JP2018080155A - Bcat1阻害剤を使用する組成物及び治療方法 - Google Patents
Bcat1阻害剤を使用する組成物及び治療方法 Download PDFInfo
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- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
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- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005893 naphthalimidyl group Chemical group 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
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- 239000004033 plastic Substances 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
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- 125000002098 pyridazinyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 208000009169 relapsing polychondritis Diseases 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000002784 sclerotic effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 208000008732 thymoma Diseases 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/88—Unsaturated compounds containing keto groups containing halogen
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
を含む(式中、
Tは−C(=O)−又は−C(=NH)−からなる群から選択され、
R1及びR2は、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C14シクロアルキル、アリール、ヘテロアリール、アリール(C1〜C6アルキル)、−CN、アミノ、(C1〜C6)アルキルアミノ、ジアルキル(C1〜C6)アミノ、ハロアルキル(C1〜C6)、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ヘテロアリール(C1〜C6アルキル)、(C4〜C15)複素環、(C4〜C15)複素環(C1〜C6アルキル)、C3〜C7シクロアルコキシ、C6〜C10アリールオキシ、並びに(a−1)、(a−2)及び(a−3)の部分からなる群から独立して選択され、
上記アルキル、アリール、シクロアルキル、複素環、ヘテロアリール、アルコキシ、シクロアルコキシ、ハロアルキル又はハロアルコキシは、−C1〜C6アルキル、ハロ、CN、CF3、−COOH、−OH、−C1〜C6アルコキシ、−NH2、−(C1〜C6アルキル)NH2、−(C1〜C6アルキル)NH(C1〜C6アルキル)、−(C1〜C6アルキル)N(C1〜C6アルキル)2、−NH(C1〜C6アルキル)、−N(C1〜C6アルキル)2、−CONH2、−NH(CO)(C1〜C6アルキル)、−N(C1〜C6アルキル)CO(C1〜C6アルキル)、−SO2−(C1〜C6アルキル)、及び−(SO)NH2からなる群から選択される1以上の置換基で更に任意に置換され、
R3は、水素、重水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C14シクロアルキル、アリール、ヘテロアリール、アリール(C1〜C6アルキル)、−CN、アミノ、(C1〜C6)アルキルアミノ、ジアルキル(C1〜C6)アミノ、ハロアルキル(C1〜C6)、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ヘテロアリール(C1〜C6アルキル)、(C4〜C15)複素環、(C4〜C15)複素環(C1〜C6アルキル)、C3〜C7シクロアルコキシ、C6〜C10アリールオキシ、並びに(a−1)、(a−2)及び(a−3)の部分からなる群から選択され、
上記アルキル、アリール、シクロアルキル、複素環、ヘテロアリール、アルコキシ、シクロアルコキシ、ハロアルキル又はハロアルコキシは、C1〜C6アルキル、ハロ、CN、CF3、−COOH、−OH、C1〜C6アルコキシ、−NH2、−(C1〜C6アルキル)NH2、−(C1〜C6アルキル)NH(C1〜C6アルキル)、−(C1〜C6アルキル)N(C1〜C6アルキル)2、−NH(C1〜C6アルキル)、−N(C1〜C6アルキル)2、−CONH2、−NH(CO)(C1〜C6アルキル)、−N(C1〜C6アルキル)CO(C1〜C6アルキル)、−SO2−(C1〜C6アルキル)、及び−(SO)NH2からなる群から選択される1以上の置換基で更に任意に置換され、
R4、R5、R6、R7及びR8は、水素、重水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C14シクロアルキル、アリール、ヘテロアリール、アリール(C1〜C6アルキル)、−CN、アミノ、(C1〜C6)アルキルアミノ、ジアルキル(C1〜C6)アミノ、ハロアルキル(C1〜C6)、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ヘテロアリール(C1〜C6アルキル)、(C4〜C15)複素環、(C4〜C15)複素環(C1〜C6アルキル)、C3〜C7シクロアルコキシ、C6〜C10アリールオキシからなる群から独立して選択され、
上記アルキル、アリール、シクロアルキル、複素環、ヘテロアリール、アルコキシ、シクロアルコキシ、ハロアルキル又はハロアルコキシは、C1〜C6アルキル、ハロ、CN、CF3、−COOH、−OH、C1〜C6アルコキシ、−NH2、−(C1〜C6アルキル)NH2、−(C1〜C6アルキル)NH(C1〜C6アルキル)、−(C1〜C6アルキル)N(C1〜C6アルキル)2、−NH(C1〜C6アルキル)、−N(C1〜C6アルキル)2、−CONH2、−NH(CO)(C1〜C6アルキル)、−N(C1〜C6アルキル)CO(C1〜C6アルキル)、−SO2−(C1〜C6アルキル)、及び−(SO)NH2からなる群から選択される1以上の置換基で更に任意に置換される)。
2−ベンジル−4−メチル−5−オキソヘキサン酸−化合物(2)、
2−ベンジル−4−メチル−5−オキソオクタ−7−エン酸−化合物(3)、
(6E,8E)−4−フェニル−5−オキソデカ−6,8−ジエン酸−化合物(4)、
5−{[1、1’−ビフェニル]−4−イル}−4−メチル−5−オキソペンタン酸−化合物(5)、
4−メチル−5−オキソ−5−フェニルペンタン酸−化合物(6)、
5−オキソ−4−フェニルヘキサン酸−化合物(7)、
2−(2−シアノエチル)−4−メチル−5−オキソヘキサン酸−化合物(8)、
5−オキソ−4−(2,4,6−トリメチルフェニル)ヘプタン酸−化合物(9)、
4−(4−アミノ−2,6−ジメチルフェニル)−5−オキソ−ヘプタン酸−化合物(10)、
4−[2−メチル−4−トリフルオロメチルフェニル]−5−オキソヘプタン酸−化合物(11)、
(6E,8E)−4−(4−アミノフェニル)−5−オキソデカ−6,8−ジエン酸−化合物(12)、
5−{4’−(ジメチルアミノ)−[1,1’−ビフェニル]−4−イル}−4−メチル−5−オキソペンタン酸−化合物(13)、
5−{4’メトキシ−2’,6’−ジメチル−[1,1’−ビフェニル]−4−イル}−4−メチル−5−オキソペンタン酸−化合物(14)、及び、
4−[4−(トリフルオロメチルベンゾイル]ヘキサ−5−エン酸−化合物(15)。
表1は、様々な式(1)の化合物によるBCAT1酵素活性の阻害を示す。
表2は、様々な式(1)の化合物で処理した後のTGF−β1刺激ヒト線維芽細胞によるコラーゲンIの産生の阻害を示す。
本明細書で使用される「アルキル」の用語は、直鎖及び分岐鎖を含む脂肪族飽和炭化水素を含むと定義される。「C1〜C6アルキル」の用語は、本明細書で参照される他の基(すなわちC1〜C6アルコキシ)のアルキル部分と同様に、1個〜6個の炭素原子の直鎖又は分岐鎖のラジカル(すなわち、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、sec−ブチル、terl−ブチル、n−ペンチル、又はn−ヘキシル)を指す。アルキル基は、1以上(例えば1個〜5個)の好適な置換基によって任意に置換されてもよい。
本発明のBCAT1阻害剤は、本明細書に定義される方法で使用され得る。典型的には、該阻害剤はin vivoでの方法及び使用に対して製剤化される。BCAT1阻害剤、例えば式(I)の化合物を含む製剤を、1以上の局所、経口、直腸、及び非経口(静脈内、皮下、又は筋肉内)の経路によって、それを必要とする被験体に投与してもよい。該製剤はまた、徐放のため疾患部位に埋め込まれる生分解性ポリマーに組み込まれてもよい。製剤の用量は、治療される病状、使用される薬物の活性、投与経路、並びに疾患の重症度及び患者の体重等のその他の臨床的因子に依存する。製剤は、具体的な投与経路に適した方法で製剤化される。
化合物(3)の合成
化合物(3)を以下の概要に従って合成することができる。反応物(16)及び反応物(17)は、商業的に入手可能であるか、又は一般的に当業者に知られている従来技術によって作製することができる。
化合物(4)を以下の概要に従って合成することができる。反応物(18)、反応物(19)、及び反応物(20)はいずれも、商業的に入手可能であるか、又は一般的に当業者に知られている従来技術によって作製することができる。
化合物(5)を以下の概要に従って合成することができる。反応物(21)、反応物(22)、及び反応物(23)はいずれも、商業的に入手可能であるか、又は一般的に当業者に知られている従来技術によって作製することができる。
BCAT1阻害剤の癌の成長を抑制する能力を、細胞増殖アッセイを使用してin vitroで評価する。細胞増殖アッセイは、典型的には適切な培地中のコンフルエントに近い細胞株の定期的な培養を含む。後に、細胞をトリプシン処理して、1つのウェル当たり2000個又は5000個の細胞で96ウェルプレート上に蒔く。細胞を阻害剤の存在下又は不在下で48時間〜96時間培養する。その後、分光光度法(MTTアッセイ、BrdUアッセイ)又は蛍光定量法(Cyquantアッセイ)を使用して細胞増殖を判定する。
in vitro線維症を、TGF−β1又はブレオマイシン等の線維症を進行させる刺激で線維芽細胞を処理した後にコラーゲン合成を測定することにより評価する。培地中へのコラーゲンの分泌を、適切なELISAキットを使用して、順化培地において定量することができる。
関節リウマチ(RA)の病理は、炎症促進性タンパク質を産生するための滑膜細胞の活性化の持続と関係する。抗リウマチ剤を、LPS等の炎症性刺激の存在下でのマクロファージ及び線維芽細胞からの炎症促進性タンパク質の分泌を阻害する能力についてin vitroで試験する。実験の終わりに、ELISA又はウェスタン免疫ブロッティング等の免疫学的アッセイによって細胞の順化培地中での分泌タンパク質を検出する。
コラーゲン誘発関節炎(CIA)は、RAのよく知られている動物炎症モデルである(Brand D. et al, Collagen-induced arthitis, Nature Protocols 2007, 2:1269-1275)。このモデルでは、関節炎(joint arthritis)はアジュバント中の異種性のII型コラーゲンによる免疫化によりラット又はマウスで誘導され、臨床上、動物の四肢の紅斑及び浮腫の存在によって示される。一般に、抗リウマチ剤は関節炎の発症時又は臨床症状が示される際に投与される。実験中、関節炎の存在について動物を採点する。
肺線維症を、1mg/kgのブレオマイシンの気管内投与の後に評価する。抗線維症薬による治療は、一般的にブレオマイシン投与の0日後に開始し、実験は14日後に終了する。肺線維症は、気管支肺胞洗浄液中の白血球数(differential leukocyte count)によって、生化学的に(Sircolアッセイ(Lareu R. et al, Essential modification of the Sircol Collagen Assay for the accurate quantification of collagen content in complex protein solutions, Acta Biomaterialia 2010, 6(8):3146-51)を使用する、均質化された肺におけるコラーゲン含有量の判定)、組織学的に(トリクロームマッソン(TM)染色によるコラーゲン沈着の判定)及び細胞学的に評価される。
化合物(2)の合成
化合物(2)を以下の概要に従って合成した。反応物(24)及び反応物(25)は市販の材料のものとした。1H NMR(400MHz,CDCl3):2.625(4,1H,quint)、2.870(5,2H,d)、1.740(6,2H,t)、2.468(8,1H,tq,)、7.245(9,1H,d)、7.245(10,1H,d)、1.069(12,3H,d)、7.276(13,1H,d)、7.276(14,1H,d)、2.151(16,3H)、7.232(17,1H,t)1H)、2.45〜2.53(m,1H)、5.95〜6.00(m,1H)、7.33〜7.42(m,5H)。
化合物(8)の合成
化合物(8)を以下の概要に従って合成した。反応物(26)及び反応物(27)は市販の材料のものとした。1H NMR(400MHz,CDCl3):2.439(4,1H,quint)、1.715(5,2H,d)、1.857(6,2H,dt)、2.451(7,1H,tq)、2.793(8,2H,t)、1.101(10,3H,d)、2.149(13,3H)
TGF−β1刺激線維芽細胞におけるBCAT1の発現
ヒト線維芽細胞を35mm培養皿上に蒔き、コンフルエントに達するまでインキュベートした。その後、7ng/mLのTGF−β1で上記ヒト線維芽細胞を48時間処理した。細胞溶解物を収集し、ウェスタン免疫ブロッティングによってBCAT1の存在について解析した。実験を4回繰り返した。図1Aは、非刺激(TGF−β1(−))細胞及びTGF−β1刺激(TGF−β1(+))細胞におけるBCAT1発現レベルを示す。図1Bは、4つの実験による正規化されたBCAT1発現レベルを示す。図1Bは、線維芽細胞のTGF−β1刺激がBCAT1発現の3倍の増加をもたらすことを示す。
化合物2、化合物7及び化合物8によるBCAT1酵素活性の阻害
本発明の化合物のBCAT1酵素活性を阻害する能力を分光光度的に確認した。この実験では、0.2μg〜0.5μgのAbcam製組み換えヒトBCAT1を、5μLのピリドキサール−5’−リン酸(PLP)、50mMの硫酸アンモニウム、0.05mMのNADH、5mMのDTT、5mMのa−ケトグルタル酸塩、10mMのロイシン、及び0.95Uのロイシン脱水素酵素(EMD Chemicals)、並びに様々な濃度の化合物2、化合物7、及び化合物8を含む、95μLの反応緩衝液に添加した。反応混合物へのBCAT1の付加は、蛍光定量的に測定される(励起:330nm〜370nm;発光450nm)NADHの消費をもたらした。その後、蛍光変化率を10分間(10サイクル;1サイクル/分)評価した。アッセイを、96ウェルプレートで3回繰り返して行った。表1では、阻害剤の不在下で反応混合物中に観察されるBCAT1活性として定義される、%対照酵素活性(% Control Enzymatic Activity:対照酵素活性に対する百分率(%))として結果を表す。表1は、化合物2、化合物7及び化合物8が、0.5nM〜50nMの範囲のIC50値でBCAT1の酵素活性を阻害可能であることを示す。
全く同じ35mmディッシュ上に蒔いたヒト線維芽細胞のコンフルエント単層を、様々な濃度の化合物2、化合物6及び化合物7で30分間前処理した後、7ng/mLのTGF−β1で48時間細胞を刺激した。実験の終わりに、コンディション培地を収集し、分泌されたコラーゲンIの存在について評価し、一方で細胞を収集して溶解させた。コラーゲンI分泌を製造業者の指示に従ってR&D Systems製のELISAキットを使用して定量し、1μg細胞溶解物当たりの任意吸光度単位として表した。表2では、阻害剤の不在下でTGF−β1で刺激された線維芽細胞培養物に由来する細胞溶解物1μg当たりの分泌されたコラーゲンIの量として定義される、%対照コラーゲン産生(% Control Collagen Production:対照コラーゲン産生に対する百分率(%))として結果を示す。表2は、化合物2、化合物6、及び化合物7が5mM〜10mMの濃度でコラーゲンI分泌を完全に阻害することを示す。
Claims (12)
- 式(1)の化合物:
(式中、
Tは−C(=O)−又は−C(=NH)−からなる群から選択され、
R1及びR2は、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C14シクロアルキル、アリール、ヘテロアリール、アリール(C1〜C6アルキル)、−CN、アミノ、(C1〜C6)アルキルアミノ、ジアルキル(C1〜C6)アミノ、ハロアルキル(C1〜C6)、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ヘテロアリール(C1〜C6アルキル)、(C4〜C15)複素環、(C4〜C15)複素環(C1〜C6アルキル)、C3〜C7シクロアルコキシ、C6〜C10アリールオキシ、並びに(a−1)、(a−2)及び(a−3)の部分からなる群から独立して選択され、
前記アルキル、アリール、シクロアルキル、複素環、ヘテロアリール、アルコキシ、シクロアルコキシ、ハロアルキル又はハロアルコキシは、−C1〜C6アルキル、ハロ、CN、CF3、−COOH、−OH、−C1〜C6アルコキシ、−NH2、−(C1〜C6アルキル)NH2、−(C1〜C6アルキル)NH(C1〜C6アルキル)、−(C1〜C6アルキル)N(C1〜C6アルキル)2、−NH(C1〜C6アルキル)、−N(C1〜C6アルキル)2、−CONH2、−NH(CO)(C1〜C6アルキル)、−N(C1〜C6アルキル)CO(C1〜C6アルキル)、−SO2−(C1〜C6アルキル)、及び−(SO)NH2からなる群から選択される1以上の置換基で更に任意に置換され、
R3は、水素、重水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C14シクロアルキル、アリール、ヘテロアリール、アリール(C1〜C6アルキル)、−CN、アミノ、(C1〜C6)アルキルアミノ、ジアルキル(C1〜C6)アミノ、ハロアルキル(C1〜C6)、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ヘテロアリール(C1〜C6アルキル)、(C4〜C15)複素環、(C4〜C15)複素環(C1〜C6アルキル)、C3〜C7シクロアルコキシ、C6〜C10アリールオキシ、並びに(a−1)、(a−2)及び(a−3)の部分からなる群から選択され、
前記アルキル、アリール、シクロアルキル、複素環、ヘテロアリール、アルコキシ、シクロアルコキシ、ハロアルキル又はハロアルコキシは、C1〜C6アルキル、ハロ、CN、CF3、−COOH、−OH、C1〜C6アルコキシ、−NH2、−(C1〜C6アルキル)NH2、−(C1〜C6アルキル)NH(C1〜C6アルキル)、−(C1〜C6アルキル)N(C1〜C6アルキル)2、−NH(C1〜C6アルキル)、−N(C1〜C6アルキル)2、−CONH2、−NH(CO)(C1〜C6アルキル)、−N(C1〜C6アルキル)CO(C1〜C6アルキル)、−SO2−(C1〜C6アルキル)、及び−(SO)NH2からなる群から選択される1以上の置換基で更に任意に置換され、
R4、R5、R6、R7及びR8は、水素、重水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C14シクロアルキル、アリール、ヘテロアリール、アリール(C1〜C6アルキル)、−CN、アミノ、(C1〜C6)アルキルアミノ、ジアルキル(C1〜C6)アミノ、ハロアルキル(C1〜C6)、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ヘテロアリール(C1〜C6アルキル)、(C4〜C15)複素環、(C4〜C15)複素環(C1〜C6アルキル)、C3〜C7シクロアルコキシ、C6〜C10アリールオキシからなる群から独立して選択され、
前記アルキル、アリール、シクロアルキル、複素環、ヘテロアリール、アルコキシ、シクロアルコキシ、ハロアルキル又はハロアルコキシは、C1〜C6アルキル、ハロ、CN、CF3、−COOH、−OH、C1〜C6アルコキシ、−NH2、−(C1〜C6アルキル)NH2、−(C1〜C6アルキル)NH(C1〜C6アルキル)、−(C1〜C6アルキル)N(C1〜C6アルキル)2、−NH(C1〜C6アルキル)、−N(C1〜C6アルキル)2、−CONH2、−NH(CO)(C1〜C6アルキル)、−N(C1〜C6アルキル)CO(C1〜C6アルキル)、−SO2−(C1〜C6アルキル)、及び−(SO)NH2からなる群から選択される1以上の置換基で更に任意に置換される)。 - Tがカルボニル基であり、
R1がCF3、C2〜C6アルキル、又はC1〜C6シクロアルキルであり、
R2が(C1〜C6)アルキル、ハロ、−CF3、CN、−COOH、−OH、C1〜C6アルコキシ、C1〜C6ハロアルコキシ、−NH2、−(C1〜C6アルキル)NH2、−(C1〜C6アルキル)NH(C1〜C6アルキル)、−(C1〜C6アルキル)N(C1〜C6アルキル)2、−NH(C1〜C6アルキル)、−N(C1〜C6アルキル)2、−CONH2、−NH(CO)(C1〜C6アルキル)、−N(C1〜C6アルキル)CO(C1〜C6アルキル)、−SO2−(C1〜C6アルキル)、及び−(SO)NH2からなる群から選択される1以上の置換基で置換されたアリール基からなる群から選択され、
R3が水素である、請求項1に記載の化合物。 - Tがカルボニル基であり、
R1がC1〜C6アルキル、ハロ、−CF3、CN、−COOH、−OH、C1〜C6アルコキシ、C1〜C6、ハロアルコキシ、−NH2、(C1〜C6アルキル)NH2、(C1〜C6アルキル)NH(C1〜C6アルキル)、−(C1〜C6アルキル)N(C1〜C6アルキル)2、−NH(C1〜C6アルキル)、−N(C1〜C6アルキル)2、−CONH2、−NH(CO)(C1〜C6アルキル)、−N(C1〜C6アルキル)CO(C1〜C6アルキル)、−SO2−(C1〜C6アルキル)、及び−(SO)NH2からなる群から選択される1以上の置換基で置換されたアリール基であり、
R2がC2〜C6アルキル、C1〜C6ハロアルキル、又はC1〜C6シクロアルキルであり、
R3が水素である、請求項1に記載の化合物。 - Tがカルボニル基であり、
R1及びR2がC1〜C6アルキル、C1〜C6ハロアルキル又はC1〜C6シクロアルキルであり、
R3がC1〜C6アルキル、ハロ、CN、−COOH、−OH、C1〜C6アルコキシ、C1〜C6ハロアルコキシ、−NH2、−(C1〜C6アルキル)NH2、−(C1〜C6アルキル)NH(C1〜C6アルキル)、−(C1〜C6アルキル)N(C1〜C6アルキル)2、−NH(C1〜C6アルキル)、−N(C1〜C6アルキル)2、−CONH2、−NH(CO)(C1〜C6アルキル)、−N(C1〜C6アルキル)CO(C1〜C6アルキル)、−SO2−(C1〜C6アルキル)、及び−(SO)NH2からなる群から選択される1以上の置換基で置換されたアリール基である、請求項1に記載の化合物。 - R1が−CH3であり、R2が−CH3であり、R3がベンジル基であり、
- R1がCH3であり、R2が−CH3であり、R3が−(CH2)2CNであり、
- 被験体においてBCAT1介在又はBCAT1関連の障害又は疾患を治療する方法であって、それを必要とする被験体に、治療に有効な量の1以上の請求項1に記載の化合物を含む製剤を投与することを含み、それによって被験体においてBCAT1介在又はBCAT1関連の障害又は疾患を治療する、方法。
- 前記化合物が、化合物(2)〜化合物(15)からなる群から選択される1以上の化合物である、請求項7に記載の方法。
- 前記化合物が、化合物(2)、化合物(6)、及び化合物(7)からなる群から選択される1以上の化合物である、請求項7に記載の方法。
- 前記BCAT1介在疾患が被験体におけるコラーゲン沈着を特徴とする疾患である、請求項7に記載の方法。
- コラーゲン沈着を特徴とする前記疾患が線維症と関連する、請求項10に記載の方法。
- 前記線維症が、肺の線維症、肝臓の線維症、腎臓の線維症、眼の線維症、骨髄に対する線維症、脾臓の線維症、腸の線維症、関節の線維症、喉頭の線維症、声帯の線維症、再狭窄と関連する血管の線維症、及び移植後の線維症からなる群から選択される、請求項11に記載の方法。
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