JP6270171B2 - 肺疾患の処置 - Google Patents
肺疾患の処置 Download PDFInfo
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- JP6270171B2 JP6270171B2 JP2015544191A JP2015544191A JP6270171B2 JP 6270171 B2 JP6270171 B2 JP 6270171B2 JP 2015544191 A JP2015544191 A JP 2015544191A JP 2015544191 A JP2015544191 A JP 2015544191A JP 6270171 B2 JP6270171 B2 JP 6270171B2
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- salt
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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Description
本出願は、その全内容を本明細書に援用する、2012年11月28日に出願された米国特許出願第61/730,749号明細書の優先権および利益を主張する。
またはその薬学的に許容される塩を被検体に投与することを含む方法に関する。
またはその薬学的に許容される塩を被検体に投与することを含む方法に関する。
またはその薬学的に許容される塩を被検体に投与することを含む方法に関する。
特定の実施形態では、例えば以下が提供される:
(項目1)
被検体の、肺の疾患または状態を処置する、肺の疾患または状態のリスクを低下させる、肺の疾患または状態を予防するまたは軽減する方法であって、治療有効量の下記式Aの化合物:
(式中、
R 1 は水素または非置換C 1 〜C 6 アルキルであり;
R 2 は水素またはα−ヒドロキシルであり;
XはC(O)OH、C(O)NH(CH 2 ) m SO 3 H、C(O)NH(CH 2 ) n CO 2 HまたはOSO 3 Hであり;
R 4 はヒドロキシルまたは水素であり;
R 7 はヒドロキシルまたは水素であり;
mは整数1、2または3であり;かつ
nは整数1、2または3である)
またはその薬学的に許容される塩
を前記被検体に投与することを含む方法。
(項目2)
R 1 は非置換C 1 〜C 6 アルキルである、項目1に記載の方法。
(項目3)
R 1 はメチル、エチルまたはプロピルである、項目2に記載の方法。
(項目4)
R 1 はエチルである、項目3に記載の方法。
(項目5)
R 1 はメチル、エチルおよびプロピルから選択され;R 4 はOHであり;R 7 はHであり;R 2 はHである、項目1に記載の方法。
(項目6)
前記化合物は
またはその薬学的に許容される塩
から選択される、項目1に記載の方法。
(項目7)
前記化合物は
またはその薬学的に許容される塩
である、項目1に記載の方法。
(項目8)
前記化合物は
またはその薬学的に許容される塩
である、項目1に記載の方法。
(項目9)
前記化合物は薬学的に許容される塩である、項目1に記載の方法。
(項目10)
前記塩はナトリウム塩またはトリエチルアンモニウム塩である、項目9に記載の方法。
(項目11)
前記肺の疾患または状態は閉塞性肺疾患(COPD)、気腫、喘息、特発性肺線維症、肺炎、結核、嚢胞性線維症、気管支炎、肺高血圧症(たとえば、特発性肺動脈高血圧症(IPAH)(原発性肺高血圧症(PPH)とも呼ばれる)および二次性肺高血圧症(SPH))、間質性肺疾患および肺癌から選択される、項目1に記載の方法。
(項目12)
前記肺の疾患または状態はCOPD、気腫、喘息、嚢胞性線維症および肺高血圧症から選択される、項目11に記載の方法。
(項目13)
前記肺の疾患または状態は肺高血圧症である、項目12に記載の方法。
(項目14)
前記肺高血圧症はIPAHまたはSPHである、項目13に記載の方法。
(項目15)
前記肺の疾患または状態は、炎症、自己免疫疾患、強皮症、関節リウマチ、急性肺障害(ALI)、急性呼吸窮迫症候群(ARDS)、心臓の先天性欠損、肺内の血栓形成(肺塞栓)、鬱血性心不全、心臓弁膜症、HIV感染症、長期にわたる血液中の低酸素レベル、薬物、乱用物質または閉塞型睡眠時無呼吸により引き起こされる、項目1に記載の方法。
(項目16)
前記肺の疾患または状態は炎症により引き起こされる、項目15に記載の方法。
(項目17)
前記被検体はヒトである、項目1に記載の方法。
(項目18)
前記化合物は全身投与される、経口投与される、静脈内投与される、筋肉内投与される、腹腔内投与される、または吸入により投与される、項目1に記載の方法。
(項目19)
被検体の肺の炎症を減少させるまたは抑制する方法であって、それを必要とする前記被検体に治療有効量の下記式Aの化合物:
(式中、
R 1 は水素または非置換C 1 〜C 6 アルキルであり;
R 2 は水素またはα−ヒドロキシルであり;
XはC(O)OH、C(O)NH(CH 2 ) m SO 3 H、C(O)NH(CH 2 ) n CO 2 HまたはOSO 3 Hであり;
R 4 はヒドロキシルまたは水素であり;
R 7 はヒドロキシルまたは水素であり;
mは1、2または3であり;かつ
nは1、2または3である)
またはその薬学的に許容される塩
を投与することを含む方法。
(項目20)
被検体の肺の修復を促進する方法であって、それを必要とする前記被検体に治療有効量の下記式Aの化合物:
(式中、
R 1 は水素または非置換C 1 〜C 6 アルキルであり;
R 2 は水素またはα−ヒドロキシルであり;
XはC(O)OH、C(O)NH(CH 2 ) m SO 3 H、C(O)NH(CH 2 ) n CO 2 HまたはOSO 3 Hであり;
R 4 はヒドロキシルまたは水素であり;
R 7 はヒドロキシルまたは水素であり;
mは1、2または3であり;かつ
nは1、2または3である)
またはその薬学的に許容される塩
を投与することを含む方法。
またはその薬学的に許容される塩を投与することを含む方法に関する。
またはその薬学的に許容される塩の使用に関する。
またはその薬学的に許容される塩に関する。
またはその薬学的に許容される塩であり、式中:
R1は水素または非置換C1〜C6アルキルであり;
R2は水素またはα−ヒドロキシルであり;
XはC(O)OH、C(O)NH(CH2)mSO3H、C(O)NH(CH2)nCO2HまたはOSO3Hであり;
R4はヒドロキシルまたは水素であり;
R7はヒドロキシルまたは水素であり;
mは1、2または3であり;かつ
nは1、2または3である。
またはその薬学的に許容される塩であり、式中、
R1Aは水素または非置換C1〜C6アルキルであり;
R2は水素またはα−ヒドロキシルであり;
R4はヒドロキシルまたは水素であり;かつ
R7はヒドロキシルまたは水素である。
またはその薬学的に許容される塩であり、式中:
R1Aは水素または非置換C1〜C6アルキルであり;
R2は水素またはα−ヒドロキシルであり;
R3はヒドロキシル、NH(CH2)mSO3HまたはNH(CH2)nCO2Hであり;
R4はヒドロキシルまたは水素であり;かつ
R7はヒドロキシルまたは水素である。
から選択される化合物またはその薬学的に許容される塩である。
から選択される化合物である。
当業者であれば、ごく通常の実験を用いて、本明細書に記載の特定の実施形態および方法に対する多くの均等物を認識するか、あるいは確認することができるであろう。そのような均等物は、本発明の範囲に包含されることを意図している。
a)メチル3α−ヒドロキシ−7−ケト−5β−コラネート(III)の調製。17.0kgの3α−ヒドロキシ−7−ケト−5β−コラン酸、68kgのメタノールおよび0.17kgのメタンスルホン酸を反応器に仕込んだ。次いで反応混合物を30〜60℃に1時間加熱し、25.5kgの脱イオン水を加えた。次いで、得られた混合物を撹拌し、良好な沈殿が得られるまで20〜25℃に冷却し、次いで0〜15℃にさらに冷却した。沈殿物を濾過し、水とメタノールとの混合物で洗浄し、約40℃にてオーブンでさらに乾燥させた。こうして15kgのメチル3α−ヒドロキシ−7−ケト−5β−コラネート(III)を得た。化学量論的収率は85.2%であった。
3α−テトラヒドロピラニルオキシ−7−ケト−5β−コラン−24−オイック酸(2A)。p−トルエンスルホン酸(115mg、0.6ml)および6α−エチル−7−ケトリトコール酸(5.0g、12mmol)をジオキサン(55ml)に溶かした溶液に、3,4−ジヒドロ−2H−ピラン(1.74ml、19mmol)を含むジオキサン(12ml)をゆっくりと滴下した。この反応混合物を室温で2時間撹拌した。次いで水(40ml)を加え、混合物を一部真空下で濃縮し、EtOAcで抽出した(4回/25ml)。合わせた有機画分をブラインで洗浄し(1回/50ml)、無水Na2SO4で乾燥させ、真空下で蒸発させて6gの化合物2Aを得た。この粗誘導体をさらに精製することなく次のステップに使用した。
WTマウス:A−食塩水(0日目);B−ブレオマイシン(0日目);C−ブレオマイシン(0日目)−化合物1(6ECDCAとも呼ばれる)(5mg/kg、1日)
FXR−/−マウス:D−食塩水(0日目);E−ブレオマイシン(0日目);F−ブレオマイシン(0日目)化合物1(6ECDCAとも呼ばれる)(5mg/kg、1日)。
ADMA(ω−N°,N°−非対称性ジメチルアルギニン)は、プラークの形成、進行および破裂に至る内皮機能不全の主要な原因である。Coke,Circulation,109(2004):1813−1819を参照されたい。多くの疾患がADMAレベルの上昇と関連している。そうした疾患には、たとえば、網膜静脈閉塞症、早期常染色体優性多発性嚢胞腎、タンパク尿、続発性アミロイドーシスおよび内皮機能不全、孤発性巣状分節性糸球体硬化症の小児、子癇前症、慢性血栓塞栓性肺高血圧症、合併症のない1型糖尿病、肺高血圧症、鎌状赤血球病、鬱病、鬱血性心不全、アルツハイマー病(ADMAレベルの低下も報告された)、循環器疾患に関連する腎臓病、高コレステロール血症、高ホモシステイン血症、高血圧、アテローム性動脈硬化症および脳卒中がある。DDAH(ジメチルアルギニンジメチルアミノヒドロラーゼ)は、ADMAを代謝することにより、血圧およびインスリン抵抗性に対して有益な作用を有する。DDAHの過剰発現は、NO合成を増加させ、血圧を低下させ得る。H.Dayoub et al.,Circulation 108(24):3042−3047。DDAHの過剰発現はまた、インスリン感受性を増強することもできる。Sydow et al.,Arterioscler Throm Vase Biol.28(2008):692−697。ADMAは、食塩感受性高血圧に一定の役割を果たしている。H.Matsuoka et al.,Hypertension 1997,29:242−247。
群1;正常食塩食(1%メチルセルロース)(N=6)
群2;高食塩食(ビヒクル;1%MC)(N=9)
群3;高食塩食(6ECDCA 10mg/kg/日)(N=6)
群4;高食塩食(6ECDCA 30mg/kg/日)(N=9)
MCT誘発性肺高血圧ラットモデル
0.5N HCl溶液に溶解させた60mg/kgのモノクロタリン(MCT)(Sigma Chemicals,セントルイス,ミズーリ州,アメリカ合衆国)の皮下注射により肺高血圧症を誘発した。簡単に説明すると、体重200〜250gの雄Sprague−Dawley(SD)ラットを、温湿度制御条件で、明暗各12時間周期、飼料および水を自由摂取として収容した。SDラットは、以下の群に無作為に割り付けた:
1)SDラットを未処置で放置し、7日後(n=5)または28日後(n=5)に屠殺する;
2)ビヒクルMCTを単回皮下注射したSDラットを7日後に屠殺する(n=5);
3)ビヒクルMCTを単回皮下注射したSDラットを28日後に屠殺する(n=10);
4)MCT[60mg/kg、n=5]を単回皮下注射したSDラットを7日後に屠殺する;
5)MCT[60mg/kg、n=15]を単回皮下注射したSDラットを28日後に屠殺する;
6)SDラットにMCT[60mg/kg]を単回皮下注射し、直ちにOCA(30mg/kg、1週間5日間連日、強制経口投与による、n=5)で7日間処置する];
7)SDラットにMCT[60mg/kg]を単回皮下注射し、直ちにOCA(30mg/kg、1週間5日間連日、強制経口投与による、n=10)で28日間処置する];
8)SDラットにMCT[60mg/kg]を単回皮下注射し、直ちにタダラフィル(10mg/kg/日、飲料水中、n=5)で7日間処置する];
9)SDラットにMCT[60mg/kg]を単回皮下注射し、直ちにタダラフィル(10mg/kg/日、飲料水中、n=10)で28日間処置する];
10)SDラットにMCT[60mg/kg]を単回皮下注射し、直ちにビヒクルOCA(強制経口投与による、n=5)で7日間処置する;
11)SDラットにMCT[60mg/kg]を単回皮下注射し、直ちにビヒクルOCA(強制経口投与による、n=10)で28日間処置する。
Claims (11)
- 特発性肺線維症を処置するまたは軽減するための組成物であって、下記式Aの化合物:
(式中、
R1 は非置換C1〜C6アルキルであり;
R2は水素またはα−ヒドロキシルであり;
XはC(O)OH、C(O)NH(CH2)mSO3H、C(O)NH(CH2)nCO2HまたはOSO3Hであり;
R4はヒドロキシルまたは水素であり;
R7はヒドロキシルまたは水素であり;
mは整数1、2または3であり;かつ
nは整数1、2または3である)
またはその薬学的に許容される塩
を含む組成物。 - R1はメチル、エチルまたはプロピルである、請求項1に記載の組成物。
- R1はエチルである、請求項2に記載の組成物。
- R1はメチル、エチルおよびプロピルから選択され;R4はOHであり;R7はHであり;R2はHである、請求項1に記載の組成物。
- 前記化合物は
またはその薬学的に許容される塩
から選択される、請求項1に記載の組成物。 - 前記化合物は
またはその薬学的に許容される塩
である、請求項1に記載の組成物。 - 前記化合物は
またはその薬学的に許容される塩
である、請求項1に記載の組成物。 - 前記化合物は薬学的に許容される塩である、請求項1に記載の組成物。
- 前記塩はナトリウム塩またはトリエチルアンモニウム塩である、請求項8に記載の組成物。
- 前記被検体はヒトである、請求項1に記載の組成物。
- 前記組成物は全身投与される、経口投与される、静脈内投与される、筋肉内投与される、腹腔内投与される、または吸入により投与されることを特徴とする、請求項1に記載の組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261730749P | 2012-11-28 | 2012-11-28 | |
US61/730,749 | 2012-11-28 | ||
PCT/US2013/072038 WO2014085474A1 (en) | 2012-11-28 | 2013-11-26 | Treatment of pulmonary disease |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2016500111A JP2016500111A (ja) | 2016-01-07 |
JP2016500111A5 JP2016500111A5 (ja) | 2017-01-12 |
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KR20150089052A (ko) | 2015-08-04 |
MX2015006710A (es) | 2016-01-15 |
PH12015501108B1 (en) | 2015-08-17 |
CA2891348C (en) | 2020-04-28 |
TWI636786B (zh) | 2018-10-01 |
US20160213689A1 (en) | 2016-07-28 |
US20180064729A1 (en) | 2018-03-08 |
JP2016500111A (ja) | 2016-01-07 |
IL239025A0 (en) | 2015-07-30 |
CN104853758A (zh) | 2015-08-19 |
MY170802A (en) | 2019-08-28 |
BR112015012312A2 (pt) | 2017-07-11 |
US20140148428A1 (en) | 2014-05-29 |
RU2015122027A (ru) | 2017-01-10 |
SG11201503697TA (en) | 2015-06-29 |
CL2015001442A1 (es) | 2015-08-28 |
EP2925328A1 (en) | 2015-10-07 |
KR102106186B1 (ko) | 2020-05-04 |
NZ708501A (en) | 2019-03-29 |
HK1211844A1 (en) | 2016-06-03 |
WO2014085474A1 (en) | 2014-06-05 |
CA2891348A1 (en) | 2014-06-05 |
IL239025B (en) | 2021-04-29 |
AU2013352288B2 (en) | 2017-11-23 |
PH12015501108A1 (en) | 2015-08-17 |
AU2013352288A1 (en) | 2015-06-04 |
TW201434469A (zh) | 2014-09-16 |
RU2693382C2 (ru) | 2019-07-02 |
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