JP7427109B2 - 副腎白質ジストロフィー又は副腎脊髄ニューロパチーの処置におけるチエノピリドン誘導体の使用 - Google Patents
副腎白質ジストロフィー又は副腎脊髄ニューロパチーの処置におけるチエノピリドン誘導体の使用 Download PDFInfo
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- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Description
式(I):
R2は、ハロゲン原子、アルキル基、ヒドロキシ、アルコキシ基、アミノ、モノ又はジアルキルアミノ基、カルボキシ基、アルキルオキシカルボニル基、モノ又はジアルキルアミノカルボニル基、カルボキサミド、シアノ、アルキルスルホニル及びトリフルオロメチル基から選択される1個又は複数(例えば、2、3、4、5、6又は7個)の基で置換されているか、又は置換されていない、インダニル又はテトラリニル基を表し、
R3は、ハロゲン原子、アルキル基、ヒドロキシ、アルコキシ基、アラルキルオキシ基、アミノ、モノ又はジアルキルアミノ基、カルボキシ基、アルキルオキシカルボニル基、モノ又はジアルキルアミノカルボニル基、カルボキサミド、シアノ、アルキルスルホニル、及びトリフルオロメチル基から選択される、1個又は複数(例えば、2、3、4又は5個)の原子又は基で置換されているか、又は置換されていない、アリール基を表す)
のチエノピリドン誘導体、又はその薬学的に許容される塩及び/若しくは溶媒和物、又は前記チエノピリドン誘導体、又はその薬学的に許容される塩及び/若しくは溶媒和物を含む医薬組成物に関する。
本明細書で使用する場合、以下の用語は、特に明記しない限り、以下の意味であると定義される。
式(I):
R2は、ハロゲン原子、アルキル基、ヒドロキシ、アルコキシ基、アミノ、モノ又はジアルキルアミノ基、カルボキシ基、アルキルオキシカルボニル基、モノ又はジアルキルアミノカルボニル基、カルボキサミド、シアノ、アルキルスルホニル及びトリフルオロメチル基から選択される1個又は複数(例えば、2、3、4、5、6又は7個)の基で置換されているか、又は置換されていない、インダニル又はテトラリニル基を表し、
R3は、ハロゲン原子、アルキル基、ヒドロキシ、アルコキシ基、アラルキルオキシ基、アミノ、モノ又はジアルキルアミノ基、カルボキシ基、アルキルオキシカルボニル基、モノ又はジアルキルアミノカルボニル基、カルボキサミド、シアノ、アルキルスルホニル、及びトリフルオロメチル基から選択される1個又は複数(例えば、2、3、4又は5個)の原子又は基で置換されているか、又は置換されていない、アリール基を表す)
のチエノピリドン誘導体、又はその薬学的に許容される塩及び/若しくは溶媒和物の特定の使用に関する。
・ R1がハロゲン原子、特に塩素原子を表す、
・ R2が置換されていないか、又は少なくとも1個のヒドロキシ基を含む1若しくは2個の置換基で置換されている、
・ R2がテトラリニル基である、
・ R3が、置換されていないか、又は1若しくは2個の置換基で置換されているフェニルを表す、
・ 式(I)の化合物が塩の形態、好ましくはナトリウム又はカリウム塩、更に好ましくはカリウム塩である、
・ 式(I)の化合物が、溶媒和物の形態、好ましくは水和物、更に好ましくは一水和物である。
・ R1がハロゲン原子、特に塩素原子を表す、
・ R2が、少なくとも1個のヒドロキシ基を含む1又は2個の置換基で置換されている、
・ R2がテトラリニル基である、
・ R3が、置換されていないフェニル基を表す、
・ 式(I)の化合物が塩の形態、好ましくはナトリウム又はカリウム塩、更に好ましくはカリウム塩である、
・ 式(I)の化合物が、溶媒和物の形態、好ましくは水和物、更に好ましくは一水和物である。
・ R1がハロゲン原子、特に塩素原子を表す、
・ R2が、少なくとも1個のヒドロキシ基を含む1又は2個の置換基で置換されている、
・ R2がインダニル基である、
・ R3が、置換されていないか、又は1若しくは2個の置換基で置換されているフェニル基を表す。
2-クロロ-4-ヒドロキシ-3-インダン-5-イル-5-フェニル-7H-チエノ[2,3-b]ピリジン-6-オン
2-クロロ-5-(4-フルオロフェニル)-4-ヒドロキシ-3-インダン-5-イル-7H-チエノ[2,3-b]ピリジン-6-オン
2-クロロ-4-ヒドロキシ-3-インダン-5-イル-5-(3-メトキシフェニル)-7H-チエノ[2,3-b]ピリジン-6-オン
2-クロロ-4-ヒドロキシ-3-インダン-5-イル-5-(4-メトキシフェニル)-7H-チエノ[2,3-b]ピリジン-6-オン
3-(2-クロロ-4-ヒドロキシ-3-インダン-5-イル-6-オキソ-7H-チエノ[2,3-b]ピリジン-5-イル)ベンゾニトリル
2-クロロ-4-ヒドロキシ-3-インダン-5-イル-5-(3-メチルフェニル)-7H-チエノ[2,3-b]ピリジン-6-オン
2-クロロ-5-(4-フルオロフェニル)-4-ヒドロキシ-3-(4-ヒドロキシインダン-5-イル)-7H-チエノ[2,3-b]ピリジン-6-オン
2-クロロ-5-(3-フルオロフェニル)-4-ヒドロキシ-3-(4-ヒドロキシインダン-5-イル)-7H-チエノ[2,3-b]ピリジン-6-オン
2-クロロ-4-ヒドロキシ-3-(4-ヒドロキシインダン-5-イル)-5-フェニル-7H-チエノ[2,3-b]ピリジン-6-オン
2-クロロ-5-(2-フルオロフェニル)-4-ヒドロキシ-3-(4-ヒドロキシインダン-5-イル)-7H-チエノ[2,3-b]ピリジン-6-オン
2-クロロ-4-ヒドロキシ-3-(5-ヒドロキシテトラリン-6-イル)-5-フェニル-7H-チエノ[2,3-b]ピリジン-6-オン
3-(2-クロロ-4-ヒドロキシ-6-オキソ-3-テトラリン-6-イル-7H-チエノ[2,3-b]ピリジン-5-イル)ベンゾニトリル
三ナトリウム2-クロロ-3-(5-オキシドテトラリン-6-イル)-5-フェニル-チエノ[2,3-b]ピリジン-4,6-ジオレート
2-クロロ-4-ヒドロキシ-5-フェニル-3-テトラリン-6-イル-7H-チエノ[2,3-b]ピリジン-6-オン
2-クロロ-5-(4-フルオロフェニル)-4-ヒドロキシ-3-(5-ヒドロキシテトラリン-6-イル)-7H-チエノ[2,3-b]ピリジン-6-オン
二ナトリウム2-クロロ-3-(5-オキシドテトラリン-6-イル)-6-オキソ-5-フェニル-7H-チエノ[2,3-b]ピリジン-4-オレート
2-クロロ-4-ヒドロキシ-3-(5-ヒドロキシテトラリン-6-イル)-5-(3-メチルフェニル)-7H-チエノ[2,3-b]ピリジン-6-オン
2-クロロ-4-ヒドロキシ-3-(5-ヒドロキシテトラリン-6-イル)-5-(4-メチルフェニル)-7H-チエノ[2,3-b]ピリジン-6-オン
2-クロロ-5-(3-フルオロフェニル)-4-ヒドロキシ-3-(5-ヒドロキシテトラリン-6-イル)-7H-チエノ[2,3-b]ピリジン-6-オン
ナトリウム2-クロロ-3-(5-ヒドロキシテトラリン-6-イル)-6-オキソ-5-フェニル-7H-チエノ[2,3-b]ピリジン-4-オレート、
カリウム2-クロロ-3-(5-ヒドロキシテトラリン-6-イル)-6-オキソ-5-フェニル-7H-チエノ[2,3-b]ピリジン-4-オレート。
下記式(Ia):
式(Ib):
式(Ic):
(A)式(II):
(B)沈殿を形成させる工程と;
(C)工程(B)で得られた沈殿を、好ましくはろ過により回収する工程と
を含む方法により調製することができる。
(a)6-アセチル-5-ヒドロキシテトラリンを、塩基の存在下で求電子性ベンジル源、好ましくは臭化ベンジルと反応させる工程と;
(b)工程(a)で得られた化合物を、ヘキサメチルジシラザン及び酢酸の存在下でシアノ酢酸エチルと反応させる工程と;
(c)工程(b)で得られた化合物を、塩基の存在下で硫黄と反応させる工程と;
(d)場合により、工程(c)で得られた化合物の塩、好ましくは塩酸塩を形成する工程と;
(e)工程(c)又は(d)で得られた化合物を、求電子性塩素源、好ましくはN-クロロスクシンイミドと反応させる工程と;
(f)工程(e)で得られた化合物をフェニルアセチルクロリドと反応させる工程と;
(g)工程(f)で得られた化合物を塩基と反応させる工程と;
(h)工程(g)で得られた化合物を、三臭化ホウ素又は三塩化ホウ素、好ましくは三塩化ホウ素と反応させる工程と;
(i)場合により、工程(h)で得られた化合物を回収する工程と
を含む、改善された方法により得ることができる。
PXL770の合成
略語
a/a:スペクトル又はクロマトグラム上の所定の化合物のピーク面積とピーク面積の合計との比。eq
分析法
XRPD
粉末X線回折(XRPD)分析は、Cu(Kアルファ線)X線管及びピクセル検出システムを備えたPanalytical Xpert Pro回折計を使用して行った。試料を透過モードで分析し、低密度ポリエチレンフィルムの間に保持した。HighScore Plus 2.2cソフトウェアを使用してXRPDパターンを分類し、処理し、インデックスを付けた。
熱重量(TG)分析は、Perkin Elmer社製Diamond Thermogravimetric/Differential Temperature Analyser(TG/DTA)を用いて実施した。キャリブレーション標準物質はインジウム及びスズであった。試料をアルミニウム試料皿に入れ、TG炉へ装入し、正確に秤量した。試料を窒素流中で30~300℃まで10℃/分の速度で加熱した。試料の分析の前に炉の温度を30℃で平衡化させた。
化合物(I)を水/イソプロパノール混合物(1/1、5部の各溶媒)中に懸濁させ、次いで0.50~0.55当量の炭酸カリウムを添加した。炭酸カリウムの添加終了時点でpHは約12であった(pH試験紙)。50℃で3時間撹拌した後、懸濁液は濃くなり、pHは約8であった(pH試験紙)。溶液が得られるまで温度を80℃に上昇させた(10~15分間)。必要に応じて、プロセスのこの時点で清澄化を行うことができる。7部の水を添加し、次いで反応混合物を40℃まで冷却した(濁った溶液が観察された)。7部の溶媒が反応器中に残るまで、溶媒を減圧下(180mbar~40mbar)、40℃で蒸留した。ここで、カリウム塩一水和物の結晶化が生じる可能性がある。4.2部の水を添加し、混合物に化合物(I)のシード(1~2%のシード)を添加した。次いで、懸濁液を7時間で40℃から5℃まで冷却し(5℃/時間)、5℃で数時間維持した。懸濁液をろ過した。ケーキを1.42部の水で2回洗浄した。収集した固体を真空下、40℃で乾燥させて、必要とされる化学純度(すなわち98%+)において化合物(Ia)を収率80%以上で得た。
PXL770の特性決定
a)化合物(Ia)の粉末X線回折(XRPD)データにより、この化合物が結晶性物質で構成されていることがわかった。化合物(Ia)のXRPDの説明をTable 1(表2)に示す。
PXL770で処置したAMN患者由来リンパ球中の超長鎖脂肪酸(VLCFA)レベルの低下
血漿及び組織(脳及び脊髄を含む)中の超長鎖脂肪酸(VLCFA)の蓄積は、AMN病の特徴である。VLCFAの負荷は疾患の重症度と共に増加し、VLCFAを低下させることで炎症反応が抑止されることが文献で示されている。したがって、特に中枢神経系においてVLCFAの過負荷を低下させることにより、AMNの疾患進行を停止し、又は回復させる可能性がある。
PXL770の存在下で培養したAMN線維芽細胞におけるABCD2の過剰発現
AMNの治療研究では、機能的に不要な(redundant)なペルオキシソーム輸送体である副腎白質ジストロフィー関連タンパク質(ABCD2、別名ALDRP)の誘導にも焦点が当てられている。ABCD2は、AMNで変異/欠失した遺伝子であるABCD1(別名ALDP)との有意な配列類似性を有するため、過剰発現させるとABCD1の欠損を補うことができる。AMN線維芽細胞の培養液にPXL770が存在すると、ABCD2レベルの発現が増加することを示すために、PXL770の非存在下及び存在下で、AMN線維芽細胞におけるABCD2レベルを比較するためのウェスタンブロットを実施した。より具体的には、以下のようにしてタンパク質抽出を行った。
AMNマウス混合グリア細胞中の超長鎖脂肪酸(VLCFA)レベルの低下
本発明者らは、AMNマウス混合グリア細胞において、無処置の場合とPXL770を種々の用量で処置した場合のVLCFA蓄積の測定試験を実施した。
PXL770存在下でのALD-KOマウス大脳皮質混合グリア細胞中のABCD2の過剰発現
ALD-KOマウス大脳皮質混合グリア細胞について、実施例4と同じ実験プロトコルを実施した。このモデルは、主にAMNのモデルである。
PXL770で処置したALD患者由来リンパ球中の超長鎖脂肪酸(VLCFA)レベルの低下
最も重症型のALD(AMN)患者由来の細胞に関する試験の後、本発明者らは、実施例1と同じ試験方法を反復して、X-ALD患者(重症炎症表現型)由来の細胞に対するPXL770の効果を分析した。
PXL770の存在下で培養したALD線維芽細胞中のABCD2の過剰発現
実施例4と同様に、ALD患者の線維芽細胞の培養液においてPXL770が存在するとABCD2の発現レベルが増加することを示すために、PXL770の非存在下及び存在下でのALD患者の線維芽細胞中のABCD2のレベルを比較するためのウェスタンブロットを実施した。
X-ALDマウスにおけるインビボ実験
雄のABCD1-KOマウス(n=15)を、PXL770(75mg/kg)を1日2回、60日間毎日、経管栄養経口投与で処置した。未処置のABCD1-KOマウス(n=15)及び野生型(WT)マウス(n=12)を対照とした。処置後のマウスを殺処分し、VLCFA分析のために大脳皮質及び血漿を採取した。分析はLipidomics Core Facilityの標準プロトコルに従って行い、データはVLCFAμg/mlレベルで表示した。代表的なVLCFAとしてヘキサコサン酸(C26:0)を選択した。
メトホルミンで処置したAMN及びALD患者由来のリンパ球中の超長鎖脂肪酸(VLCFA)レベルの低下
実施例3及び7に記載の実験は同じ研究室によってメトホルミンで実施され、Singhら、Journal of Neurochemistry、2016年;第138巻、86~100頁に記載されている。
PXL770及びメトホルミンの直接比較
PXL770及びメトホルミンのインビトロにおける超長鎖脂肪酸(VLCFA)を低下させる有効性を比較するため、試験では、健常対照細胞及びAMNヒト患者由来初代線維芽細胞におけるVLCFAとして最も多く存在するヘキサコサン酸のレベル評価に焦点を当てる。細胞株はCoriell Cell Repositories社から入手した。線維芽細胞は、15%FBSを含むDMEM中で培養した。培養物は1:5の比で分割した。健常な患者からの線維芽細胞を対照として使用した。全ての処置は、ウシ胎児血清(FBS、15%)を含有する完全培地中で行った。全ての培養細胞は、37℃、5%CO2で維持した。
メトホルミン存在下で培養したAMN及びALD患者の線維芽細胞中のABCD2の過剰発現
実施例4及び6に記載の実験は同じ研究室によってメトホルミンで実施され、Singhら、Journal of Neurochemistry、2016年;第138巻、86~100頁に記載されている。
メトホルミン存在下におけるAMN-KOマウス大脳皮質混合グリア細胞中のABCD2の過剰発現
実施例6と同じ実験プロトコルは同じ研究室によってメトホルミンで実施され、Singhら、Journal of Neurochemistry、2016年;第138巻、86~100頁に記載されている。
X-ALDマウスによるインビボ実験
雄のABCD1-KOマウス(n=8)を、PXL770(75mg/kg)を1日2回、90日間毎日、経管栄養経口投与で処置した。未処置のABCD1-KOマウス(n=8)及び野生型(WT)マウス(n=8)を対照とした。処置後のマウスを殺処分し、VLCFA分析のために脊髄を採取した。分析はLipidomics Core Facilityの標準プロトコルに従って行い、データはVLCFAμg/mlレベルで表示した。代表的なVLCFAとしてヘキサコサン酸(C26:0)を選択した。
種々のチエノピリドンで処置したAMN患者由来線維芽細胞中の超長鎖脂肪酸(VLCFA)レベルの低下
実施例3に記載した実験を種々のチエノピリドン化合物、すなわち以下の化合物を用いて再現し、それぞれ0.1~5μMの濃度で試験した。
PXL770:カリウム2-クロロ-3-(5-ヒドロキシテトラリン-6-イル)-6-オキソ-5-フェニル-7H-チエノ[2,3-b]ピリジン-4-オレート、
PXL700:2-クロロ-4-ヒドロキシ-3-インダン-5-イル-5-(3-ピリジル)-7H-チエノ[2,3-b]ピリジン-6-オン、
PXL702:2-クロロ-4-ヒドロキシ-3-(4-ヒドロキシインダン)-5-イル)-5-フェニル-7H-チエノ[2,3-b]ピリジン-6-オン、
PXL695:2-クロロ-5-(3-フルオロフェニル)-4-ヒドロキシ-3-(4-ヒドロキシインダン-5-イル)-7H-チエノ[2,3-b]ピリジン-6-オン。
Claims (11)
- 副腎白質ジストロフィー及び/又は副腎脊髄ニューロパチーの処置における使用のための医薬組成物であって、(i)式(II):
- (i)式(II):
- 前記化合物が、式(Ia):
- ヒト患者に対して、0.5mg~3000mgの1日用量で、1日1回又は2回投与される、請求項1~3のいずれか一項に記載の医薬組成物。
- 20mg~1000mgの1日用量で、1日1回又は2回投与される、請求項4に記載の医薬組成物。
- 60mg~500mgの1日用量で、1日1回又は2回投与される、請求項5に記載の医薬組成物。
- 中枢性脱髄、副腎皮質機能不全又は副腎機能不全を処置するのに有効である、請求項1~6のいずれか一項に記載の医薬組成物。
- 副腎白質ジストロフィー及び/又は副腎脊髄ニューロパチーに罹患した対象に対して、超長鎖脂肪酸(VLCFA)のレベルを低下させるための、請求項1~6のいずれか一項に記載の医薬組成物。
- 2~10歳の対象における副腎白質ジストロフィーの処置における使用のための、請求項1~8のいずれか一項に記載の医薬組成物。
- 成人対象における副腎脊髄ニューロパチーの処置における使用のための、請求項1~8のいずれか一項に記載の医薬組成物。
- 経口経路により投与される、請求項1~10のいずれか一項に記載の医薬組成物。
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