JP6544522B2 - Preventive and / or therapeutic agent for inflammatory diseases - Google Patents
Preventive and / or therapeutic agent for inflammatory diseases Download PDFInfo
- Publication number
- JP6544522B2 JP6544522B2 JP2015541587A JP2015541587A JP6544522B2 JP 6544522 B2 JP6544522 B2 JP 6544522B2 JP 2015541587 A JP2015541587 A JP 2015541587A JP 2015541587 A JP2015541587 A JP 2015541587A JP 6544522 B2 JP6544522 B2 JP 6544522B2
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- JP
- Japan
- Prior art keywords
- pyrrolo
- dimethyl
- benzyl
- oxy
- piperidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 pyridin-3-ylmethyl Chemical group 0.000 claims description 118
- 150000001875 compounds Chemical class 0.000 claims description 84
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 42
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
本発明は、炎症性疾患の予防及び/又は治療剤として有用なピロロピリミジン誘導体に関する。より詳細には、本発明は、BAFF(B cell activating factor belonging to TNF superfamily)とその受容体との結合を阻害する一連のピロロピリミジン誘導体の炎症性疾患、特に炎症性腸疾患及び血管炎等の予防及び/又は治療剤としての用途に関する。 The present invention relates to pyrrolopyrimidine derivatives useful as an agent for preventing and / or treating inflammatory diseases. More particularly, the present invention relates to inflammatory diseases of a series of pyrrolopyrimidine derivatives that inhibit the binding of BAFF (B cell activating factor belonging to TNF superfamily) to its receptor, in particular inflammatory bowel diseases and vasculitis etc. It relates to the use as a preventive and / or therapeutic agent.
B細胞の生存及び成熟因子として発見されたBAFF(非特許文献1、特許文献1)は、別名BLyS、TALL−1、THANK、zTNF4、TNFSF13B、又はKayリガンド(特許文献1参照)としても知られ、炎症性サイトカインであるTNF−αのスーパーファミリーのメンバーとして位置づけられている。BAFFのB細胞に対する主な作用として、アポトーシスに拮抗的に作用するBcl−2を誘導して、B細胞の生存延長や、免疫グロブリンであるIgM産生亢進などといったB細胞の活性化を誘導して自己抗体の過剰産生を亢進することが報告されている(非特許文献2)。 BAFF discovered as a survival and maturation factor for B cells (Non-patent Document 1, Patent Document 1) is also known as BLyS, TALL-1, THANK, zTNF4, TNFSF13B or Kay ligand (see Patent Document 1). It is positioned as a member of the inflammatory cytokine TNF-α superfamily. As the main action of BAFF on B cells, it induces Bcl-2 that acts in an antagonistic manner on apoptosis to induce B cell activation such as prolongation of B cell survival or enhancement of immunoglobulin IgM production. It has been reported that the overproduction of autoantibodies is enhanced (Non-patent Document 2).
BAFFの受容体としてはBCMA(B Cell Maturation Antigen、別名TNFRSF17、非特許文献3)、TACI(Transmembrane Activator and CAML-Interactor、別名TNFRSF13B、非特許文献4)、及びBR3(別名TNFSFR13C、BAFF Receptor、BAFF−Rと省略されることもある。非特許文献5)の3種類の膜貫通型タンパクが報告され、これら受容体はリガンドと同様にTNF受容体スーパーファミリーのメンバーである。 As receptors for BAFF, BCMA (B Cell Maturation Antigen, also known as TNFRSF17, non-patent document 3), TACI (Transmembrane Activator and CAML-Interactor, also known as TNFRSF13B, non-patent document 4), and BR3 (also called TNFSFR13C, BAFF Receptor, BAFF) Three types of transmembrane proteins reported in Non-patent Document 5) have been reported, and these receptors as well as ligands are members of the TNF receptor superfamily.
本発明者らは、BAFFとBAFF受容体との結合作用を阻害する一連のピロロピリミジン誘導体を見出しており、それらの化合物が、自己免疫疾患(関節リウマチ、全身性エリテマトーデス、シェーグレン症候群、全身性強皮症、多発性硬化症、分類不能型免疫不全症等)、後天性免疫不全症候群及び非ホジキンリンパ腫(前駆B細胞リンパ芽球性リンパ腫、慢性Bリンパ球性白血病、前駆細胞性白血病、小リンパ球性リンパ腫、リンパ形質細胞性リンパ腫、免疫細胞腫、マントル細胞リンパ腫、濾胞性リンパ腫、辺縁リンパ腫、ヘアリー細胞白血病、形質細胞腫、形質細胞性骨髄腫、びまん性大細胞型リンパ腫、バーキットリンパ腫等)の予防及び/又は治療剤として有用であることを報告している(特許文献2)。 The present inventors have found a series of pyrrolopyrimidine derivatives that inhibit the binding activity of BAFF and the BAFF receptor, and these compounds have been found to be autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic strong) Skin cancer, multiple sclerosis, incurable immunodeficiency etc.), acquired immunodeficiency syndrome and non-Hodgkin's lymphoma (precursor B cell lymphoblastic lymphoma, chronic B lymphocytic leukemia, precursor cell leukemia, small lymphatic Bulbous lymphoma, lymph plasma cell lymphoma, immunocytoma, mantle cell lymphoma, follicular lymphoma, marginal lymphoma, hairy cell leukemia, plasmacytoma, plasma cell myeloma, diffuse large cell lymphoma, Burkitt's lymphoma And the like) has been reported to be useful as a preventive and / or therapeutic agent for
しかしながら、BAFFとBAFF受容体との結合を阻害する化合物が、炎症性疾患、特に炎症性腸疾患及び血管炎等の炎症性疾患の予防及び/又は治療に有用であることは何ら報告されていない。 However, no compounds that inhibit the binding of BAFF to the BAFF receptor have been reported to be useful for the prevention and / or treatment of inflammatory diseases, particularly inflammatory diseases such as inflammatory bowel disease and vasculitis. .
本発明の目的は、炎症性疾患、特に炎症性腸疾患及び血管炎等の炎症性疾患の予防及び/又は治療剤として優れた化合物を提供することを目的とする。 An object of the present invention is to provide a compound excellent as an agent for preventing and / or treating inflammatory diseases, particularly inflammatory diseases such as inflammatory bowel disease and vasculitis.
本発明者らは、上記課題に鑑み、鋭意検討した結果、BAFFとその受容体との結合を阻害する作用を有する、後述の、一般式(1)で表される化合物(本明細書中、一般式(1)で表されるピロロピリミジン誘導体、あるいは本発明のピロロピリミジン誘導体と称する場合がある)が、ヒト末梢単球及びB細胞におけるBAFFの生物学的作用を抑制することを見出し、より病態に近いモデルでの薬剤効果を検証することに成功して本発明を完成するに至った。 In view of the above problems, the present inventors have intensively studied and as a result, a compound represented by General Formula (1) (described in the specification) which has an action to inhibit the binding of BAFF to its receptor. It has been found that a pyrrolopyrimidine derivative represented by the general formula (1) or sometimes referred to as a pyrrolopyrimidine derivative of the present invention suppresses the biological action of BAFF in human peripheral monocytes and B cells, We succeeded in verifying the drug effect in a model close to the pathological condition and completed the present invention.
即ち、本発明は、以下を提供する。
[1]一般式(1):That is, the present invention provides the following.
[1] General formula (1):
[式中、環Aは次式: [Wherein, ring A has the following formula:
から選択される基(ここで、Bは、−CH2−、−O−、又は−NH−を示し、R4は、(C1−6アルキル)アミノ基、(C3−6シクロアルキル)アミノ基、ピリジニル基、又は2−オキソピロリジニル基を示し、Lは、式−(CH2)p−、−CH2C(O)−、又は−C(O)CH2−を示し、nは、0〜2の整数を示し、oは、1〜3の自然数を示し、pは、0〜3の整数を示す。)を示し、
R1、R2は、互いに同一又は異なっていてもよく、水素原子、C1−6アルキル基を示し、
R3は、C3−6シクロアルキル基、ハロゲン原子で置換されていてもよいC6−10アリール基、(C6−10アリール)C1−6アルキル基を示し、
mは、0〜2の整数を示す。]
で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含有してなる炎症性疾患の予防及び/又は治療剤。
[2]一般式(1)で表される化合物が、
7−ベンジル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[4−{(7−ベンジル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)アゼパン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イルオキシ)メチル}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(4−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピロリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[3−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(2−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}アゼパン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
4−{2−(アゼパン−1−イル)エトキシ}−7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペラジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
4−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}エチル]モルホリン、
7−ベンジル−5,6−ジメチル−4−{2−(ピロリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−シクロプロピルアセトアミド、
N−シクロプロピル−2−(4−[{7−(4−フルオロフェニル)−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル}オキシ]ピペリジン−1−イル)アセトアミド、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソプロピルアセトアミド、
N−(sec−ブチル)−2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]アセトアミド、
1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、及び、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソブチルアセトアミド
からなる群から選択される少なくとも1つの化合物である、上記[1]記載の剤。
[3]一般式(1)で表される化合物が、7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン又は1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オンである、上記[1]記載の剤。
[4]一般式(1)で表される化合物が、ヒト末梢細胞に直接作用することを特徴とする、上記[1]〜[3]のいずれかに記載の剤。
[5]炎症性疾患が、炎症性腸疾患又は血管炎である、上記[1]〜[4]のいずれかに記載の剤。
[6]炎症性腸疾患がクローン病である、上記[5]記載の剤。
[7]血管炎が、高安大動脈炎又は巨細胞性動脈炎である、上記[5]記載の剤。
[8]一般式(1):A group selected from (wherein, B represents -CH 2- , -O-, or -NH-, and R 4 represents a (C 1-6 alkyl) amino group, (C 3-6 cycloalkyl) amino group, a pyridinyl group, or a 2-oxopyrrolidinyl group, L is the formula - (CH 2) p -, - CH 2 C (O) -, or -C (O) CH 2 - indicates, n is an integer of 0 to 2, o is a natural number of 1 to 3, and p is an integer of 0 to 3.
R 1 and R 2 may be the same as or different from each other, and represent a hydrogen atom or a C 1-6 alkyl group,
R 3 represents a C 3-6 cycloalkyl group, a C 6-10 aryl group optionally substituted with a halogen atom, a (C 6-10 aryl) C 1-6 alkyl group,
m shows the integer of 0-2. ]
An agent for the prophylaxis and / or treatment of an inflammatory disease, which comprises the compound represented by the formula: or a salt thereof, or a solvate thereof as an active ingredient.
[2] The compound represented by the general formula (1) is
7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) azepan-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (4-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- (2- [3-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- (2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} azepan-1-yl] -2-oxoethyl) pyrrolidine -2- on,
4- {2- (Azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperazin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
4- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} ethyl] morpholine,
7-benzyl-5,6-dimethyl-4- {2- (pyrrolidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-cyclopropylacetamide;
N-Cyclopropyl-2- (4-[{7- (4-fluorophenyl) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy] piperidin-1-yl ) Acetamide,
2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isopropylacetamide;
N- (sec-Butyl) -2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] acetamide ,
1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine -2- on, and
From the group consisting of 2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isobutylacetamide The agent according to the above [1], which is at least one compound selected.
[3] The compound represented by the general formula (1) is 7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine or 1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidine-1 The agent according to the above [1], which is -yl] -2-oxoethyl) pyrrolidin-2-one.
[4] The agent according to any one of the above [1] to [3], wherein the compound represented by the general formula (1) directly acts on human peripheral cells.
[5] The agent according to any one of the above [1] to [4], wherein the inflammatory disease is inflammatory bowel disease or vasculitis.
[6] The agent according to the above-mentioned [5], wherein the inflammatory bowel disease is Crohn's disease.
[7] The agent according to [5] above, wherein the vasculitis is Takayasu's aortitis or giant cell arteritis.
[8] General formula (1):
[式中、環Aは次式: [Wherein, ring A has the following formula:
から選択される基(ここで、Bは、−CH2−、−O−、又は−NH−を示し、R4は、(C1−6アルキル)アミノ基、(C3−6シクロアルキル)アミノ基、ピリジニル基、又は2−オキソピロリジニル基を示し、Lは、式−(CH2)p−、−CH2C(O)−、又は−C(O)CH2−を示し、nは、0〜2の整数を示し、oは、1〜3の自然数を示し、pは、0〜3の整数を示す。)を示し、
R1、R2は、互いに同一又は異なっていてもよく、水素原子、C1−6アルキル基を示し、
R3は、C3−6シクロアルキル基、ハロゲン原子で置換されていてもよいC6−10アリール基、(C6−10アリール)C1−6アルキル基を示し、
mは、0〜2の整数を示す。]
で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含有してなる、B細胞からの過剰なIgG産生により増悪する疾患の予防及び/又は治療剤。
[9]一般式(1)で表される化合物が、
7−ベンジル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[4−{(7−ベンジル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)アゼパン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イルオキシ)メチル}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(4−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピロリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[3−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(2−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}アゼパン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
4−{2−(アゼパン−1−イル)エトキシ}−7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペラジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
4−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}エチル]モルホリン、
7−ベンジル−5,6−ジメチル−4−{2−(ピロリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−シクロプロピルアセトアミド、
N−シクロプロピル−2−(4−[{7−(4−フルオロフェニル)−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル}オキシ]ピペリジン−1−イル)アセトアミド、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソプロピルアセトアミド、
N−(sec−ブチル)−2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]アセトアミド、
1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、及び、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソブチルアセトアミド
からなる群から選択される少なくとも1つの化合物である、上記[8]記載の剤。
[10]一般式(1)で表される化合物が、7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン又は1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オンである、上記[8]記載の剤。
[11]B細胞からの過剰なIgG産生がBAFFによるものである、上記[8]〜[10]のいずれかに記載の剤。
[12]該疾患が、炎症性腸疾患又は血管炎である、上記[8]〜[11]のいずれかに記載の剤。
[13]炎症性腸疾患がクローン病である、上記[12]記載の剤。
[14]血管炎が、高安大動脈炎又は巨細胞性動脈炎である、上記[12]記載の剤。A group selected from (wherein, B represents -CH 2- , -O-, or -NH-, and R 4 represents a (C 1-6 alkyl) amino group, (C 3-6 cycloalkyl) amino group, a pyridinyl group, or a 2-oxopyrrolidinyl group, L is the formula - (CH 2) p -, - CH 2 C (O) -, or -C (O) CH 2 - indicates, n is an integer of 0 to 2, o is a natural number of 1 to 3, and p is an integer of 0 to 3.
R 1 and R 2 may be the same as or different from each other, and represent a hydrogen atom or a C 1-6 alkyl group,
R 3 represents a C 3-6 cycloalkyl group, a C 6-10 aryl group optionally substituted with a halogen atom, a (C 6-10 aryl) C 1-6 alkyl group,
m shows the integer of 0-2. ]
An agent for the prophylaxis and / or treatment of a disease that is exacerbated by excessive IgG production from B cells, comprising the compound represented by the formula: or a salt thereof, or a solvate thereof as an active ingredient.
[9] The compound represented by the general formula (1) is
7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) azepan-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (4-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- (2- [3-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- (2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} azepan-1-yl] -2-oxoethyl) pyrrolidine -2- on,
4- {2- (Azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperazin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
4- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} ethyl] morpholine,
7-benzyl-5,6-dimethyl-4- {2- (pyrrolidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-cyclopropylacetamide;
N-Cyclopropyl-2- (4-[{7- (4-fluorophenyl) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy] piperidin-1-yl ) Acetamide,
2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isopropylacetamide;
N- (sec-Butyl) -2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] acetamide ,
1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine -2- on, and
From the group consisting of 2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isobutylacetamide The agent according to [8] above, which is at least one compound selected.
[10] The compound represented by the general formula (1) is 7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine or 1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidine-1 The agent according to the above [8], which is -yl] -2-oxoethyl) pyrrolidin-2-one.
[11] The agent according to any of the above-mentioned [8]-[10], wherein excessive IgG production from B cells is due to BAFF.
[12] The agent according to any one of the above [8] to [11], wherein the disease is inflammatory bowel disease or vasculitis.
[13] The agent of the above-mentioned [12], wherein the inflammatory bowel disease is Crohn's disease.
[14] The agent of the above-mentioned [12], wherein the vasculitis is Takayasu's aortitis or giant cell arteritis.
[15]一般式(1)で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、それを必要とする患者に投与することを含む、炎症性疾患の予防及び/又は治療方法。
[16]一般式(1)で表される化合物が、
7−ベンジル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[4−{(7−ベンジル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)アゼパン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イルオキシ)メチル}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(4−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピロリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[3−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(2−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}アゼパン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
4−{2−(アゼパン−1−イル)エトキシ}−7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペラジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
4−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}エチル]モルホリン、
7−ベンジル−5,6−ジメチル−4−{2−(ピロリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−シクロプロピルアセトアミド、
N−シクロプロピル−2−(4−[{7−(4−フルオロフェニル)−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル}オキシ]ピペリジン−1−イル)アセトアミド、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソプロピルアセトアミド、
N−(sec−ブチル)−2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]アセトアミド、
1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、及び、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソブチルアセトアミド
からなる群から選択される少なくとも1つの化合物である、上記[15]記載の方法。
[17]一般式(1)で表される化合物が、7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン又は1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オンである、上記[15]記載の方法。
[18]一般式(1)で表される化合物が、ヒト末梢細胞に直接作用することを特徴とする、上記[15]〜[17]のいずれかに記載の方法。
[19]炎症性疾患が、炎症性腸疾患又は血管炎である、上記[15]〜[18]のいずれかに記載の方法。
[20]炎症性腸疾患がクローン病である、上記[19]記載の方法。
[21]血管炎が、高安大動脈炎又は巨細胞性動脈炎である、上記[19]記載の方法。
[22]一般式(1)で表される化合物、若しくはその塩、又はそれらの溶媒和物の有効量を、それを必要とする患者に投与することを含む、B細胞からの過剰なIgG産生により増悪する疾患の予防及び/又は治療方法。
[23]一般式(1)で表される化合物が、
7−ベンジル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[4−{(7−ベンジル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)アゼパン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イルオキシ)メチル}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(4−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピロリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[3−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(2−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}アゼパン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
4−{2−(アゼパン−1−イル)エトキシ}−7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペラジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
4−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}エチル]モルホリン、
7−ベンジル−5,6−ジメチル−4−{2−(ピロリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−シクロプロピルアセトアミド、
N−シクロプロピル−2−(4−[{7−(4−フルオロフェニル)−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル}オキシ]ピペリジン−1−イル)アセトアミド、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソプロピルアセトアミド、
N−(sec−ブチル)−2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]アセトアミド、
1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、及び、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソブチルアセトアミド
からなる群から選択される少なくとも1つの化合物である、上記[22]記載の方法。
[24]一般式(1)で表される化合物が、7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン又は1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オンである、上記[22]記載の方法。
[25]B細胞からの過剰なIgG産生がBAFFによるものである、上記[22]〜[24]のいずれかに記載の方法。
[26]該疾患が、炎症性腸疾患又は血管炎である、上記[22]〜[25]のいずれかに記載の方法。
[27]炎症性腸疾患がクローン病である、上記[26]記載の方法。
[28]血管炎が、高安大動脈炎又は巨細胞性動脈炎である、上記[26]記載の方法。[15] Prevention of inflammatory diseases and / or comprising administering an effective amount of a compound represented by the general formula (1), or a salt thereof, or a solvate thereof to a patient in need thereof Method of treatment.
[16] The compound represented by the general formula (1) is
7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) azepan-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (4-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- (2- [3-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- (2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} azepan-1-yl] -2-oxoethyl) pyrrolidine -2- on,
4- {2- (Azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperazin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
4- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} ethyl] morpholine,
7-benzyl-5,6-dimethyl-4- {2- (pyrrolidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-cyclopropylacetamide;
N-Cyclopropyl-2- (4-[{7- (4-fluorophenyl) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy] piperidin-1-yl ) Acetamide,
2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isopropylacetamide;
N- (sec-Butyl) -2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] acetamide ,
1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine -2- on, and
From the group consisting of 2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isobutylacetamide The method according to the above [15], which is at least one compound selected.
[17] The compound represented by the general formula (1) is 7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine or 1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidine-1 The method according to the above [15], which is -yl] -2-oxoethyl) pyrrolidin-2-one.
[18] The method according to any one of the above [15] to [17], wherein the compound represented by the general formula (1) acts directly on human peripheral cells.
[19] The method according to any one of the above [15] to [18], wherein the inflammatory disease is inflammatory bowel disease or vasculitis.
[20] The method of the above-mentioned [19], wherein the inflammatory bowel disease is Crohn's disease.
[21] The method of the above-mentioned [19], wherein the angiitis is Takayasu's aortitis or giant cell arteritis.
[22] Excessive IgG production from B cells, which comprises administering an effective amount of the compound represented by the general formula (1), or a salt thereof, or a solvate thereof to a patient in need thereof A method of preventing and / or treating a disease which is exacerbated
[23] The compound represented by the general formula (1) is
7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) azepan-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (4-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- (2- [3-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- (2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} azepan-1-yl] -2-oxoethyl) pyrrolidine -2- on,
4- {2- (Azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperazin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
4- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} ethyl] morpholine,
7-benzyl-5,6-dimethyl-4- {2- (pyrrolidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-cyclopropylacetamide;
N-Cyclopropyl-2- (4-[{7- (4-fluorophenyl) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy] piperidin-1-yl ) Acetamide,
2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isopropylacetamide;
N- (sec-Butyl) -2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] acetamide ,
1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine -2- on, and
From the group consisting of 2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isobutylacetamide The method according to the above [22], which is at least one compound selected.
[24] The compound represented by the general formula (1) is 7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine or 1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidine-1 The method according to the above [22], which is -yl] -2-oxoethyl) pyrrolidin-2-one.
[25] The method according to any of the above-mentioned [22]-[24], wherein excessive IgG production from B cells is due to BAFF.
[26] The method according to any of the above-mentioned [22]-[25], wherein the disease is inflammatory bowel disease or vasculitis.
[27] The method of the above-mentioned [26], wherein the inflammatory bowel disease is Crohn's disease.
[28] The method according to the above-mentioned [26], wherein the angiitis is Takayasu's aortitis or giant cell arteritis.
[29]炎症性疾患の予防及び/又は治療の為の、一般式(1)で表される化合物、若しくはその塩、又はそれらの溶媒和物。
[30]一般式(1)で表される化合物が、
7−ベンジル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[4−{(7−ベンジル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)アゼパン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イルオキシ)メチル}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(4−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピロリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[3−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(2−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}アゼパン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
4−{2−(アゼパン−1−イル)エトキシ}−7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペラジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
4−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}エチル]モルホリン、
7−ベンジル−5,6−ジメチル−4−{2−(ピロリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−シクロプロピルアセトアミド、
N−シクロプロピル−2−(4−[{7−(4−フルオロフェニル)−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル}オキシ]ピペリジン−1−イル)アセトアミド、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソプロピルアセトアミド、
N−(sec−ブチル)−2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]アセトアミド、
1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、及び、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソブチルアセトアミド
からなる群から選択される少なくとも1つの化合物である、上記[29]記載の化合物、若しくはその塩、又はそれらの溶媒和物。
[31]一般式(1)で表される化合物が、7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン又は1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オンである、上記[29]記載の化合物、若しくはその塩、又はそれらの溶媒和物。
[32]一般式(1)で表される化合物が、ヒト末梢細胞に直接作用することを特徴とする、上記[29]〜[31]のいずれかに記載の化合物、若しくはその塩、又はそれらの溶媒和物。
[33]炎症性疾患が、炎症性腸疾患又は血管炎である、上記[29]〜[32]のいずれかに記載の化合物、若しくはその塩、又はそれらの溶媒和物。
[34]炎症性腸疾患がクローン病である、上記[33]記載の化合物、若しくはその塩、又はそれらの溶媒和物。
[35]血管炎が、高安大動脈炎又は巨細胞性動脈炎である、上記[33]記載の化合物、若しくはその塩、又はそれらの溶媒和物。
[36]B細胞からの過剰なIgG産生により増悪する疾患の予防及び/又は治療の為の、一般式(1)で表される化合物、若しくはその塩、又はそれらの溶媒和物。
[37]一般式(1)で表される化合物が、
7−ベンジル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[4−{(7−ベンジル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)アゼパン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イルオキシ)メチル}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(4−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピロリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[3−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(2−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}アゼパン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
4−{2−(アゼパン−1−イル)エトキシ}−7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペラジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
4−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}エチル]モルホリン、
7−ベンジル−5,6−ジメチル−4−{2−(ピロリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−シクロプロピルアセトアミド、
N−シクロプロピル−2−(4−[{7−(4−フルオロフェニル)−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル}オキシ]ピペリジン−1−イル)アセトアミド、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソプロピルアセトアミド、
N−(sec−ブチル)−2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]アセトアミド、
1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、及び、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソブチルアセトアミド
からなる群から選択される少なくとも1つの化合物である、上記[36]記載の化合物、若しくはその塩、又はそれらの溶媒和物。
[38]一般式(1)で表される化合物が、7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン又は1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オンである、上記[36]記載の化合物、若しくはその塩、又はそれらの溶媒和物。
[39]B細胞からの過剰なIgG産生がBAFFによるものである、上記[36]〜[38]のいずれかに記載の化合物、若しくはその塩、又はそれらの溶媒和物。
[40]該疾患が、炎症性腸疾患又は血管炎である、上記[36]〜[39]のいずれかに記載の化合物、若しくはその塩、又はそれらの溶媒和物。
[41]炎症性腸疾患がクローン病である、上記[40]記載の化合物、若しくはその塩、又はそれらの溶媒和物。
[42]血管炎が、高安大動脈炎又は巨細胞性動脈炎である、上記[40]記載の化合物、若しくはその塩、又はそれらの溶媒和物。[29] A compound represented by General Formula (1), or a salt thereof, or a solvate thereof for the prevention and / or treatment of an inflammatory disease.
[30] The compound represented by the general formula (1) is
7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) azepan-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (4-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- (2- [3-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- (2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} azepan-1-yl] -2-oxoethyl) pyrrolidine -2- on,
4- {2- (Azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperazin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
4- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} ethyl] morpholine,
7-benzyl-5,6-dimethyl-4- {2- (pyrrolidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-cyclopropylacetamide;
N-Cyclopropyl-2- (4-[{7- (4-fluorophenyl) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy] piperidin-1-yl ) Acetamide,
2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isopropylacetamide;
N- (sec-Butyl) -2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] acetamide ,
1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine -2- on, and
From the group consisting of 2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isobutylacetamide The compound according to the above [29], which is at least one compound to be selected, or a salt thereof, or a solvate thereof.
[31] The compound represented by the general formula (1) is 7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine or 1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidine-1 The compound according to the above [29], which is -yl] -2-oxoethyl) pyrrolidin-2-one, or a salt thereof, or a solvate thereof.
[32] The compound according to any one of the above [29] to [31], or a salt thereof, or a compound thereof, which is characterized in that the compound represented by the general formula (1) directly acts on human peripheral cells Solvates of
[33] The compound according to any one of the above [29] to [32], or a salt thereof, or a solvate thereof, wherein the inflammatory disease is inflammatory bowel disease or vasculitis.
[34] The compound of the above-mentioned [33], or a salt thereof, or a solvate thereof, wherein the inflammatory bowel disease is Crohn's disease.
[35] The compound of the above-mentioned [33], or a salt thereof, or a solvate thereof, wherein the vasculitis is Takayasu's aortitis or giant cell arteritis.
[36] A compound represented by General Formula (1), or a salt thereof, or a solvate thereof for the prevention and / or treatment of a disease exacerbated by excessive IgG production from B cells.
[37] The compound represented by the general formula (1) is
7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) azepan-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (4-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- (2- [3-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- (2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} azepan-1-yl] -2-oxoethyl) pyrrolidine -2- on,
4- {2- (Azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperazin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
4- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} ethyl] morpholine,
7-benzyl-5,6-dimethyl-4- {2- (pyrrolidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-cyclopropylacetamide;
N-Cyclopropyl-2- (4-[{7- (4-fluorophenyl) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy] piperidin-1-yl ) Acetamide,
2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isopropylacetamide;
N- (sec-Butyl) -2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] acetamide ,
1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine -2- on, and
From the group consisting of 2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isobutylacetamide The compound according to the above [36], which is at least one compound to be selected, or a salt thereof, or a solvate thereof.
[38] The compound represented by the general formula (1) is 7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine or 1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidine-1 The compound according to the above [36], which is -yl] -2-oxoethyl) pyrrolidin-2-one, or a salt thereof, or a solvate thereof.
[39] The compound according to any of the above [36] to [38], or a salt thereof, or a solvate thereof, wherein excess IgG production from B cells is due to BAFF.
[40] The compound according to any one of the above [36] to [39], or a salt thereof, or a solvate thereof, wherein the disease is inflammatory bowel disease or vasculitis.
[41] The compound of the above-mentioned [40], or a salt thereof, or a solvate thereof, wherein the inflammatory bowel disease is Crohn's disease.
[42] The compound of the above-mentioned [40], or a salt thereof, or a solvate thereof, wherein the vasculitis is Takayasu's aortitis or giant cell arteritis.
本発明のピロロピリミジン誘導体は、ヒト末梢細胞(B細胞、単球)におけるBAFFにより誘導される生物学的作用(IgG産生、IL−6産生)を抑制することができる。従って、炎症性疾患、特に炎症性腸疾患及び血管炎等の炎症性疾患の予防及び/又は治療剤を提供することができる。また、炎症性腸疾患及び血管炎等のB細胞からの過剰なIgG産生により増悪する疾患の予防及び/又は治療剤を提供することができる。 The pyrrolopyrimidine derivatives of the present invention can suppress the biological effects (IgG production, IL-6 production) induced by BAFF in human peripheral cells (B cells, monocytes). Therefore, it is possible to provide an agent for preventing and / or treating inflammatory diseases, in particular inflammatory diseases such as inflammatory bowel disease and vasculitis. In addition, a preventive and / or therapeutic agent for diseases exacerbated by excessive IgG production from B cells such as inflammatory bowel disease and vasculitis can be provided.
以下、本発明を説明する。本明細書において使用される用語は、特に言及しない限り、当該分野で通常用いられる意味を有する。 Hereinafter, the present invention will be described. The terms used herein have meanings commonly used in the art unless otherwise stated.
本明細書中で使用するとき、「炎症性疾患」とは、炎症を伴う疾患または状態であり、感染性胃腸炎、クローン病、潰瘍性大腸炎等の炎症性腸疾患、高安大動脈炎、巨細胞性動脈炎(側頭動脈炎)等の血管炎が例示される。本明細書中、好ましくは、炎症性疾患は、クローン病、高安大動脈炎及び巨細胞性動脈炎(側頭動脈炎)である。 As used herein, "inflammatory disease" is a disease or condition associated with inflammation, and inflammatory bowel disease such as infectious gastroenteritis, Crohn's disease, ulcerative colitis, Takayasu's aortitis, giant Vasculitis such as cellular arteritis (temporal arteritis) is exemplified. In the present specification, preferably, the inflammatory diseases are Crohn's disease, Takayasu's aortitis and giant cell arteritis (temporal arteritis).
本明細書中で使用するとき、「B細胞からの過剰なIgG産生」とは、生体における正常範囲内のIgG産生を超えて生体に疾患や病的症状を与える程度にIgG産生が増加したような場合をいう。 As used herein, "excessive IgG production from B cells" refers to increased IgG production to the extent that the disease or pathological condition is given to the living body beyond IgG production within the normal range in the living body. It means the case.
本明細書中で使用するとき、「C1−6アルキル基」とは、炭素数1〜6の直鎖状又は分枝状の炭化水素基、好ましくは飽和鎖状炭化水素基を意味する。「C1−6アルキル基」としては、特に限定されないが、例えば、メチル基、エチル基、n−プロピル基、イソプロピル基、n−ブチル基、イソブチル基、sec−ブチル基、tert−ブチル基、n−ペンチル基、イソペンチル基、ネオペンチル基、n−ヘキシル基、イソヘキシル基等が挙げられる。なお、本明細書中、「(C1−6アルキル)アミノ基」及び「(C6−10アリール)C1−6アルキル基」でも「C1−6アルキル」なる定義が使用されているが、これらも上記「C1−6アルキル」と同義である。As used herein, “C 1-6 alkyl group” means a linear or branched hydrocarbon group having 1 to 6 carbon atoms, preferably a saturated linear hydrocarbon group. The “C 1-6 alkyl group” is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group An n-pentyl group, an isopentyl group, a neopentyl group, an n-hexyl group, an isohexyl group and the like can be mentioned. In the present specification, the definition “C 1-6 alkyl” is also used in “(C 1-6 alkyl) amino group” and “(C 6-10 aryl) C 1-6 alkyl group” These are also the same as the above "C 1-6 alkyl".
本明細書中で使用するとき、「(C1−6アルキル)アミノ基」としては、前記したC1−6アルキル基でモノ又はジ置換されたアミノ基が挙げられる。例えば、メチルアミノ基、エチルアミノ基、n−プロピルアミノ基、イソプロピルアミノ基、n−ブチルアミノ基、イソブチルアミノ基、sec−ブチルアミノ基、tert−ブチルアミノ基、n−ペンチルアミノ基、イソペンチルアミノ基、ネオペンチルアミノ基、n−ヘキシルアミノ基、イソヘキシルアミノ基等の炭素数1〜6個の直鎖又は分枝状のアルキルアミノ基が挙げられる。As used herein, “(C 1-6 alkyl) amino group” includes amino groups mono- or di-substituted with the aforementioned C 1-6 alkyl group. For example, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, n-pentylamino group, isopentyl C1-C6 linear or branched alkylamino groups, such as an amino group, neopentyl amino group, n-hexyl amino group, isohexyl amino group, etc. are mentioned.
本明細書中で使用するとき、「C3−6シクロアルキル」は、炭素数3〜6の飽和の環状炭化水素基を示す。「C3−6シクロアルキル」としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等が挙げられる。As used herein, " C3-6 cycloalkyl" refers to a saturated cyclic hydrocarbon group of 3 to 6 carbon atoms. As the " C3-6 cycloalkyl", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like can be mentioned.
なお、本明細書中、「(C3−6シクロアルキル)アミノ基」としては、前記した「C3−6シクロアルキル」で置換されたアミノ基が挙げられる。「(C3−6シクロアルキル)アミノ基」としては、例えば、シクロプロピルアミノ基、シクロブチルアミノ基、シクロペンチルアミノ基、シクロヘキシルアミノ基等の炭素数3〜6の(シクロアルキル)アミノ基が挙げられる。In addition, as a "( C3-6 cycloalkyl) amino group" in this specification, the amino group substituted by above-mentioned " C3-6 cycloalkyl" is mentioned. Examples of the “(C 3-6 cycloalkyl) amino group” include (cycloalkyl) amino groups having 3 to 6 carbon atoms such as cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group and the like. Be
本明細書中で使用するとき、「C6−10アリール基」は、炭素数6〜10の芳香族炭化水素基を示す。「C6−10アリール基」としては、例えば、フェニル基、ナフチル基、アズレニル基等が挙げられる。なお、本明細書中、「ハロゲン原子で置換されていてもよいC6−10アリール基」及び「(C6−10アリール)C1−6アルキル基」でも「C6−10アリール」なる定義が使用されているが、これらの定義中の「C6−10アリール」も前記したものと同義である。また、「ハロゲン原子」としては、例えば、フッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられる。As used herein, “C 6-10 aryl group” represents an aromatic hydrocarbon group having 6 to 10 carbon atoms. As a " C6-10 aryl group", a phenyl group, a naphthyl group, an azulenyl group etc. are mentioned, for example. In this specification, it becomes "optionally substituted by a halogen atom C 6-10 aryl group" and "(C 6-10 aryl) C 1-6 alkyl group" nor "C 6-10 aryl" Definition Is used, but " C.sub.6-10 aryl" in these definitions is also as defined above. Moreover, as a "halogen atom", a fluorine atom, a chlorine atom, a bromine atom, an iodine atom etc. are mentioned, for example.
本明細書中で使用するとき、「(C6−10アリール)C1−6アルキル基」としては、1個以上の前記した「C6−10アリール基」で置換されたC1−6アルキル基が挙げられる。「(C6−10アリール)C1−6アルキル基」としては、例えば、ベンジル基、フェネチル基、フェニルプロピル基、フェニルブチル基、フェニルペンチル基、フェニルへキシル基、ナフチルメチル基、ナフチルエチル基、ナフチルプロピル基、ナフチルブチル基、アズレニルメチル基、アズレニルエチル基、アズレニルプロピル基、アズレニルブチル基等が挙げられる。As used herein, “(C 6-10 aryl) C 1-6 alkyl group” is a C 1-6 alkyl substituted with one or more of the aforementioned “C 6-10 aryl group” Groups are mentioned. Examples of “(C 6-10 aryl) C 1-6 alkyl group” include benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group, phenylhexyl group, naphthylmethyl group, naphthylethyl group And naphthylpropyl, naphthylbutyl, azulenylmethyl, azulenylethyl, azulenylpropyl, azulenylbutyl and the like.
「ハロゲン原子で置換されていてもよいC6−10アリール基」としては、1個以上のハロゲン原子で置換されたC6−10アリール基が挙げられる。1個以上のハロゲン原子で置換されたC6−10アリール基としては、例えば、ハロゲン置換フェニル基、ハロゲン置換ナフチル基、ハロゲン置換アズレニル基等が挙げられ、より好ましくは、4位がハロゲン原子で置換されたフェニル基等が挙げられる。Examples of the "C 6-10 aryl group optionally substituted by halogen atom" include a C 6-10 aryl group substituted by one or more halogen atoms. The C 6-10 aryl group substituted by one or more halogen atoms includes, for example, a halogen-substituted phenyl group, a halogen-substituted naphthyl group, a halogen-substituted azulenyl group and the like, and more preferably, the 4-position is a halogen atom And substituted phenyl groups and the like.
一般式(1)中、R1、R2における「C1−6アルキル基」としては、C1−4アルキル基が好ましく、メチル基がより好ましい。As a "C1-6 alkyl group" in R < 1 > , R < 2 > in General formula (1), a C1-4 alkyl group is preferable and a methyl group is more preferable.
一般式(1)中、R3における「C3−6シクロアルキル基」としては、C5−6シクロアルキル基が好ましく、シクロペンチル基がより好ましい。As a " C3-6 cycloalkyl group" in R 3 in General formula (1), a C5-6 cycloalkyl group is preferable and a cyclopentyl group is more preferable.
一般式(1)中、R3における「ハロゲン原子で置換してもよいC6−10アリール基」としては、フェニル基、4−フルオロフェニル基が好ましい。In the general formula (1), as the “C 6-10 aryl group which may be substituted by a halogen atom” in R 3 , a phenyl group and a 4-fluorophenyl group are preferable.
一般式(1)中、R3における「(C6−10アリール)C1−6アルキル基」としては、フェニル置換C1−6アルキル基が好ましく、ベンジル基がより好ましい。In the general formula (1), the "(C 6-10 aryl) C 1-6 alkyl group" of R 3, preferably a phenyl substituted C 1-6 alkyl group, a benzyl group is more preferable.
一般式(1)中、R4における「(C1−6アルキル)アミノ基」としては、(C1−4アルキル)アミノ基が好ましく、イソプロピルアミノ基、イソブチルアミノ基、sec−ブチルアミノ基がより好ましい。In the general formula (1), as the “(C 1-6 alkyl) amino group” in R 4 , a (C 1-4 alkyl) amino group is preferable, and an isopropylamino group, an isobutylamino group and a sec-butylamino group are preferable. More preferable.
一般式(1)中、R4における「(C3−6シクロアルキル)アミノ基」としては、(C3−4シクロアルキル)アミノ基が好ましく、シクロプロピルアミノ基がより好ましい。As "( C3-6 cycloalkyl) amino group" in R 4 in General formula (1), ( C3-4 cycloalkyl) amino group is preferable and a cyclopropyl amino group is more preferable.
本発明の好ましい一般式(1)で表されるピロロピリミジン誘導体の具体例として、下記化合物を挙げることができる。
7−ベンジル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン;
1−(2−[4−{(7−ベンジル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン;
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン;
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン;
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン;
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン);
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン;
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン;
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)アゼパン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン;
1−(2−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イルオキシ)メチル}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン;The following compounds can be mentioned as specific examples of the pyrrolopyrimidine derivative represented by the preferred general formula (1) of the present invention.
7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine;
1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine);
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) azepan-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine;
1- (2- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on;
1−{2−(4−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン;
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン;
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピロリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン;
1−(2−[3−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン;
1−{2−(2−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン;
1−(2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}アゼパン−1−イル]−2−オキソエチル)ピロリジン−2−オン;
4−{2−(アゼパン−1−イル)エトキシ}−7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン;
7−ベンジル−5,6−ジメチル−4−{2−(ピペリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン;
7−ベンジル−5,6−ジメチル−4−{2−(ピペラジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン;
4−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}エチル]モルホリン;1- {2- (4-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one;
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one;
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one;
1- (2- [3-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on;
1- {2- (2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one;
1- (2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} azepan-1-yl] -2-oxoethyl) pyrrolidine -2- on;
4- {2- (Azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine;
7-benzyl-5,6-dimethyl-4- {2- (piperidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine;
7-benzyl-5,6-dimethyl-4- {2- (piperazin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine;
4- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} ethyl] morpholine;
7−ベンジル−5,6−ジメチル−4−{2−(ピロリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン;
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン;
2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−シクロプロピルアセトアミド;
N−シクロプロピル−2−(4−[{7−(4−フルオロフェニル)−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル}オキシ]ピペリジン−1−イル)アセトアミド;
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソプロピルアセトアミド;
N−(sec−ブチル)−2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]アセトアミド;
1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン;及び、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソブチルアセトアミド。7-benzyl-5,6-dimethyl-4- {2- (pyrrolidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine;
2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-cyclopropylacetamide;
N-Cyclopropyl-2- (4-[{7- (4-fluorophenyl) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy] piperidin-1-yl ) Acetamide;
2- [4-{(7-Cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isopropylacetamide;
N- (sec-Butyl) -2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] acetamide ;
1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine -2- on; and
2- [4-{(7-Cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isobutylacetamide.
本発明の一般式(1)で表されるピロロピリミジン誘導体、若しくはその塩、又はそれらの溶媒和物としては、本発明のピロロピリミジン誘導体のみならず、その医薬として許容される塩、それらの各種の水和物や溶媒和物、及び結晶多形を有する物質、及びこれらの物質のプロドラッグとなる物質を包含している。また、不斉炭素原子を有する場合には、ラセミ体のみならず、光学活性体も包含される。 As the pyrrolopyrimidine derivative represented by the general formula (1) of the present invention, or a salt thereof, or a solvate thereof, not only the pyrrolopyrimidine derivative of the present invention but also pharmaceutically acceptable salts thereof, various compounds thereof These substances include substances having hydrates and solvates, and crystal polymorphs, and substances which become prodrugs of these substances. Moreover, when it has an asymmetric carbon atom, not only a racemate but also an optically active substance is included.
本発明の一般式(1)で表されるピロロピリミジン誘導体として許容される塩としては、具体的には、化合物を塩基性化合物として扱う場合は、無機酸(例えば、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等)や有機酸(例えば、メタンスルホン酸、エタンスルホン酸、p−トルエンスルホン酸等)との酸付加塩等が挙げられる。一方、化合物を酸性化合物として扱う場合には、無機塩(例えば、ナトリウム塩、カリウム塩、リチウム塩、バリウム塩、カルシウム塩、マグネシウム塩等)等が挙げられる。 Specifically, as a salt acceptable as the pyrrolopyrimidine derivative represented by the general formula (1) of the present invention, when the compound is treated as a basic compound, an inorganic acid (eg, hydrochloric acid, hydrobromic acid, Hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and acid addition salts with organic acids (eg, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.) can be mentioned. On the other hand, when the compound is treated as an acidic compound, inorganic salts (eg, sodium salt, potassium salt, lithium salt, barium salt, calcium salt, magnesium salt etc.) and the like can be mentioned.
本発明の一般式(1)で表されるピロロピリミジン誘導体やその医薬として許容される塩の溶媒和物としては、水和物や各種の溶媒和物(例えば、エタノールなどのアルコールとの溶媒和物)が挙げられる。 As a solvate of the pyrrolo pyrimidine derivative represented by General formula (1) of this invention, or its pharmaceutically acceptable salt, a hydrate and various solvates (For example, solvation with alcohol, such as ethanol, etc.) Thing) is mentioned.
本発明の一般式(1)で表されるピロロピリミジン誘導体として好ましいのは、7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン又は1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オンである。 Preferred as the pyrrolopyrimidine derivative represented by the general formula (1) of the present invention is 7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy ] -7H-pyrrolo [2,3-d] pyrimidine or 1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) Oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one.
本発明の一般式(1)で表されるピロロピリミジン誘導体は、特開2012−116777号公報に記載の公知の方法を参考にして製造することができる。 The pyrrolopyrimidine derivative represented by the general formula (1) of the present invention can be produced with reference to a known method described in JP-A-2012-116777.
本発明の炎症性疾患の予防及び/又は治療剤は、一般式(1)で表されるピロロピリミジン誘導体、その塩、又はそれらの溶媒和物(以下、便宜上、本発明の化合物と称する場合がある)であって、医薬組成物として使用することができる。その場合、本発明の化合物を単独で用いてもよいが、通常は医薬として許容される担体、及び/又は希釈剤を配合して使用される。 The preventive and / or therapeutic agent for an inflammatory disease of the present invention is a pyrrolopyrimidine derivative represented by the general formula (1), a salt thereof, or a solvate thereof (hereinafter referred to as the compound of the present invention for convenience. And can be used as a pharmaceutical composition. In that case, the compound of the present invention may be used alone, but it is usually used in combination with a pharmaceutically acceptable carrier and / or diluent.
投与経路は、特に限定されないが、治療目的に応じて適宜選択することができる。例えば、経口剤、注射剤、坐剤、吸入剤等のいずれでもよい。これらの投与形態に適した医薬組成物は、公知の製剤方法を利用することによって製造できる。 The administration route is not particularly limited, but can be appropriately selected according to the therapeutic purpose. For example, oral agents, injections, suppositories, inhalants and the like may be used. Pharmaceutical compositions suitable for these dosage forms can be prepared by utilizing known formulation methods.
経口用固形製剤を調製する場合は、一般式(1)で表されるピロロピリミジン誘導体に医薬として許容される賦形剤、更に必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味剤、矯臭剤等を加えた後、常法を利用して、錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤等を製造することができる。添加剤は、当該分野で一般的に使用されているものでよい。例えば、賦形剤としては、乳糖、白糖、塩化ナトリウム、ブドウ糖、デンプン、炭酸カルシウム、カオリン、微結晶セルロース、珪酸等が挙げられる。結合剤としては、水、エタノール、プロパノール、単シロップ、ブドウ糖液、デンプン液、ゼラチン液、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルスターチ、メチルセルロース、エチルセルロース、シェラック、リン酸カルシウム、ポリビニルピロリドン等が挙げられる。崩壊剤としては、乾燥デンプン、アルギン酸ナトリウム、カンテン末、炭酸水素ナトリウム、炭酸カルシウム、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、乳糖等が挙げられる。滑沢剤としては、精製タルク、ステアリン酸塩、ホウ砂、ポリエチレングリコール等が挙げられる。矯味剤としては、白糖、橙皮、クエン酸、酒石酸等が挙げられる。 When preparing a solid preparation for oral use, a pyrrolopyrimidine derivative represented by the general formula (1), a pharmaceutically acceptable excipient, and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, After adding a flavoring agent, a flavoring agent and the like, tablets, coated tablets, granules, powders, capsules and the like can be produced using a conventional method. The additives may be those commonly used in the art. For example, as the excipient, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like can be mentioned. As the binder, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like can be mentioned. Disintegrants include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose and the like. The lubricant includes purified talc, stearate, borax, polyethylene glycol and the like. Examples of the flavoring agent include sucrose, orange peel, citric acid and tartaric acid.
経口用液体製剤を調製する場合は、一般式(1)で表されるピロロピリミジン誘導体に、矯味剤、緩衝剤、安定化剤、矯臭剤等を加えて常法を利用して、内服液剤、シロップ剤、エリキシル剤等を製造することができる。矯味剤としては上記に挙げられたものでよく、緩衝剤としてはクエン酸ナトリウム等が挙げられ、安定化剤としてはトラガント、アラビアゴム、ゼラチン等が挙げられる。 When preparing a liquid preparation for oral use, an internal preparation, pyrrolopyrimidine derivative represented by the general formula (1), a flavoring agent, a buffer, a stabilizer, a flavoring agent, etc., and using a conventional method, Syrups, elixirs and the like can be produced. As the flavoring agent, those mentioned above may be mentioned, as the buffer, sodium citrate and the like can be mentioned, and as the stabilizer, tragacanth, gum arabic, gelatin and the like can be mentioned.
注射剤を調製する場合は、一般式(1)で表されるピロロピリミジン誘導体に、pH調節剤、緩衝剤、安定化剤、等張化剤、局所麻酔剤等を添加し、常法を利用して、皮下、筋肉及び静脈内注射剤を製造することができる。pH調製剤及び緩衝剤としては、クエン酸ナトリウム、酢酸ナトリウム、リン酸ナトリウム等が挙げられる。安定化剤としては、ピロ亜硫酸ナトリウム、EDTA(エデト酸ナトリウム)、チオグリコール酸、チオ乳酸等が挙げられる。局所麻酔剤としては、塩酸プロカイン、塩酸リドカイン等が挙げられる。等張化剤としては、塩化ナトリウム、ブドウ糖等が挙げられる。 When preparing an injection, a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic and the like are added to the pyrrolopyrimidine derivative represented by the general formula (1), and a conventional method is used. Thus, subcutaneous, muscle and intravenous injections can be produced. Examples of pH adjusters and buffers include sodium citrate, sodium acetate, sodium phosphate and the like. As the stabilizing agent, sodium pyrosulfite, EDTA (sodium edetate), thioglycolic acid, thiolactic acid and the like can be mentioned. The local anesthetic includes procaine hydrochloride, lidocaine hydrochloride and the like. Examples of tonicity agents include sodium chloride and glucose.
坐剤を調製する場合は、一般式(1)で表されるピロロピリミジン誘導体に公知の坐剤用担体、例えば、ポリエチレングリコール、ラノリン、カカオ脂、脂肪酸トリグリセライド等、更に必要に応じて界面活性剤(例えば、ツイーン(登録商標))等を加えた後、常法を利用して製造することができる。 When preparing a suppository, carriers for suppositories known to pyrrolopyrimidine derivatives represented by the general formula (1), such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like, and, if necessary, a surfactant After adding (for example, Tween (registered trademark)) etc., it can manufacture using a conventional method.
上記以外に、常法を利用して適宜好ましい製剤とすることもできる。 In addition to the above, it is also possible to appropriately make a preferable formulation by using a conventional method.
本発明のピロロピリミジン誘導体は、実施例にてデータで示されるように、ヒト末梢細胞(B細胞、単球)におけるBAFFにより誘導される生物学的作用(IgG産生、IL−6産生)を抑制する作用を有する。かかる薬理作用は、本発明のピロロピリミジン誘導体が、炎症性疾患、特に炎症性腸疾患及び血管炎等の炎症性疾患の予防及び/又は治療剤として、あるいは炎症性腸疾患及び血管炎等のB細胞からの過剰なIgG産生により増悪する疾患の予防及び/又は治療剤として有用であること意味する。また、炎症性疾患の予防・治療薬の開発に有用なツールとなり得る研究用試薬としても有用であることを示唆している。
また、本発明のピロロピリミジン誘導体のかかる薬理作用により、本発明は炎症性疾患の予防及び/又は治療方法、並びにB細胞からの過剰なIgG産生により増悪する疾患の予防及び/又は治療方法を提供することができる。The pyrrolopyrimidine derivative of the present invention suppresses the biological effects (IgG production, IL-6 production) induced by BAFF in human peripheral cells (B cells, monocytes) as shown by the data in the examples. Have an action to The pharmacological action of the pyrrolopyrimidine derivative of the present invention is an agent for preventing and / or treating inflammatory diseases, particularly inflammatory diseases such as inflammatory bowel disease and vasculitis, or B such as inflammatory bowel disease and vasculitis. It is meant to be useful as a preventive and / or therapeutic agent for diseases exacerbated by excessive IgG production from cells. It also suggests that it is useful as a research reagent that can be a useful tool for the development of a preventive / therapeutic drug for inflammatory diseases.
Also, by such pharmacological action of the pyrrolopyrimidine derivative of the present invention, the present invention provides a method for preventing and / or treating inflammatory diseases, and a method for preventing and / or treating diseases exacerbated by excessive IgG production from B cells. can do.
本明細書中で用いられる場合、被験体(対象)は哺乳動物であり得る。このような哺乳動物としては、例えば、霊長類(例、ヒト、サル、チンパンジー)、げっ歯類(例、マウス、ラット、モルモット)、ペット(例、イヌ、ネコ、ウサギ)、使役動物又は家畜(例、ウシ、ウマ、ブタ、ヒツジ、ヤギ)が挙げられるが、ヒトが好ましい。 As used herein, a subject can be a mammal. Such mammals include, for example, primates (eg, humans, monkeys, chimpanzees), rodents (eg, mice, rats, guinea pigs), pets (eg, dogs, cats, rabbits), working animals or livestock (Eg, cows, horses, pigs, sheep, goats) but humans are preferred.
本発明の一般式(1)で表されるピロロピリミジン誘導体の投与量は年齢、体重、症状、投与形態及び投与回数等によって異なるが、通常は成人に対して一般式(1)で表される化合物として1日あたり0.1mgから1000mg、好ましくは1mgから1000mg、より好ましくは1mgから500mgを、1回又は数回に分けて経口投与又は非経口投与するのが好ましい。 Although the dose of the pyrrolopyrimidine derivative represented by the general formula (1) of the present invention varies depending on the age, body weight, symptoms, administration form and administration frequency, etc., it is usually represented by the general formula (1) for adults. It is preferable to orally or parenterally administer 0.1 mg to 1000 mg, preferably 1 mg to 1000 mg, more preferably 1 mg to 500 mg of the compound as a compound once or several times.
以下に実施例を用いて本発明を詳述するが、本発明は以下の実施例に何ら限定されるものではない。また、使用する試薬及び材料は特に限定されない限り商業的に入手可能である。 EXAMPLES The present invention will be described in detail by way of examples, but the present invention is not limited to the following examples. Also, reagents and materials to be used are commercially available unless otherwise specified.
本実施例では有効成分である一般式(1)で表されるピロロピリミジン誘導体として化合物A及び化合物Bを用いた。
化合物A:特開2012-116777(特許文献1)の実施例22に記載の方法で製造した。In this example, Compound A and Compound B were used as pyrrolopyrimidine derivatives represented by General Formula (1), which are active ingredients.
Compound A: Prepared by the method described in Example 22 of JP-A-2012-116777 (Patent Document 1).
化合物B:特開2012-116777(特許文献1)の実施例27に記載の方法で製造した。 Compound B: Prepared by the method described in Example 27 of JP-A-2012-116777 (Patent Document 1).
実施例1:ヒト末梢単球からのBAFF誘導IL−6産生亢進に及ぼす効果
ヒト末梢血よりロゼットセップ法(Yoshimoto K., et al. Arthritis Res Ther. 2011;13(5):R170. doi: 10.1186/ar3493)を用いて単球を単離した。
単離した単球を、10%胎児ウシ血清(JRH Biosciences社製)を含むRPMI-1640培地(ATCC製)中、24穴プレート(コーニング社製)1ウェルあたり2.5×105 cells/mlの濃度で播種して4日間培養した。培養開始時に、終濃度2μg/mlの組換えヒト可溶性BAFF(rBAFF:Chemicon社製)を当該培地に加え、化合物Aを6μM、30μM、または化合物Bを6μM、30μMとなるようにそれぞれ添加した。また、対照として、rBAFF及び化合物のいずれも添加していないもの、及びrBAFFのみ添加したもの、を同様に培養した。培養後、培養上清を回収し、上清中のIL−6量を特異的ELISA法にて定量した。ELISA法にはマウス抗ヒトIL−6抗体(BD Pharmingen社製)、ビオチン標識マウス抗ヒトIL−6抗体(BD Pharmingen社製)及びHRP標識ストレプトアビジン(BD Pharmingen社製)を用いた。ELISA発色用試薬としてTMB One Solution(Promega社製)を用いた。
結果を図1に示す。図1に示されるように、BAFFに誘導された、単球からのIL−6産生の亢進は、化合物A及び化合物Bの添加により抑制された。 Example 1: Effect on BAFF-induced enhancement of IL-6 production from human peripheral monocytes The rosette sep method from human peripheral blood (Yoshimoto K., et al. Arthritis Res Ther. 2011; 13 (5): R170. Doi: Monocytes were isolated using 10.1186 / ar3493).
The isolated monocytes were 2.5 × 10 5 cells / ml per well in a 24-well plate (manufactured by Corning) in RPMI-1640 medium (manufactured by ATCC) containing 10% fetal bovine serum (manufactured by JRH Biosciences). And the cells were cultured for 4 days. At the start of culture, recombinant human soluble BAFF (rBAFF: Chemicon) at a final concentration of 2 μg / ml was added to the medium, and Compound A was added to 6 μM, 30 μM, or Compound B to 6 μM or 30 μM, respectively. In addition, as controls, those to which neither rBAFF nor compound was added, and those to which only rBAFF was added were similarly cultured. After culture, the culture supernatant was recovered, and the amount of IL-6 in the supernatant was quantified by a specific ELISA method. For the ELISA method, mouse anti-human IL-6 antibody (manufactured by BD Pharmingen), biotin-labeled mouse anti-human IL-6 antibody (manufactured by BD Pharmingen), and HRP-labeled streptavidin (manufactured by BD Pharmingen) were used. TMB One Solution (manufactured by Promega) was used as a reagent for ELISA color development.
The results are shown in FIG. As shown in FIG. 1, the BAFF-induced enhancement of IL-6 production from monocytes was suppressed by the addition of Compound A and Compound B.
実施例2:ヒト末梢B細胞からのBAFF誘導IgG産生亢進に及ぼす効果−1
抗CD19抗体標識マイクロビーズと反応させたヒト末梢血から自動細胞分離装置autoMACS(ミルティニー社製)を用いて末梢B細胞を単離した。単離したB細胞を10%胎児ウシ血清(JRH Biosciences社製)を含むRPMI-1640培地(ATCC製)中、24穴プレート(コーニング社製)1ウェルあたり2.5×105 cells/mlの濃度で播種した。B細胞刺激条件下、終濃度2μg/mlの組換えヒト可溶性BAFF(rBAFF:Chemicon社製)を当該培地に加え、化合物Aを8μM、15μMとなるようにそれぞれ添加した。B細胞刺激は、抗IgM抗体(10μg/ml;AbD serotec社)、CD40-ligand(20ng/ml;Peprotech社)、rIL−4(100ng/ml;BD Bioscience社)存在下で細胞を培養することによって行なった。
培養後、培養上清を回収し、上清中のIgG量を特異的ELISA法にて定量した。ELISA法にはマウス抗ヒトIgG抗体(BD Pharmingen社製)、ビオチン標識マウス抗ヒトIgG抗体(BD Pharmingen社製)及びHRP標識ストレプトアビジン(BD Pharmingen社製)を用いた。ELISA発色用試薬としてTMB One Solution(Promega社製)を用いた。
対照として、B細胞刺激、rBAFF添加及び化合物添加のいずれも行なわずに培養したもの、B細胞刺激及び化合物添加を行なわずに培養したもの(rBAFF添加のみ)、rBAFF添加及び化合物添加を行なわずに培養したもの(B細胞刺激のみ)、化合物添加を行なわずに培養したもの(B細胞刺激及びrBAFF添加を実施)を同様に測定した。
結果を図2に示す。図2に示されるように、BAFFに誘導された、B細胞からのIgG産生の亢進は、化合物Aの添加により抑制された。 Example 2: Effect on BAFF-induced enhancement of IgG production from human peripheral B cells-1
Peripheral B cells were isolated from human peripheral blood reacted with anti-CD19 antibody-labeled microbeads using an automatic cell separation device autoMACS (manufactured by Mirtini). The isolated B cells were 2.5 × 10 5 cells / ml per well of a 24-well plate (manufactured by Corning) in RPMI-1640 medium (manufactured by ATCC) containing 10% fetal bovine serum (manufactured by JRH Biosciences). Sowing at concentration. Under B cell stimulation conditions, recombinant human soluble BAFF (rBAFF: manufactured by Chemicon) at a final concentration of 2 μg / ml was added to the medium, and Compound A was added to 8 μM and 15 μM, respectively. For B cell stimulation, culture the cells in the presence of anti-IgM antibody (10 μg / ml; AbDserotec), CD40-ligand (20 ng / ml; Peprotech), rIL-4 (100 ng / ml; BD Bioscience) It did by.
After culture, the culture supernatant was recovered, and the amount of IgG in the supernatant was quantified by a specific ELISA method. For the ELISA method, mouse anti-human IgG antibody (manufactured by BD Pharmingen), biotin-labeled mouse anti-human IgG antibody (manufactured by BD Pharmingen), and HRP-labeled streptavidin (manufactured by BD Pharmingen) were used. TMB One Solution (manufactured by Promega) was used as a reagent for ELISA color development.
As controls, those cultured without B cell stimulation, rBAFF addition and compound addition, those cultured without B cell stimulation and compound addition (rBAFF addition only), without rBAFF addition and compound addition Cultures (B cell stimulation only) and culture without compound addition (B cell stimulation and rBAFF addition were performed) were similarly measured.
The results are shown in FIG. As shown in FIG. 2, BAFF-induced enhancement of IgG production from B cells was suppressed by the addition of Compound A.
実施例3:ヒト末梢B細胞からのBAFF誘導IgG産生亢進に及ぼす効果−2
化合物Aに代えて化合物Bを用いた点以外は実施例2と同様にして、化合物BのB細胞からのBAFF誘導IgG産生亢進に及ぼす効果を調べた。
結果を図3に示す。図3に示されるように、BAFFに誘導された、B細胞からのIgG産生の亢進は、化合物Bの添加により抑制された。 Example 3: Effect on enhancement of BAFF-induced IgG production from human peripheral B cells-2
The effect of Compound B on the enhancement of BAFF-induced IgG production from B cells was examined in the same manner as in Example 2 except that Compound B was used instead of Compound A.
The results are shown in FIG. As shown in FIG. 3, BAFF-induced enhancement of IgG production from B cells was suppressed by the addition of Compound B.
実施例4:ヒト末梢B細胞と末梢単球の共培養によるIgG及びIL−6産生亢進に及ぼす効果
抗CD19抗体標識マイクロビーズと反応させたヒト末梢血(健常人1)及び抗CD14抗体標識マイクロビーズと反応させた同一検体末梢血から自動細胞分離装置をautoMACS(ミルティニー社製)を用いて末梢B細胞及び末梢単球を単離した。10%胎児ウシ血清(JRH Biosciences社製)を含むRPMI-1640培地(ATCC製)中、24穴プレート(コーニング社製)1ウェルあたり、単離したB細胞を0.75×105 cells/ml、単離した単球を1.5×105 cells/mlの濃度で共培養して4日間培養した。培養開始時に、終濃度2μg/mlの組換えヒト可溶性BAFF(rBAFF:Chemicon社製)を当該培地に加えた。
培養後、培養上清を回収し、上清中のIgG量及びIL−6量をそれぞれ特異的ELISA法にて定量した。IgG量の測定は実施例2に、IL−6量の測定は実施例1に準じた方法で行なった。
対照として、B細胞のみ培養したもの、B細胞にrBAFFを添加して培養したもの、B細胞と単球とを共培養したもの、を同様に測定した。
結果を図4に示す。図4に示されるように、単球とB細胞とを共培養することにより、さらにrBAFF存在下でいっそうIgG及びIL−6の産生が亢進することがわかった。
次に、この共培養系によるIgG及びIL−6の産生亢進が本発明の剤によりどのような影響を受けるか調べた。
抗CD19抗体標識マイクロビーズと反応させたヒト末梢血(健常人2)及び抗CD14抗体標識マイクロビーズと反応させた同一検体末梢血から自動細胞分離装置autoMACS(ミルティニー社製)を用いて末梢B細胞及び末梢単球を単離した。10%胎児ウシ血清(JRH Biosciences社製)を含むRPMI-1640培地(ATCC製)中、24穴プレート(コーニング社製)1ウェルあたり、単離したB細胞を0.75×105 cells/ml、単離した単球を1.5×105 cells/mlの濃度で共培養して4日間培養した。培養開始時に、終濃度2μg/mlの組換えヒト可溶性BAFF(rBAFF:Chemicon社製)及び化合物(化合物A又はB)を当該培地に加えた。化合物A及びBは、それぞれ15μM及び30μMで用いた。
培養後、培養上清を回収し、上清中のIgG量及びIL−6量をそれぞれ特異的ELISA法にて定量した。IgG量の測定は実施例2に、IL−6量の測定は実施例1に準じた方法で行なった。
対照として、B細胞にrBAFFを添加して培養したもの(ネガティブ対照)、rBAFF存在下でB細胞と単球とを共培養したもの(ポジティブ対照)、を同様に測定した。
結果を図5に示す。図5に示されるように、rBAFF存在下、単球とB細胞とを共培養することによりIgG及びIL−6の産生が亢進するが、化合物A及びBはいずれもその亢進を抑制することがわかった。 Example 4: Effect on co-culture of human peripheral B cells and peripheral monocytes on IgG and IL-6 production enhancement Human peripheral blood (healthy person 1) reacted with anti-CD19 antibody-labeled microbeads and anti-CD14 antibody-labeled micro Peripheral B cells and peripheral monocytes were isolated from the same sample peripheral blood reacted with the beads by using an automatic cell separation apparatus with autoMACS (manufactured by Miltini). Isolated B cells per well of a 24-well plate (manufactured by Corning) in RPMI-1640 medium (manufactured by ATCC) containing 10% fetal bovine serum (manufactured by JRH Biosciences) at 0.75 × 10 5 cells / ml The isolated monocytes were cocultured at a concentration of 1.5 × 10 5 cells / ml and cultured for 4 days. At the start of culture, a final concentration of 2 μg / ml of recombinant human soluble BAFF (rBAFF: manufactured by Chemicon) was added to the medium.
After culture, the culture supernatant was recovered, and the amount of IgG and IL-6 in the supernatant were quantified by the specific ELISA method. The measurement of the amount of IgG was performed according to Example 2, and the measurement of the amount of IL-6 according to Example 1.
As a control, a culture in which only B cells were cultured, a culture in which rBAFF was added to B cells and a culture in which B cells and monocytes were cocultured were similarly measured.
The results are shown in FIG. As shown in FIG. 4, it was found that co-culture of monocytes and B cells further enhanced the production of IgG and IL-6 in the presence of rBAFF.
Next, it was investigated how the production of IgG and IL-6 by this co-culture system is affected by the agent of the present invention.
The same sample from human peripheral blood (healthy people 2) reacted with anti-CD19 antibody-labeled microbeads and the same sample reacted with anti-CD14 antibody-labeled microbeads Peripheral B cells using an automatic cell separation device autoMACS (manufactured by Miltyny) And peripheral monocytes were isolated. Isolated B cells per well of a 24-well plate (manufactured by Corning) in RPMI-1640 medium (manufactured by ATCC) containing 10% fetal bovine serum (manufactured by JRH Biosciences) at 0.75 × 10 5 cells / ml The isolated monocytes were cocultured at a concentration of 1.5 × 10 5 cells / ml and cultured for 4 days. At the start of culture, recombinant human soluble BAFF (rBAFF: manufactured by Chemicon) and a compound (compound A or B) at a final concentration of 2 μg / ml were added to the medium. Compounds A and B were used at 15 μM and 30 μM, respectively.
After culture, the culture supernatant was recovered, and the amount of IgG and IL-6 in the supernatant were quantified by the specific ELISA method. The measurement of the amount of IgG was performed according to Example 2, and the measurement of the amount of IL-6 according to Example 1.
As controls, B cells cultured with rBAFF added (negative control) and B cells co-cultured with monocytes in the presence of rBAFF (positive control) were similarly measured.
The results are shown in FIG. As shown in FIG. 5, co-culture of monocytes and B cells in the presence of rBAFF enhances the production of IgG and IL-6, but both compounds A and B can inhibit the enhancement. all right.
以上の結果より、以下の点が明らかになった。
1)本発明の化合物はB細胞からのIgG産生を直接抑制する。
2)単球とB細胞を共培養することによりB細胞からのIgG産生には単球の寄与が大きいということが明らかとなり、さらに、本発明の化合物はそのIgG産生を抑制する。
従って、本発明は、B細胞からの過剰なIgG産生により増悪するような疾患(例、炎症性腸疾患(例、感染性胃腸炎、クローン病、潰瘍性大腸炎)、血管炎(例、高安大動脈炎、巨細胞性動脈炎(側頭動脈炎)))の予防及び/又は治療剤として有用である。From the above results, the following points have become clear.
1) The compounds of the present invention directly inhibit IgG production from B cells.
2) Co-culture of monocytes and B cells revealed that monocytes have a large contribution to IgG production from B cells, and further, the compound of the present invention suppresses its IgG production.
Thus, the present invention relates to diseases which are exacerbated by excessive IgG production from B cells (eg, inflammatory bowel disease (eg, infectious gastroenteritis (eg, infectious gastroenteritis, Crohn's disease, ulcerative colitis)), vasculitis (eg, Takayasu) It is useful as a preventive and / or therapeutic agent for aortitis and giant cell arteritis (temporal arteritis)).
さらに、本発明化合物がインビボでも優れた薬理作用を示すことを血管炎のモデルマウスを用いて確認した。
実施例5:血管炎モデルマウスの生存率に及ぼす影響
血管炎モデルマウスとしてMRL/lprマウス(日本チャールス・リバー株式会社から購入)を用いた。MRL/lprマウスは、4〜5ヶ月月齢で約80%以上に全身性に血管炎を発症する。これに加えて、血管炎のみならず、糸球体腎炎、関節炎、唾液腺炎などが同一個体に自然発症することも知られている(J Jpn Coll Angiol, 2009, 49 11-16.)。
実験は下記のようにして行った。
グループ1:生理食塩水のみ投与(cont)
グループ2:化合物A 0.2mg/kg投与(化合物A)
グループ3:化合物B 0.2mg/kg投与(化合物B)
7週齢のMRL/lprマウス(雌性)を用い、投与は週3回行った。
結果を図6に示す。生食投与群(cont)と比較すると、明らかに化合物投与群の生存率が高いことがわかる。Furthermore, it was confirmed using the model mouse of vasculitis that the compound of the present invention exhibits excellent pharmacological action even in vivo.
Example 5: Effect on Survival Rate of Vasculitis Model Mouse MRL / lpr mouse (purchased from Japan Charles River Co., Ltd.) was used as a vasculitis model mouse. MRL / lpr mice develop systemic vasculitis more than about 80% at 4 to 5 months of age. In addition to this, it is also known that glomerulonephritis, arthritis, sialadenitis, etc. spontaneously develop in the same individual as well as vasculitis (J Jpn Coll Angiol, 2009, 49 11-16.).
The experiment was performed as follows.
Group 1: saline only (cont)
Group 2: Compound A 0.2 mg / kg administration (Compound A)
Group 3: Compound B 0.2 mg / kg administration (Compound B)
Administration was performed 3 times a week using 7-week-old MRL / lpr mice (female).
The results are shown in FIG. It can be seen that the survival rate of the compound administration group is clearly higher than that of the saline administration group (cont).
実施例6:血中抗dsDNA抗体価に及ぼす影響
実施例5と同様にして血管炎モデルマウスを3群に分けた。経時的に血液を採取し、血中の抗dsDNA抗体価を測定した。抗dsDNA抗体は抗核抗体の一種であり、SLE患者血清中に高頻度・特異的に検出されることが知られている。
血中抗dsDNA抗体価は「レビス 抗dsDNA−マウス ELISA KIT」(シバヤギ社製)で測定した。具体的な手順は以下の通りである。
1)キット中の抗原固相化プレートをキット添付洗浄液で3回洗浄
2)希釈検体と標準抗マウスdsDN抗体溶液を添加し、室温で2時間静置
3)洗浄液で3回洗浄後、標識抗体(ペルオキシダーゼ結合抗マウスIgG抗体)を添加し、室温で2時間静置
4)洗浄液で3回洗浄後、発色液(TMB溶液)を添加し、発色
5)反応停止液(1M H2SO4)を添加して反応を停止し、OD450nmを測定
結果を図7に示す。生食投与群(cont)と比較すると、明らかに化合物投与群の血中抗dsDNA抗体価が低下していることが分かる。 Example 6: Influence on blood anti-dsDNA antibody titer In the same manner as in Example 5, the vasculitis model mice were divided into three groups. Blood was collected over time, and the anti-dsDNA antibody titer in blood was measured. Anti-dsDNA antibody is a type of antinuclear antibody, and is known to be detected frequently and specifically in the serum of SLE patients.
The blood anti-dsDNA antibody titer was measured by "Levis anti-dsDNA-mouse ELISA KIT" (manufactured by Shiba Goat Co., Ltd.). The specific procedure is as follows.
1) Wash the antigen-immobilized plate in the kit 3 times with the kit-supplied washing solution
2) Add diluted sample and standard anti-mouse dsDN antibody solution and let stand at room temperature for 2 hours
3) After washing 3 times with a washing solution, add a labeled antibody (peroxidase-conjugated anti-mouse IgG antibody) and leave it for 2 hours at room temperature
4) After washing 3 times with a washing solution, add a color developing solution (TMB solution)
5) The reaction was stopped by adding a reaction termination solution (1 MH 2 SO 4 ), and the OD450 nm was measured. The results are shown in FIG. It can be seen that the blood anti-dsDNA antibody titer in the compound administration group is clearly reduced as compared to the saline administration group (cont).
本発明のピロロピリミジン誘導体は、ヒト末梢細胞(B細胞、単球)におけるBAFFにより誘導される生物学的作用(IgG産生、IL−6産生)を抑制することができ、従って、炎症性疾患、特に炎症性腸疾患や血管炎等の予防及び/又は治療剤を提供することができる。また、本発明のピロロピリミジン誘導体は、B細胞からの過剰なIgG産生を抑制することが可能であり、従って、炎症性腸疾患や血管炎等のB細胞からの過剰なIgG産生により増悪するような疾患の予防及び/又は治療剤として有用である。
本出願は、日本で出願された特願2013−210440(出願日2013年10月7日)を基礎としておりその内容は本明細書に全て包含されるものである。The pyrrolopyrimidine derivatives of the present invention can suppress the biological effects (IgG production, IL-6 production) induced by BAFF in human peripheral cells (B cells, monocytes), and thus, an inflammatory disease, In particular, a preventive and / or therapeutic agent for inflammatory bowel disease, vasculitis and the like can be provided. In addition, the pyrrolopyrimidine derivative of the present invention is capable of suppressing excessive IgG production from B cells, and thus is exacerbated by excessive IgG production from B cells such as inflammatory bowel disease and vasculitis. Are useful as preventive and / or therapeutic agents for various diseases.
This application is based on patent application No. 2013-210440 filed in Japan (filing date October 7, 2013), the contents of which are incorporated in full herein.
Claims (6)
[式中、環Aは次式:
から選択される基(ここで、Bは、−CH2−、−O−、又は−NH−を示し、R4は、(C1−6アルキル)アミノ基、(C3−6シクロアルキル)アミノ基、ピリジニル基、又は2−オキソピロリジニル基を示し、Lは、式−(CH2)p−、−CH2C(O)−、又は−C(O)CH2−を示し、nは、0〜2の整数を示し、oは、1〜3の自然数を示し、pは、0〜3の整数を示す。)を示し、
R1、R2は、互いに同一又は異なっていてもよく、水素原子、C1−6アルキル基を示し、
R3は、C3−6シクロアルキル基、ハロゲン原子で置換されていてもよいC6−10アリール基、(C6−10アリール)C1−6アルキル基を示し、
mは、0〜2の整数を示す。]
で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含有してなる血管炎の予防及び/又は治療剤。 General formula (1):
[Wherein, ring A has the following formula:
A group selected from (wherein, B represents -CH 2- , -O-, or -NH-, and R 4 represents a (C 1-6 alkyl) amino group, (C 3-6 cycloalkyl) amino group, a pyridinyl group, or a 2-oxopyrrolidinyl group, L is the formula - (CH 2) p -, - CH 2 C (O) -, or -C (O) CH 2 - indicates, n is an integer of 0 to 2, o is a natural number of 1 to 3, and p is an integer of 0 to 3.
R 1 and R 2 may be the same as or different from each other, and represent a hydrogen atom or a C 1-6 alkyl group,
R 3 represents a C 3-6 cycloalkyl group, a C 6-10 aryl group optionally substituted with a halogen atom, a (C 6-10 aryl) C 1-6 alkyl group,
m shows the integer of 0-2. ]
The preventive and / or therapeutic agent of the vasculitis which comprises the compound represented by these, or its salt, or those solvates as an active ingredient.
7−ベンジル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[4−{(7−ベンジル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピロリジン−3−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−2−イル}メトキシ]−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)アゼパン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
1−(2−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イルオキシ)メチル}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(4−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−{2−(3−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピロリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[3−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピロリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
1−{2−(2−[{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}メチル]ピペリジン−1−イル)−2−オキソエチル}ピロリジン−2−オン、
1−(2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}アゼパン−1−イル]−2−オキソエチル)ピロリジン−2−オン、
4−{2−(アゼパン−1−イル)エトキシ}−7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−{2−(ピペラジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
4−[2−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}エチル]モルホリン、
7−ベンジル−5,6−ジメチル−4−{2−(ピロリジン−1−イル)エトキシ}−7H−ピロロ[2,3−d]ピリミジン、
7−ベンジル−5,6−ジメチル−4−[{1−(ピリジン−3−イルメチル)ピペリジン−4−イル}オキシ]−7H−ピロロ[2,3−d]ピリミジン、
2−[4−{(7−ベンジル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−シクロプロピルアセトアミド、
N−シクロプロピル−2−(4−[{7−(4−フルオロフェニル)−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル}オキシ]ピペリジン−1−イル)アセトアミド、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソプロピルアセトアミド、
N−(sec−ブチル)−2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]アセトアミド、
1−(2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−2−オキソエチル)ピロリジン−2−オン、及び、
2−[4−{(7−シクロペンチル−5,6−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)オキシ}ピペリジン−1−イル]−N−イソブチルアセトアミド
からなる群から選択される少なくとも1つの化合物である、請求項1に記載の剤。 The compound represented by the general formula (1) is
7-benzyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [4-{(7-benzyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidin-2-one;
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) pyrrolidin-3-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-2-yl} methoxy] -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) azepan-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
1- (2- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) methyl} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (4-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- {2- (3-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] pyrrolidin-1-yl) -2- Oxoethyl} pyrrolidin-2-one,
1- (2- [3-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} pyrrolidin-1-yl] -2-oxoethyl) pyrrolidine -2- on,
1- {2- (2-[{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} methyl] piperidin-1-yl) -2-) Oxoethyl} pyrrolidin-2-one,
1- (2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} azepan-1-yl] -2-oxoethyl) pyrrolidine -2- on,
4- {2- (Azepan-1-yl) ethoxy} -7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4- {2- (piperazin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
4- [2-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} ethyl] morpholine,
7-benzyl-5,6-dimethyl-4- {2- (pyrrolidin-1-yl) ethoxy} -7H-pyrrolo [2,3-d] pyrimidine,
7-benzyl-5,6-dimethyl-4-[{1- (pyridin-3-ylmethyl) piperidin-4-yl} oxy] -7H-pyrrolo [2,3-d] pyrimidine,
2- [4-{(7-benzyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-cyclopropylacetamide;
N-Cyclopropyl-2- (4-[{7- (4-fluorophenyl) -5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy] piperidin-1-yl ) Acetamide,
2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isopropylacetamide;
N- (sec-Butyl) -2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] acetamide ,
1- (2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -2-oxoethyl) pyrrolidine -2- on, and
From the group consisting of 2- [4-{(7-cyclopentyl-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) oxy} piperidin-1-yl] -N-isobutylacetamide The agent according to claim 1, which is at least one compound selected.
[式中、環Aは次式:
から選択される基(ここで、Bは、−CH2−、−O−、又は−NH−を示し、R4は、(C1−6アルキル)アミノ基、(C3−6シクロアルキル)アミノ基、ピリジニル基、又は2−オキソピロリジニル基を示し、Lは、式−(CH2)p−、−CH2C(O)−、又は−C(O)CH2−を示し、nは、0〜2の整数を示し、oは、1〜3の自然数を示し、pは、0〜3の整数を示す。)を示し、
R1、R2は、互いに同一又は異なっていてもよく、水素原子、C1−6アルキル基を示し、
R3は、C3−6シクロアルキル基、ハロゲン原子で置換されていてもよいC6−10アリール基、(C6−10アリール)C1−6アルキル基を示し、
mは、0〜2の整数を示す。]
で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含有してなるBAFF刺激によるヒト活性化B細胞のIgG産生抑制剤。 General formula (1):
[Wherein, ring A has the following formula:
A group selected from (wherein, B represents -CH 2- , -O-, or -NH-, and R 4 represents a (C 1-6 alkyl) amino group, (C 3-6 cycloalkyl) amino group, a pyridinyl group, or a 2-oxopyrrolidinyl group, L is the formula - (CH 2) p -, - CH 2 C (O) -, or -C (O) CH 2 - indicates, n is an integer of 0 to 2, o is a natural number of 1 to 3, and p is an integer of 0 to 3.
R 1 and R 2 may be the same as or different from each other, and represent a hydrogen atom or a C 1-6 alkyl group,
R 3 represents a C 3-6 cycloalkyl group, a C 6-10 aryl group optionally substituted with a halogen atom, a (C 6-10 aryl) C 1-6 alkyl group,
m shows the integer of 0-2. ]
An agent for suppressing IgG production of human activated B cells by BAFF stimulation , which comprises the compound represented by the above, or a salt thereof, or a solvate thereof as an active ingredient.
[式中、環Aは次式:
から選択される基(ここで、Bは、−CH2−、−O−、又は−NH−を示し、R4は、(C1−6アルキル)アミノ基、(C3−6シクロアルキル)アミノ基、ピリジニル基、又は2−オキソピロリジニル基を示し、Lは、式−(CH2)p−、−CH2C(O)−、又は−C(O)CH2−を示し、nは、0〜2の整数を示し、oは、1〜3の自然数を示し、pは、0〜3の整数を示す。)を示し、
R1、R2は、互いに同一又は異なっていてもよく、水素原子、C1−6アルキル基を示し、
R3は、C3−6シクロアルキル基、ハロゲン原子で置換されていてもよいC6−10アリール基、(C6−10アリール)C1−6アルキル基を示し、
mは、0〜2の整数を示す。]
で表される化合物、若しくはその塩、又はそれらの溶媒和物を有効成分として含有してなる、ヒトB細胞とヒト単球とBAFFとの共培養におけるIL−6産生及びIgG産生抑制剤。 General formula (1):
[Wherein, ring A has the following formula:
A group selected from (wherein, B represents -CH 2- , -O-, or -NH-, and R 4 represents a (C 1-6 alkyl) amino group, (C 3-6 cycloalkyl) amino group, a pyridinyl group, or a 2-oxopyrrolidinyl group, L is the formula - (CH 2) p -, - CH 2 C (O) -, or -C (O) CH 2 - indicates, n is an integer of 0 to 2, o is a natural number of 1 to 3, and p is an integer of 0 to 3.
R 1 and R 2 may be the same as or different from each other, and represent a hydrogen atom or a C 1-6 alkyl group,
R 3 represents a C 3-6 cycloalkyl group, a C 6-10 aryl group optionally substituted with a halogen atom, a (C 6-10 aryl) C 1-6 alkyl group,
m shows the integer of 0-2. ]
An agent for suppressing IL-6 production and IgG production in co-culture of human B cells, human monocytes and BAFF, comprising the compound represented by the formula: or a salt thereof, or a solvate thereof as an active ingredient.
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