JPWO2021168161A5 - - Google Patents
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- JPWO2021168161A5 JPWO2021168161A5 JP2022549839A JP2022549839A JPWO2021168161A5 JP WO2021168161 A5 JPWO2021168161 A5 JP WO2021168161A5 JP 2022549839 A JP2022549839 A JP 2022549839A JP 2022549839 A JP2022549839 A JP 2022549839A JP WO2021168161 A5 JPWO2021168161 A5 JP WO2021168161A5
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Description
本明細書では種々の態様及び実施形態を開示したが、当業者には他の態様及び実施形態が明白であろう。本明細書で開示した種々の態様及び実施形態は説明のためであり、限定する意図ではなく、真の範囲及び精神は、下記特許請求の範囲によって示される。
本発明のまた別の態様は、以下のとおりであってもよい。
〔1〕非肝線維症を治療する方法であって、それを必要とする被験者に、下記式L:
a. R’は、H又はアセチルであり;
b. R1は、2~15炭素原子長の飽和又は不飽和の直線状又は分岐脂肪族炭素鎖であり;
c. R2は、下記:
i. H;
ii. 非置換、N置換、又はN,N二置換アミド;
iii. N置換又は非置換アシル保護アミン;
iv. N置換又は非置換アミン;
v. カルボン酸;
vi. ニトリル;
vii. エステル;
viii. ケトン;
ix. ヒドロキシ、ジヒドロキシ、トリヒドロキシ、又はポリヒドロキシアルキル;及び
x. 置換又は非置換アリール;
xi. 任意に、水素、ケトン、ヒドロキシル、ニトリル、カルボン酸、エステル、1,3-ジオキソラン、ハロゲン、及びオキソから成る群より選択される置換基を含有してよい飽和又は不飽和の直線状又は分岐脂肪族鎖;
xii. ハロゲン、エステル、及びニトロから成る群より選択される置換基を含有する芳香族基;及び
xiii. (xi)の飽和又は不飽和の直線状又は分岐脂肪族鎖及び(xii)の芳香族基の組み合わせ
から成る群より選択され;及び
d. R23は、飽和又は不飽和の直鎖又は分岐した任意に置換されていてもよい脂肪族炭素鎖である)
のシクロスポリン類似体、又はその医薬的に許容される塩、溶媒和物、立体異性体を含む組成物を投与することを含む、前記方法。
〔2〕前記それを必要とする被験者が、非肝線維症を患っている被験者である、前記〔1〕に記載の方法。
〔3〕前記被験者の非肝線維症の量を減少させることを含む、前記〔1〕~〔2〕のいずれか1項に記載の方法。
〔4〕前記被験者の非肝線維症の量が、5%、10%、20%、又はそれ以上減少する、前記〔3〕に記載の方法。
〔5〕前記被験者の非肝線維症の形成を減少させることを含む、前記〔1〕~〔2〕のいずれか1項に記載の方法。
〔6〕前記被験者の非肝線維症の形成が、5%、10%、20%、又はそれ以上減少する、前記〔5〕に記載の方法。
〔7〕前記非肝線維症が、肺、腎臓、心臓、皮膚、眼、胃腸管、腹膜、骨髄、筋、血管、脈管構造の線維症、又はその任意の組み合わせを含む、前記〔1〕~〔6〕のいずれか1項に記載の方法。
〔8〕前記それを必要とする被験者が、特発性肺線維症(IPF)、心臓線維症、皮膚線維症、腎線維症、又はその組み合わせから成る群より選択される線維性障害を患っている被験者である、前記〔1〕~〔6〕のいずれか1項に記載の方法。
〔9〕線維症の発生を予防するか又は遅延させる方法であって、それを必要とする被験者に、下記式L:
a. R’は、H又はアセチルであり;
b. R1は、2~15炭素原子長の飽和又は不飽和の直線状又は分岐脂肪族炭素鎖であり;
c. R2は、下記:
i. H;
ii. 非置換、N置換、又はN,N二置換アミド;
iii. N置換又は非置換アシル保護アミン;
iv. N置換又は非置換アミン;
v. カルボン酸;
vi. ニトリル;
vii. エステル;
viii. ケトン;
ix. ヒドロキシ、ジヒドロキシ、トリヒドロキシ、又はポリヒドロキシアルキル;及び
x. 置換又は非置換アリール;
xi. 任意に、水素、ケトン、ヒドロキシル、ニトリル、カルボン酸、エステル、1,3-ジオキソラン、ハロゲン、及びオキソから成る群より選択される置換基を含有してよい飽和又は不飽和の直線状又は分岐脂肪族鎖;
xii. ハロゲン、エステル、及びニトロから成る群より選択される置換基を含有する芳香族基;及び
xiii. (xi)の飽和又は不飽和の直線状又は分岐脂肪族鎖及び(xii)の芳香族基の組み合わせ
から成る群より選択され;及び
d. R23は、飽和又は不飽和の直鎖又は分岐した任意に置換されていてもよい脂肪族炭素鎖である)
のシクロスポリン類似体、又はその医薬的に許容される塩、溶媒和物、立体異性体を含む組成物を投与することを含む、前記方法。
〔10〕前記それを必要とする被験者が、線維症を発症するリスクがある被験者である、前記〔9〕に記載の方法。
〔11〕前記それを必要とする被験者が、線維症の進行がない被験者である、前記〔9〕~〔10〕のいずれか1項に記載の方法。
〔12〕前記被験者の線維症を発症するリスクが、未治療被験者に比べて、少なくとも5%、10%、20%又はそれ以上減少する、前記〔10〕~〔11〕のいずれか1項に記載の方法。
〔13〕線維症の発生が、前記被験者において少なくとも1カ月、1年、又はそれ以上遅延する、前記〔9〕~〔12〕のいずれか1項に記載の方法。
〔14〕線維症形成を減少させることを含み、前記線維症形成が、未治療被験者に比べて、被験者において少なくとも1カ月、1年、又はそれ以上減少する、前記〔9〕~〔13〕のいずれか1項に記載の方法。
〔15〕線維症を減少させるか又は線維症を回復させる方法であって、それを必要とする被験者に、下記式L:
a. R’は、H又はアセチルであり;
b. R1は、2~15炭素原子長の飽和又は不飽和の直線状又は分岐脂肪族炭素鎖であり;
c. R2は、下記:
i. H;
ii. 非置換、N置換、又はN,N二置換アミド;
iii. N置換又は非置換アシル保護アミン;
iv. N置換又は非置換アミン;
v. カルボン酸;
vi. ニトリル;
vii. エステル;
viii. ケトン;
ix. ヒドロキシ、ジヒドロキシ、トリヒドロキシ、又はポリヒドロキシアルキル;及び
x. 置換又は非置換アリール;
xi. 任意に、水素、ケトン、ヒドロキシル、ニトリル、カルボン酸、エステル、1,3-ジオキソラン、ハロゲン、及びオキソから成る群より選択される置換基を含有してよい飽和又は不飽和の直線状又は分岐脂肪族鎖;
xii. ハロゲン、エステル、及びニトロから成る群より選択される置換基を含有する芳香族基;及び
xiii. (xi)の飽和又は不飽和の直線状又は分岐脂肪族鎖及び(xii)の芳香族基の組み合わせ
から成る群より選択され;及び
d. R23は、飽和又は不飽和の直鎖又は分岐した任意に置換されていてもよい脂肪族炭素鎖である)
のシクロスポリン類似体、又はその医薬的に許容される塩、溶媒和物、立体異性体を含む組成物を投与することを含む、前記方法。
〔16〕前記それを必要とする被験者が、線維症を患っている被験者である、前記〔15〕に記載の方法。
〔17〕前記被験者の線維症形成を抑制することを含む、前記〔9〕~〔16〕のいずれか1項に記載の方法。
〔18〕前記線維症が非肝線維症である、前記〔9〕~〔17〕のいずれか1項に記載の方法。
〔19〕非肝線維症が、肺、腎臓、心臓、皮膚、眼、胃腸管、腹膜、骨髄、筋、血管、脈管構造の線維症、又はその任意の組み合わせを含む、前記〔18〕に記載の方法。
〔20〕前記それを必要とする被験者が、肺線維症、心臓線維症、皮膚線維症、腎線維症、肝線維症、又はその組み合わせから成る群より選択される線維性障害を患っている被験者である、前記〔9〕~〔17〕のいずれか1項に記載の方法。
〔21〕前記それを必要とする被験者が、特発性肺線維症(IPF)を患っている被験者である、前記〔9〕~〔17〕のいずれか1項に記載の方法。
〔22〕前記線維症が肝線維症である、前記〔9〕~〔17〕のいずれか1項に記載の方法。
〔23〕前記肝線維症が肝硬変である、前記〔22〕に記載の方法。
〔24〕前記肝硬変が、ウイルス性肝炎、住血吸虫症及び慢性アルコール症と関連する、前記〔23〕に記載の方法。
〔25〕式Lのシクロスポリン類似体が、下記CRV431である、前記〔1〕~〔24〕のいずれか1項に記載の方法。
〔27〕前記非肝線維症又は線維症が、治療薬、損傷、又はその組み合わせによって誘発される、前記〔1〕~〔26〕のいずれか1項に記載の方法。
〔28〕前記非肝線維症又は線維症が、外傷、炎症、組織修復、免疫反応、細胞の過形成、腫瘍、その組み合わせ後に起こる細胞外マトリックス成分の蓄積と関連する、前記〔1〕~〔26〕のいずれか1項に記載の方法。
〔29〕前記非肝線維症又は線維症が、主要臓器疾患、線維増殖性障害、外傷に伴う瘢痕、又はその組み合わせと関連する、前記〔1〕~〔26〕のいずれか1項に記載の方法。
〔30〕前記線維症が、間質性肺疾患、肝硬変、非アルコール性脂肪性肝疾患、非アルコール性脂肪性肝炎、腎疾患、心疾患又は血管疾患、眼疾患、全身性及び局所性強皮症、ケロイド、肥厚性瘢痕、アテローム性動脈硬化症、再狭窄、デュピュイトラン拘縮、手術合併症、化学療法薬誘発線維症、放射線誘発線維症、事故による損傷及び熱傷、後腹膜線維症、腹膜線維症/腹膜瘢痕、又はその組み合わせと関連する、前記〔9〕~〔26〕のいずれか1項に記載の方法。
〔31〕前記間質性肺疾患と関連する線維症が、サルコイドーシス、珪肺症、薬物反応、感染症、コラーゲン血管疾患、関節リウマチ、全身性硬化症、強皮症、肺線維症、特発性肺線維症、通常型間質性肺炎、間質性肺疾患、原因不明線維化性肺胞炎、閉塞性細気管支炎、気管支拡張症、又はその組み合わせである、前記〔30〕に記載の方法。
〔32〕被験者の線維症形成を、未治療被験者に比べて少なくとも5%、10%、20%、50%、70%、90%、又はそれ以上減少させることを含む、前記〔9〕~〔31〕のいずれか1項に記載の方法。
〔33〕前記被験者の線維症形成を、未治療被験者に比べて遅延させることを含む、前記〔9〕~〔31〕のいずれか1項に記載の方法。
〔34〕前記被験者が哺乳動物である、前記〔1〕~〔33〕のいずれか1項に記載の方法。
〔35〕前記被験者がヒトである、前記〔1〕~〔33〕のいずれか1項に記載の方法。
〔36〕前記組成物が、1種以上の医薬的に許容される賦形剤を含む、前記〔1〕~〔35〕のいずれか1項に記載の方法。
〔37〕前記組成物が、1種以上の追加治療薬を含む、前記〔1〕~〔36〕のいずれか1項に記載の方法。
〔38〕前記それを必要とする被験者に1種以上の追加治療薬を投与することをさらに含む、前記〔1〕~〔36〕のいずれか1項に記載の方法。
〔39〕前記1種以上の追加治療薬が、追加の抗線維化薬を含む、前記〔37〕又は〔38〕に記載の方法。
〔40〕前記1種以上の追加治療薬が、II型インターフェロン受容体作動薬、ピルフェニドン及びピルフェニドン類似体、ニンテダニブ及びニンテダニブ類似体、抗血管新生薬、抗炎症薬、IL-1拮抗薬、アンジオテンシン変換酵素(ACE)阻害薬、アンジオテンシン受容体遮断薬及びアルドステロン拮抗薬、マイトマイシンC(MMC)、5-フルオロウラシル(5-FU)、アデニリルシクラーゼ活性化薬、β-アドレナリン受容体(adenoreceptor)作動薬、フラボノイド、マスト細胞安定化薬、ホスホジエステラーゼ阻害薬、プロシアニジン、又はその組み合わせを含む、前記〔37〕又は〔38〕に記載の方法。
〔41〕前記1種以上の追加治療薬の少なくとも1つが、前記被検者に、前記組成物と同時投与される、前記〔37〕~〔40〕のいずれか1項に記載の方法。
〔42〕前記1種以上の追加治療薬の少なくとも1つが、前記被験者に、前記組成物の投与前、前記組成物の投与後、又は前記組成物の投与前後に投与される、前記〔37〕~〔40〕のいずれか1項に記載の方法。
〔43〕前記組成物が、前記被験者に静脈内投与、経口投与、非経口投与によって投与される、前記〔1〕~〔42〕のいずれか1項に記載の方法。
〔44〕前記組成物が、粉末、丸剤、錠剤、マイクロタブレット、ペレット、マイクロペレット、カプセル剤、マイクロタブレット含有カプセル剤、液剤、エアロゾル、又はナノ粒子の形態である、前記〔1〕~〔43〕のいずれか1項に記載の方法。
〔45〕前記組成物が、前記被験者に、10mg~250mgの、前記シクロスポリン類似体又はその医薬的に許容される塩、溶媒和物、立体異性体の有効な1日用量で投与される、前記〔1〕~〔44〕のいずれか1項に記載の方法。
〔46〕線維症の予防若しくは治療に使用するため、又は線維症形成の予防若しくは減少に使用するため、又は線維症の回復に使用するため、又は線維症の量の減少のため、又は線維症の発生の遅延のための、下記式L:
a. R’は、H又はアセチルであり;
b. R1は、2~15炭素原子長の飽和又は不飽和の直線状又は分岐脂肪族炭素鎖であり;
c. R2は、下記:
i. H;
ii. 非置換、N置換、又はN,N二置換アミド;
iii. N置換又は非置換アシル保護アミン;
iv. N置換又は非置換アミン;
v. カルボン酸;
vi. ニトリル;
vii. エステル;
viii. ケトン;
ix. ヒドロキシ、ジヒドロキシ、トリヒドロキシ、又はポリヒドロキシアルキル;及び
x. 置換又は非置換アリール;
xi. 任意に、水素、ケトン、ヒドロキシル、ニトリル、カルボン酸、エステル、1,3-ジオキソラン、ハロゲン、及びオキソから成る群より選択される置換基を含有してよい飽和又は不飽和の直線状又は分岐脂肪族鎖;
xii. ハロゲン、エステル、及びニトロから成る群より選択される置換基を含有する芳香族基;及び
xiii. (xi)の飽和又は不飽和の直線状又は分岐脂肪族鎖及び(xii)の芳香族基の組み合わせ
から成る群より選択され;及び
d. R23は、飽和又は不飽和の直鎖又は分岐した任意に置換されていてもよい脂肪族炭素鎖である)
のシクロスポリン類似体、又はその医薬的に許容される塩、溶媒和物、立体異性体を含む医薬組成物。
〔47〕前記シクロスポリン類似体が下記CRV431である、前記〔46〕に記載の医薬組成物。
〔49〕前記医薬組成物が、粉末、丸剤、錠剤、マイクロタブレット、ペレット、マイクロペレット、カプセル剤、マイクロタブレット含有カプセル剤、液剤、エアロゾル、又はナノ粒子の形態である、前記〔46〕~〔48〕のいずれか1項に記載の医薬組成物。
〔50〕前記〔46〕~〔49〕のいずれか1項に記載の医薬組成物;及び
ラベルを含むキットであって、前記ラベルは、下記:
(a)前記キットが、線維症の予防又は治療用であること、
(b)前記キットが、線維症形成の減少又は抑制用であること、
(c)前記キットが、線維症の回復用であること、
(d)前記キットが、線維症の量の減少用であること、及び
(e)前記キットが、線維症の発生の遅延用であること
の1つ以上を示している、前記キット。
〔51〕線維症を発症するリスクがある被験者を識別するための説明書、線維症を患っている被験者を識別するための説明書、又は両方をさらに含む、前記〔50〕に記載のキット。
Although various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are illustrative and not intended to be limiting, with the true scope and spirit being indicated by the following claims.
Another aspect of the present invention may be as follows.
[1] A method for treating non-hepatic fibrosis, in which a subject in need thereof is given the following formula L:
a. R' is H or acetyl;
b. R1 is a saturated or unsaturated straight or branched aliphatic carbon chain from 2 to 15 carbon atoms in length;
c. R2 is as follows:
i.H;
ii. unsubstituted, N-substituted or N,N-disubstituted amide;
iii. N-substituted or unsubstituted acyl protected amines;
iv. N-substituted or unsubstituted amines;
v. Carboxylic acid;
vi. Nitrile;
vii. ester;
viii. Ketones;
ix. Hydroxy, dihydroxy, trihydroxy, or polyhydroxyalkyl; and
x. Substituted or unsubstituted aryl;
xi. Saturated or unsaturated linear or branched aliphatic chain;
xii. an aromatic group containing a substituent selected from the group consisting of halogen, ester, and nitro; and
xiii. A combination of a saturated or unsaturated linear or branched aliphatic chain of (xi) and an aromatic group of (xii)
selected from the group consisting of; and
d. R23 is a saturated or unsaturated straight or branched optionally substituted aliphatic carbon chain)
or a pharmaceutically acceptable salt, solvate, stereoisomer thereof.
[2] The method according to [1] above, wherein the subject in need thereof is a subject suffering from non-hepatic fibrosis.
[3] The method according to any one of [1] to [2] above, which comprises reducing the amount of non-hepatic fibrosis in the subject.
[4] The method according to [3] above, wherein the amount of non-hepatic fibrosis in the subject is reduced by 5%, 10%, 20%, or more.
[5] The method according to any one of [1] to [2] above, which comprises reducing the formation of non-hepatic fibrosis in the subject.
[6] The method according to [5] above, wherein the formation of non-hepatic fibrosis in the subject is reduced by 5%, 10%, 20%, or more.
[7] [1] above, wherein the non-hepatic fibrosis includes fibrosis of the lungs, kidneys, heart, skin, eyes, gastrointestinal tract, peritoneum, bone marrow, muscles, blood vessels, vasculature, or any combination thereof; ~ The method described in any one of [6].
[8] The subject in need thereof is suffering from a fibrotic disorder selected from the group consisting of idiopathic pulmonary fibrosis (IPF), cardiac fibrosis, skin fibrosis, renal fibrosis, or a combination thereof. The method according to any one of [1] to [6] above, wherein the subject is a subject.
[9] A method for preventing or delaying the onset of fibrosis, in which a subject in need thereof is provided with the following formula L:
a. R' is H or acetyl;
b. R1 is a saturated or unsaturated straight or branched aliphatic carbon chain from 2 to 15 carbon atoms in length;
c. R2 is as follows:
i.H;
ii. unsubstituted, N-substituted or N,N-disubstituted amide;
iii. N-substituted or unsubstituted acyl protected amines;
iv. N-substituted or unsubstituted amines;
v. Carboxylic acid;
vi. Nitrile;
vii. ester;
viii. Ketones;
ix. Hydroxy, dihydroxy, trihydroxy, or polyhydroxyalkyl; and
x. Substituted or unsubstituted aryl;
xi. Saturated or unsaturated linear or branched aliphatic chain;
xii. an aromatic group containing a substituent selected from the group consisting of halogen, ester, and nitro; and
xiii. A combination of a saturated or unsaturated linear or branched aliphatic chain of (xi) and an aromatic group of (xii)
selected from the group consisting of; and
d. R23 is a saturated or unsaturated straight or branched optionally substituted aliphatic carbon chain)
or a pharmaceutically acceptable salt, solvate, stereoisomer thereof.
[10] The method according to [9] above, wherein the subject in need thereof is a subject at risk of developing fibrosis.
[11] The method according to any one of [9] to [10] above, wherein the subject in need of the same is a subject without progression of fibrosis.
[12] The subject's risk of developing fibrosis is reduced by at least 5%, 10%, 20% or more compared to untreated subjects, according to any one of [10] to [11] above. Method described.
[13] The method according to any one of [9] to [12] above, wherein the onset of fibrosis is delayed in the subject by at least one month, one year, or more.
[14] The method of [9] to [13] above, comprising reducing fibrosis formation, wherein the fibrosis formation is reduced in a subject by at least 1 month, 1 year, or more compared to an untreated subject. The method described in any one of the paragraphs.
[15] A method for reducing fibrosis or reversing fibrosis, in which a subject in need thereof is given the following formula L:
a. R' is H or acetyl;
b. R1 is a saturated or unsaturated straight or branched aliphatic carbon chain from 2 to 15 carbon atoms in length;
c. R2 is as follows:
i.H;
ii. unsubstituted, N-substituted or N,N-disubstituted amide;
iii. N-substituted or unsubstituted acyl protected amines;
iv. N-substituted or unsubstituted amines;
v. Carboxylic acid;
vi. Nitrile;
vii. ester;
viii. Ketones;
ix. Hydroxy, dihydroxy, trihydroxy, or polyhydroxyalkyl; and
x. Substituted or unsubstituted aryl;
xi. Saturated or unsaturated linear or branched aliphatic chain;
xii. an aromatic group containing a substituent selected from the group consisting of halogen, ester, and nitro; and
xiii. A combination of a saturated or unsaturated linear or branched aliphatic chain of (xi) and an aromatic group of (xii)
selected from the group consisting of; and
d. R23 is a saturated or unsaturated straight or branched optionally substituted aliphatic carbon chain)
or a pharmaceutically acceptable salt, solvate, stereoisomer thereof.
[16] The method according to [15] above, wherein the subject in need thereof is a subject suffering from fibrosis.
[17] The method according to any one of [9] to [16] above, which comprises suppressing fibrosis formation in the subject.
[18] The method according to any one of [9] to [17] above, wherein the fibrosis is non-hepatic fibrosis.
[19] The non-hepatic fibrosis includes fibrosis of the lungs, kidneys, heart, skin, eyes, gastrointestinal tract, peritoneum, bone marrow, muscles, blood vessels, vasculature, or any combination thereof; Method described.
[20] The subject in need of the same is suffering from a fibrotic disorder selected from the group consisting of pulmonary fibrosis, cardiac fibrosis, skin fibrosis, renal fibrosis, liver fibrosis, or a combination thereof. The method according to any one of [9] to [17] above.
[21] The method according to any one of [9] to [17] above, wherein the subject in need thereof is a subject suffering from idiopathic pulmonary fibrosis (IPF).
[22] The method according to any one of [9] to [17] above, wherein the fibrosis is liver fibrosis.
[23] The method according to [22] above, wherein the liver fibrosis is cirrhosis.
[24] The method according to [23] above, wherein the liver cirrhosis is associated with viral hepatitis, schistosomiasis, and chronic alcoholism.
[25] The method according to any one of [1] to [24] above, wherein the cyclosporine analog of formula L is CRV431 below.
[27] The method according to any one of [1] to [26], wherein the non-hepatic fibrosis or fibrosis is induced by a therapeutic agent, injury, or a combination thereof.
[28] Said non-hepatic fibrosis or fibrosis is associated with the accumulation of extracellular matrix components that occurs after trauma, inflammation, tissue repair, immune reaction, cellular hyperplasia, tumor, or a combination thereof. 26].
[29] The non-hepatic fibrosis or fibrosis according to any one of [1] to [26] above, wherein the non-hepatic fibrosis or fibrosis is associated with a major organ disease, a fibroproliferative disorder, a scar associated with trauma, or a combination thereof. Method.
[30] The fibrosis is caused by interstitial lung disease, liver cirrhosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, renal disease, heart disease or vascular disease, eye disease, systemic and local sclerosis. disease, keloids, hypertrophic scars, atherosclerosis, restenosis, Dupuytren's contracture, surgical complications, chemotherapy-induced fibrosis, radiation-induced fibrosis, accidental injuries and burns, retroperitoneal fibrosis, peritoneum The method according to any one of [9] to [26] above, which is associated with fibrosis/peritoneal scarring or a combination thereof.
[31] The fibrosis associated with the interstitial lung disease is sarcoidosis, silicosis, drug reaction, infection, collagen vascular disease, rheumatoid arthritis, systemic sclerosis, scleroderma, pulmonary fibrosis, idiopathic pulmonary disease. The method according to [30] above, which is fibrosis, common interstitial pneumonia, interstitial lung disease, unexplained fibrosing alveolitis, bronchiolitis obliterans, bronchiectasis, or a combination thereof.
[32] Reducing fibrosis formation in a subject by at least 5%, 10%, 20%, 50%, 70%, 90%, or more as compared to an untreated subject, [9] to [ 31].
[33] The method according to any one of [9] to [31] above, which comprises delaying fibrosis formation in the subject compared to an untreated subject.
[34] The method according to any one of [1] to [33] above, wherein the subject is a mammal.
[35] The method according to any one of [1] to [33] above, wherein the subject is a human.
[36] The method according to any one of [1] to [35] above, wherein the composition contains one or more pharmaceutically acceptable excipients.
[37] The method according to any one of [1] to [36], wherein the composition comprises one or more additional therapeutic agents.
[38] The method according to any one of [1] to [36] above, further comprising administering one or more additional therapeutic agents to the subject in need thereof.
[39] The method according to [37] or [38], wherein the one or more additional therapeutic agents include an additional antifibrotic drug.
[40] The one or more additional therapeutic agents include type II interferon receptor agonists, pirfenidone and pirfenidone analogs, nintedanib and nintedanib analogs, anti-angiogenic drugs, anti-inflammatory drugs, IL-1 antagonists, angiotensin converters Enzyme (ACE) inhibitors, angiotensin receptor blockers and aldosterone antagonists, mitomycin C (MMC), 5-fluorouracil (5-FU), adenylyl cyclase activators, β-adrenoceptor agonists , a flavonoid, a mast cell stabilizer, a phosphodiesterase inhibitor, a procyanidin, or a combination thereof, the method according to [37] or [38].
[41] The method according to any one of [37] to [40], wherein at least one of the one or more additional therapeutic agents is administered to the subject simultaneously with the composition.
[42] [37] above, wherein at least one of the one or more additional therapeutic agents is administered to the subject before, after, or before and after administering the composition. ~ The method described in any one of [40].
[43] The method according to any one of [1] to [42], wherein the composition is administered to the subject by intravenous administration, oral administration, or parenteral administration.
[44] The above-mentioned [1] to [1], wherein the composition is in the form of powder, pill, tablet, microtablet, pellet, micropellet, capsule, microtablet-containing capsule, liquid, aerosol, or nanoparticle. 43].
[45] The composition is administered to the subject at an effective daily dose of 10 mg to 250 mg of the cyclosporine analog or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. The method described in any one of [1] to [44].
[46] For use in the prevention or treatment of fibrosis, or for use in the prevention or reduction of fibrosis formation, or for use in the recovery of fibrosis, or for the reduction of the amount of fibrosis, or for use in the prevention or reduction of fibrosis formation, For the delay in the occurrence of L, the following formula L:
a. R' is H or acetyl;
b. R1 is a saturated or unsaturated straight or branched aliphatic carbon chain from 2 to 15 carbon atoms in length;
c. R2 is as follows:
i.H;
ii. unsubstituted, N-substituted or N,N-disubstituted amide;
iii. N-substituted or unsubstituted acyl protected amines;
iv. N-substituted or unsubstituted amines;
v. Carboxylic acid;
vi. Nitrile;
vii. ester;
viii. Ketones;
ix. Hydroxy, dihydroxy, trihydroxy, or polyhydroxyalkyl; and
x. Substituted or unsubstituted aryl;
xi. Saturated or unsaturated linear or branched aliphatic chain;
xii. an aromatic group containing a substituent selected from the group consisting of halogen, ester, and nitro; and
xiii. A combination of a saturated or unsaturated linear or branched aliphatic chain of (xi) and an aromatic group of (xii)
selected from the group consisting of; and
d. R23 is a saturated or unsaturated straight or branched optionally substituted aliphatic carbon chain)
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
[47] The pharmaceutical composition according to [46] above, wherein the cyclosporine analogue is CRV431 below.
[49] The pharmaceutical composition is in the form of powder, pill, tablet, microtablet, pellet, micropellet, capsule, microtablet-containing capsule, liquid, aerosol, or nanoparticle, [46] to The pharmaceutical composition according to any one of [48].
[50] The pharmaceutical composition according to any one of [46] to [49] above; and
A kit comprising a label, said label:
(a) the kit is for the prevention or treatment of fibrosis;
(b) the kit is for reducing or inhibiting fibrosis formation;
(c) the kit is for the recovery of fibrosis;
(d) said kit is for reducing the amount of fibrosis; and
(e) the kit is for delaying the onset of fibrosis;
said kit showing one or more of the following.
[51] The kit according to [50] above, further comprising instructions for identifying a subject at risk of developing fibrosis, instructions for identifying a subject suffering from fibrosis, or both.
Claims (16)
下記式:The following formula:
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PCT/US2021/018639 WO2021168161A1 (en) | 2020-02-19 | 2021-02-19 | Use of cyclosporine analogues for treating fibrosis |
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JPWO2021168161A5 true JPWO2021168161A5 (en) | 2024-02-28 |
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EP (1) | EP4106791A1 (en) |
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CN (1) | CN115427060A (en) |
AU (1) | AU2021224676A1 (en) |
BR (1) | BR112022016522A2 (en) |
CA (1) | CA3171882A1 (en) |
IL (1) | IL295452A (en) |
MX (1) | MX2022010201A (en) |
TW (1) | TW202143994A (en) |
WO (1) | WO2021168161A1 (en) |
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Publication number | Priority date | Publication date | Assignee | Title |
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US5372807A (en) | 1990-05-14 | 1994-12-13 | University Of Medicine And Dentistry Of New Jersey | Polymers containing antifibrotic agents, compositions containing such polymers, and methods of preparation and use |
US20020006901A1 (en) * | 1999-02-05 | 2002-01-17 | Aldo T. Iacono | Use of aerosolized cyclosporine for prevention and treatment of pulmonary disease |
JP5612067B2 (en) * | 2009-03-19 | 2014-10-22 | ユニバーシティ ダンガース | Non-invasive method for assessing liver fibrosis progression |
WO2018106928A1 (en) * | 2016-12-08 | 2018-06-14 | Contravir Pharmaceuticals, Inc. | Treatment and prevention of hbv diseases by cyclosporine analogue molecules modified at amino acides 1 and 3 |
TW201902507A (en) * | 2017-04-14 | 2019-01-16 | 美商康特維爾製藥公司 | Combination therapy for treating viral infections |
FI3886813T3 (en) | 2018-11-26 | 2023-05-04 | Hepion Pharmaceuticals Inc | Pharmaceutical formulations of cyclosporine analogs |
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- 2021-02-19 IL IL295452A patent/IL295452A/en unknown
- 2021-02-19 CA CA3171882A patent/CA3171882A1/en active Pending
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- 2021-02-19 JP JP2022549839A patent/JP2023514837A/en active Pending
- 2021-02-19 KR KR1020227031378A patent/KR20220143059A/en unknown
- 2021-02-19 EP EP21713171.3A patent/EP4106791A1/en active Pending
- 2021-02-19 WO PCT/US2021/018639 patent/WO2021168161A1/en unknown
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- 2021-02-19 MX MX2022010201A patent/MX2022010201A/en unknown
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