WO2003091223A1 - Derive de pyrimidine - Google Patents

Derive de pyrimidine Download PDF

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Publication number
WO2003091223A1
WO2003091223A1 PCT/JP2003/005216 JP0305216W WO03091223A1 WO 2003091223 A1 WO2003091223 A1 WO 2003091223A1 JP 0305216 W JP0305216 W JP 0305216W WO 03091223 A1 WO03091223 A1 WO 03091223A1
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group
pyrimidinyl
hydrazone
hydrazino
apci
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PCT/JP2003/005216
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English (en)
Japanese (ja)
Inventor
Hiroyuki Tsuruoka
Yuichi Kanno
Tohru Tatsuta
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Sankyo Company, Limited
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Priority to AU2003231459A priority Critical patent/AU2003231459A1/en
Publication of WO2003091223A1 publication Critical patent/WO2003091223A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms

Definitions

  • the present invention relates to a pyrimidine derivative having a mixed lymphocyte culture reaction (hereinafter, abbreviated as MLR) inhibitory action, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. It relates to a drug contained as an active ingredient.
  • MLR mixed lymphocyte culture reaction
  • rejection reactions to transplants are caused by the reaction between autologous lymphocytes on the recipient side and non-autologous cells in the transplanted tissue to activate and proliferate the lymphocytes. It is caused by eliminating attacks.
  • This rejection reaction can be attributed to 1) recognition of non-self cells, 2) increased expression of costimulatory molecules or production of proliferative cytokins on the surface of lymphocytes, 3) activation and proliferation of lymphocytes, 4) proliferation It is a multi-step reaction consisting of steps such as attacking the graft with lymphocytes that have been performed. Recognition of non-self cells by lymphocytes is performed through major histocompatibility complex (Maj or Histoco immediately at ibil Uy; MHC). Lymphocytes that are activated by recognizing non-self cells due to differences in MHC produce cytokins called inulin leukin 2 (hereinafter abbreviated as IL-2). Various immune cells are activated to proliferate.
  • MHC major histocompatibility complex
  • Activated lymphocytes activate proliferation of various immune cells via costimulatory molecules expressed on the membrane surface.
  • Proliferative activated T cells, B cells, such as killer one T cell attack eliminate transplanted lymphocytes' tissue cells (IMMUN0BI0L0G Y 3 rd edi t ion , 67).
  • MLR is considered to be a simple evaluation system that reflects the proliferative response of autologous lymphocytes to non-autologous lymphocytes in this rejection reaction. It is one. Some of the compounds found to be effective in suppressing transplant rejection, which have recently been found to be effective in this system It has become a Gaaka (IM UNOBIOLOGY 3 rd edition, 505 ). Therefore, compounds that inhibit MLR are expected to be useful drugs that suppress rejection in bone marrow transplantation and organ transplantation and maintain long-term survival of transplanted bone marrow and organs.
  • the experimental system for evaluating MLR is an experimental system that reflects cell-mediated immunity such as lymphocyte cell proliferation and cell killing activity, and humoral immunity such as antibody production. Is considered to be effective also for the following diseases involving excessive humoral immune function.
  • Excessive cellular immunity and humoral immunity can be caused by chronic inflammatory diseases such as rheumatoid arthritis, or organ-specific autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, dysuria, and glomeruli.
  • Chronic inflammatory diseases such as rheumatoid arthritis, or organ-specific autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, dysuria, and glomeruli.
  • Nephritis, primary biliary cirrhosis, chronic active hepatitis, pernicious anemia, Hashimoto's thyroiditis, atrophic gastritis, myasthenia gravis, psoriasis, and systemic erythematosus a non-organ-specific autoimmune disease with Siedalen syndrome, It is thought to be involved in allergic diseases, rhinitis, asthma, and atopic dermatitis. [Imnmnol.
  • 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, has low cytotoxicity, and is useful in bone marrow transplantation, organ transplantation, Inhibitor of transplant rejection, inhibitor of cancer cells by selective cell killing activity (eg, inhibitor of cancerous lymphocytes), or rheumatoid arthritis, an inflammatory disease, organ-specific autoimmunity 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 siedare Prophylactic agent and Z or therapeutic agent (preferably, bone marrow) for organ-specific autoimmune diseases (for example, systemic lupus erythematosus) or allergic diseases
  • the present invention provides a compound represented by the general formula (I):
  • R 1 and R 3 are the same or different and are a hydrogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy lower alkyl group, a (mono-lower alkylamino) lower alkyl group, a (G lower alkylamino) lower alkyl group, an aryl An aryl group independently substituted by 1 to 5 groups or an arbitrary group selected from substituent group a,
  • R 2 and R 4 are the same or different and are independently an aryl group, a heterocyclic group, an aryl group or a substituent group which is independently substituted with 1 to 5 arbitrary groups selected from a substituent group a.
  • a 1 and A 2 are the same or different and each have a formula NR 7 — (wherein, R 7 represents a hydrogen atom or a lower alkyl group) or an oxygen atom;
  • R 5 is a cycloalkyl group independently substituted with 1 to 5 arbitrary groups selected from a cycloalkyl group, an aryl group, a heterocyclic group, a lower alkylthio group, a substituent group a, An aryl group independently substituted with 1 to 5 arbitrary groups selected from substituent group a, a heterocyclic group independently substituted with 1 to 3 arbitrary groups selected from substituent group a, A group having the formula 1 D—R 8 , a group having the formula 1 CH 2 —E—R 8 (wherein
  • D represents a group having one NH—, an oxygen atom or a sulfur atom
  • E represents an oxygen atom, a sulfur atom or a single bond
  • R 8 is a cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, a cycloalkyl group independently substituted with 1 to 5 substituents selected from a substituent group a, and a substituent group a Selected from an aryl group independently substituted with 1 to 5 substituents, a heterocyclic group independently substituted with 1 to 3 substituents from any group selected from the substituent group a, or a substituent group a Represents an aralkyl group independently substituted with 1 to 5 arbitrary groups.
  • the formula —A 3 — N CR 9 R 1Q (where
  • a 3 represents a group having the formula NR 11 — (wherein R 11 represents a hydrogen atom or a lower alkyl group) or an oxygen atom;
  • R 9 is any selected from a hydrogen atom, a lower alkyl group, a lower alkoxy lower alkyl group, a (mono-lower alkylamino) lower alkyl group, a (di-lower alkylamino) lower alkyl group, an aryl group or a substituent group a Represents an aryl group independently substituted by 1 to 5 groups,
  • R 1Q represents an aryl group, a heterocyclic group, an aryl group substituted with 1 to 5 substituents independently from an arbitrary group selected from substituent group a, or an arbitrary group selected from substituent group a.
  • 1 to 3 independently substituted saturated carbocyclic groups or a saturated heterocyclic group substituted with an arbitrary group selected from substituent group a.
  • R 6 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, a (mono-lower alkylamino) lower alkyl group, a (di-lower alkylamino) lower alkyl group, an aralkyl group or an anilino group;
  • Substituent group a is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogeno lower alkylthio group, a halogeno lower alkyloxy group, a cycloalkyl group, a hydroxy group, a carboxy group, a carboxymethyl group.
  • Lower alkoxycarbonyl amino, mono-lower alkylamino, di-lower alkylamino, lower aliphatic acylamino, nitro, cyano, sulfonyl, lower alkylsulfonyl, octogeno lower alkylsulfonyl, aryl Sulfonyl group, heterocyclic group sulfonyl group, lower alkylsulfinyl group, arylsulfinyl group, dirubamoyl group, mono-lower alkyl force rubamoyl group, di-lower alkyl force rubamoyl group, lower alkyl (aryl) Rubamoyl group, ethylidenehydrazinocarbonyl group, rubamoyloxy group, mono-lower alkyl rubamoyloxy group, g-lower alkyl rubamoyloxy group, carbamoylamino group, mono-lower alkyl
  • a pharmacologically acceptable salt thereof, an ester or other derivative thereof, and a pharmaceutical composition containing the same as an active ingredient preferably,
  • R 1 and R 3 are a hydrogen atom, a pyrimidine derivative or a pharmaceutically acceptable salt thereof,
  • a pyrimidine derivative or a pharmaceutically acceptable salt thereof wherein R 1 and R 3 are the same or different and are a lower alkyl group,
  • a pyrimidine derivative or a pharmaceutically acceptable salt thereof wherein R 1 and R 3 are the same or different and are each a C 2 alkyl group;
  • R 1 and R 3 are a pyrimidine derivative or a pharmaceutically acceptable salt thereof, which is a methyl group
  • R 1 and R 3 are the same or different and are selected from a lower alkoxy lower alkyl group, a (mono-lower alkylamino) lower alkyl group, a (di-lower alkylamino) lower alkyl group, an aryl group and a substituent group a.
  • R 1 and R 3 are the same or different and are a aryl group or an aryl group independently substituted with 1 to 5 arbitrary groups selected from the substituent group a, or a pharmaceutically acceptable pyrimidine derivative thereof. salt,
  • R 2 is the same or different as R 1 and Z or R 4 is the same or different as R 3 , including the carbon atom to which they are each attached, saturated carbocyclic group, saturated heterocyclic group, substituted Base group a Forms a saturated carbocyclic group independently substituted with 1 to 5 groups by an arbitrary group selected from the group consisting of: or a saturated heterocyclic group independently substituted by 1 to 3 groups by an arbitrary group selected from the substituent group a A pyrimidine derivative or a pharmaceutically acceptable salt thereof,
  • R 2 is together and / or R 4 and R 1 together with R 3, same or different, including the carbon atom to which each it we are attached, a benzene ring condensed with optionally c 4 one c 7 saturated carbocyclic group, 5- to 6-membered saturated heterocyclic group, 1 is five independently substituted with any group selected from substituent group a, a benzene ring condensed with optionally C 4 one C 7 saturated carbonates TamakiHajimemata is acceptable on a pyrimidine derivative or a pharmacologically to form a 5- or 6-membered saturated heterocyclic group substituted 1 to 3 independently any group selected from substituent group a,
  • R 2 together with R 1 and / or in R 4 is together with R 3, same or different, each including a carbon atom to which it we are attached, may be fused with a benzene ring C 5 - C 6 saturated carbocyclic group, tetrahydrothiophene ring group, tetrahydropyran ring group, piperidine ring group, benzene ring, which is independently substituted with 1 to 5 arbitrary groups selected from substituent group a
  • a C 5 -C 6 saturated carbocyclic group which may be condensed or a tetrahydrothiophene ring, a tetrahydropyran ring or a piperidine ring group which is independently substituted by 1 to 3 groups selected from a substituent group a.
  • R 2 together with R 1 and / or in R 4 is together with R 3, same or different, each including a carbon atom to which it we are attached, may be fused with a benzene ring C 5 - Forming a C 5 —C 6 saturated carbocyclic group which may be condensed with a benzene ring, which is independently substituted with 1 to 5 C 6 saturated carbocyclic groups or any group selected from substituent group a A pyrimidine derivative or a pharmacologically acceptable salt thereof,
  • R 2 together with R 1 and R or R 4 together with R 3 , identical or different, each including the carbon atom to which they are attached, an indane group, 1,2,3,4-tetrahydro A naphthalene group or indane or 1, 2, 3,
  • a pyrimidine derivative forming a 4-tetrahydronaphthylene group (the substituent is a group selected from the group consisting of a lower alkoxy group, a lower aliphatic acylamino group, a lower alkylsulfonyl group and a cyano group) or a pyrimidine derivative thereof;
  • a pharmacologically acceptable salt (15) in any one selected from (1) to (3),
  • R 2 is together with R 1 and Z or R 4 together with R 3 , identical or different, each including the carbon atom to which they are attached, an indane group, 1, 2, 3, 4—
  • a pyrimidine derivative or a pharmaceutically acceptable salt thereof which forms an indane or 1,2,3,4-tetrahydronaphthylene group substituted with 1 to 3 tetrahydronaphthalene groups or lower alkoxy groups,
  • R 2 and R 4 are the same or different and each independently represent an aryl group, a 5- to 6-membered heterocyclic group which may be condensed with a benzene ring, or an arbitrary group selected from substituent group a;
  • a pyrimidine derivative or a 5- or 6-membered heterocyclic group which is independently substituted with 1 to 3 substituted aryl groups or an arbitrary group selected from substituent group a and which may be condensed with a benzene ring, or Pharmacologically acceptable salts,
  • R 2 and R 4 are the same or different and are C 6 —.
  • 1 ⁇ and 1 4 are the same or different, phenyl group, naphthyl group, thienyl group, Ji Azoriru group, a pyridyl group, a quinolyl group, 1, 3-base Nzojiokizora group, optionally selected from Substituent Group a A phenyl or naphthyl group independently substituted with 1 to 5 groups, or 1 to 3 independently substituted with any group selected from substituent group a A pyrimidine derivative or a pharmacologically acceptable salt thereof, which is a chenyl, thiazolyl, pyridyl, quinolyl, or 1,3-benzodioxolanyl group,
  • R 2 and R 4 may be the same or different and are phenyl, naphthyl, phenyl, thiazolyl, pyridyl, quinolyl, 1,3-benzodioxolanyl, or 1 to 3 substituents; Phenyl, naphthyl, phenyl, thiazolyl, pyridyl, quinolyl or 1,3-benzodioxolanyl group (the substituent is a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group , A cyano group, a lower alkoxycarbonyl group, an aliphatic acylamino group, a lower alkylsulfonyl group, an aminosulfonyl group, a mono-lower alkylaminosulfonyl group, a monocycloalkylaminosulfonyl group and a di-lower al
  • R 2 and R 4 are the same or different and are phenyl, 2,3,6-trifluorophenyl, 4-methylsulfonylphenyl, 4-ethylsulfonylphenyl, 2,6-difluorophenyl, 2,3 Dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-, 3- or 4-cyanophenyl, 3,4-dimethoxy-6-dimethoxyphenyl, 4-methoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 4-phenyl Cetylaminophenyl, 2-chloro-5-nitrophenyl, 3-hydroxy-6-nitrophenyl, 4-aminosulfonylphenyl, 4-methylaminosulfonylphenyl, 4-ethylaminosulfonylphenyl, 4-propylamino Sulfonylphenyl, 4-cyclopropylaminosulfonylphenyl, 4-dimethylaminosulf
  • R 2 and R 4 are the same or different and are phenyl, 4-cyanophenyl, 4-methylsulfonylphenyl, .4-ethylsulfonylphenyl, 4-acetylaminophenyl, 3,4-dimethoxy-6-nitrophenyl 4-aminosulfonylphenyl, 4-methylaminosulfonylphenyl, 4-ethylaminosulfonylphenyl, 4-propylaminosulfonylphenyl, 4-cyclopropylaminosulfonylphenyl, 4-dimethylaminosulfonylphenyl, 4-dimethylaminosulfonylphenyl, A pyrimidine derivative or a pharmacologically acceptable salt thereof, which is a pyridine-14-yl or thiophene-12-yl group,
  • a 1 and A 2 are pyrimidine derivatives or pharmaceutically acceptable salts thereof, which are oxygen radicals, (24) in any one selected from (1) to (23),
  • R 5 is independently selected from a cycloalkyl group, an aryl group, a heterocyclic group, a cycloalkyl group substituted with 1 to 5 arbitrary groups selected from a substituent group a, and a substituent group a
  • a pyrimidine derivative which is a heterocyclic group independently substituted with 1 to 3 aryl groups or 1 to 3 independently substituted with an arbitrary group selected from substituent group a, or a pharmacologically acceptable derivative thereof, Acceptable salts,.
  • R 5 is a pyrimidine derivative or a pharmaceutically acceptable salt thereof, which is a cycloalkyl group or a heterocyclic group,
  • R 5 is C 3 . 6 a pyrimidine derivative or a pharmacologically acceptable salt thereof, which is a 5- or 6-membered complex ring group which may be condensed with a cycloalkyl group or a benzene ring,
  • R 5 is a cyclopropyl group, an indolyl group or an indolinyl group Derivatives or pharmacologically acceptable salts thereof,
  • a pyrimidine derivative or a pharmaceutically acceptable salt thereof wherein R 5 is a group having the formula —D—R 8 (wherein R 8 has the same meaning as described above);
  • D is a pyrimidine derivative having one NH— or a pharmacologically acceptable salt thereof
  • R 8 is a C s -C 1Q aryl group, a 5- or 6-membered aromatic heterocyclic group which may be condensed with a benzene ring, C 6 —C 1Q aryl group independently substituted with 1 to 5 arbitrary groups selected from substituent group a or 1 to 3 independently selected from any group selected from substituent group a
  • R 8 is a C 6 -C 1 Q aryl group, a pyridyl group, a phenyl group, a benzoyl group, a benzodioxolanyl group, a benzodioxanyl group or C 6 — C, which is independently substituted with 1 to 3 arbitrary groups selected from the substituent group a.
  • a pyrimidine derivative which is an aryl group or a pharmacologically acceptable salt thereof,
  • R 8 represents a phenyl group, a pyridyl group, a phenyl group, a benzodioxolanyl group, a benzodioxanyl group, or one to three substituted groups.
  • a pyrimidine derivative which is a phenyl group substituted with a group (the substituent is a group selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group and an aryl group); Its pharmacologically acceptable salts,
  • R 8 is phenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluoro Phenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluoro Phenyl, 2,4,5-trifluorophenyl, 3,4,5-trifluorophenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2-, 3- or 4-methoxyphenyl, 2-ethoxyphenyl, 2-methylthiophenyl, 3,5-dimethoxyphenyl, 2-fluoro-4-chlorophenyl, 2-fluoro-5-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluoro- 5-Methylphenyl, 2-fluoro
  • R 8 is a pyrimidine derivative or a pharmacologically acceptable salt thereof, which is a phenyl or 2-methoxyphenyl group.
  • a 3 is a pyrimidine derivative having —NH— or a pharmacologically acceptable salt thereof
  • R 9 is acceptable salts pyrimidine derivative or a pharmacologically a methyl group or a hydrogen atom, (38)
  • R 1D is, phenyl, 4 —Cyanophenyl, 4-methylsulfonylphenyl, 4—Acetylaminophenyl, 3,4-dimethoxy-6-2-nitrophenyl, pyridin-4-yl or pyrimidine derivative which is a thiophen-12-yl group or its pharmacology
  • R 1D is, phenyl, 4 —Cyanophenyl, 4-methylsulfonylphenyl, 4—Acetylaminophenyl, 3,4-dimethoxy-6-2-nitrophenyl, pyridin-4-yl or pyrimidine derivative which is a thiophen-12-yl group or its pharmacology
  • R 1D is, phenyl, 4 —Cyanophenyl, 4-methylsulfonyl
  • R 1 " together with R 9 , is the same or different and includes an indane group, a 1,2,3,4-tetrahydronaphthalene group or a lower alkoxy group, each containing a carbon atom to which they are bonded;
  • R 5 is a pyrimidine derivative or a pharmacologically acceptable salt thereof, which is a hydrogen atom.
  • R 6 is a lower alkyl group, a lower alkoxy group, a lower alkoxy lower alkyl group, a (mono-lower alkylamino) lower alkyl group, a (di-lower alkylamino) lower alkyl group or an aralkyl group, a pyrimidine derivative or a pharmaceutically acceptable derivative thereof. Salt,
  • R 6 is a lower alkyl group, a lower alkoxy group or an aralkyl group, a pyrimidine derivative or a pharmaceutically acceptable salt thereof
  • R 6 is a C, —C 2 alkyl group, a C 2 alkoxy group or a benzyl group, a pyrimidine derivative or a pharmaceutically acceptable salt thereof,
  • the pharmaceutical composition suppresses rejection of grafts in bone marrow transplantation, organ transplantation, etc. or prevents inflammatory diseases, organ-specific autoimmune diseases, non-organ-specific autoimmune diseases or allergic diseases, and Z Or a pharmaceutical composition according to (45), which is a composition for treatment.
  • the pharmaceutical composition is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, diabetes, glomerulonephritis, primary biliary cirrhosis, chronic active hepatitis, pernicious anemia, Hashimoto's thyroiditis, atrophic gastritis
  • the pharmaceutical composition according to (45) which is a composition for preventing and treating Z or treating myasthenia gravis, psoriasis, siedalen syndrome, systemic lupus erythematosus-death, rhinitis, asthma or atopic dermatitis.
  • composition (50) The pharmaceutical composition according to (45), wherein the pharmaceutical composition is a composition for suppressing cancerous lymphocytes.
  • a pharmaceutical composition according to (45) which is a composition for inhibiting or responding to a disease or preventing and / or treating rheumatoid arthritis.
  • the pharmaceutical composition suppresses rejection of grafts in bone marrow transplantation, organ transplantation, etc. or prevents inflammatory diseases, organ-specific autoimmune diseases, non-organ-specific autoimmune diseases or allergic diseases, and Z or The use according to (52), which is a composition for treatment.
  • the pharmaceutical composition is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, diabetes, glomerulonephritis, primary biliary cirrhosis, chronic active hepatitis, pernicious anemia, Hashimoto's thyroiditis, atrophic gastritis,
  • composition for suppressing rejection of a graft in bone marrow transplantation / organ transplantation or preventing or treating rheumatoid arthritis.
  • the disease is rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, diabetes, glomerulonephritis, primary biliary cirrhosis, chronic active hepatitis, pernicious anemia, Hashimoto's thyroiditis, atrophic gastritis, severe muscle disease
  • the method according to (60) which is asthenia, psoriasis, Siedalen syndrome, systemic lupus erythematosus, rhinitis, asthma or atopic dermatitis.
  • RR 3 , R 6 , RR ⁇ R 11 and the lower alkyl group in the definition of the substituent group a include, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, s-butyl, t-butyl.
  • Pentyl isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2- 1 to 6 carbon atoms such as dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl groups a linear or branched alkyl group, preferably a C t one C 4 alkyl group, and more preferably is an C 2 alkyl group, most preferably, It is a methyl group.
  • R 6 and the lower alkoxy group in the definition of the substituent group a are the lower alkoxy groups Alkyl group bonded to an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, iso-ventoxy, 2-methylbutoxy, 1-methylbutoxy Ethylpropoxy, 2-ethylpropoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethyl
  • a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms such as butoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy; It is a 4 alkoxy group, more preferably a 1 C 2 alkoxy group, and most preferably a methoxy
  • the lower alkoxy lower alkyl group in the definition of R 1 , R 3 , R 6 and R 9 represents a group in which one of the lower alkoxy groups is bonded to the lower alkyl group, for example, methoxymethyl, Ethoxymethylile, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, s-butoxymethyl, t-butoxymethyl, 2-methoxyethyl, 2-ethoxyxetil, 2-propoxyshetyl, 2-propoxyxethyl, 2-butoxyxethyl, 2-I-butoxyxetil, 2- (s-butoxy) ethyl, 2- (t-butoxy) ethyl, 1-methoxyethyl, 1-ethoxyxyl, 1-Proboxixyl, 1-Iproxoxethyl, 1-butoxyxethyl, 1 1-isobutoxyshethyl, 1- (s-butoxy) ethyl, 1-
  • the mono-lower alkylamino group in the definition of the substituent group a represents a group in which one lower alkyl group is bonded to an amino group, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, Isoptylamino, s-butylamino, t-butylamino, pentylamino, isopentyl W
  • the alkyl group represents a group in which one of the mono-lower alkylamino groups is bonded to the lower alkyl group, for example, methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, Isobutylaminomethyl, sec-butylaminomethyl, t-butylaminomethyl, 2-methylaminoethyl, 2-ethylaminoethyl, 2-propylaminoethyl, 2-isopropylaminoethyl, 2-butylaminoethyl, 2 _Isobutylaminoethyl, 2- (s-butylamino) ethyl, 2- (t-butylamino) ethyl, 1-methylaminoethyl, 1-eth
  • the di-lower alkylamino group in the definition of the substituent group a indicates a group in which two of the lower alkyl groups are bonded to an amino group, such as dimethylamino, Ruamino, N- Echiru -N- Mechiruamino, di like dipropylamino, Kishiruamino group Jibuchiruamino, to dipentyl ⁇ amino or di - is C i one C 6 Arukiruamino group, preferably, di C, one C 4 alkyl an amino group, more preferably a di - - (: 2 Arukiruamino group, most preferably a Jimechiruamino group.
  • the (di-lower alkylamino) lower alkyl group in the definition of RR 3 , R 6 and R 9 represents a group in which one of the di-lower alkylamino groups is bonded to the lower alkyl group;
  • the aryl moiety of the aryl group substituted with 1 to 5 is, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms such as phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl or fluorenyl group. Yes, preferably C 6 —.
  • Aryl group more preferably phenyl or naphthyl group, and most preferably phenyl group.
  • R 2, R 4, RKR s and R 1 (1 of the 1 to 3 heterocyclic group substituted with a substituent in the heterocyclic group and substituent group from a to selected a group of defined
  • the heterocyclic moiety is a 5- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms,
  • RR 4 and R lfl preferably a 5- or 6-membered heterocyclic group which may be condensed with a benzene ring, more preferably furyl, phenyl, pyrrolyl which may be condensed with a benzene ring, Pyrazolyl, imidazolyl, thiazolyl, pyranyl, pyridyl, 1,3-dioxolanyl or 1,3-dioxanyl group, more preferably thienyl group, thiazolyl group, pyridyl group, quinolyl group or 1,3-benzodioxolael And further more preferably a phenyl group, a thiazolyl group, a pyridyl group, a quinolyl group or a 1,3-benzodioxolar group, more preferably a pyridin-3-yl or pyridine group 1 4 1 ⁇ f, thiophen
  • R 5 is preferably a 5- or 6-membered heterocyclic group which may be condensed with a benzene ring, more preferably an indolyl or indolinyl group, and most preferably one monoindolinyl group.
  • R 8 is preferably a 5- or 6-membered heterocyclic group which may be condensed with a benzene ring, more preferably pyridyl, phenyl, 1,3-benzodioxoral or benzodiazo. It is a xanyl group, most preferably a pyridine-13-yl, 1,3-benzodioxolan-15-yl or 1,4-benzodioxane-16-yl group.
  • R 2 is together with R 1
  • R 4 is together with R 3
  • Z or R 1Q is together with R 9 , each containing a carbon atom to which they are bonded.
  • the saturated carbocyclic moiety of the saturated carbocyclic group substituted by 1 to 5 groups selected from the ring group and the substituent group a is, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane Such a saturated carbocyclic group having 3 to 10 carbon atoms.
  • the above-mentioned saturated carbocyclic group is a 5, 6, 7, 8-tetrahydroisoquinoline group which may be condensed with another cyclic group such as a benzene ring / heterocyclic ring.
  • a saturated carbocyclic group preferably a benzene ring condensed with a good C 4 one C 7 saturated carbocyclic group which may, more preferably, may be condensed with a benzene ring c 5 - c
  • R 2 is together with R 1
  • R 4 is together with R 3
  • Z or R 1Q is together with R 9 , each including a carbon atom to which they are bonded, and a saturated heterocyclic ring
  • the saturated heterocyclic moiety of the saturated heterocyclic group substituted with 1 to 3 substituents with a group selected from the group and the substituent group a is, for example, trahydropyran, tetrahydrothiophene, morpholine, thiomorpholine, pyrrolidine , Pyrroline, imidazolidine, pyrazolidine, piperidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, villazolidine, dioxolan or dioxane, preferably a 5- or 6-membered saturated heterocyclic group, and most preferably Is a tetrahydrothiophene ring group, a tetrahydrobiran ring group or a piperidine
  • R 5 , R 8 and the cycloalkyl group in the definition of the substituent group a and the cycloalkyl portion of the cycloalkyl group substituted with 1 to 5 groups selected from the substituent group a are, for example, And a saturated carbocyclic group having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norpolnyl or adamantyl.
  • the cycloalkyl group may be condensed with another cyclic group such as a benzene ring, and is, for example, indanyl, benzocyclohexyl or benzocycloheptyl.
  • R 5 preferably C 3 —.
  • the aralkyl part of the aralkyl group substituted with 1 to 5 aralkyl groups and a group selected from the substituent group a in the definition of R 6 , R 8 and the substituent group a is the lower group of the aryl group.
  • the octogen atom in the definition of the substituent group a is a fluorine, chlorine, bromine or iodine atom, preferably a fluorine atom or a chlorine atom, and most preferably a fluorine atom.
  • RR 3 and the halogeno lower alkyl group in the definition of the substituent group a represent a group in which the lower alkyl group is substituted with a halogen atom, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, Fluoromethyl, 2,2,2-Trifluoroethyl, 2,2,2-Trifluoroethyl, 2-Promoethyl, 2-Chloroethyl, 2-Fluoroethyl, 2-Eodoethyl, 3-Chloropropyl, 4-Fluorobutyl, 6 - hexyl Yodo or 2, 2 - halogeno one C 6 alkyl groups such as Jiburomoechiru group, preferably, halogenoalkyl - a Ji 4 Arukiru group, more preferably a halogeno - an alkyl group, more preferably, Furu
  • R 5 and the lower alkylthio group in the definition of the substituent group a represent a group in which the lower alkyl group is bonded to a sulfur atom, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, S-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethylbutyl 1 to 6 carbon atoms such as thio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio or 2,3-dimethylbutylthi
  • the octogeno lower alkylthio group in the definition of the substituent group a indicates a group in which a halogen atom is substituted on the lower alkylthio group, for example, trifluoromethylthio, trichloromethylthio, difluoromethylthio, dichloromethylthio.
  • the halogeno lower alkyloxy group in the definition of the substituent group a indicates a group in which the octa-lower lower alkyl group is bonded to an oxygen atom, for example, trifluoromethyloxy, trichloromethyloxy, difluoromethyloxy, Dichloromethyloxy, dibromomethyloxy, fluoromethyloxy, 2,2,2-trifluoroethyloxy, 2,2,2-trichloroethyloxy, 2-bromoethyloxy, 2-chloroethyloxy Cyloxy, 2-fluoroethyloxy, 2-chloroethyloxy, 3-chloropropyloxy, 4-fluorobutyloxy, 6-hydroxyhexyloxy or 2,2-dibromoethyloxy halogeno C such as groups, - a C 6 Arukiruokishi group, preferably a halogeno one C 4 Arukiruokishi group, more preferably a
  • the lower alkoxy group in the definition of the substituent group a represents a group in which the lower alkoxy group is bonded to a carbonyl group, for example, methoxycarbonyl, Ethoxycarbonyl, propoxyl-proponyl, isopropoxyl-l-onil, butoxycarponyl, isobutoxyl-carponil, s-butoxyl-carponil, t-butoxyl-l-ponyl, pentoxycarponyl, isopentoxyl-carponyl, 2-methylbutoxyl-carponyl, neopentoxycarbonyl, Hexyloxy-capillonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1 A (C f Ce alkoxy) carbonyl group such as, 2,2-
  • the lower aliphatic acylamino group in the definition of the substituent group a represents a lower aliphatic acyl group (a group in which a saturated or unsaturated chain hydrocarbon group is bonded to a carbonyl group, for example, acetyl, propionyl, A straight-chain or branched lower aliphatic acetyl group having 2 to 7 carbon atoms such as a butyryl, isoptyryl, valeryl, isovaleryl, bivaloyl, hexanoyl, acryloyl, methacryloyl or crotonyl group) is an amino group And represents, for example, acetylamino, propionylamino, butyrylamino, isoptyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino,
  • the lower alkylsulfonyl group in the definition of the substituent group a represents a group in which the lower alkyl group is bonded to a sulfonyl group.
  • examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, Butylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentyl Sulfonyl, isopentylsulfonyl, 2-methylbutylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, isohexylsulfonyl, 4-methylpentylsulfonyl, 3-methylpentylsulf
  • the halogeno lower alkylsulfonyl group in the definition of the substituent group a indicates a group in which the aforementioned halogeno lower alkyl group is bonded to a sulfonyl group, for example, trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethyl Sulfonyl, dichloromethylsulfonyl, dimethyl monomethylsulfonyl, fluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, 2,2,2-trichloroethylsulfonyl, 2-bromoethylsulfonyl, 2-chloroethylsulfonyl, 2-fluoroethylsulfonyl, 2-chloroethylsulfonyl, 3-chloropropylsulfonyl, 4-fluorobutyl
  • the arylsulfonyl group in the definition of the substituent group a represents a group in which the aryl group is bonded to a sulfonyl group, such as phenylsulfonyl, indenylsulfonyl, naphthylsulfonyl, phenanthrenylsulfonyl, Anthracenyls
  • a sulfonyl group such as phenylsulfonyl, indenylsulfonyl, naphthylsulfonyl, phenanthrenylsulfonyl, Anthracenyls
  • An aromatic hydrocarbon sulfonyl group having 6 to 14 carbon atoms such as a rufonyl or fluorenylsulfonyl group, and preferably C 6 —.
  • the heterocyclic group sulfonyl group in the definition of the substituent group a indicates a group in which the heterocyclic group is bonded to a sulfonyl group, for example, furylsulfonyl, phenylylsulfonyl, pyrrolylsulfonyl, azepinylsulfonyl, pyrazolyl Sulfonyl, imidazolylsulfonyl, oxazolylsulfonyl, isoxazolylsulfonyl, thiazolylsulfonyl, isothiazolylsulfonyl, 1,2,3-oxadiazolylsulfonyl, triazolylsulfonyl, tetrazolyl Aromatic heterocyclic groups such as sulfonyl, thiadiazolylsulfonyl, pyranylsulfonyl, pyrazolyl S
  • the lower alkylsulfinyl group in the definition of the substituent group a indicates a group in which the lower alkyl group is bonded to a sulfiel group, such as methylsulfiel, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, Isobutylsulfinyl, s-butylsulfinyl, t-butylsulfinyl, pentylsulfenyl, isopentylsulfinyl, 2-methylbutylsulfinyl, neopentylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, isohexylsulfinyl, 4-methylpentyl Sulfinyl, 3-methylpentylsulf
  • the arylsulfenyl group in the definition of the substituent group a indicates a group in which the aryl group is bonded to a sulfinyl group, and examples thereof include phenylsulfinyl, indenylsulfiel, naphthylsulfinyl, and phenanthrenyl.
  • An aromatic hydrocarbon sulfinyl group having 6 to 14 carbon atoms such as a sulfinyl, anthracenylsulfinyl or fluorenylsulfinyl group, and preferably C 6 —.
  • the mono-lower alkyl group rubamoyl group in the definition of the substituent group a indicates a group in which one of the lower alkyl groups is bonded to the carbamoyl group, for example, methylcarbamoyl, edilcarbamoyl, propyl carbamoyl, Isopropyl carbamoyl, butyl carbamoyl, isobutyl carbamoyl, S-butyl carbamoyl, t- butylcarbamoyl, pentylcarbamoyl, isopentylcarbamoyl butylcarbamoyl, 2 - methyl Petit carbamoyl, neopentyl carbamoyl, a mono- one C 6 alkyl force Rupamo I le groups such as 1 one Echirupuropiru force Rubamoiru or the alkoxy carbamoyl group, preferably Is a mono-
  • the di-lower alkyl group rubamoyl group in the definition of the substituent group a represents a group in which two of the lower alkyl groups are bonded to a carpamoyl group, for example, dimethylcarbamoyl, getylcarbamoyl, N-ethyl N— methylcarbamoyl, dipropionate pills force Rubamoiru, dibutylcarbamoyl, Gee, such as carboxymethyl carbamoyl group to di pentylcarbamoyl or di (: an alkyl force Rubamoiru group, preferably a di one C 4 alkyl force Rubamoiru group, further preferably Is a di-d-C 2 alkylcarbamoyl group, most preferably a dimethylcarbamoyl group.
  • the lower alkyl (aryl) rubamoyl group in the definition of the substituent group a indicates a group in which the aryl group is bonded to the mono-lower alkyl rubamoyl group, for example, N-methyl N-phenylcarbamoyl, N-ethyl N-phenylcarbamoyl, N-phenyl N-propylcaproluvyl, N-isopropyl N-phenylcarbamoyl, N-butyl N-phenylcarbamoyl, N-pentyl N-phenylcarbamoyl, N —Hexyl N-phenylcarbamoyl group, N-methyl N-naphthyl carbamoyl, N-ethyl N-naphthylcarbamoyl, N-naphthyl N-propyl carbamoyl, N-isopropyl N
  • the ethylidenehydrazinocarbonyl group in the definition of the substituent group a is, for example, [111- (phenyl) ethylidene] hydrazinocarbonyl, [111- (4-pyridyl) ethylidene] hydrazinocarbonyl or [1- (Methyl) ethylidene] hydrazinocarbonyl group, and preferably [1- (4-pyridyl) ethylidene] hydrazino carbonyl group.
  • the mono-lower alkyl group rubamoyloxy group in the definition of the substituent group a represents a group in which one of the above mono-lower alkylcarbamoyl groups is bonded to an oxygen atom, for example, methylcarbamoyloxy, ethylcarbamoyl Propyl, propyl carbamoyloxy, isopropyl rubamoyloxy, butylcarbamoyloxy, isobutylcarbamoyloxy, s-butylcarbamoyloxy, t-butylcarbamoyloxy, pentylcarbamoyloxy, isopentylcarbamoyloxy, 2-methylmethyl carbamoyl O carboxymethyl, neopentyl carbamoyl O carboxymethyl, model no C such as 1 over E Chirupuropiru force Rubamoiruokishi or the carboxymethyl-carbamoy
  • the di-lower alkyl rubamoyloxy group in the definition of the substituent group a represents a group in which one of the above di-lower alkyl rubamoyl groups is bonded to an oxygen atom, for example, dimethylcarbamoyloxy,
  • a di-C 6 alkyl radical rubamoyloxy group such as rucarbamoyloxy, N-ethyl N-methylcarbamoyloxy, dipropyl carbamoyloxy, dibutylcarbamoyloxy, dipentylcarbamoyloxy or dihexylcarbamoyloxy;
  • it is a di-C, 1 C 4 alkyl radical rubamoyloxy group, more preferably, a di-C 2 alkyl carbamoyloxy group, most preferably, a dimethylcarbamoyloxy group.
  • the mono-lower alkyl rubamoylamino group in the definition of the substituent group a represents a group in which one mono-lower alkyl rubamoyl group is bonded to an amino group, for example, methylcarbamoylamino, ethylcarbamoylamino Mino, Propyl carbamoylamino, isopropylcarbamoylamino, butylcarbamoylamino, soptylcarbamoylamino, s-butylcarbamoylamino, t-butylcarbamoylamino
  • an amino group for example, methylcarbamoylamino, ethylcarbamoylamino Mino, Propyl carbamoylamino, isopropylcarbamoylamino, butylcarbamoylamino, soptylcarbamoylamino, s-but
  • the di-lower alkyl rubamoylamino group in the definition of the substituent group a represents a group in which one di-lower alkyl rubamoyl group is bonded to an amino group, for example, dimethylcarbamoylamino, carbamoyl ⁇ Mino, N- Echiru N- methylcarbamoyl ⁇ amino, dipropyl force Rubamoiruamino, di-heptyl carbamoylthiopheno such Gee C, - a C 6 alkyl force Rubamoiruamino group, preferably a, - C, - C 4 alkyl force Rubamoiruamino And more preferably a di-c 2 alkylcarbamoylamino group, most preferably a dimethylcarbamoylamino group.
  • the lower alkylsulfonylamino group in the definition of the substituent group a indicates a group in which an amino group is bonded to the lower alkylsulfonyl group, for example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, Isopropyl sulfonylamino, butylsulfonylamino, isobutylsulfonylamino, S-butylsulfonylamino, t-butylsulfonylamino, pentylsulfonylamino, isopentylsulfonylamino, 2-methylbutylsulfonylamino, neobe 1-ethylpropylsulfonylamino, hexylsulfo Nilamino, isohexylsulfonyla
  • the mono-lower alkylaminosulfonyl group in the definition of the substituent group a represents a group in which the mono-lower alkylamino group is bonded to a sulfonyl group, for example, methylaminosulfonyl, ethylaminosulfonyl, propylamino Sulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, isobutylaminosulfonyl, s-butylaminosulfonyl, t-butylaminosulfonyl, pentylaminosulfonyl, isopentylaminosulfonyl, 2-methylbutylaminosulfonyl, neopentylaminosulfonyl, 11 Ethylpropylaminosulfonyl, hexylaminosulfonyl, isohexylami
  • the di-lower alkylaminosulfonyl group in the definition of the substituent group a indicates a group in which the di-lower alkylamino group is bonded to a sulfonyl group, for example, dimethylaminosulfonyl, getylaminosulfonyl, N— Echiru N- Mechiruami Nosuruhoniru, dipropylamino sulfonyl, dibutyl aminosulfonyl, a di ten 6 ⁇ Le kills aminosulfonyl groups such as cyclohexyl ⁇ amino sulfonyl group to Jipen chill aminosulfonyl or di, preferably, di C, A C 4 alkylaminosulfonyl group, more preferably a di-C 2 alkylaminosulfonyl group, and most preferably a dimethylaminosulfonyl group.
  • the mono-cycloalkylaminosulfonyl group in the definition of the substituent group a represents a group in which a monocycloalkylamino group is bonded to a sulfonyl group, for example, cyclopropylaminosulfonyl, cyclobutylaminosulfonyl, cyclopentylaminosulfonyl or cyclohexyl ⁇ amino mono- such as sulfonyl group C 3 to consequent opening - (a 3 6 cycloalkyl aminosulfonyl group, preferably, mono- C 3 - (a 3 4 cycloalkylamino sulfonyl Lulu group, most suitably Is a cyclopropylaminosulfonyl group.
  • the mono-lower alkoxy lower alkylaminosulfonyl group in the definition of the substituent group a indicates a group in which the lower alkoxy group is bonded to the mono-lower alkylaminosulfonyl group, for example, methoxymethylaminosulfonyl, Methoxyethylaminosulfonyl, methoxypropylaminosulfonyl, methoxybutylaminosulfonyl, methoxypentylaminosulfonyl, methoxyhexylaminosulfoxypropylaminosulfonyl, propoxymethylaminosulfonyl, propoxy shetylaminosulfonyl or propoxypropylaminosulfonyl group mono- C, such as one C 6 alkoxy C r - a C 6 alkyl ⁇ amino sulfonyl group, preferably a mono - is an C 3 alkoxy one c
  • the mono-lower alkoxycarbonyl lower alkylaminosulfonyl group in the definition of the substituent group a represents a group in which the lower alkoxycarbonyl group is bonded to the mono-lower alkylaminosulfonyl group.
  • - C 6 Arukokishikarupo sulfonyl (3, - a C 6 alkyl ⁇ amino sulfonyl group, preferably, mono- C, one C 3 alkoxy force Lupo sulfonyl (: is one C 4 alkyl ⁇ amino sulfonyl group, Most preferably, it is a methoxycarbonylmethylaminosulfonyl or ethoxycarbonylmethylaminosulfonyl group.
  • the mono-l-rubamoyl lower alkylaminosulfonyl group in the definition of the substituent group a indicates a group in which a l-rubamoyl group is bonded to the mono-lower alkylaminosulfonyl group, for example, l-rubamoyl methylamino sulfonyl, force Rubamoirue chill aminosulfonyl, force Luba carbamoyloxy propyl aminosulfonyl, force Rubamoirubu chill aminosulfonyl, with a force Rubamoiru one c 6 alkylaminosulfonyl groups such as forces Rubamoiru pen hexyl aminosulfonyl group to chill aminosulfonyl or force Rubamoiru
  • the mono-lower aliphatic acylaminosulfonyl in the definition of the substituent group a The group represents a group in which the above-mentioned mono-lower aliphatic acylamino group is bonded to a sulfonyl group.
  • C2-C7 linear or branched lower fatty acids such as aminosulfonyl, pivaloylaminosulfonyl, hexanoylaminosulfonyl, acryloylaminosulfonyl, methacryloylaminosulfonyl or crotonylaminosulfonyl groups a family ⁇ sill aminosulfonyl group, preferably, mono- C 2 - a C 3 aliphatic ⁇ sill aminosulfonyl group, and most preferably, Ru ⁇ cetyl aminosulfonyl group der.
  • the hydroxy lower alkyl group in the definition of the substituent group a indicates a group in which one hydroxy group is substituted by the lower alkyl group, and examples thereof include hydroxymethyl, 2-hydroxyethyl, and 1-hydroxyethyl.
  • the aryloxy group in the definition of the substituent group a indicates a group in which the above aryl group is bonded to an oxygen atom, for example, phenyloxy, indenyloxy, naphthyloxy, phenanthrenyloxy, anthracenyloxy or fluorenyloxy.
  • An aromatic hydrocarbon group having 6 to 14 carbon atoms such as a C 6 -C 1 Q group, preferably a C 6 -C 1Q aryloxy group, more preferably a phenyloxy or naphthyloxy group; Preferably, it is a phenyloxy group.
  • a phenyl group independently substituted with 1 to 3 arbitrary groups selected from the substituent group a, more preferably 1 to 3 substituents
  • the substituent is a group selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkoxy group, a halogeno lower alkyl group, and a hydroxy group.
  • a phenyl group substituted with one to three substituents is a group selected from the group consisting of a lower alkyl group and an octogen atom).
  • R 2 , R 4 and R 1 () preferably C 6 —C [independently substituted with 1 to 5 arbitrary groups selected from the substituent group a.
  • Aryl group more preferably a phenyl or naphthyl group independently substituted with 1 to 5 arbitrary groups selected from the substituent group a, more preferably 1 to 3 substituted
  • a phenyl or naphthyl group substituted with a group (the substituent is a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group, a cyano group, a carboxy group, a lower alkoxycarbonyl group, an aliphatic acylamino group, Halobamoyl, lower alkylsulfonyl, hydroxy lower alkyl, lower alkylsulfonylamino, aminosulfonyl, mono-lower alkylaminosulfonyl, mono-cycloalkylami
  • Der is, more preferably, substituted by 1 to 3 substituents, phenyl or naphthyl group (the substituent is a fluorine atom, a chlorine atom, C, - C 2 alkyl groups, C [- C 2 alkoxy group, hydroxy group, nitro group, Shiano group, (!
  • C one C 2 alkoxy) carboxamide sulfonyl group c 2 - c 3 aliphatic Ashiruamino group, c, - c 2 alkylsulfonyl group, Aminosuruhoni group, one A C 3 alkylaminosulfonyl group, a C 3 —C 4 cycloalkylaminosulfonyl group and a di-C 1, 1 C 2 alkylaminosulfonyl group.
  • R 5 and R 8 preferably C 6 — independently substituted with 1 to 5 arbitrary groups selected from the substituent group a. And more preferably C 6 —C, which is independently substituted with 1 to 3 arbitrary groups selected from the substituent group a.
  • Aryl group more preferably, a phenyl group substituted with 1 to 3 substituents (the substituent is Selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a mono lower alkylamino group, a G lower alkylamino group, a nitro group, a cyano group and an aryl group.
  • substituent is Selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a mono lower alkylamino group, a G lower alkylamino group, a nitro group, a cyano group and an aryl group.
  • a phenyl group substituted with 1 to 3 substituents may be a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, And more preferably a phenyl group substituted with 1 to 3 substituents (the substituent is a fluorine atom, a chlorine atom, a C,- ⁇ alkyl group). , halogeno ten 2 ⁇ alkyl group, C, -C 2 alkoxy, C, -C 2 alkylthio group, and a C 6 -.
  • a C 1Q Ari group selected from Le group more preferably, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluoro Phenyl, 3, 4-difluorophenyl 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 3,4,5-trifluorophenyl, 2-methylphenyl, 4-methylphenyl, 2,4 -Dimethylphenyl, 2-, 3_ or 4-methoxyphenyl, 2-ethoxyphenyl, 2-methylthiophenyl, 3,5-dimethoxyphenyl, 2-fluoro-4-chlorophenyl, 2_ Fluoro-5-chlorophenyl, 2-fluoro-4-methylphenyl, 2-fluoro-5-methylphenyl,
  • heterocyclic group independently substituted with 1 to 3 arbitrary groups selected from the substituent group a in the definition of R 2 , R 4 , RK R 8 and R 1D include, for example, 3-, 4- or 5-fluorothiophene-2-yl, 3-, 4- or 5-chlorothiophene-2-yl, 3-, 4- or 5-methylthiophene-2-yl , 3-, 4- or 5-ethylthiophen-2-yl, 3-, 4- or 5-nitrothiophen-2-yl, 3-, 4- or 5-carboxythiophen-2-yl 3-, 1- or 5-methylfuran-2-yl, 3-, 4- or 5-ethylfuran-2-yl, 3-, 4- or 5-hydroxymethylfuran-21-yl, 3-, 4- or 5-carboxyfuran-2-yl, 4,5-dimethylfuran-2-yl, 1-methyl-pyrrole-12-yl, 2,4-dimethyl-2,3 —Thiazoyl 5-yl, 8
  • R 2 , R 4 and R 1Q preferably a 5- to 6-membered heterocyclic ring which may be condensed with a benzene ring, which is independently substituted with 1 to 3 arbitrary groups selected from substituent group a More preferably, furyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, which is independently substituted with 1 to 3 arbitrary groups selected from the substituent group a and may be condensed with a benzene ring, Thienyl which is a thiazolyl, a pyranyl, a pyridyl, a 1,3-dioxolanyl or a 1,3-dioxanyl group, more preferably 1 to 3 independently substituted by any group selected from the substituent group a.
  • Lubamoyl group It is a group selected from the group consisting of a lower alkylsulfonyl group, a hydroxy lower alkyl group, a lower alkylsulfonylamino group, an aryl group and an oxo group.
  • a phenyl, thiazolyl, pyridyl, quinolyl or 1,3-benzodioxolanyl group substituted with 1 to 3 substituents the substituent is a halogen atom, A lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group, a cyano group, a lower alkoxycarbonyl group, an aliphatic acylamino group, and a lower alkylsulfonyl group.
  • the substituted with 1 to 3 substituents, thienyl, thiazolyl, pyridyl, 1 quinolyl young properly, 3-benzo-di O key Sora sulfonyl group the substituent is a fluorine atom, a chlorine atom, CC 2 alkyl group, C, - C 2 alkoxy group, hydroxy group, nitro group, Shiano group, (!
  • R 5 and R 8 it is preferably a 5- to 6-membered heterocyclic group which may be independently condensed with a benzene ring, which is independently substituted with 1 to 3 arbitrary groups selected from the substituent group a. More preferably, it is a 5- to 6-membered aromatic heterocyclic group independently substituted with 1 to 3 arbitrary groups selected from the substituent group a, more preferably selected from the substituent group a.
  • a pyridyl or phenyl group which is independently substituted with 1 to 3 substituents, and even more preferably a pyridyl or phenyl group, which is substituted with 1 to 3 substituents.
  • the groups include a halogen atom, a lower alkyl group, an octogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a mono-lower alkylamino group, a di-lower alkylamino group, a nitro group, a cyano group and the like. From reel reel It is a group-option.), And the most preferred, which is substituted by 1 to 3 substituents, pyridyl or thienyl group (the substituent is a halogen atom, lower W
  • R 2 is together with R 1
  • R 4 is together with R 3 and Z
  • R 1 () is together with R 9 , each comprising a carbon atom to which they are attached.
  • saturated carbocyclic group substituted by 1 to 5 groups selected from the group a include, for example, 3,5-tetramethylcyclohexane-111-pyridene, 3-, 5- or 6- Fluoro-2,3-dihydroindene-1-ylidene, 3-, 5- or 6-chloro-2,3-dihydroindene-1-ylidene, 3-, 5- or 6-methoxy-2,3-dihydroindene-11 Ilidene, 3-, 5- or 6-acetylamino-2,3-dihydroindene-1-ylidene, 3-, 5- or 6-nitro-12,3-dihydroindene-1-ylidene or 5,6-dimethoxy-2 , 3-dihydric indene 1-ylidene group;
  • a C 4 -C 7 saturated carbocyclic group which is independently substituted with 1 to 5 arbitrary groups selected from the substituent group a and may be condensed with a benzene ring, more preferably
  • R 2 is formed together with R 1
  • R 4 is formed together with R 3
  • R or R 1 () is formed together with R ′ 9 , each including the carbon atom to which they are bonded.
  • the saturated heterocyclic group which is independently substituted with 1 to 3 arbitrary groups include, for example, 1-t-butoxycarbonylpyridine-141-ylidene or 1-benzylpyridine-141-ylidene group And is preferably a 5- to 6-membered saturated heterocyclic group independently substituted with 1 to 3 arbitrary groups selected from the substituent group a, and more preferably a substituent group a A tetrahydrothiophene ring, a tetrahydropyran ring or a piperidine ring group independently substituted by 1 to 3 substituents with an arbitrary group selected, more preferably a tetrahydrothiophene ring substituted by 1 to 3 substituents A phen ring, a tetrahydric pyran ring or a piperidine ring group (the substituent is a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group,
  • a piperidine ring group (the substituent is a group selected from the group consisting of a lower alkoxy group, a lower aliphatic acylamino group, a lower alkylsulfonyl group and a cyano group).
  • the pharmacologically acceptable salt is a pyrimidine derivative having the general formula (I) or (II) of the present invention, which has a basic group such as an amino group, when reacted with an acid.
  • the compound has an acidic group such as a carboxy group, it can be converted into a salt by reacting with a base.
  • salt based on a basic group preferably, hydrofluoride, hydrochloride, hydrobromide, hydrooctylogenate such as hydroiodide, nitrate, perchlorate, Inorganic acid salts such as sulfates and phosphates; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, benzenesulfonates and salts such as p-toluenesulfonate Organic acid salts such as reel sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; and glycine salt, lysine And salts of amino acids such as salts, arginine salts, orditin salts, glutamate salts, and aspartate salts, most preferably hydrohalide salts, inorganic acid salts, in
  • the salt based on an acidic group is preferably a sodium salt, a potassium salt, or a sodium salt.
  • Alkali metal salts such as lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts; octylamine salts, dibenzylamine salts Salts, morpholine salts, darcosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methyl dalkamine salts, guanidine salts, getylamine salts, triethylamine salts, dicyclohexylamine salts, N, N, dibenzylethylenediamine Organic salts such as mine salt, black mouth pro-force salt, pro-force salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium
  • the pyrimidine derivative having the general formula (I) or (II), its pharmaceutically acceptable salt, its ester or its pond derivative of the present invention has various asymmetric carbon atoms in its molecule. Isomers. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, by the general formula (I) or (II). 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' (II), its pharmaceutically acceptable salt, its ester or other derivatives of the present invention has a double bond in its molecule. Having geometric isomers.
  • the present invention includes all geometric isomers and mixtures of geometric isomers in any proportion.
  • the pyrimidine derivative having the general formula (I) or (II) of the present invention, its pharmaceutically acceptable salt, its ester or other derivative can be obtained by leaving it in the air or by recrystallization. , Absorbs water, becomes wet with water and hydrates In some cases, such hydrates are also included in the salts of the present invention.
  • the ester in the above refers to the ester of the compound (I) or (II) of the present invention because it can be converted to an ester.
  • Examples of such an ester include an ester of a hydroxy group.
  • a general protecting group is a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis.
  • Preferred general protecting groups for the ester of a hydroxy group include formyl, acetyl, propionyl, butyryl, isoptyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanol, 3-methylnonanoyl, and 8-methylnonanol.
  • Alkoxyl-lponyl groups such as lower alkoxyl-lponyl groups substituted with halogens or tri-l-lower alkylsilyl groups such as carbonyl groups, 2,2,2-trichloromouth ethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; tetrahydropyran One two one Or tetrahydropyranyl such as 3-bromotetrahydropyran-1-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-12-yl, 4-methoxytetrahydrothiopyran-14-yl or Tetrahydrothiopyranyl group; tetrahydrofuranyl or tetrahydrothiofuranyl group such as tetrahydrofuran-1-yl and tetrahydrothiofuran-12-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl
  • Substituted ethyl groups such as halogenated ethyl groups such as 2,2,2-trichloromethyl; benzyl, hynaphthylmethyl, ⁇ -naphthylylmethyl, diphenylmethyl, triphenylmethyl, naphthyldiphenylmethyl, 9-anthrylmethyl
  • Lower alkyl groups substituted with 1 to 3 aryl groups 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiph
  • Aryl ring substituted with lower alkyl, lower alkoxy, nitro, halogen, cyano groups such as enylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl
  • An aralkyl group such as a lower alkyl group substituted with 1 to 3 aryl groups; an
  • the general protecting group for the ester of a carboxy group is preferably the lower alkyl group described above: ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1 1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl — 1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl,
  • Lower alkenyl groups such as 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-1-pentenyl 1-hexenyl, 2-hexenyl, 3_hexenyl, 4-hexenyl, 5-hexenyl; Ethynyl, 2-propiel, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butenyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 1-ethyl -2-butynyl, 3-butenyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pen W
  • Thynyl 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl_3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2- Lower alkynyl groups such as hexynyl, 3-hexynyl, 4-hexyl, and 5-hexynyl; the above-mentioned halogeno lower alkyl; 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3, A hydroxy lower alkyl group such as 4-dihydroxybutyl and 4-hydroxybutyl; a lower aliphatic acyl-lower alkyl group such as acetylmethyl; the aralkyl group; the silyl group, preferably a lower alkyl group or an aralkyl group; Group.
  • a protective group that can be cleaved in vivo by a biological method such as hydrolysis is a protective group that is cleaved in a human body by a biological method such as hydrolysis to generate a free acid or a salt thereof.
  • a biological method such as hydrolysis to generate a free acid or a salt thereof.
  • administer it to a test animal such as a rat or mouse by intravenous injection and then examine the body fluid of the animal to detect the original compound or its pharmacologically acceptable salt. Can be determined by what you can do,
  • the protecting group which can be cleaved by a biological method such as hydrolysis in the living body to the ester of the hydroxy group preferably, formyloxymethyl, acetooxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl , Butyryloxymethyl, Pivaloyloxymethyl, Valeryloxymethyl, Isoparelliroxymethyl, Hexanoyloxymethyl, 1-Formyloxyxetil, 1-Acetoxyxetil, 1-Propionyloxyxetil, 1-Ptyrilyl 1-pivaloyloxetil, 1-valeryloxetil, 1-isovaleryloxetil, 1-hexanolyloxetil, 1-formyloxypropyl, 1-acetoxy Propyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pi Lyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyl
  • an ester of a carboxy group is preferably methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, or 1-methoxyethyl.
  • the other derivative may be a derivative other than the above-mentioned pharmaceutically acceptable salts and the above-mentioned esters. Is shown.
  • Such derivatives include, for example, compounds
  • Specific examples of the compound having the general formula (I) or (II) of the present invention include, for example, the compounds described in Examples 1 to 872 below. It is not limited. '' In Examples 1 to 872,
  • Example 522 tri (4-pyridinyl) -triethanone N- (2- (2-fluoroalirino) _6_ ⁇ 2- [tri (4-pyridinyl) ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone
  • Example 526 4- (pyridinyl) -1-ethanone N- (2-anilino-6- ⁇ 2-[[4- (4-pyridinyl) ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone;
  • Example 586 1- (4-pyridinyl) -toethanone N- (2- (3-methoxyanilino) -6- ⁇ 2- [2- (1-pyridinyl) edylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone
  • Example 697 4- (4-methylsulfamoyl-phenyl) -1-ethanone N- (2-aniline) Reno-1 6- ⁇ 2-[4- (4-methylsulfamoylofenyl) ethylidene] hydrazino ⁇ -
  • Example 7 07 1- (4-pyridyl) -triethanone N- (2- (benzo [1,3] dioxol-5-ylamino) -1 6- ⁇ 2- [tri (4-pyridyl) ethylidene] hydrazino ⁇ -4-pyrimidyl) hydrazone,
  • Example 7 10 1- (4-ethylsulfonylphenyl) -toluene non-N- (2-anilino-1-6-[2- [1- (4-ethylsulfonylphenyl) ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 73 4- (4-cyclopropylsulfamoylenyl)-1-ethanone N- (2-anilino-6- ⁇ 2- [1- (4-cyclopropylsulfamoylylenyl)) Ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 7 3 5 1- (4-Methylsulfamoylofenyl) -1-ethanone N- (2- (2,4,
  • Example 7 36 1_ (4-methylsulfamoylofenyl) -toethanone N- (2- (2-fluoroallylino) 16- ⁇ 2- [1- (4-methylsulfamoylofenyl) ) Ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 7 51 1 _ (4-ethylsulfamoylenyl) -triethanone N- (2-anilino-6- ⁇ 2- [1- (4-ethylethylsulfamoylenyl) ethylidene] Hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 7 7 1 1- (4-Methylsulfamoylofenyl) -triethanone N- (2- (2,3,4-trifluoroalirino) 1 6- ⁇ 2- [tri (4-methylsulfuryl) Famoylofenilile) tylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 7 4 tri (4-methylsulfamoyl ether) -1 -ethanone N- (2- (2-fluoro-4-chloroanilino) -1-6- ⁇ 2- [tri (4-methyl Sulfamoyl-phenyl) ethylidene] hydrazino 4-pyrimidinyl) hydrazone,
  • Example 7 84 tri (4-methylsulfamoylofenyl) -triethanone N- (2- (3-methoxyanilino) -1-6- (2- [tri (4-methylsulfamoylofenyl) ethylidene) ] Hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 7 9 9 1- (4-methylsulfamoylenyl) -toethanone N- (2-anilino-5-ethoxy-6- ⁇ 2- [1- (4-methylsulfamoylofyl) Enyl) ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 8 03 1- (4-methylsulfamoylphenyl) -thuetanone N- (2- (3,5-difluoroanilino) -6- ⁇ 2- [1- (4- Methylsulfamoylphenyl) ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 8 04 1- (4-methylsulfamoylphenyl) -1-ethanone N- (2- (3,4,5-trifluoroalirino) -6- ⁇ 2- [tri (4-methylsulfa Moylphenol) ethylene den] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 80 1- (4-methylsulfamoylphenyl) -1-ethanone N- (2-anilino_5-benzyl-6- ⁇ 2- [1- (4-methylsulfamoylphenyl) ) Ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 809 1- (4-methylsulfamoylphenyl) -toethanone- (2- (3,4-difluoroalilino) -6- ⁇ 2- [1- (4-methylsulfayl Moylphen) ethylidene] hydrazino ⁇ 4-pyrimidinyl) hydrazone,
  • Example 826 1- (4-methylsulfamoylphenyl) -1-ethanone N- (2- (3-fluoroalirino) 6- ⁇ 2- [tri (4-methylsulfamoylphenyl) Le) ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 82 8 1- (4-Methylsulfamoylphenyl) -toethanone N- (2- (benzo [1,3] dioxo-l-5-yl-amino) -6- ⁇ 2_ [1- (4-Methylsulfamoylphenyl) ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 8 35 tri (4-methylsulfamoylphenyl) -1-ethanone N- (2- (2,4-difluoroalirino) -6- ⁇ 2- [tri (4-methylsulfayl) Moylphen) ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 8 36 tri (4-methylsulfamoylphenyl) -1-ethanone N- (2- (2-methoxyanilino) -6- ⁇ 2- [tri (4-methylsulfamoylphenyl)] Ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 83 8 1- (4-Methylsulfamoylphenyl) -toluene non-N- (2- (2-7-ruorole-5-chloroanilino) -1-6- (2- [1- (4-methyl Sulfamoylphenyl) eti W 03
  • Example 8 39 1- (4-methylsulfamoylphenyl) -1 -ethanone N- (2- (4-octaluminylino) -6- ⁇ 2- [tri (4-methylsulfuryl) Famoylphenyl) ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 8 4 1- (4-methylsulfamoylphenyl) -toethanone- (2- (2-fluoro-4-methoxyanilino) -6- ⁇ 2- [1- (4-methylsulfamo Ilphenyl) e tyriden] hydrazino ⁇ -4-pyrimidinyl) hydrazone,
  • Example 8 49 1- (4-methylsulfamoylphenyl) -1--1-ethanone N- (2- (3-methoxy-4-1-fluoroanilino) -6- ⁇ 2- [1- (4- Methylsulfamoylphenyl) ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone, and
  • Example 8 59 1- (4-ethylsulfamoylphenyl) -thuetanone N- (2- (3-fluoroanilino) -6- ⁇ 2- [1- (4-ethylsulfamoylphenyl) ) Ethylidene] hydrazino ⁇ -4-pyrimidinyl) hydrazone
  • Method A is a method for producing compound (I).
  • RR 2 , RR 4 , R 5 , R 6 and R 7 have the same meanings as described above, and R la , R 2a , R 3a , R 4a , R 5a and R 6a are R , R 2 , R 3 , R 4 , R 5 and R 6 , wherein the amino, hydroxy and / or carboxy groups contained as substituents are amino, hydroxy and Z or Other than a carboxy group, it represents the same group as defined in the definition of RRR 3 , R 4 , R 5 and R 6 ; A gen atom, an arylsulfonate group or an alkylsulfonate group.
  • the protecting group of the amino group which may be protected in the definition of la , R 2 ⁇ R 3a , R 4a , R 5a and R 6a is the protecting group of the amino group used in the field of organic synthetic chemistry. If it is not particularly limited, for example, an aliphatic acyl group; an aromatic acyl group; an alkoxy group; an alkenyloxycarbonyl group; an alkenyloxy group; A ruponyl group; a silyl group; or a group similar to the aralkyl group, or N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 412 trobenzylidene, salicylidene, 5-chlorosalicylidene, Substituted methylene groups that form Schiff bases such as diphenylmethylene, (5-chloro-2-hydroxyphenyl) phenylmethylene There, preferably, aliphatic Ashiru group, an aromatic Ashiru group
  • the protecting group for the hydroxy group which may be protected in the definition of R la , R 2a , R 3a , RR 5a and R 6a is a protecting group for a hydroxy group used in the field of synthetic organic chemistry.
  • the protecting group of the carboxy group which may be protected in the definition of R la , R ⁇ R 3a , R 4a , R 5a and R 6a is a protecting group of a carbonyl group used in the field of organic synthetic chemistry.
  • the A 1 step In compound (I), a step of A 1 and A 2 to produce a compound which is an oxygen atom (I a), in an inert solvent in the presence of a base, the general formula (III) Is reacted with a compound having the general formulas (IV) and (V), and then, if desired, the amino group, hydroxy group and Z or carboxy group in R la , RR 3a , R 4a , R 5a and R 6a . It is carried out by removing the protecting group of the group.
  • the inert solvent used for reacting compound (III) with compounds (IV) and (V) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Amides such as ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, ⁇ -methyl-2-pyrrolidone, ⁇ -methylpyrrolidinone, hexamethylphosphoric acid triamide, geethylether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and dichlorobenzene; preferably amides or ethers (most preferable).
  • Bases used in reacting compound (III) with compounds (IV) and (V) include, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate Alkali metal bicarbonates such as lithium bicarbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, and lithium hydride; sodium hydroxide, potassium hydroxide, barium hydroxide, and hydroxide Alkali metal hydroxides such as lithium; inorganic bases such as sodium fluoride and alkali metal fluorides such as potassium fluoride; sodium methoxide, sodium methoxide, potassium methoxide, potassium methoxide Alkali metal alkoxides such as potassium t-butoxide, lithium methoxide; methyl Mercaptan alkali metals such as sodium rucaptan and ethylmerbutane sodium; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, dis
  • the reaction temperature at which the compound (III) is reacted with the compounds (IV) and (V) varies depending on the starting compound, the inert solvent used, the type of the base, etc., but is usually from o ° c to 110 (preferably 60 to 100 ° C).
  • reaction time for reacting compound (III) with compounds (IV) and (V) varies depending on the starting compound, the inert solvent used, the type of base, the reaction temperature, etc., but is usually 30 minutes to 48 hours. (Preferably 15 to 24 hours).
  • the removal of the protecting group for the amino group, the hydroxy group and the Z or carboxy group varies depending on the type, but generally, methods well known in the art of organic synthetic chemistry, for example, TW Green, (Protective Groups in Organic Synthesis), John Wiley & Sons: JFW McOmis, (Protective Groups in Organic Chemistry), P1 enum Press.
  • the step A2 is to produce a compound (lb) in which, in the compound (I), A 1 and A 2 are groups having the formula NR 7 — (R 7 has the same meaning as described above).
  • the inert solvent used when reacting compound (III) with compounds (VI) and (VII) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • the same inert solvents as those used in Step A1 of Method A can be used.
  • Reaction temperature for reacting compound (III) with compounds (VI) and (VII) The degree varies depending on the starting compound, the inert solvent used, and the like, but is usually from 0 ° C. to 15 Ot: (preferably from 60 ° C. to 100 ° C.).
  • reaction time when the compound (III) is reacted with the compounds (VI) and (VII) varies depending on the starting compound, the inert solvent used, the reaction temperature, etc., but is usually 30 minutes to 48 hours. (Preferably 24 to 48 hours).
  • Step A3 is a step of producing a compound having the general formula (VIII), and converting compound (III) into hydrazine monohydrate in the presence or absence (preferably, absence) of an inert solvent. It is carried out by reacting with a hydrate.
  • the inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • Examples thereof include formamide, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ - Amides such as dimethylacetamide, ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane, dichlorobenzene
  • halogenated hydrocarbons aromatic hydrocarbons such as benzene, toluene and xylene, methanol, ethanol, ⁇ -propanol, i-propanol, ⁇ -butanol, topbutanol, isomayl alcohol, Diethylene glycol, glycerin, octanol, Hexanol click port, an alcohol such as Mechiruse port cello
  • Step A4 is a step for producing a compound (I b-1) in which A 1 and A 2 are groups having the formula —NH— in the compound (I).
  • the inert solvent used when reacting compound (VIII) with compounds (IX) and (X) is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Amides such as formamide, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethers such as diethylene glycol dimethyl ether, dichloromethane, Halogenated hydrocarbons such as 1,2-dichloroethane and dichlorobenzene, aromatic hydrocarbons such as benzene, toluene, and xylene, methanol, ethanol, ⁇ -propanol, i-propanol, diethylene glycol, and glycerin Alcohols such as dimethylsulfo Sid, sulfoxides such as sulfolane, nitrile
  • reaction temperature at which the compound (VIII) is reacted with the compounds (IX) and (X) varies depending on the starting compound, the inert solvent used and the like, but is usually from room temperature to 120 ° C (preferably 90 ° C). To 100.C).
  • the reaction time when the compound (VIII) is reacted with the compounds (IX) and (X) varies depending on the starting compound, the inert solvent used, the reaction temperature, etc., but is usually from 1 hour to 24 hours (preferably , 15 hours to 24 hours).
  • Removal of the protecting group for the amino group, the hydroxy group and / or the carboxy group may be carried out, if desired, in the above-mentioned Method A, Step A1, by the amino group, the hydroxy group in R la , R 2a , R 3a , R 4a , R 5a and R 6a . And the method for removing the protecting group of Be done.
  • each target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, then an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent. If necessary, the obtained target compound can be combined with a conventional method, for example, recrystallization, reprecipitation, etc., using a method commonly used for separation and purification of organic compounds as appropriate. It can be separated and purified by elution.
  • Method B is a method for producing compound (II).
  • RR la , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R and X are as defined above. .
  • Step B1 is a step for producing a compound (IIa) in which A 1 and A 2 are oxygen atoms in the compound (II), and the compound represented by the general formula (XI) in an inert solvent in the presence of a base: Is reacted with compounds (IV) and (V), and if necessary, protection of amino, hydroxy and / or carbonyl groups in R la , R 2a , R 3a , RR 5a and R 6a
  • This step is carried out by removing the group, and this step is carried out in the same manner as the above-mentioned Method A, Step A1.
  • Step B2 is to produce a compound (lib) wherein A 1 and A 2 in the compound (II) are groups having the formula —NR 7 — (R 7 has the same meaning as described above).
  • Step B3 is a step of producing a compound having the general formula (XII), and converting compound (XI) to hydrazine 1 in the presence or absence (preferably, absence) of an inert solvent. This step is carried out in the same manner as the above-mentioned Method A, Step A3.
  • Step B4 is a step of producing a compound (IIb-l) of the compound (II), wherein A 1 and A 2 are groups having the formula —NH—, and in the presence of an inert solvent, the compound After reacting (XII) with compounds (IX) and (X), if desired, the amino group, hydroxy group and Z or carboxy group in R la , -R 2a , R 3a , R 4a , R 5a and R 6a This step is performed by removing the protecting group of the group, and this step is performed in the same manner as in the above-mentioned Method A, Step A4. After completion of the reaction in each step in Method B, each target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound.
  • anhydrous magnesium sulfate After washing with water etc., anhydrous magnesium sulfate, It is obtained by drying over anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent.
  • the obtained target compound can be obtained by a conventional method, for example, recrystallization, reprocessing.
  • Separation and purification can be carried out by appropriately combining ordinary methods commonly used for separation and purification of organic compounds such as precipitation, applying chromatography, and eluting with an appropriate eluent.
  • Method C the compound is a starting compound of Method A in (III), R 5a is a compound which is a group having the formula one NH- R 8a (I lia) and R 5a are the formula one - having a R 8a
  • This is a method for producing a compound (IIIb) which is a group represented by
  • R 5a , R 6a and X have the same meanings as described above, and R 8a is a group in which the amino group, hydroxy group and Z or carboxy group contained as substituents in R 8 are protected.
  • R 8a is a group in which the amino group, hydroxy group and Z or carboxy group contained as substituents in R 8 are protected.
  • Step CI is a step of producing the compound (Ilia) in an inert solvent (preferably ketones such as acetone, amides, ethers, alcohols, halogenated hydrocarbons, Water or a mixed solvent of the above solvents, most preferably a mixed solvent of water and ketones), a compound having the general formula (XIII) and a compound having the general formula (XIV) at room temperature to 80 ° C. (Preferably 40 ° C to 60 ° C) for 3 hours to The reaction is carried out for 24 hours (preferably 15 hours to 20 hours).
  • Step C2 is a step of producing compound (IIIb), and compound (XIII) in an inert solvent (preferably ketones or ethers, most preferably ketones).
  • each target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, then an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated.
  • the desired compound obtained can be combined with a conventional method, for example, recrystallization, reprecipitation, etc., which is commonly used for the separation and purification of organic compounds, and then applied to the appropriate eluent by chromatography. It can be separated and purified by elution.
  • Method D is a process for producing compound (X I) which is a starting compound of method B.
  • Step D1 is a step of preparing a compound having the general formula (XVIII), and is performed in an inert solvent (preferably, an amide, ether, alcohol, or halogenated compound).
  • an inert solvent preferably, an amide, ether, alcohol, or halogenated compound.
  • Step D2 is a step of producing compound (XI),
  • the compound (XVIII) is a halogenating agent (preferably a phosphorus oxyhalide such as phosphorus oxychloride, phosphorus oxybromide or phosphorus oxyiodide, most preferably phosphorus oxychloride) and 20 to The reaction is carried out at 120 (preferably 80 ° C. to 100 ° C.) for 30 minutes to 24 hours (preferably 4 hours to 8 hours) to convert the hydroxy group in compound (XVI II) into a halogen atom Done by
  • X represents an arylsulfonate group or an alkylsulfonate group
  • the compound (XVIII) in the presence or absence of an inert solvent (preferably in the presence of a halogenated hydrocarbon)
  • an inert solvent preferably in the presence of a halogenated hydrocarbon
  • a sulfonylating agent preferably, tosyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, etc.
  • each target compound is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is removed.
  • the organic layer containing the target compound is separated, washed with water or the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, or the like, and then the solvent is distilled off.
  • the obtained target compound can be combined with a conventional method, for example, recrystallization, reprecipitation, etc., using a method commonly used for separation and purification of organic compounds as appropriate. It can be separated and purified by elution.
  • the method E is a method for producing a compound (XV la) in which R 5a is a group having the formula —NH R 8a in the compound (XVI) which is a starting compound of the method D.
  • Step E1 is a step for producing the compound (XVIa) in an inert solvent (preferably amides, ethers, alcohols, water or a mixed solvent of the above solvents; Preferably, an amide or alcohol) or a compound having the general formula (XIX) is converted to a guanidine derivative (for example, cyanamide ⁇ HCl 1 H-pyrazole-1-force lipoxyamidine, 3,5-dimethylpyrazole nitrate-1-carboxylate)
  • a carboxamidine compound activated by a pyrazole such as amidine; preferably, cyanamide or 1 H-pyrazole-l-carboxamidine hydrochloride; and room temperature to 120 ° C (preferably 8 The reaction is carried out at 0 ° C.
  • each target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound.
  • anhydrous magnesium sulfate It is obtained by drying over anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and distilling off the solvent.
  • the obtained target compound can be combined with a conventional method, for example, recrystallization, reprecipitation, etc., using a method commonly used for separation and purification of organic compounds as appropriate. It can be separated and purified by elution.
  • the method F is a method for producing the compounds (IV) and (V), which are the starting compounds of the methods A and B.
  • Step F1 is a step of producing the compound (IV).
  • an inert solvent preferably ethers or alcohols
  • the compound having the general formula (XX) is treated with hydroxyamine at room temperature to 12
  • the reaction is carried out at 0 ° C (preferably 60 ° C to 100 ° C) for 30 minutes to 24 hours (preferably 15 hours to 18 hours).
  • the step F2 is a step of producing the compound (V), and is carried out by reacting the compound having the general formula (XXI) with hydroxylamine in an inert solvent. This is performed in the same manner as in the F1 step.
  • each target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is removed.
  • an immiscible organic solvent such as water and ethyl acetate is removed.
  • the organic layer containing the target compound is separated, washed with water or the like, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, or the like, and then the solvent is distilled off.
  • the desired compound obtained can be combined with a conventional method, for example, recrystallization, reprecipitation, etc., which is commonly used for the separation and purification of organic compounds, and then applied to the appropriate eluent by chromatography. It can be separated and purified by elution.
  • the starting compounds (VI), (VI1), (I), (X), (XIII) to (XVII) and ⁇ ( ⁇ ) to ( ⁇ ) are known compounds or known compounds. It is easily manufactured according to a method or a similar method. The invention's effect
  • the pyrimidine derivative having the above general formula (I) or (II), its pharmaceutically acceptable salt, its ester or other derivative of the present invention has excellent MLR inhibitory activity, low cytotoxicity, Inhibitors of transplant rejection in transplantation, organ transplantation, etc., inhibitors of cancer cells by selective cell killing activity (eg, inhibitors of cancer-affected lymphocytes), or rheumatoid arthritis, an inflammatory disease And 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 Shederdalen syndrome), non-organ-specific autoimmune diseases (eg, systemic lupus erythematosus), allergic diseases (eg, rhinitis, asthma or atopy) Useful
  • a pharmaceutically acceptable salt thereof, an ester or other derivative thereof is used as the above-mentioned therapeutic or prophylactic agent, Is mixed with an appropriate pharmacologically acceptable excipient, diluent, etc.
  • they can be administered orally by means of tablets, capsules, granules, powders or syrups, or parenterally by injections or suppositories.
  • These preparations may contain excipients (eg, lactose, sucrose, dextrose, mannitol, sorbitol), sugar derivatives such as starch; corn starch, potato starch, starch derivatives such as starch, dextrin; Organic excipients such as gum arabic; dextran; pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium silicate and magnesium aluminate; hydrogen phosphate Phosphates such as calcium; carbonates such as calcium carbonate; inorganic excipients such as sulfates such as calcium sulfate; and lubricants (eg, stearic acid, calcium stearate) Metal stearate, such as magnesium stearate; talc; colloidal silica Waxes such as veegum and gay ;; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fuma
  • the dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.1 mg (preferably 0.5 mg) per day, the upper limit is 400 Omg (preferably 40 Omg) per dose.
  • a minimum dose of 0.1 mg (preferably 0.05 mg) per day and a maximum dose of 50 mg (preferably 30 mg) per day for adults should be 1 mg / day. It is desirable to administer it up to 6 times according to the symptoms.
  • the liquid chromatograph-to-mass spectrometry (LCMS) measuring device used was HP-1100 LCZMSD manufactured by Hewlett-Packard.
  • the column used was CD-C18 manufactured by Inktact in a reverse layer system.
  • the analytical conditions were a column temperature of 40 ° C, and acetonitrile and water (containing 0.01% trifluoroacetic acid) as the mobile phase.
  • the flow rate was 1.5 ml / min and the acetonitrile was a linear gradient from 8% to 99% for 10 minutes.
  • Atmospheric pressure chemical ionization (APC I) was used for the mass spectrometer.
  • Measurement device for nuclear magnetic resonance spectrum hereinafter abbreviated as ⁇ -band R spectrum
  • ⁇ -Awake R spectrum data were measured with a JEOL JNM-GX 270 FT-NMR or a Variance 400 instrument. Chemical shift values are described at ⁇ 5 ppm using tetramethylsilane as a reference substance. Fission patterns are indicated by s for singlet, d for doublet, t for triplet, q for quadruple, etc. In the following, DMF means dimethylformamide.
  • N- (2,6-dihydrazinopyrimidin-4-yl) _ (2-methoxyphenyl) amine (78 mg, 0.3 mol ol) prepared in Reference Example 2 was dissolved in dioxane (2 ml) and 4-acetyl was dissolved.
  • 'Pyridine (0.198 ml, 1.8 ol) was added, and the mixture was refluxed for 15 hours.
  • the solvent was distilled off under reduced pressure, and the residue was suspended by adding a mixed solvent of ether and ethyl acetate.
  • the precipitated solid was pulverized, collected by filtration, and washed again with a mixed solvent of ether and ethyl acetate to obtain the desired product (40 mg, 29 mg).
  • N- (2,6-dichloropyrimidine-4-yl) -phenylamine (480 mg, 2 mmol) produced in Reference Example 3, and the mixture was added at 90 ° C. Stirred for hours.
  • the reaction system was cooled to room temperature, water was added to the reaction solution, and the precipitated solid was collected by filtration. The obtained solid was washed with water and ethyl acetate, and dried under reduced pressure to obtain N- (2,6-dihydrazino-pyrimidine-4-yl) -phenylamine as a crude product.
  • Example 6 4-Hydroxybenzaldehyde N- [4_ ⁇ 2-[(4-hydroxyphenyle) methylidene] hydrazino ⁇ -6- (2-methoxyanilino) -2-pyrimidinyl] hydrazone MS (APCI, m / z) : 470 (M + l
  • Example 161 3,5-Dichro-2--2-N- [4- ⁇ 2-[(3,5-dichloro-2-Hydroxyphenyhydrazino) -6- (2-methoxyanilino) -2] -Pyrimidinyl] hydrazone
  • Example 277 4-'N- [4-anilino-6- (2- ⁇ [4- (trifluoromethoxy) phenino'-2-pyrimidinyl] hydrazone

Abstract

L'invention concerne un dérivé de pyrimidine représenté par la formule générale (I), dans cette formule, R1 et R3 représentent chacun un atome d'hydrogène, un groupe alkyle inférieur, ou tout autre élément analogue; R2 et R4 représente chacun un groupe aryle, un groupe hétérocyclique, ou tout autre élément analogue; A1 et A2 représentent chacun un atome d'oxygène ou tout autre élément analogue; R5 représente un groupe ayant la formule: -D-R8, dans laquelle, D représente un groupe comprenant NH- et tout autre élément analogue et R8 représente un groupe aryle ou tout autre élément analogue; R6 représente un atome d'hydrogène ou tout autre élément analogue, un sel pharmaceutiquement acceptable de celui-ci, un ester de celui-ci, ou tout autre dérivé de celui-ci. Le dérivé de pyrimidine décrit dans cette invention présente une excellente action d'inhibition de MLR.
PCT/JP2003/005216 2002-04-23 2003-04-23 Derive de pyrimidine WO2003091223A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005037801A1 (fr) * 2003-10-21 2005-04-28 Sankyo Company, Limited Compose pyrimidine
WO2005037802A1 (fr) * 2003-10-16 2005-04-28 Sankyo Company, Limited Derive de 5-arylpyrimidine
US8013154B2 (en) 2007-10-09 2011-09-06 Niyaz Noormohamed M Insecticidal substituted azinyl derivatives
US8058279B2 (en) 2007-10-09 2011-11-15 Dow Agrosciences Llc Insecticidal pyrimidinyl aryl hyrdrazones
US8067588B2 (en) 2007-10-09 2011-11-29 Dow Agrosciences Llc Insecticidal (1,3,5)-triazinyl phenyl hydrazones
EP2473486B1 (fr) 2009-09-02 2015-10-28 Vifor (International) Ag Pyrimidines en tant qu'antagonistes de l'hepcidine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001507687A (ja) * 1996-12-21 2001-06-12 アストラゼネカ・アクチエボラーグ ピロロ〔３，４−ｄ〕ピリミジノン誘導体および医薬としてのその使用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001507687A (ja) * 1996-12-21 2001-06-12 アストラゼネカ・アクチエボラーグ ピロロ〔３，４−ｄ〕ピリミジノン誘導体および医薬としてのその使用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DANAGULYAN G.G.: "Synthesis and biological activity of certain O-pyrimidinylketoximes", CHEMISTRY OF HETEROCYCLIC COMPOUNDS (TRANSLATION OF KHIMIYA GETEROTSIKLICHESKIKH SOEDINENII), vol. 33, no. 7, 1998, NEW YORK, pages 831 - 837, XP002969431 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005037802A1 (fr) * 2003-10-16 2005-04-28 Sankyo Company, Limited Derive de 5-arylpyrimidine
WO2005037801A1 (fr) * 2003-10-21 2005-04-28 Sankyo Company, Limited Compose pyrimidine
US8013154B2 (en) 2007-10-09 2011-09-06 Niyaz Noormohamed M Insecticidal substituted azinyl derivatives
US8058279B2 (en) 2007-10-09 2011-11-15 Dow Agrosciences Llc Insecticidal pyrimidinyl aryl hyrdrazones
US8067588B2 (en) 2007-10-09 2011-11-29 Dow Agrosciences Llc Insecticidal (1,3,5)-triazinyl phenyl hydrazones
US8188273B2 (en) 2007-10-09 2012-05-29 Dow Agrosciences, Llc. Insecticidal (1,3,5)-triazinyl phenyl hydrazones
US8455649B2 (en) 2007-10-09 2013-06-04 Dow Agrosciences, Llc Insecticidal substituted azinyl derivatives
US8507671B2 (en) 2007-10-09 2013-08-13 Dow Agrosciences Llc Insecticidal substituted azinyl derivatives
US8598182B2 (en) 2007-10-09 2013-12-03 Dow Agrosciences, Llc. Insecticidal pyrimidinyl aryl hyrdrazones
EP2473486B1 (fr) 2009-09-02 2015-10-28 Vifor (International) Ag Pyrimidines en tant qu'antagonistes de l'hepcidine

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