) amino
  • R 3 is 3-pyridyl group, 1-indolinyl group, phenylamino group, Pirijirua amino group or a phenyl site (fluorine atom, chlorine atom, methyl group and methoxy group)
  • Ri mono-safe enyl ⁇ amino groups der substituted one or two independently any group that is selected from, R 4 Is a hydrogen atom, a lower alkyl group, a
  • R 1 is a methyl group
  • R 2 is a 4-pyridyl group, a 4-methylsulfonylphenyl group, a 4-ethylsulfonylphenyl group, a 4-aminosulfonylphenyl group, a 4-methylaminosulfonylphenyl group, 4-ethylaminosulfonylphenyl group, 4-cyclopropylpyraminosulfonylphenyl group or 4-carboxymethylaminosulfonylphenyl group
  • A is 1 NH—
  • R 3 is 3-pyridyl group , 1-indolinyl group, phenylamino group, 3-pyridylamino group, 2-fluorophenylamino group, 5-fluoro-2-methylphenylamino group or 2-methoxyphenylamino group
  • R 4 is a hydrogen atom
  • Phenyl group 1-naphthyl group, 3-phenyl group
  • R 1 is a methyl group
  • R 2 is a 4-pyridyl group, a 4-methylsulfonylphenyl group, a 4-aminosulfonylphenyl group, a 4-methylaminosulfonylphenyl group, and a 4-cyclopropylpropylaminosulfonyl group A phenyl group or a 4-hydroxypropylaminoaminosulfonylphenyl group, A is one NH—
  • R 3 is a 3-pyridyl group, 1-indolinyl group, a phenylamino group, a 3-pyridylamino group, A 2-fluorophenylamino group, a 5-fluoro-2-methylphenylamino group or a 2-methoxyphenylamino group, wherein R 4 is a hydrogen atom, a phenyl group, a 1-naphthyl group, a 3-phenyl group, , 3-benzod
  • R 1 is a methyl group
  • R 2 is a 4-pyridyl group, a 4-methylsulfonylphenyl group or a 4 _methylaminosulfonylphenyl group
  • A is —NH_
  • R 3 is A 3-pyridyl group, a phenylamino group, a 3-pyridylamino group or a 5-fluoro-2-methylphenylamino group
  • R 4 is a hydrogen atom, a phenyl group, a 3-phenyl group, a 1,3-benzodioxolan-5 —Yl group, 2-fluorophenyl group or 2-methylphenyl group
  • R 5 is a hydrogen atom, 1-pyrazolyl group, 1-imidazolyl group, 1-azetidinyl group, 1- [4- (4-pyridyl) )] Pyrazolyl, amino, methylamino, 2- (2-hydroxyethoxy) ethyla
  • New 2 (4-Furuoro - phenyl) - 6- ⁇ '- [Bok (4- main evening Nsuruhoniru - phenyl) - Echiriden] - hydrazino ⁇ -5-phenyl - New 4 - (2-pyridin-4 Yl-ethyl) -pyrimidine-2,4-diamine, 4- (1- ⁇ [2- (2-fluoro-phenylamino) -5-phenyl-6- (2-pyridine-4-yl-ethylamino) ) -Pyrimidine-4-yl] -hydrazono ⁇ -ethyl) - ⁇ -methyl-benzenesulfonamide,
  • a pyrimidine derivative selected from the group consisting of or a pharmacologically acceptable salt thereof,
  • a pyrimidine derivative selected from the group consisting of or a pharmacologically acceptable salt thereof,
  • N-methyl_4_ (tri ⁇ [5-phenyl-2- (pyridine-3-ylamino) -pyrimidine-4-yl] -hydrazono ⁇ -ethyl) -benzenesulfonamide, N-methyl-4- ⁇ tri [(5-phenyl-2-pyridin-3-yl-pyrimidine-4-yl) -hydrazono] -ethyl ⁇ -benzenesulfonamide,
  • a pyrimidine derivative selected from the group consisting of or a pharmacologically acceptable salt thereof,
  • a pyrimidine derivative selected from the group consisting of or a pharmacologically acceptable salt thereof,
  • a pharmaceutical composition comprising, as an active ingredient, a pyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (48).
  • a medicament for inhibiting a mixed lymphocyte culture reaction comprising, as an active ingredient, the pyrimidine derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (48).
  • a pharmaceutical composition for inhibiting cancer cells comprising, as an active ingredient, a pyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (48);
  • a pharmaceutical composition for inhibiting cancerous lymphocytes comprising as an active ingredient a pyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (48).
  • the pharmaceutical composition suppresses rejection of grafts in bone marrow transplantation, organ transplantation, etc., or prevents and treats inflammatory diseases, organ-specific autoimmune diseases, non-organ-specific autoimmune diseases, or allergic diseases.
  • the pharmaceutical composition described in (56) is a pharmaceutical composition for suppressing rejection of a transplant in bone marrow transplantation, organ transplantation, or the like, or for preventing or treating rheumatoid arthritis.
  • (66) Disease is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, diabetes, glomerulonephritis, primary biliary cirrhosis, chronic active hepatitis, pernicious anemia, Hashimoto's thyroiditis, atrophic gastritis, myasthenia gravis
  • the method according to (64), wherein the disease is psoriasis, psoriasis, Sheddalen syndrome, systemic lupus erythematosus, rhinitis, asthma or atopic dermatitis.
  • the “lower alkyl group” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, and 1-ethylpropyl.
  • Xyl 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3- A linear or branched alkyl group having 1 to 6 carbon atoms such as a dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl group, preferably a C, —C 4 alkyl And more preferably methyl, ethyl or It is an n-propyl group, still more preferably a C 1, —C 2 alkyl group, and particularly preferably a methyl group.
  • the “aryl group” is, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms such as phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl or fluorenyl group, preferably C 6 — .
  • An aryl group more preferably a phenyl or naphthyl group, even more preferably a phenyl or 1-naphthyl group, and particularly preferably a phenyl group.
  • heterocyclic group refers to a 5- to 7-membered heterocyclic group containing 1 to 4 sulfur atoms, oxygen atoms or Z and nitrogen atoms, and is, for example, furyl ′, chenyl, pyrrolyl, azepinyl "Aromatic heterocyclic groups” such as, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl groups , Tetrahydroviranyl, tetrahydrothenyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,
  • R 4 is preferably a 2-phenyl, 3-phenyl, 1,3-benzodioxolan-1-51 or 1,4-benzodioxane-16-yl group, more preferably Is a 3-phenyl, 1,3-benzodioxolan-5-yl or 1,4-benzodioxane-6-yl group, and still more preferably a 3-phenyl or 1,3-benzodioxolan-5.
  • —Yl group particularly preferably a 3-phenyl group, and in R 5 , preferably 1-pyrazolyl, 1-imidazolyl, 1-pyrrolyl, 1-pyrrolyl, A [1,2,3] -triazolyl, a 1-1 [1,2,4] -triazolyl, a 4- [1,2,4] triazolyl, a 1-azetidinyl or a 1-pyrrolidinyl group, more preferably 1-pyrazolyl, 1-imidazolyl, 1-pyrrolyl, 1-azetidinyl or 1-pyrrolidinyl group, and even more preferably, 1-pyrazolyl, 1-imidazolyl, 1-pyrrolyl or 1-azetidinyl group, particularly Preferably, it is a 1-pyrazolyl, 1-midazolyl or 1-pyrrolyl group.
  • the “cycloalkyl group” is a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, and is preferably a cyclopropyl group.
  • the “lower alkyl group substituted with a cycloalkyl group” refers to a group in which the “lower alkyl group” is bonded to the “cycloalkyl group”, for example, cyclopropylpyrmethyl, cyclopropylethyl, A cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl or cyclohexylmethyl group, preferably a cyclopropylmethyl group.
  • the “aralkyl group” refers to a group in which the “lower alkyl group” is bonded to the “aryl group”, for example, benzyl, ⁇ -naphthylmethyl, 3-naphthylmethyl, indenylmethyl, Diphenylmethyl, triphenylmethyl, 1-phenyl, 2-phenyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3 —Naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthy
  • the “lower alkoxy group” refers to a group in which the above “lower alkyl group” is bonded to an oxygen atom, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, Toxi, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methyl ⁇ , 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1.3-dimethylbutoxy or 2,3-dimethylbutoxy group, Preferably, it is a 1 C 4 alkoxy group, more preferably, a 1 C 2 alkoxy group, and even more preferably, a methoxy group.
  • the “halogen atom” is a fluorine, chlorine, bromine or iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.
  • the “lower alkylsulfonyl group” refers to a group in which the above “lower alkyl group” is bonded to a sulfonyl group, for example, methylsulfonyl, ethylsulfonyl, propylpyrusulfonyl, isopropylsulfonyl, butylsulfonyl, isobutyl Sulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, 2-methylbutylsulfonyl, neopentylsulfonyl, 1-X tylpropylsulfonyl, hexylsulfonyl, 4-methylpentylsulfonyl, 3 1-methylpentylsulfonyl, 2-methylpentyls
  • “mono-lower alkylaminosulfonyl group” refers to a group in which one amino group in which the above “lower alkyl group” is bonded to a sulfonyl group, such as methylaminosulfonyl and ethylamino.
  • "mono - cycloalkyl alkylaminosulfonyl group” Shikuropuropi Le aminosulfonyl, cyclobutylamino aminosulfonyl, cyclohexyl ⁇ amino sulfonyl group to cyclopentylamino aminosulfonyl or consequent opening, preferably, mono- c 3 - c It is a 4- cycloalkylaminosulfonyl group, more preferably a cyclopropylaminosulfonyl group.
  • “mono- (hydroxy lower alkyl) aminosulfonyl group” refers to a group in which one hydroxy group is substituted at the “lower alkyl” site of the above “mono-lower alkylaminosulfonyl group”.
  • Hydroxymethylaminosulfonyl 2-hydroxyethylaminosulfonyl, 1-hydroxyethylaminosulfonyl, 3-hydroxypropylaminosulfonyl, 4-hydroxybutylaminosulfonyl, 5-hydroxypentylaminosulfonyl or 6-hydroxyhexylamino a sulfonyl group, preferably a hydroxy and an C 4 alkylaminosulfonyl group, more preferably hydroxy is an C 2 alkylaminosulfonyl group, even more favorable suitable are 2-hydroxyethyl E chill amino It is a sulfonyl group.
  • “mono- (carboxy lower alkyl) aminosulfonyl group” refers to a group in which one carboxy group is substituted at the “lower alkyl” site of the “mono-lower alkylaminosulfonyl group”, for example, Carboxymethylaminosulfonyl, 2-carboxyethylaminosulfonyl, 1-potoxyloxysulfonyl, 3-carboxypropylaminosulfonyl, 4-carboxybutylaminosulfonyl, 5-potoxyloxypentylaminosulfonyl or 6-carboxyhexylaminosulfonyl group, preferably carboxy CC 4 alkylaminosulfonyl group, more preferably carboxy (alkylaminosulfonyl group, even more preferably Suitably, it is a carboxymethylaminosulfonyl group.
  • nitrogen-containing saturated heterocyclic sulfonyl group refers to a group in which a sulfonyl is bonded to a 3 to 7 "-membered saturated heterocyclic group containing 1 to 3 nitrogen atoms, for example, morpholine-1-y Rusulfonyl, thiomorpholine-1-ylsulfonyl, aziridine-1-yl-sulfonyl, azetidine-1-ylusulfonyl, pyrrolidine-1-ylusulfonyl, piperidine.1-yl-sulfonyl, pyrroline-11-yl- Sulfonyl, imidazolidine-1 -ylsulfonyl, pyrazolidine-1.1-ylusulfonyl, piperidine-1 -1 -ylsulfonyl, piperazine-1 -1 -ylsulfonyl, isoxazolidin
  • halogeno lower alkyl group refers to a group in which the same or different “halogen atom” which is the same or different from the above “lower alkyl group” has 1 to 5 substituents, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl.
  • the “lower alkylthio group” indicates a group in which the above “lower alkyl group” is bonded to a sulfur atom, and includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentyl Thio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio Linear or branched alkylthio having 1 to 6 carbon atoms such as 1,1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio or 2,
  • the “lower alkylsulfinyl group” refers to a group in which the “lower alkyl group” is bonded to a sulfinyl group, such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfenyl, and isobutylsulfinyl.
  • “mono-lower alkylamino group” refers to a group in which one of the above “lower alkyl groups” is bonded to an amino group, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s —Butylamino, t—butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, hexylamino, isohexylamino, 4-methylpentylamino, 3— Methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino
  • the “di-lower alkylamino group” represents a group in which two identical or different “lower alkyl groups” are bonded to an amino group, such as dimethylamino, getylamino, N-ethyl-N-methylamino, Dipropylamino, dibutylamino, Di-C 6 -alkylamino group such as dipentylamino or dihexylamino group, preferably di-C, -C 4 alkylamino group, more preferably di-C! -C 2 An alkylamino group, most preferably a dimethylamino group.
  • the “di-lower alkylaminosulfonyl group” refers to a group in which the above “di-lower alkylamino group” is bonded to a sulfonyl group, such as dimethylaminosulfonyl, getylaminosulfonyl, N-ethyl-N A di-C 6 alkylaminosulfonyl group such as methylaminosulfonyl, dipropylaminosulfonyl, dibutylaminosulfonyl, dipentylaminosulfonyl or dihexylaminosulfonyl group; a C ⁇ alkylaminosulfonyl group, more preferably a di-one c 2 alkylaminosulfonyl group, most preferably a Jimechirua Minosuruhoniru group.
  • a sulfonyl group such as dimethylaminosulfonyl, getyl
  • the “aryloxy group” represents a group in which the above “aryl group” is bonded to an oxygen atom, and is, for example, phenyloxy, indenyloxy, naphthyloxy, phenanthrenyloxy, anthracenyloxy or fluorinated.
  • a C 6 — is a phenyloxy group.
  • the ⁇ halogenoaryl group '' is the ⁇ aryl group '' in which the same or different ⁇ halogen atom '' is substituted with 1 to 5 and is, for example, a fluorophenyl, chlorophenyl, bromophenyl or difluorophenyl group. Preferably, it is a 4-fluorophenyl group.
  • the “halogenoaryloxy group” is the aforementioned “aryloxy group” in which the same or different “halogen atoms” are substituted with 1 to 5; for example, fluorophenyloxy, chlorophenyloxy, bromophenyloxy, It is a xy or difluorophenyloxy group, preferably a 4-fluorophenyloxy group.
  • “mono-acylamino group” refers to a group in which a carbonyl group in which one “lower alkyl group” or one “aryl group” is bonded to an amino group, for example, acetylamino or acetylamino. It is a benzoylamino group.
  • hydroxy lower alkoxy group refers to a group in which a hydroxy group is bonded to the above “lower alkoxy group”, and is, for example, hydroxymethoxy, hydroxyethoxy, or hydroxypropoxy group, preferably hydroxyethoxy group. It is.
  • the ⁇ substituent group a '' is preferably a group consisting of a lower alkylsulfonyl, an aminosulfonyl, a mono-lower alkylaminosulfonyl and a mono-cycloalkylaminosulfonyl group, more preferably A group consisting of methylsulfonyl, ethylsulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl and cyclopropylaminosulfonyl; more preferably a group consisting of methylsulfonyl and methylaminosulfonyl; is there.
  • the “substituent group b” is preferably a group consisting of a halogen atom, a lower alkyl, a lower alkoxy and a pyridyl group, more preferably a fluorine atom, a chlorine atom, methyl, methoxy and It is a group consisting of a monopyridyl group, still more preferably a group consisting of a fluorine atom, methyl, methoxy and a 4-pyridyl group.
  • the “substituent group c” preferably comprises a hydroxy, lower alkoxy, hydroxy-lower alkoxy, heterocyclic ring and aryl group substituted by one group selected from an arbitrary group selected from substituent group b.
  • Group more preferably hydroxy, methoxy, 2-hydroxyethoxy, 3-pyridyl, 4-pyridyl, 1,3-benzodioxolan-1-yl, mono-methoxyphenyl, g It is a group consisting of methoxyphenyl and aminosulfonylphenyl groups, still more preferably a group consisting of hydroxy, 4-pyridyl and 3,4-dimethoxyphenyl groups.
  • an aryl group independently substituted with 1 to 5 arbitrary groups selected from the substituent group a is an arbitrary group selected from the substituent group a in the above “aryl group”.
  • a independently substituted 1 to 5 groups preferably an aryl group independently substituted with 1 to 3 arbitrary groups selected from the substituent group a, and more preferably (lower Alkylsulfonyl, aminosulfonyl, mono-lower alkylaminosulfonyl and monocycloalkylaminosulfonyl groups), and is a phenyl group substituted at the 4-position with an arbitrary group.
  • a minosulfonylphenyl group particularly preferably a 4-methylsulfonylphenyl, 4-aminosulfophenyl, 4-methylaminosulfonylphenyl or 4-cyclopropylaminosulfoylphenyl group, most preferably A 4-methylsulfonylphenyl or 4-methylaminosulfonylphenyl group.
  • the ⁇ heterocyclic group independently substituted by 1 to 3 substituent (s) selected from an arbitrary group selected from the substituent group (a) '' is an arbitrary group selected from the substituent group (a) in the above (heterocyclic group).
  • a cycloalkyl group independently substituted with 1 to 3 arbitrary groups selected from the substituent group b is an arbitrary group selected from the substituent group b in the above “cycloalkyl group”.
  • a group in which 1 to 3 groups are independently substituted preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group in which one fluorine atom, chlorine atom, methyl or methoxy group is substituted, more preferably Represents a 2-fluorocyclopropyl or 2-methylcyclohexyl group.
  • an aryl group independently substituted with 1 to 5 arbitrary groups selected from the substituent group b is an arbitrary group selected from the substituent group b in the above “aryl group”.
  • a group independently substituted with 1 to 5 groups for example, a phenyl group independently substituted with 1 or 2 groups selected from the substituent group b, preferably halogen A phenyl group independently substituted by one or two atoms, a methyl group or a methoxy group;
  • R 6 is more preferably 4-fluorophenyl, 2-fluorophenyl, 5-fluoro-2-methylphenyl or 2 —Methoxyphenyl, still more preferably 4-fluorophenyl, 2-fluorophenyl or 5-fluoro-21-methylphenyl, particularly preferably 4-fluorophenyl or 2-fluorophenyl
  • you to R 4 information more preferably, 4-fluorophenyl, 2-fluorophenyl, 2-methyl phenyl or 3-
  • the ⁇ heterocyclic group independently substituted by 1 to 3 substituent (s) selected from an arbitrary group selected from the substituent group b '' is an arbitrary group selected from the substituent group b in the above “heterocyclic group”.
  • an aralkyl group independently substituted with 1 to 5 arbitrary groups selected from the substituent group b is an arbitrary group selected from the substituent group b in the “aralkyl group”.
  • a group independently having 1 to 5 substituents for example, a benzyl group substituted with 1 or 2 arbitrary groups selected from the substituent group b, preferably a halogen atom, a methyl or a methoxy group Is independently a benzyl group substituted with one or two benzyl groups.
  • the “—NHR 6 group” is preferably any group in which a monoarylamino, mono-heterocyclicamino or phenyl moiety is selected from (octogen, lower alkyl and lower alkoxy groups). It is a mono- or mono-substituted monophenylamino group, more preferably, a cycloalkylamino, phenylamino, 3-pyridylamino or phenyl moiety is (fluorine, chlorine, methyl and methoxy).
  • a mono-acylamino group in which 1 to 5 independently substituted an arbitrary 1- to 5-acyl group is selected from the substituent group b is the same as the above “mono-acylamino group” than the substituent group b.
  • the optional group selected is independently a substituted group of 1 to 5, preferably a methoxyacetylamino or a 3,4-dimethoxyphenylcarbonylamino group.
  • an aryloxy group independently substituted with 1 to 5 arbitrary groups selected from the substituent group b” is an arbitrary group selected from the substituent group b in the above “aryloxy group”.
  • a independently substituted 1 to 5 groups for example, a phenyloxy group independently substituted by 1 or 2 arbitrary groups selected from the substituent group b, preferably a halogen atom, methyl or 1 is independently a methoxy group; ⁇ is a 2-substituted phenyloxy group.
  • a lower alkyl group independently substituted with 1 to 5 arbitrary groups selected from a substituent group c is an arbitrary group selected from the substituent group c in the above “lower alkyl group”. Is independently a group having 1 to 5 substituents, preferably (1 to 3 substituents with an arbitrary group selected from (hydroxy, lower alkoxy, hydroxy lower alkoxy, heterocycle and substituent group b)
  • the “—NR 7 R 8 group” is preferably a mono-lower alkylamino, di-lower alkylamino or lower alkyl moiety (hydroxy, lower alkoxy, hydroxy lower alkoxy, heterocyclic and substituent group b
  • a mono-lower alkylamino group which is independently substituted with 1 to 5 arbitrary groups selected from 1 to 3 aryl groups substituted with 1 to 3 arbitrary groups selected from Is methylamino, dimethylamino, 2-hydroxyethylamino, 2-methoxyethylamino, 2- (2-hydroxyethoxy) ethylamino or the lower alkyl moiety is (hydroxy, 3-pyridyl, 4-pyridyl, 1, 3-benzodioxolan-1-yl, monomethoxyphenyl, dimethoxyphenyl, and aminosulfonylphenyl) 1 or A 2-substituted mono-lower alkylamino group, still more preferably
  • the “—OR 7 group” is preferably methoxy, 2- (2-hydroxyethoxy) ethyloxy, 2- (4-pyridyl) ethyloxy, 2- (1,3-benzodioxolan — 5— Le) ethyloxy, 3,4-dimethoxyphenethyloxy or 4-aminosulfonylphenethyloxy, more preferably 2- (4-pyridyl) ethyloxy.
  • preferred R 1 is a methyl, ethyl or n-propyl group, and more preferred R 1 is a methyl group.
  • preferred R 2 is a heterocyclic group or an aryl group independently substituted by 1 to 3 groups selected from a substituent group a, and more preferred R 2 is a pyridyl group or Is substituted at the 4-position with any group selected from (lower alkylsulfonyl, aminosulfonyl, mono-lower alkylaminosulfonyl, mono-cycloalkylaminosulfonyl, and mono- (carboxy lower alkyl) aminosulfonyl)
  • An even more preferred R 2 is a 4-pyridyl group, a 4-methylsulfonyl phenyl group.
  • R 2 is a 4-pyridyl group, a 4-methylsulfonylphenyl group, a 4-aminosulfonylphenyl group, a 4-methylaminosulfonylphenyl group, A cyclopropylaminosulfonylphenyl group or a 4-methoxypropylaminosulfonylphenyl group; the most preferred R 2 is a 4-pyridyl group, a 4-methylsulfonylphenyl group or a 4-methylaminosulfonylphenyl group; is there.
  • preferred A is —NH—.
  • R 3 is preferably an aryl group, a heterocyclic group, a monoarylamino group, a mono-heterocyclic amino group or a phenyl moiety selected from (halogen atom, lower alkyl group and lower alkoxy group).
  • R 3 is a 3-pyridyl group, a 1-indolinyl group, a phenylamino group, a 3-pyridylamino group or a phenyl moiety having a fluorine atom (fluorine atom , A chlorine atom, a methyl group and a methoxy group) are independently a mono-phenylamino group substituted by 1 or 2 arbitrary groups selected from an even more preferable R 3 is a 3_pyridyl group, 1-indolinyl group, phenylamino group, 3_pyridylamino group, 4-fluorophenylamino group, 2-fluorophenylamino group; 5-fluoro-2-methyl A Fueniruamino group or a 2 Metokishifue two Ruamino groups, particularly preferred R 3 is Fueniruamino group, 3-Pirij
  • preferred R 4 is a hydrogen atom, a lower alkyl group, an aryl group, a heterocyclic group, an aralkyl group or an aryl independently substituted with 1 to 5 arbitrary groups selected from substituent group b.
  • R 4 is more preferably a hydrogen atom, a lower alkyl group, a phenyl group, a naphthyl group, an aromatic heterocyclic group, a fused bicyclic heteroaryl group, a benzyl group or a (halogen atom, a lower alkyl group and A phenyl group independently substituted by one or two groups selected from a lower alkoxy group), and even more preferred R 4 is a hydrogen atom, a phenyl group, a 1-naphthyl group, a 3-phenyl group 1,3-benzodioxolan-1-yl, 1,4-benzodioxane-16-yl, benzyl or any group selected from (fluorine, chlorine, methyl, and methoxy) so
  • R 4 is particularly preferably a hydrogen atom, a phenyl group, a 3-phenyl group, a benzyl group, a 4-fluorophenyl group,
  • preferred R 5 is a hydrogen atom, a heterocyclic group, a heterocyclic group substituted by one heterocyclic group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group or a lower alkyl moiety.
  • R 5 is a hydrogen atom, a 1-pyrazolyl group, a 1-imidazolyl group, a 1-azetidinyl group, or a 1-pyrrolidinyl group.
  • “Pharmacologically acceptable salt thereof” means that the pyrimidine derivative having the general formula (I) of the present invention is reacted with an acid when it has a basic group such as an amino group, When the compound has an acidic group such as a sulfoxyl group, it can be converted to a salt by reacting with a base.
  • the salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; benzenesulfonates; and salts such as p-toluenesulfonate.
  • a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate
  • sulfuric acid Inorganic acid salts such as salts and phosphates
  • lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate
  • Organic salts such as reelsulfonate, acetate, malate, fumarate, succinate, quanate, ascorbate, tartrate, oxalate and maleate; and Glycine salts, lysine salts, arginine salts, orditin salts, glutamic acid salts, amino acid salts such as aspartate salts, and most preferably, hydrogen halide salts, inorganic acid salts or organic acid salts. It is.
  • the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt, and a lithium salt, an alkaline earth metal salt such as a calcium salt and a magnesium salt, an aluminum salt, an iron salt, and the like.
  • Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenyldalicine alkyl ester salts, ethylenediamine salts, N-methyldalcamine salts, guanidine salts, getylamine salts, Triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, clomouth proforce salt, proforce salt, genoleamine salt, N-benzylphenethylamine salt, piperazine Salt, tetramethylammonium salt, tris (hydroxymethyl) a
  • An amino salt such as an organic salt such as a minomethane salt; and an amino acid salt such as a glycine salt, a lysine salt, an arginine salt, an ordinine salt, a glutamate salt, and an aspartate salt.
  • the pyrimidine derivative having the general formula (I) or a pharmaceutically acceptable salt thereof of the present invention has various isomers since an asymmetric carbon atom is present in the molecule.
  • all of these isomers and a mixture of these isomers are represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all such isomers and mixtures of these isomers in any proportion.
  • the pyrimidine derivative having the general formula (I) or a pharmaceutically acceptable salt thereof of the present invention has a geometric isomer because a double bond is present in the molecule.
  • all geometric isomers and mixtures of geometric isomers are represented by a single formula, that is, general formula (I). Accordingly, the present invention includes all geometric isomers and mixtures of geometric isomers in any proportion. '
  • the pyrimidine derivative having the general formula (I) or a pharmacologically acceptable salt thereof of the present invention absorbs water and adsorbs water when left in the air or recrystallized to remove water. It may be a hydrate, and such a hydrate is also included in the salt of the present invention.
  • Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in Table 1 below, but the present invention is not limited to these groups. The meanings of the abbreviations in Table 1 below are as follows. That is,
  • Me represents a methyl group
  • 4-MeNH S 0 2 C 6 H 4 represents a 4-methylaminosulfonylphenyl group
  • PhNH represents a phenylamino group
  • Ph (A) NH represents a 5-fluoro-2-methylphenylamino group
  • 1 -Py ra represents 1 pyrazolyl group
  • Py r a (A) represents a 1- [4- (4-pyridyl)] pyrazolyl group
  • E t NH (A) represents a 2- (2-hydroxyethoxy) ethylamino group
  • E tNH (B) represents a 2- (4-pyridyl) ethylamino group
  • E tNH (C) is a 2- (1,3-benzodioxolane-1 5-1 ⁇ f) ethylamino group
  • PhCH 2 CH 2 NH (A) represents a 3,4-dimethoxyphenethylamino group
  • PhCH 2 CH 2 NH (B) represents a 4-aminosulfonylphenethylamino group
  • P h (B) represents a 1,3-benzodioxolan-5-yl group.
  • Pyra (B) represents a 1- [3-((4-pyridyl)] pyrazolyl group
  • E tNH (D) represents a 2-methoxyethylamino group
  • Na ph represents a 1-naphthyl group
  • P h (C) represents a 2 _fluoro-5-methylphenyl group
  • Ph (D) represents a 3-chloro-2-fluorophenyl group
  • Ph (E) represents a 2,3-dimethylphenyl group
  • Ph (F) represents a 4 _ carboxymethylaminosulfonylphenyl group
  • c Pr represents a cyclopropyl group
  • Et represents an ethyl group
  • Py r r (A) represents a 1-methylsulfonyl-3-pyrrolyl group
  • E tNH (E) represents a 2_ (2-phenyl) ethylamino group
  • PhCH 2 CH 2 NH (C) represents a 2,5-dimethoxyphenethylamino group
  • E tNH (F) represents a 2- (5-imidazolyl) ethylamino group
  • Py (A) represents a 5-phenyl_3-pyridyl group
  • Ph (G) represents a 1,4-benzodioxane-6-yl group
  • Ph (H) represents a 3- (4-fluorophenoxy) phenyl group
  • cHe X represents a cyclohexyl group
  • Ph (I) represents a 2-chloro-6-fluorophenyl group
  • Pipe (A) represents a ⁇ 4- [1- (4-methylaminosulfonylphenyl) -ethylidene-hydrazinocarbonyl] piperidino ⁇ group
  • Pipe (B) represents a 1- ⁇ 3-[1- (4-methylaminosulfonylphenyl) -ethylidene-hydrazinocarbonyl] piperidino ⁇ group
  • P i p C) represents a ⁇ 1- [1- (4-methylsulfonylphenyl) -ethylidene-hydrazinocarbonyl] piperidino ⁇ group
  • P i p e (D) represents one ⁇ 3— [1 -— (4-methylsulfonylphenyl) —ethylidene—hydrazinocarbonyl] piperidino ⁇ group;
  • P h (J) represents a 4-hydroxy-13,5-dimethylphenyl group
  • P h CH 2 CH 2 NH (D) represents a 2- (3,4-dimethoxyphenyl) 1-2-hydroxyethylamino group
  • Ph (K) represents a 4- (2-hydroxyethylaminosulfonyl) phenyl group
  • EtNH (H) represents a (tetrahydrofuran-1-yl) methylamino group
  • c Bu represents a cyclobutyl group
  • Py (B) represents a 2-methoxy-5-pyridyl group
  • Py (C) represents a 2,6-dimethoxy-3-pyridyl group
  • PhCH 2 NH (A) represents a 3,4-dimethoxyphenylmethylamino group
  • PhCH 2 CH 20 (A) represents a 3,4-dimethoxyphenethyloxy group
  • PhCH 2 CH 2 NH (E) represents a 4-ethoxy-13-methoxyphenethylamino group
  • Ph CH 2 CH 2 NH (F) represents a 3-ethoxy-14-methoxyphenethylamino group
  • PhCH 2 CH 2 NH (G) represents a 3,4-dichlorophenethylamino group
  • P h (L) represents a 5-methoxy-2-methylphenyl group
  • E tNH (I) represents a 2- (morpholine-4-yl) -ethylamino group /
  • E t NH (J) represents 2 — ([1,3] dioxolan — 2—yl) —ethylamino group;
  • E tNH (K) represents a 2- (1-pyrrolidinyl) ethylamino group
  • E tNH (L) represents a 2- (1-piperidinyl) monoethylamino group
  • i Pr represents an isopropyl group
  • Py r r (B) represents a 3- (4-pyridyl) -1-pyrrolyl group
  • PhCH 2 NH (B) is 6,7-dimethoxy-1,3,4-dihydro-1H-isoquinol Represents a 2-yl group
  • P h (M) represents a 4_ (2-hydroxypropylaminosulfonyl) phenyl group
  • P h ( ⁇ ) ′ represents a 4- (morpholine- 1-4-sulfonyl) monophenyl group
  • P h CH 2 CH 2 NH (H) represents a 2- (3,4-dimethoxyphenyl) —1— [1,3] dioxolanetylamino group.

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Abstract

La présente invention concerne un dérivé de pyrimidine qui possède un effet inhibiteur de MLR excellent ou, un sel de ce composé répondant aux normes pharmaceutiques. Cette invention concerne plus spécifiquement un dérivé de pyrimidine représenté par la formule générale (I) ci-dessous ou un sel de ce composé répondant aux normes pharmaceutiques. (I) (dans cette formule, R1 représente un groupe alkyle inférieur, R2 représente un groupe aryle ou un groupe similaire, A représente NH- ou un élément similaire, R3 représente un groupe NHR6 ou un groupe similaire (dans lequel R6 représente un groupe aryle ou un groupe similaire), R4 représente un atome d'hydrogène ou un élément similaire et R5 représente un groupe hétérocyclique ou un groupe similaire.)
PCT/JP2004/015955 2003-10-21 2004-10-21 Compose pyrimidine WO2005037801A1 (fr)

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WO2009019167A1 (fr) 2007-08-08 2009-02-12 Merck Serono S.A. Dérivés de 6-amino-pyrimidine-4-carboxamide et composés associés qui se fixent au récepteur de sphingosine-1-phosphate (s1p) dans le traitement de la sclérose en plaques
US8389718B2 (en) 2010-07-20 2013-03-05 Vestaron Corporation Insecticidal triazines and pyrimidines
US8431110B2 (en) 2005-05-23 2013-04-30 Hmi Medical Innovations, Llc. Compounds and method of identifying, synthesizing, optimizing and profiling protein modulators
WO2014085225A1 (fr) * 2012-11-27 2014-06-05 The University Of North Carolina At Chapel Hill Composés à base de pyrimidine utilisables à des fins de traitement du cancer
AU2010306650B2 (en) * 2009-10-16 2016-10-13 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
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US9937183B2 (en) 2013-09-09 2018-04-10 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US10106543B2 (en) 2013-09-09 2018-10-23 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
CN109928935A (zh) * 2017-12-19 2019-06-25 沈阳化工研究院有限公司 一种苯胺基嘧啶类化合物及其医药用途
US10947237B2 (en) 2015-03-11 2021-03-16 BioVersys AG Antimicrobial compounds and methods of making and using the same

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US11714080B2 (en) 2005-05-23 2023-08-01 HMI Medical Innovations, LLC Compounds and methods of identifying, synthesizing, optimizing and profiling protein modulators
US8431110B2 (en) 2005-05-23 2013-04-30 Hmi Medical Innovations, Llc. Compounds and method of identifying, synthesizing, optimizing and profiling protein modulators
US11692998B2 (en) 2005-05-23 2023-07-04 HMI Medical Innovations, LLC Compounds and methods of identifying, synthesizing, optimizing and profiling protein modulators
US10955408B2 (en) 2005-05-23 2021-03-23 HMI Medical Innovations, LLC Compounds and methods of identifying, synthesizing, optimizing and profiling protein modulators
US9222933B2 (en) 2005-05-23 2015-12-29 HMI Medical Innovations, LLC Compounds and method of identifying, synthesizing, optimizing and profiling protein modulators
US10473643B2 (en) 2005-05-23 2019-11-12 HMI Medical Innovations, LLC Compounds and methods of identifying, synthesizing, optimizing and profiling protein modulators
US9645137B2 (en) 2005-05-23 2017-05-09 HMI Medical Innovations, LLC Compounds and method of identifying, synthesizing, optimizing and profiling protein modulators
US8399448B2 (en) 2007-08-08 2013-03-19 Merck Serono Sa 6-amino-pyrimidine-4-carboxamide derivatives and related compounds which bind to the sphingosine 1-phosphate (S1P) receptor for the treatment of multiple sclerosis
US9150519B2 (en) 2007-08-08 2015-10-06 Merck Serono Sa 6-amino-pyrimidine-4-carboxamide derivatives and related compounds which bind to the sphingosine 1-phosphate (S1P) receptor for the treatment of multiple sclerosis
WO2009019167A1 (fr) 2007-08-08 2009-02-12 Merck Serono S.A. Dérivés de 6-amino-pyrimidine-4-carboxamide et composés associés qui se fixent au récepteur de sphingosine-1-phosphate (s1p) dans le traitement de la sclérose en plaques
US10259825B2 (en) 2009-10-16 2019-04-16 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US9845297B2 (en) 2009-10-16 2017-12-19 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US9573962B2 (en) 2009-10-16 2017-02-21 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
AU2010306650B2 (en) * 2009-10-16 2016-10-13 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US8785630B2 (en) 2010-07-20 2014-07-22 Vestaron Corporation Insecticidal triazines and pyrimidines
US8389718B2 (en) 2010-07-20 2013-03-05 Vestaron Corporation Insecticidal triazines and pyrimidines
WO2014085225A1 (fr) * 2012-11-27 2014-06-05 The University Of North Carolina At Chapel Hill Composés à base de pyrimidine utilisables à des fins de traitement du cancer
US9937183B2 (en) 2013-09-09 2018-04-10 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US10106543B2 (en) 2013-09-09 2018-10-23 Melinta Therapeutics, Inc. Antimicrobial compounds and methods of making and using the same
US10947237B2 (en) 2015-03-11 2021-03-16 BioVersys AG Antimicrobial compounds and methods of making and using the same
CN109928935A (zh) * 2017-12-19 2019-06-25 沈阳化工研究院有限公司 一种苯胺基嘧啶类化合物及其医药用途
CN109928935B (zh) * 2017-12-19 2023-03-10 沈阳化工研究院有限公司 一种苯胺基嘧啶类化合物及其医药用途

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