JP2013503872A - 脂肪酸ナイアシン抱合体およびそれらの使用 - Google Patents
脂肪酸ナイアシン抱合体およびそれらの使用 Download PDFInfo
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Abstract
Description
本出願は、2009年9月1日出願の米国仮出願第61/238,903号、2010年2月26日出願の米国仮出願第61/308,524号、および2010年3月10日出願の米国仮出願第61/310,952号の利益を主張する。そうした出願の全体の開示は、参照により本明細書に組み込まれる。
式中、R1、R2、およびR3は、それぞれ独立して、−H、−D、−Cl、−F、−CN、−NH2、−NH(C1−C3アルキル)、−N(C1−C3アルキル)2、−NH(C(O)C1−C3アルキル)、−N(C(O)C1−C3アルキル)2、−C(O)H、−C(O)C1−C3アルキル、−C(O)OC1−C3アルキル、−C(O)NH2、−C(O)NH(C1−C3アルキル)、−C(O)N(C1−C3アルキル)2、−C1−C3アルキル、−O−C1−C3アルキル、−S(O)C1−C3アルキルおよび−S(O)2C1−C3アルキルからなる群から選択され、W1およびW2は、それぞれ独立して、無、O、S、NH、NRであるか、あるいはW1およびW2が同時にOとなり得ないことを条件として、W1およびW2は一緒になってイミダゾリジンまたはピペラジン基を形成し得、a、b、cおよびdは、それぞれ独立して−H、−D、−CH3、−OCH3、−OCH2CH3、−C(O)OR、−O−Z、もしくはベンジルであるか、またはa、b、cおよびdのうち2つが、それらが結合する単一の炭素と一緒になってシクロアルキルもしくは複素環を形成し、n、o、pおよびqは、それぞれ独立して0または1であり、Lは、それぞれ独立して−O−、−S−、−S(O)−、−S(O)2−、−S−S−、
式中、Lの表記は、表示されているように左から右の一方向に制限されておらず、むしろLの左側または右側のどちらかが式Iの化合物のW1側に結合され得る。gは、それぞれ独立して2、3または4であり、hは、それぞれ独立して1、2、3または4であり、mは、0、1、2または3であり、R6は、それぞれ独立してHもしくはC1−C6アルキルであるか、または両方のR6基は、それらが結合する窒素と一緒になった場合、複素環を形成し、R7は、それぞれ独立してe、H、またはOH、NH2、CO2R、CONH2、フェニル、C6H4OH、イミダゾールもしくはアルギニンで任意に置換し得る直鎖または分岐鎖C1−C10アルキルであり、eは、それぞれ独立してHまたは天然アミノ酸の側鎖の任意の1つであり、Zは、それぞれ独立して、少なくとも下記の1つ
であり、rは、それぞれ独立して2、3、または7であり、sは、それぞれ独立して3、5、または6であり、tは、それぞれ独立して0または1であり、vは、それぞれ独立して1、2、または6であり、R4とR5は、それぞれ独立して、−H、−D、−C1−C4アルキル、−ハロゲン、−OH、−C(O)C1−C4アルキル、−O−アリール、−O−ベンジル、−OC(O)C1−C4アルキル、−C1−C3アルケン、−C1−C3アルキン、−C(O)C1−C4アルキル、−NH2、−NH(C1−C3アルキル)、−N(C1−C3アルキル)2、−NH(C(O)C1−C3アルキル)、−N(C(O)C1−C3アルキル)2、−SH、−S(C1−C3アルキル)、−S(O)C1−C3アルキル、−S(O)2C1−C3アルキルであり、Rは、それぞれ独立して−H、−C(O)−C1−C3アルキル、またはOR、NR2もしくはハロゲンで任意に置換される直鎖または分岐鎖C1−C4アルキルであり、ただし、m、n、o、pおよびqがそれぞれ0であり、W1とW2はそれぞれ無であり、
Zは
(定義)
(化合物)
およびその薬学的に許容可能な塩、水和物、溶媒和物、プロドラッグ、鏡像異性体、および立体異性体を提供し、
式中、R1、R2、R3、R4、R5、R6、R7、R、W1、W2、L、a、c、b、d、e、g、h、m、n、o、p、q、Z、r、s、tおよびvは、少なくとも下記の1つ
が化合物中にあるという条件下で、上記の式Iで定義された通りである。
a)精製水、水素添加または部分的に水素添加された植物油などのトリグリセリド油、またはそれらの混合物、トウモロコシ油、オリーブ油、ひまわり油、紅花油、EPAやDHAなどの魚油またはそれらのエステルもしくはトリグリセリドまたはそれらの混合物、オメガ−3脂肪酸またはその誘導体、ラクトース、デキストロース、スクロース、マンニトール、ソルビトール、セルロース、ナトリウム、サッカリン、グルコースおよび/またはグリシンなどの希釈剤、
b)シリカ、タルカム、ステアリン酸、そのマグネシウムまたはカルシウム塩、オレイン酸ナトリウム、ステアリン酸ナトリウム、ステアリン酸マグネシウム、安息香酸ナトリウム、酢酸ナトリウム、塩化ナトリウムおよび/またはポリエチレングリコールなどの潤滑剤、錠剤も同様に、
c)必要に応じて、例えばケイ酸アルミニウムマグネシウム、デンプン糊、ゼラチン、トラガント、メチルセルロース、カルボキシメチルセルロースナトリウム、炭酸マグネシウム、グルコースまたはβ−ラクトースのような天然の糖、トウモロコシ甘味料、アカシア、トラガカントまたはアルギン酸ナトリウムなどの天然および合成ゴム、ワックスおよび/またはポリビニルピロリドンなどの結合剤、
d)デンプン、寒天、メチルセルロ−ス、ベントナイト、キサンタンガム、アルギン酸またはそのナトリウム塩、または発泡性混合物などの崩壊剤、
e)吸収剤、着色剤、香味剤および甘味剤、
f)ツイーン80、ラブラソール(Labrasol)、HPMC、DOSS、カプロイル909、ラブラファック、ラブラフィル(Labrafil)、ペセオール(Peceol)、トランスキュトール(transcutol)、カプムル(Capmul)MCM、カプムル(Capmul)PG−12、カプテックス(captex)355、ゲルシア(Gelucire)、ビタミンE TGPSまたはその他の許容可能な乳化剤などの乳化剤や分散剤、および/または、
g)シクロデキストリン、ヒドロキシプロピル−シクロデキストリン、PEG400、PEG200など化合物の吸収を高める薬剤、のような薬学的に許容可能な担体を含む。
(製造方法)
(脂肪酸ナイアシン誘導体の製造方法)
スキーム中、R7、a、rおよびsは、上記に定義されている。
(実施例1)
HepG2細胞のアポB分泌における脂肪酸ナイアシン誘導体の効果
脂肪酸ナイアシン抱合体I−7は、3種の濃度(50μΜ、100μΜ、200μΜ)においてHepG2細胞で評価された。アポB分泌のレベルは5mMの濃度でナイアシンと比較され、評価された。ナイアシンに比べ、脂肪酸ナイアシン抱合体1−7は、非常に低い薬物濃度でアポBの顕著な阻害を示した。
(実施例2)
SREBP−lc標的遺伝子における脂肪酸ナイアシン誘導体の効果
HepG2細胞(ATCC)は96ウェルプレートに1ウェル当たり20,000細胞で播種された。一晩接着後、増殖培地(DMEM中に10%FBSを含有)が除去され、細胞は1%無脂肪酸ウシ血清アルブミン(BSA、Sigma社)を含むDMEMで24時間血清欠乏状態にされた。細胞はその後、4つの物質のうち1つにより、1%BSAまたはモル比5:1の0.1%オレイン酸と無脂肪酸BSAの複合体で50μΜの最終濃度で処理された(4つの物質は、化合物I−7、化合物I−8、遊離ナイアシンと遊離DHAの組み合わせ、または遊離ナイアシンと遊離EPAの組み合わせである)。細胞は6時間培養され、その後PBSで洗浄された。RNAは標準プロトコル(Applied Biosystem StepOne Real−time PCRの手順書で説明されている)に従って、cells to cDNA試薬を用い逆転写された。3種の特定遺伝子FASN(脂肪酸シンターゼ)、SCD(ステアロイルCoAデサチュラーゼ)およびApoA1(アポリポタンパク質A1)の転写物のリアルタイムPCRは、TaqManアッセイにより実施された。3つの例全てにおいて、18S−VIC(登録商標)は、正規化コントロールとして使用された。図2に示すように、HepG2細胞が化合物I−7および化合物I−8の50μΜの存在下においてオレイン酸で刺激された時、FASNとSCDの遺伝子発現に統計学的に有意な抑制が観察され、ApoAl遺伝子発現に増加が観察された。遊離ナイアシンと遊離DHAまたはナイアシンと遊離EPAのいずれかの組み合わせを含む2つのグループは、50μΜの最終濃度で、前記の3つの特定遺伝子の発現に有意な変化を生じなかった。
(化合物)
(実施例3)
N−(2−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミドエチル)ニコチンアミド(I−7)の調製
(実施例4)
N−(2−(5Z,8Z,11Z,14Z,17Z)−エイコサ−5,8,11,14,17−ペンタンアミドエチル)ニコチンアミド(I−8)の調製
(実施例5)
N−(2−(2−(2−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミドエチル)ジスルファニル)エチル)ニコチンアミド(I−3)の調整
(実施例6)
(2−(2−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミドエトキシ)エチル)ニコチンアミド(I−1)の調整
(実施例7)
N−(2−((2−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミドエチル)(メチル)アミノ)エチル)ニコチンアミド(I−2)の調整
(実施例8)
(2S,3R)−メチル3−((S)−2−((4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミド)プロパノイルオキシ)−2−(ニコチンアミド)ブタノエート(I−9)の調整
(実施例9)
(2S、3R)−メチル3−((S)−2−((5Z,8Z,11Z,14Z,17Z)−イコサ−5,8,11,14,17−ペンタンアミド)プロパノイルオキシ)−2−(ニコチンアミド)ブタノエート(I−10)の調整
(実施例10)
(S)−メチル6−((4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミド)−2−(ニコチンアミド)ヘキサノエート(I−11)の調製
(実施例11)
(S)−6−((4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミド)−2−(ニコチンアミド)ヘキサン酸(I−12)の調製
(実施例12)
(S)−メチル2−((5Z,8Z,11Z,14Z,17Z)−エイコサ−5,8,11,14,17−ペンタンアミド)−6−(ニコチンアミド)ヘキサノエート(I−13)の調製
(実施例13)
(S)−2−((5Z,8Z,11Z,14Z,17Z)−エイコサ−5,8,11,14,17−ペンタンアミド)−6−(ニコチンアミド)ヘキサン酸(I−14)の調製
(均等物)
Claims (35)
- ナイアシンおよびオメガ−3脂肪酸または生体内でオメガ−3脂肪酸に代謝される脂肪酸から選択される脂肪酸を含む分子抱合体であって、前記抱合体は少なくとも1つのアミドを含む、分子抱合体。
- 式Iの化合物:
(式中、
R1、R2、およびR3は、それぞれ独立して、−H、−D、−Cl、−F、−CN、−NH2、−NH(C1−C3アルキル)、−N(C1−C3アルキル)2、−NH(C(O)C1−C3アルキル)、−N(C(O)C1−C3アルキル)2、−C(O)H、−C(O)C1−C3アルキル、−C(O)OC1−C3アルキル、−C(O)NH2、−C(O)NH(C1−C3アルキル)、−C(O)N(C1−C3アルキル)2、−C1−C3アルキル、−O−C1−C3アルキル、−S(O)C1−C3アルキルおよび−S(O)2C1−C3アルキルからなる群から選択され、
W1およびW2は、それぞれ独立して、無、O、S、NH、NRであるか、あるいはW1およびW2が同時にOとなり得ないことを条件として、W1およびW2は一緒になってイミダゾリジンまたはピペラジン基を形成し得、
a、b、cおよびdは、それぞれ独立して、−H、−D、−CH3、−OCH3、−OCH2CH3、−C(O)OR、−O−Z、もしくはベンジルであるか、またはa、b、cおよびdのうち2つが、それらが結合する単一の炭素と一緒になってシクロアルキルもしくは複素環を形成し、
n、o、pおよびqは、それぞれ独立して0または1であり、
Lは、それぞれ独立して−O−、−S−、−S(O)−、−S(O)2−、−S−S−、
gは、それぞれ独立して2、3または4であり、
hは、それぞれ独立して1、2、3または4であり、
R6は、それぞれ独立してHもしくはC1−C6アルキルであるか、または両方のR6基は、それらが結合する窒素と一緒になった場合、複素環を形成し得、
R7は、それぞれ独立してe、H、またはOH、NH2、CO2R、CONH2、フェニル、C6H4OH、イミダゾールもしくはアルギニンで任意に置換し得る直鎖または分岐鎖C1−C10アルキルであり、
eは、それぞれ独立してHまたは天然アミノ酸の側鎖の任意の1つであり、
Zは、それぞれ独立して、少なくとも下記の1つ
rは、それぞれ独立して2、3、または7であり、
sは、それぞれ独立して3、5、または6であり、
tは、それぞれ独立して0または1であり、
vは、それぞれ独立して1、2、または6であり、
R4とR5は、それぞれ独立して、水素、重水素、−C1−C4アルキル、−ハロゲン、−OH、−C(O)C1−C4アルキル、−O−アリール、−O−ベンジル、−OC(O)C1−C4アルキル、−C1−C3アルケン、−C1−C3アルキン、−C(O)C1−C4アルキル、−NH2、−NH(C1−C3アルキル)、−N(C1−C3アルキル)2、−NH(C(O)C1−C3アルキル)、−N(C(O)C1−C3アルキル)2、−SH、−S(C1−C3アルキル)、−S(O)C1−C3アルキル、−S(O)2C1−C3アルキルであり、
Rは、それぞれ独立して−Hまたは−C1−C3アルキルであり、
ただし、m、n、o、pおよびqがそれぞれ0であり、W1とW2はそれぞれ無であり、Zは
m、n、o、pおよびqがそれぞれ0であり、W1とW2が互いに無である場合、Zは
- Zが
- tが1である、請求項3に記載の化合物。
- rが2であり、sが6である、請求項4に記載の化合物。
- rが3であり、sが5である、請求項4に記載の化合物。
- rが7であり、sが3である、請求項4に記載の化合物。
- Lが−S−S−である、請求項5に記載の化合物。
- Lが−O−である、請求項5に記載の化合物。
- Lが
- Lが
- Lが
- Lが
である、請求項5に記載の化合物。 - n、o、pおよびqがそれぞれ1である、請求項5に記載の化合物。
- n、o、pおよびqのうち2つがそれぞれ1である、請求項5に記載の化合物。
- W1およびW2がそれぞれNHである、請求項5に記載の化合物。
- mが1であり、n、o、pおよびqがそれぞれ1であり、LがOである、請求項5に記載の化合物。
- mが1であり、n、o、pおよびqがそれぞれ1であり、Lが−S−S−である、請求項5に記載の化合物。
- mが1であり、nおよびoがそれぞれ0であり、pおよびqがそれぞれ1であり、Lが
- mが1であり、n、o、pおよびqがそれぞれ0であり、Lが
- m、nおよびoがそれぞれ0であり、pおよびqがそれぞれ1である、請求項5に記載の化合物。
- mが1、nおよびoがそれぞれ0であり、pおよびqがそれぞれ1であり、Lが
- mが1であり、nおよびoがそれぞれ1であり、pおよびqがそれぞれ0であり、Lが
- mが1であり、n、o、pおよびqがそれぞれ1、Lが
- mが1であり、n、o、p、およびqがそれぞれ1であり、LがNR6である、請求項5に記載の化合物。
- m、n、oがそれぞれ0であり、pおよびqがそれぞれ1、1つのcが−CH3であり、他方のcが−CH3である,請求項5に記載の化合物。
- mが1であり、nおよびoがそれぞれ1であり、pおよびqがそれぞれ0であり、Lが
- 前記化合物が、N−(2−(2−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミドエトキシ)エチル)ニコチンアミド;N−(2−(2−(2−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミドエチル)ジスルファニル)エチル)ニコチンアミド;およびN−(2−(2−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19ヘキサンアミドエチルアミノ)エチル)ニコチンアミドからなる群から選択される、請求項2に記載の化合物。
- 前記化合物が、1,3−ジヒドロキシプロパン−2−イル6−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミド−2−(ニコチンアミド)ヘキサノエート;および1,3−ジヒドロキシプロパン−2−イル4−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミド−2−(ニコチンアミド)ブタノエートからなる群から選択される、請求項2に記載の化合物。
- 前記化合物が、N−(2−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミドエチル)ニコチンアミド;N−(2−(5Z,8Z,llZ,14Z,17Z)−エイコサ−5,8,11,14,17−ペンタンアミドエチル)ニコチンアミド;およびN−(1−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミド−2−メチルプロパン−2−イル)ニコチンアミドからなる群から選択される、請求項2に記載の化合物。
- 前記化合物が、(S)−6−((4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミド)−2−(ニコチンアミド)ヘキサン酸;(S)−2−((4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミド)−6−(ニコチンアミド)ヘキサン酸;(S)−6−((5Z,8Z,11Z,14Z,17Z)−エイコサ−5,8,l1,14,17−ペンタンアミド)−2−(ニコチンアミド)ヘキサン酸;(S)−2−((5Z,8Z,llZ,14Z,17Z)−エイコサ−5,8,1l,14,17−ペンタンアミド)−6−(ニコチンアミド)ヘキサン酸;および2−(2−(4Z,7Z,10Z,13Z,16Z,19Z)−ドコサ−4,7,10,13,16,19−ヘキサンアミドエチル)−4−(ニコチンアミド)ブタン酸からなる群から選択される、請求項2に記載の化合物。
- 前記化合物が、(S)−((R)−l−(ニコチンアミド)プロパン−2−イル)2−((5Z,8Z,11Z,14Z,17Z)−エイコサ−5,8,11,14,17−ペンタンアミド)プロパン酸;(S)−((R)−1−(ニコチンアミド)プロパン−2−イル)2−((5Z,8Z,11Z,14Z,17Z)−エイコサ−5,8,11,14,17−ペンタンアミド)−3−メチルブタノエートからなる群から選択される、請求項2に記載の化合物。
- 請求項2に記載の化合物および薬学的に許容可能な担体を含む、医薬組成物。
- 代謝性疾患を治療するための方法であって、前記方法は、それを必要とする患者に有効量の請求項2に記載の化合物を投与することを含む、方法。
- 前記代謝性疾患が、高トリグリセリド血症、高コレステロール血症、脂肪肝疾患、アテローム性動脈硬化症、冠性心疾患、2型糖尿病、糖尿病性腎症、糖尿病性神経障害、糖尿病性網膜症、メタボリック症候群または心血管疾患から選択される、請求項34に記載の方法。
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