JP2021523197A - Nrf2活性化化合物のプロドラッグおよびその使用 - Google Patents
Nrf2活性化化合物のプロドラッグおよびその使用 Download PDFInfo
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229960004029 silicic acid Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
- C07C323/41—Y being a hydrogen or an acyclic carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
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Abstract
Description
核因子赤血球2関連因子2は、NFE2L2またはNrf2としても公知で、ヒトにおいてNFE2L2遺伝子によってコードされる転写因子である。Nrf2は、損傷および炎症によって誘発される酸化的損傷に対して保護する抗酸化タンパク質の発現を調節する塩基性ロイシンジッパー(bZIP)タンパク質である。
本開示の局面は、Nrf2を活性化する化合物のプロドラッグを含む。そのようなプロドラッグは、例えば、乾癬および多発性硬化症などの、自己免疫および炎症性疾患および障害の処置において有用であり得る。本開示の態様は、このプロドラッグを含む薬学的組成物、様々な疾患および障害の処置におけるこのプロドラッグの使用法、このプロドラッグの調製プロセスおよびこのプロセスにおいて有用な中間体にも関する。
で表される化合物、またはその塩もしくは立体異性体であり、式中、
R2はスルホニル、カルボキシル、カルボキシルエステル、およびアミノアシルからなる群より選択され;
R3は活性剤、抗酸化剤、アミノ酸、アミノ酸誘導体、ペプチド、およびペプチド誘導体からなる群より選択され;
R4は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
X1およびX2はそれぞれ独立にNおよびCHから選択され、ここでX1およびX2の少なくとも1つはNであり;かつ
nは1〜6の整数である。
の化合物、またはその塩もしくは立体異性体であり、式中、
R3は活性剤、抗酸化剤、アミノ酸、アミノ酸誘導体、ペプチド、およびペプチド誘導体からなる群より選択され;
R4は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
R5はアルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
X1およびX2はそれぞれ独立にNおよびCHから選択され、ここでX1およびX2の少なくとも1つはNであり;かつ
nは1〜6の整数である。
本開示の局面は、Nrf2を活性化する化合物のプロドラッグを含む。そのようなプロドラッグは、例えば、乾癬および多発性硬化症などの、自己免疫および炎症性疾患および障害の処置において有用であり得る。本開示の態様は、このプロドラッグを含む薬学的組成物、様々な疾患および障害の処置におけるこのプロドラッグの使用法、このプロドラッグの調製プロセスおよびこのプロセスにおいて有用な中間体にも関する。
以下の用語は、特に記載がないかぎり、以下の意味を有する。任意の定義されていない用語はそれらの分野で理解されている意味を有する。
以下の置換基および値は、様々な局面および態様の代表的な例を提供するためのものである。これらの代表的な値は、そのような局面および態様をさらに定義および例示するためのもので、他の態様を除外する、または本開示の範囲を限定するものではない。これに関して、特定の値または置換基が好ましいという表現は、特に記載がないかぎり、本開示から他の値または置換基をいかなる様式でも除外するものではない。
本開示の化合物の態様は、以下の式(I):
またはその塩もしくは立体異性体で表され、式中、
R2はスルホニル、カルボキシル、カルボキシルエステル、およびアミノアシルからなる群より選択され;
R3は活性剤、抗酸化剤、アミノ酸、アミノ酸誘導体、ペプチド、およびペプチド誘導体からなる群より選択され;
R4は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
X1およびX2はそれぞれ独立にNおよびCHから選択され、ここでX1およびX2の少なくとも1つはNであり;かつ
nは1〜6の整数である。
一定の態様において、式(I)の化合物には、X1がNであり、かつX2がNである化合物が含まれる。したがって、本開示の化合物は、以下の式(Ia):
またはその塩もしくは立体異性体で表され得、式中、
R2はスルホニル、カルボキシル、カルボキシルエステル、およびアミノアシルからなる群より選択され;
R3は活性剤、抗酸化剤、アミノ酸、アミノ酸誘導体、ペプチド、およびペプチド誘導体からなる群より選択され;
R4は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;かつ
nは1〜6の整数である。
またはその塩もしくは立体異性体で表され得、式中、
R2はスルホニル、カルボキシル、カルボキシルエステル、およびアミノアシルからなる群より選択され;
R3は活性剤、抗酸化剤、アミノ酸、アミノ酸誘導体、ペプチド、およびペプチド誘導体からなる群より選択され;
R4は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;かつ
nは1〜6の整数である。
式(I)の一定の態様において、R2はスルホニルである。したがって、本開示の化合物の態様は、以下の式(II):
またはその塩もしくは立体異性体で表され得、式中、
R3は活性剤、抗酸化剤、アミノ酸、アミノ酸誘導体、ペプチド、およびペプチド誘導体からなる群より選択され;
R4は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
R5はアルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
X1およびX2はそれぞれ独立にNおよびCHから選択され、ここでX1およびX2の少なくとも1つはNであり;かつ
nは1〜6の整数である。
一定の態様において、式(II)の化合物には、X1がNであり、かつX2がNである化合物が含まれる。したがって、本開示の化合物は、以下の式(IIa):
またはその塩もしくは立体異性体で表され得、式中、
R3は活性剤、抗酸化剤、アミノ酸、アミノ酸誘導体、ペプチド、およびペプチド誘導体からなる群より選択され;
R4は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
R5はアルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
nは1〜6の整数である。
またはその塩もしくは立体異性体で表され得、式中、
R3は活性剤、抗酸化剤、アミノ酸、アミノ酸誘導体、ペプチド、およびペプチド誘導体からなる群より選択され;
R4は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
R5はアルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
nは1〜6の整数である。
該当する場合、本項における本発明の化合物の記載は式(I)、(Ia)、(Ib)、(II)、(IIa)、および(IIb)に適用される。
化合物1:N5-((2R)-1-((カルボキシメチル)アミノ)-3-((1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-テトラゾル-1-イル)-2-トシルエチル)チオ)-1-オキソプロパン-2-イル)-L-グルタミン;
化合物2:N5-((2R)-1-((カルボキシメチル)アミノ)-3-((3-メトキシ-3-オキソ-1-(5-オキソ-4-(ピリジン-3-イル)-4,5-ジヒドロ-1H-テトラゾル-1-イル)プロピル)チオ)-1-オキソプロパン-2-イル)-L-グルタミン;
化合物3:N-アセチル-S-(1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-1,2,4-トリアゾル-1-イル)-2-(フェニルスルホニル)エチル)-L-システイン酸メチル;
化合物4:N-アセチル-S-(1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-1,2,4-トリアゾル-1-イル)-2-(フェニルスルホニル)エチル)-L-システイン;
化合物5:(2R)-2-アミノ-3-(1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-1,2,4-トリアゾル-1-イル)-2-(フェニルスルホニル)エチルチオ)プロパン酸;
化合物6:(2S)-2-アミノ-5-((2R)-1-(カルボキシメチルアミノ)-3-(1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-1,2,4-トリアゾル-1-イル)-2-(フェニルスルホニル)エチルチオ)-1-オキソプロパン-2-イルアミノ)-5-オキソペンタン酸;
化合物7:2-アセトアミド-4-(1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-1,2,4-トリアゾル-1-イル)-2-(フェニルスルホニル)エチルチオ)ブタン酸;
化合物8:(2R)-2-アセトアミド-3-(1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-1,2,4-トリアゾル-1-イル)-2-(フェニルスルホニル)エチルチオ)プロパンアミド;
化合物9:N-アセチル-S-(3-メトキシ-3-オキソ-1-(5-オキソ-4-(ピリジン-3-イル)-4,5-ジヒドロ-1H-テトラゾル-1-イル)プロピル)-L-システイン酸メチル;および
化合物10:N-アセチル-S-(1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-テトラゾル-1-イル)-2-トシルエチル)-L-システイン酸メチル。
N5-((2R)-1-((カルボキシメチル)アミノ)-3-((1,4-ジメトキシ-1,4-ジオキソブタン-2-イル)チオ)-1-オキソプロパン-2-イル)-L-グルタミン(化合物11)
2-(((R)-2-(アセチル-λ2-アザネイル)-3-メトキシ-3-オキソプロピル)チオ)コハク酸ジメチル(化合物12)
一定の態様において、開示する化合物は、自己免疫または炎症性疾患または障害などの疾患または障害の処置のために有用である。したがって、少なくとも1つの開示する化合物を含む薬学的組成物も本明細書において記載する。例えば、本開示は、薬学的に許容される担体および本開示の化合物またはその薬学的に許容される塩もしくは溶媒和物もしくは立体異性体の治療的有効量を含む薬学的組成物を提供する。
本発明の化合物は、自己免疫または炎症性疾患または障害などの、対象の疾患または障害を処置するために有用である。投与経路は、処置する状態、使用する製剤および/または装置、処置する患者などを含むが、それらに限定されない、様々な因子に従って選択してもよい。開示する方法において有用な投与経路には、静脈内(iv)、腹腔内(ip)、直腸、局所、眼、鼻、および経皮などの経口および非経口経路が含まれるが、それらに限定されない。これらの剤形のための製剤を本明細書に記載する。
本開示に記載の化合物は、処置を必要としている対象の、酸化ストレス(例えば、損傷または自己免疫もしくは炎症性疾患もしくは障害が原因の酸化ストレス)が原因の疾患または障害などの、疾患または障害を処置するのに有用である。一定の実例において、疾患または障害は、1つまたは複数の抗酸化タンパク質などの、抗酸化剤による処置が可能なものである。一定の実例において、疾患または障害は、処置を必要としている対象において、抗酸化タンパク質の発現の増大による処置が可能なものである。一定の実例において、疾患または障害は、処置を必要としている対象において、抗酸化タンパク質の発現の増大による処置が可能なものであって、ここで抗酸化タンパク質の発現はNrf2により調節される。
下記は、本開示の化合物の活性を特徴づける際に有用なアッセイの例である。
1. グルタチオン枯渇アッセイ
1つの局面において、本発明の化合物は、インビボで反応性チオール基のマイケル受容体として作用することにより、それらの治療効果を発揮する。例えば、Lehmann et al. Dimethylfumarate Induces Immunosuppression via Glutathione Depletion and Subsequent Induction of Heme Oxygenase 1, Journal of Investigative Dermatology (2007) 127, 835-845を参照されたい。したがって、本発明の化合物は、以下のとおり、グルタチオンとの反応によりインビトロで評価してもよい。
1. マウス実験的自己免疫性脳脊髄炎アッセイ
自己免疫疾患に対する化合物のインビボ有効性を、実験的自己免疫性脳脊髄炎(EAE)のマウスモデルにおいて示すことができる。
多発性硬化症などの自己免疫疾患を処置するための化合物のインビボ治療効果は、実験的自己免疫性脳脊髄炎(EAE)動物モデルにおいて評価することができる。
乾癬を処置するための化合物のインビボ治療効果を、実験動物モデルにおいて評価することができる。例えば、重症複合免疫不全(SCID)マウスモデルを用いて、ヒトの乾癬を処置するための化合物の有効性を評価することができる。
多発性硬化症を処置するための化合物のインビボ治療効果を、実験動物モデルにおいて評価することができる。
を用いて能動的に誘導する。各マウスを麻酔し、100μLのリン酸緩衝食塩水に乳化した200μgのMOGペプチドおよび15μgのキラヤ(Quilija)樹皮からのサポニン抽出物を投与する。25μL量を4つの側腹領域に皮下注射する。マウスに、PBS 200μL中200ngの百日咳毒素も腹腔内注射する。2回目の百日咳毒素の同一の注射を48時間後に投与する。
本発明の化合物は自己免疫および炎症性疾患および障害の処置のために有用であるため、そのような化合物は研究ツールとしても有用である。本開示は、生体系もしくは試料を試験するための研究ツールとして、または乾癬もしくは多発性硬化症などの自己免疫および炎症性疾患および障害の処置のために使用し得る新しい化学化合物を発見するための研究ツールとして、本発明の化合物を使用するための方法も提供する。
開示する化合物を合成するのに有用な、一般に公知の化学合成スキームおよび条件を提供する多くの一般的参照文献が利用可能である(例えば、Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001;またはVogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978参照)。
式中、R'およびR''はそれぞれ独立に、本明細書に記載の任意の好都合な基であり得る。いくつかの場合に、R'はアルキルまたは置換アルキルである。いくつかの場合に、R''はアルキル(例えば、メチル)、置換アルキル、ヘテロアリール(例えば、3-ピリジル)、置換ヘテロアリール、アリールまたは置換アリールである。
式中、R'およびR''はそれぞれ独立に、本明細書に記載の任意の好都合な基であり得る。いくつかの場合に、R'はアルキルまたは置換アルキルである。いくつかの場合に、R''はアルキル(例えば、メチル)、置換アルキル、ヘテロアリール(例えば、3-ピリジル)、置換ヘテロアリール、アリールまたは置換アリールである。
式中、Xは脱離基(例えば、ハロゲン)であり、かつR'およびR''はそれぞれ独立に、本明細書に記載の任意の好都合な基であり得る。いくつかの場合に、R'はアルキルまたは置換アルキルである。いくつかの場合に、R''はアルキル(例えば、メチル)、置換アルキル、ヘテロアリール(例えば、3-ピリジル)、置換ヘテロアリール、アリールまたは置換アリールである。
式中、R'およびR''はそれぞれ独立に、本明細書に記載の任意の好都合な基であり得る。いくつかの場合に、R'はアルキルまたは置換アルキルである。いくつかの場合に、R''はアルキル(例えば、メチル)、置換アルキル、ヘテロアリール(例えば、3-ピリジル)、置換ヘテロアリール、アリールまたは置換アリールである。
MeOH/H2O(5mL、1:1)中の(E)-1-メチル-4-(2-トシルビニル)-1,4-ジヒドロ-5H-テトラゾル-5-オン(100、100mg、0.36mmol)、グルタチオン(GSH)(200、110mg、0.36mmol)の溶液に、TEA(5μL、3.6mg、36μmol)を加えた。次いで、不均質な反応混合物を60℃で2日間撹拌し、室温まで冷却し、濃縮して、白色固体を得た。逆相クロマトグラフィにより101mg(48%)のN5-((2R)-1-((カルボキシメチル)アミノ)-3-((1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-テトラゾル-1-イル)-2-トシルエチル)チオ)-1-オキソプロパン-2-イル)-L-グルタミン(1)の1:1ジアステレオマー混合物を白色固体で得た。
MeOH/H2O(5mL、1:1)中のジメチルフマレート(400、100mg、0.69mmol)、GSH(200、215mg、0.70mmol)の溶液に、TEA(10μL、7.3mg、72μmol)を加えた。次いで、不均質な反応混合物を60℃で2時間と、室温で3日間撹拌し、室温まで冷却し、濃縮して、白色固体を得た。逆相クロマトグラフィにより139mg(44%)のN5-((2R)-1-((カルボキシメチル)アミノ)-3-((1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-テトラゾル-1-イル)-2-トシルエチル)チオ)-1-オキソプロパン-2-イル)-L-グルタミン(11)の1:1ジアステレオマー混合物を白色固体で得た。
MeOH/H2O(5mL、1:1)中のメチル(E)-3-(5-オキソ-4-(ピリジン-3-イル)-4,5-ジヒドロ-1H-テトラゾル-1-イル)アクリレート(600、100mg、0.4mmol)、GSH(200、0.125mg、0.41mmol)の溶液に、TEA(6μL、4.4mg、43μmol)を加えた。次いで、不均質な反応混合物を60℃で3日間撹拌し、室温まで冷却し、濃縮して、白色固体を得た。逆相クロマトグラフィにより75mg(33%)のN5-((2R)-1-((カルボキシメチル)アミノ)-3-((3-メトキシ-3-オキソ-1-(5-オキソ-4-(ピリジン-3-イル)-4,5-ジヒドロ-1H-テトラゾル-1-イル)プロピル)チオ)-1-オキソプロパン-2-イル)-L-グルタミン(2)の1:1ジアステレオマー混合物を白色固体で得た。
MeOH/H2O(3mL、1:1)中の(E)-4-メチル-2-(2-(フェニルスルホニル)ビニル)-2,4-ジヒドロ-3H-1,2,4-トリアゾル-3-オン(800、400mg、1.5mmol)、N-Ac-L-Cys-OMe(900、300mg、1.7mmol)の溶液に、TEA(21μL、15.2mg、150μmol)を加えた。次いで、不均質な反応混合物を50℃で2日間撹拌し、室温まで冷却し、濃縮して、白色固体を得た。カラムクロマトグラフィにより、2〜10%MeOH/DCMで溶出して、506mg(76%)のN-アセチル-S-(1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-1,2,4-トリアゾル-1-イル)-2-(フェニルスルホニル)エチル)-L-システイン酸メチル(3)の3:2ジアステレオマー混合物を白色固体で得た。
MeOH/H2O(3mL、1:1)中の(E)-4-メチル-2-(2-(フェニルスルホニル)ビニル)-2,4-ジヒドロ-3H-1,2,4-トリアゾル-3-オン(800、50mg、0.19mmol)、N-Ac-L-Cys-OH(1100、35mg、0.21mmol)の溶液に、TEA(150μL、110mg、1.1mmol)を加えた。次いで、不均質な反応混合物を50℃で2日間撹拌し、室温まで冷却し、濃縮して、白色固体を得た。逆相クロマトグラフィにより49mg(61%)のN-アセチル-S-(1-(4-メチル-5-オキソ-4,5-ジヒドロ-1H-1,2,4-トリアゾル-1-イル)-2-(フェニルスルホニル)エチル)-L-システイン(4)の2:1ジアステレオマー混合物を白色固体で得た。
メタノール(2mL)中のメチル(E)-3-(5-オキソ-4-(ピリジン-3-イル)-4,5-ジヒドロ-1H-テトラゾル-1-イル)アクリレート(0.1g、0.40mmol)、アセチル-L-システイン酸メチル(0.08g、0.44mmol)、およびトリエチルアミン(6μl、0.04mmol)の混合物を室温で5時間撹拌した。次いで、反応混合物を減圧下で濃縮して残渣を得、これをクロマトグラフィにより、酢酸エチル/ヘキサン(7/3)で溶出して精製し、N-アセチル-S-(3-メトキシ-3-オキソ-1-(5-オキソ-4-(ピリジン-3-イル)-4,5-ジヒドロ-1H-テトラゾル-1-イル)プロピル)-L-システイン酸メチル(9)をオフホワイト固体で得た(0.12g、73%)。
自己免疫性脳炎(EAE)インビボアッセイ
本明細書に開示する化合物を、B.2.実験的自己免疫性脳脊髄炎動物モデルと題する段落で前述した方法に従い、マウスの自己免疫性脳炎(EAE)インビボアッセイで試験する。例えば、本開示の化合物は、免疫化の日に開始して60mg/kgで投与した場合、疾患麻痺の発症を予防するのに有用である。
化合物を、NrF2(核因子(エリスロイド由来2)様2)移行アッセイにおいて、米国特許第8,101,373号に示された方法を適合させることにより試験し、前記開示は参照により本明細書に組み入れられる。本化合物によるアッセイでのNrF2活性化の結果は、それらの抗炎症活性の指標である。
Claims (15)
- 式(I):
の化合物、またはその塩もしくは立体異性体であって、
式中、
R2はスルホニル、カルボキシル、カルボキシルエステル、およびアミノアシルからなる群より選択され;
R3は活性剤、抗酸化剤、アミノ酸、アミノ酸誘導体、ペプチド、およびペプチド誘導体からなる群より選択され;
R4は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
X1およびX2はそれぞれ独立にNおよびCHから選択され、ここでX1およびX2の少なくとも1つはNであり;かつ
nは1〜6の整数である、
前記化合物、またはその塩もしくは立体異性体。 - R2がスルホニルまたはカルボキシルエステルである、請求項1記載の化合物。
- 式(II):
の化合物、またはその塩もしくは立体異性体であって、
式中、
R3は活性剤、抗酸化剤、アミノ酸、アミノ酸誘導体、ペプチド、およびペプチド誘導体からなる群より選択され;
R4は水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
R5はアルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、および置換ヘテロアリールからなる群より選択され;
X1およびX2はそれぞれ独立にNおよびCHから選択され、ここでX1およびX2の少なくとも1つはNであり;かつ
nは1〜6の整数である、
前記化合物、またはその塩もしくは立体異性体
である、請求項1記載の化合物。 - R5がアリールまたは置換アリールである、請求項3記載の化合物。
- nが1である、請求項1記載の化合物。
- nが2である、請求項1記載の化合物。
- R3がグルタチオンである、請求項1記載の化合物。
- R3がアミノ酸またはアミノ酸誘導体である、請求項1記載の化合物。
- X1がNであり、かつX2がNである、請求項1記載の化合物。
- X1がNであり、かつX2がCHである、請求項1記載の化合物。
- 請求項1記載の化合物と、薬学的に許容される担体とを含む、薬学的組成物。
- 対象における疾患または障害を処置するのに十分な、請求項1記載の化合物の薬学的有効量を、対象に投与する段階を含む、その必要がある対象における疾患または障害を処置する方法であって、
該疾患または障害が自己免疫疾患または炎症性疾患である、
前記方法。 - 前記疾患または障害が乾癬または多発性硬化症である、請求項14記載の方法。
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US10774066B2 (en) | 2020-09-15 |
US10889562B2 (en) | 2021-01-12 |
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CN112004808A (zh) | 2020-11-27 |
EP3793991A1 (en) | 2021-03-24 |
US20190367472A1 (en) | 2019-12-05 |
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