JP4557492B2 - Mch調節活性を有するアリール化合物およびビアリール化合物 - Google Patents
Mch調節活性を有するアリール化合物およびビアリール化合物 Download PDFInfo
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- JP4557492B2 JP4557492B2 JP2002576192A JP2002576192A JP4557492B2 JP 4557492 B2 JP4557492 B2 JP 4557492B2 JP 2002576192 A JP2002576192 A JP 2002576192A JP 2002576192 A JP2002576192 A JP 2002576192A JP 4557492 B2 JP4557492 B2 JP 4557492B2
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Description
本発明は、メラニン濃縮ホルモン(MCH)用のアンタゴニスト、および肥満、糖尿病および関連した障害の処置におけるそれらの使用に関する。本発明は、一般に、MCHレセプター調節剤活性を有する新規化合物、1種以上のこのような調節剤を含有する薬学的組成物、このような調節剤を調製する方法およびこのような調節剤を使用して肥満、糖尿病および関連した障害を処置する方法を開示している。本発明は、具体的には、ある種の新規アリールおよびビアリール化合物を開示している。本願は、米国仮特許出願第60/277,534号(これは、2001年3月21日に出願された)から優先権を主張している。
MCH(19−アミノ酸環状ペプチド)は、一昔前、硬骨魚で最初に確認され、これは、色の変化を調節すると思われる。さらに最近では、視床下部外側野(これは、摂食挙動を調節する脳の器官である)で主に合成されるMCHが、哺乳動物における摂食挙動の調節装置として、その潜在的な役割について、研究課題となっている。MCHを中枢系に投与すると、齧歯類において、食物摂取を刺激し脂肪分の蓄積を促進することが知られている。MCHを過剰発現するマウスが肥満体であることも知られている。Shimadaら、Nature,Vol.396(1998年12月17日)、pp.670〜673で報告されているように、MCHが欠乏したマウスは、減食(摂食低下)が原因で、体重が減り、痩せた。彼らの発見を考慮して、この文献の著者は、MCH作用のアンタゴニストが肥満の処置に有効であり得ることを示唆した。米国特許第5,908,830号は、糖尿病または肥満を処置する組合せ療法を開示しており、これは、代謝速度増大剤および摂食挙動調節剤の投与を含み、後者の例は、MCHアンタゴニストである。米国特許第6,043,246号は、神経ペプチドYレセプタアンタゴニストとして、特に、代謝系の疾患(肥満および糖尿病を含めて)を処置する薬剤として有用であると言われている尿素誘導体を開示している。公開されたPCT特許出願WO00/27845は、スピロ−インドリンとして特徴付けられる種類の化合物を記述しており、これは、選択的な神経ペプチドYY5アンタゴニストと言われ、肥満およびそれに関連した合併症を処置するのに有用である。本願出願人に譲渡された係属中の米国仮特許出願第60/232,255号(2000年9月14日に出願された)は、アリール置換尿素神経ペプチドYY5アンタゴニスト、および肥満、過食症(摂食増大)および糖尿病の処置におけるそれら使用を開示し請求している。
本発明は、その多くの実施形態では、MCHレセプターのアンタゴニストとしての新規種類の化合物、このような化合物を調製する方法、1種以上のこのような化合物を含有する薬学的組成物、1種以上のこのような化合物を含有する薬学的組成物、1種以上のこのような化合物を含有する医薬品処方物を調製する方法、およびMCHレセプターに関連した1種以上の疾患を処置、予防または改善する方法を提供する。1実施形態では、本願は、式Iで示した一般構造を有する化合物を開示しており、この化合物には、この化合物の鏡像異性体、立体異性体、回転異性体、互変異性体およびプロドラッグ、ならびにこの化合物またはこのプロドラッグの薬学的に受容可能な塩または溶媒和物が含まれる:
Mは、HまたはRである;
Zは、
ここで、Ar2は、非置換または置換フェニルであり、ここで、この置換基は、0個〜5個であり、同一または異なり得、そして独立して、F、Cl、Br、I、R、OR、NO2およびCF3からなる群から選択される;
nは、0〜6である;
pは、1〜6である;
R1は、同一または異なり得、そして独立して、R;NH2;NHR;N(R)2;N(R)2→O;NH(CH2)nOR;N(R)SO2R;NH(CH2)n−N(R)2;N(R)SO2(R);
ここで、nは、上で定義したとおりであり、ここで、Yは、0個〜5個の同一または異なり得る部分であり、そして独立して、H;OH;NH2;
ここで、nは、上で定義したとおりであり、そしてtは、1〜5である;そしてR2は、Hまたはアルキルである。
Ar1について:フェニルまたはピリジル(さらに好ましくは、式Iの環にて、4−フェニルまたは4−ピリジル)であり、このフェニルまたはピリジルにある1個以上の置換基は、CN、OCF3およびハロゲンからなる群から選択され、より好ましくは、CN、OCF3、FおよびClから選択した置換基を備えたフェニルであり、さらに好ましくは、これらの好ましい置換基の少なくとも1個が式Iで示したベンジル位置へのこの環の結合に関して、この環の3位置または4位置にあるときである。
a.治療有効量の第一化合物であって、この第一化合物は、式Iの化合物(または式IIの化合物または式IIIの化合物)、そのプロドラッグ、またはこの化合物の薬学的に受容可能な塩またはこのプロドラッグの薬学的に受容可能な塩である;および
b.治療有効量の第二化合物であって、この第二化合物は、肥満抑制薬および/または食欲抑制薬(例えば、β3アゴニスト、サイロミメティック薬またはNPYアンタゴニスト)であり、この第一および第二化合物の量は、肥満を処置する所望の効果を生じる。
a.治療有効量の第一化合物であって、この第一化合物は、式Iの化合物(または式IIの化合物または式IIIの化合物)、そのプロドラッグ、またはこの化合物の薬学的に受容可能な塩はもしくはこのプロドラッグの薬学的に受容可能な塩である;および第一の単位投薬形状薬学的に受容可能なキャリア、ビヒクルまたは希釈剤;
b.治療有効量の第二化合物であって、この第二化合物は、肥満抑制薬および/または食欲抑制薬(例えば、β3アゴニスト、サイロミメティック薬またはNPYアンタゴニスト)であり、この第一および第二化合物の量は、肥満を処置する所望の効果を生じる;および第二の単位投薬量形状の薬学的に受容可能なキャリア、ビヒクルまたは希釈剤;ならびに、
c.この第一および第二投薬形状を含有させる手段であって、ここで、この第一および第二化合物の量は、肥満を処置する所望の効果を生じる。
上記組合せ方法、組合せ組成物および組合せキットにおいて好ましい肥満抑制薬および/または食欲抑制薬の例示的な非限定の例としては、以下:
a.治療有効量の第一化合物であって、この第一化合物は、式Iの化合物(または式IIの化合物または式IIIの化合物)、そのプロドラッグ、またはこの化合物の薬学的に受容可能な塩またはこのプロドラッグの薬学的に受容可能な塩である;および
b.治療有効量の第二化合物であって、この第二化合物は、アルドースレダクターゼ阻害剤、グリコーゲンホスホリラーゼ阻害剤、ソルビトールデヒドロゲナーゼ阻害剤、タンパク質チロシンホスファターゼ1B阻害剤、ジペプチジルプロテアーゼ阻害剤、インスリン(経口で生物利用可能なインスリン製剤を含む)、インスリンミメティック、メトホルミン、アカルボース、PPAR−γリガンド(例えば、トログリタゾン、ロサグリタゾン、ピオグリタゾンまたはGW−1929)、スルホニル尿素、グリパジド、グリブリドまたはクロルプロパミドである;ここで、この第一および第二化合物の量は、糖尿病を処置する所望の効果を生じる。
a.治療有効量の第一化合物であって、この第一化合物は、式Iの化合物(または式IIの化合物または式IIIの化合物)、そのプロドラッグ、またはこの化合物の薬学的に受容可能な塩またはこのプロドラッグの薬学的に受容可能な塩である;および薬学的に受容可能なキャリア、ビヒクルまたは希釈剤;
b.治療有効量のアルドースレダクターゼ阻害剤、グリコーゲンホスホリラーゼ阻害剤、ソルビトールデヒドロゲナーゼ阻害剤、タンパク質チロシンホスファターゼ1B阻害剤、ジペプチジルプロテアーゼ阻害剤、インスリン(経口生物利用可能なインスリン製剤を含めて)、インスリンミメティック、メトホルミン、アカルボース、PPAR−γリガンド(例えば、トログリタゾン、ロサグリタゾン、ピオグリタゾンまたはGW−1929)、スルホニル尿素、グリパジド、グリブリドまたはクロルプロパミド、および第二の単位投薬形状の薬学的に受容可能なキャリア、ビヒクルまたは希釈剤;および
c.この第一および第二投薬形状を含有させる手段であって、ここで、この第一および第二化合物の量は、糖尿病を処置する所望の効果を生じる。
1実施形態では、本発明は、MCHレセプターの阻害剤として、式I、式IIもしくは式IIIの化合物、またはその薬学的に受容可能な誘導体を開示している。式I、式IIおよび式IIIにある種々の部分の定義は、上で示されている。
アリールとは、6個〜14個の炭素原子および少なくとも1個のベンゼノイド環を有する炭素環式基であり、この炭素環式基の全ての利用できる置換可能な炭素原子は、可能な結合点と見なされる。好ましいアリール基には、フェニル、1−ナフチル、2−ナフチルおよびインダニル、特に、フェニルおよび置換フェニルが挙げられる。
ハロゲンとは、フッ素、塩素、臭素およびヨウ素を意味する。
カプセルとは、これらの活性成分を含有する組成物を保持するか含有する特殊な容器または囲壁を意味し、これは、メチルセルロース、ポリビニルアルコール、または変性ゼラチンまたはデンプンから作製される。硬質カプセルは、典型的には、比較的に高いゲル強度の骨格とブタ皮膚ゼラチンとのブレンドから作製される。このカプセルそれ自体は、少量の染料、不透明化剤、可塑剤および防腐剤を含有し得る。
以下の図式、調製および実施例の記述で使用される略語は、以下である:
(使用する略語)
Ar=アルゴン
Boc=第三級ブチルオキシカルボニル
tBuOH=第三級ブタノール
CH2Cl2=ジクロロメタン
ClCH2CH2Cl=1,2−ジクロロエタン
CDI=カルボニルジイミダゾール
DIC=1,3−ジシクロヘキシルカルボジイミド
DMF=N,N−ジメチルホルムアミド
DIEA=N,N−ジイソプロピルエチルアミン
Et=エチル
EtOH=エタノール
EtOAc=酢酸エチル
HOBt=1−ヒドロキシベンゾトリアゾール
H2SO4=硫酸
HCl=塩化水素
H2O=水
K2CO3=炭酸カリウム
LDA=リチウムジイソプロピルアミド
LiOH=水酸化リチウム
LiAlH4=水素化リチウムアルミニウム
Me=メチル
MeI=ヨウ化メチル
MeOH=メタノール
Me2S=ジメチルスルフィド
NMMO=4−メチルモルホリンN−オキシド
Na(OAc)3BH=トリアセトキシホウ水素化ナトリウム
NaCl=塩化ナトリウム
NaH=水素化ナトリウム
NaHCO3=炭酸水素ナトリウム
NaIO4=過ヨウ素酸ナトリウム
Na2CO3=炭酸ナトリウム
NaOH=水酸化ナトリウム
Na2SO4=硫酸ナトリウム
Na2S2O3=チオ硫酸ナトリウム
O3=オゾン
O2=酸素
OsO4=四酸化オスミウム
Pd(PPh3)4=テトラキス(トリフェニルホスフィン)パラジウム(0)
SOCl2=塩化チオニル
TEA=トリエチルアミン
TFA=トリフルオロ酢酸
TMSOTf=トリフルオロメタンスルホン酸トリメチルシリル
THF=テトラヒドロフラン
HMCHR−CHO=チャイニーズハムスターの卵巣細胞から調製した膜であって、これは、ヒトメラニン濃縮ホルモンを過剰発現する。
BSA=ウシ血清アルブミン
MCH=メラニン濃縮ホルモン
MCHR=メラニン濃縮ホルモンレセプタ
本発明の化合物およびその中間体を調製するいくつかの方法は、以下の反応図式で図示されている。出発物質は、公知の手順を使用して、または図示したようにして、製造される。
((R,S)2−(4−ブロモフェニル)−ペント−4−エニルアミン(一般手順))
((R,S)−1−[2−(3’−シアノ−ビフェニル−4−イル)−4−シクロペンチルアミノ]−3−(3,5−ジクロロ−フェニル)−尿素)
((R,S)−N−[2−(3’−シアノ−ビフェニル−4−イル)−4−メチルアミノ−ブチル]−3,4−ジフルオロ−ベンズアミド)
((R,S)−3,5−ジクロロ−N−[2−(3’−シアノ−ビフェニル−4−イル)−4−ジメチルアミノ−ブチル]ベンゼンスルホンアミド)
((R,S)−[2−(3’−シアノ−ビフェニル−4−イル)−4−イソプロピルアミノ−ブチル]−カルバミン酸4−クロロ−フェニルエステル)
((R,S)−1−(1−{3−(3’−シアノ−ビフェニル−4−イル)−4−[3−(3,5−ジクロロ−フェニル)−ウレイド]−ブチル}−ピロリジン−3−イル)−3−エチル−尿素)
((R,S)−3,5−ジクロロ−N−(1−{3−(3’−シアノ−ビフェニル−4−イル)−4−[3−(3,5−ジクロロ−フェニル)−ウレイド]−ブチル}−ピロリジン−3−イル)−ベンズアミド)
((R,S)−N−(1−{3−(3’−シアノ−ビフェニル−4−イル)−4−[3−(3,5−ジクロロ−フェニル)−ウレイド]−ブチル}−ピペリジン−4−イル)−メタンスルホンアミド)
((R,S)−N−(3,5−ビス−トリフルオロメチル−ベンジル)−4−(シクロヘキシル−メチル−アミノ)−2−(3,4−ジクロロ−フェニル)−ブチルアミド)
(2−(3’−シアノ−ビフェニル−4−イル)−N−(3,5−ジクロロ−フェニル)−4−メチルアミノ−ブチルアミド)
(4’−{1−[3−(3,5−ジクロロフェニル)−2−オキソ−イミダゾリジン−1−イルメチル]−3−ジメチルアミノプロピル}−ビフェニル−3−カルボニトリル)
((3,5−ジクロロ−フェニル)−カルバミン酸3−ジメチルアミノ−1−(4−ピリジン−4−イルフェニル)−プロピルエステル)
10μgのhMCHR−CHO過剰発現膜(Receptor Biology,Inc.(Beltsville,Maryland製、または内部で製造した)および100μg/ウェルのWGA−SPAビーズ(Amersham Pharmacia Biotech,Inc.Piscataway,New Jersey製)/100μlの反応混合物を、MCHRアッセイ緩衝液(25mM HEPES(pH7.4)、10mM NaCl、10mM MgCl2、5mM MnCl2、0.1%BSA)中で調製した。MCHRアッセイ緩衝液中において、リガンド[125I]−MCH(Perkin Elmer Life Sciences,Inc.Boston,Massachusetts製)の2.0nMストックを調製した。DMSO中にて、試験化合物の40×ストック溶液を調製し、次いで、以下のようにして、96ウェルアッセイプレート(Corning #3604,Corning,New York)に加えた:5μlの試験化合物、試験化合物またはDMSO、45μlのMCHRアッセイ緩衝液、100μlの反応混合物、50μlの配位子ストック(最終[リガンド]=0.5nM)。このアッセイプレートを、プレート振盪機にて、5分間振盪し、次いで、2時間インキュベートした後、Microbeta Triluxカウンタ(PerkinElmer Wallac,Inc.Gaithersburg,Maryland製)にて、cpm/ウェルを決定した。IC50値について、全結合−非特異的結合の阻害%(2.5μMのMCH)を決定した。
Claims (18)
- 式Iで示した一般構造を有する化合物であって、該化合物には、該化合物の鏡像異性体、立体異性体、回転異性体、および互変異性体、ならびに該化合物の薬学的に受容可能な塩または溶媒和物が含まれる:
Mは、HまたはRであり、Rは、C1〜C6直鎖アルキルもしくは分枝アルキル、またはC3〜C7シクロアルキルである;
Zは、
ここで、Ar2は、置換フェニルであり、ここで、該置換基は、1個〜2個であり、同一または異なり得、そして独立して、FおよびClから選択される;
nは、2である;
pは、1である;
R1は、
そしてR2は、Hまたはアルキルである、
化合物。 - Mが、Hである、請求項1に記載の化合物。
- Ar1が、4−フェニルである、請求項1に記載の化合物。
- 前記4−フェニルが、CN、FおよびClの少なくとも1個またはそれらの組合せで置換されている、請求項3に記載の化合物。
- 前記4−フェニルが、3’位において前記置換基で置換されている、請求項4に記載の化合物。
- Rが、C1〜C4直鎖アルキル、C1〜C4分枝アルキルまたはC3〜C7シクロアルキルである、請求項1に記載の化合物。
- Rが、メチル、エチルまたはプロピルである、請求項6に記載の化合物。
- Rが、イソプロピルである、請求項6に記載の化合物。
- Rが、シクロブチルである、請求項6に記載の化合物。
- 式IIで示した一般構造を有する請求項1に記載の化合物であって、
M、Z、n、pおよびR1は、請求項1に定義されたとおりである;
kは、1である;そして
Xは、フェニルである、
化合物。 - Mが、Hである、請求項10に記載の化合物。
- Rが、C1〜C4直鎖アルキルまたは分枝アルキルである、請求項10に記載の化合物。
- 活性成分として、請求項1〜12のいずれか一項に記載の少なくとも1種の化合物を含有する、薬学的組成物。
- さらに、薬学的に受容可能なキャリアを含有する、請求項13に記載の薬学的組成物。
- 請求項1に記載の化合物であって、該化合物は、以下に列挙した構造を有する化合物:
- 糖尿病および肥満を処置する薬学的組成物であって、該組成物は、処置有効量の請求項15に記載の少なくとも1種の化合物および薬学的に受容可能なキャリアを含有する、組成物。
- 肥満を処置する薬学的組成物であって、該組成物は、以下を含有する:
処置有効量の請求項1〜12および15のいずれか一項に記載の少なくとも1種の化合物、または該化合物の薬学的に受容可能な塩;
処置有効量の1種以上の化合物であって、該化合物は、β3アゴニスト、スリオミメティック薬、肥満抑制薬、食欲抑制薬およびNPYアンタゴニストからなる群から選択される、化合物;および
薬学的に受容可能なキャリア。 - 肥満を処置する薬学的組成物であって、該組成物は、以下を含有する:
処置有効量の請求項1〜12および15のいずれか一項に記載の少なくとも1種の化合物、または該化合物の薬学的に受容可能な塩;
処置有効量の1種以上の化合物であって、該化合物は、アルドースレダクターゼ阻害剤、グリコーゲンホスホリラーゼ阻害剤、ソルビトールデヒドロゲナーゼ阻害剤、タンパク質チロシンホスファターゼ1B阻害剤、ジペプチジルプロテアーゼ阻害剤、インシュリン、インシュリンミメティック、メトホルミン、アカルボース、PPAR−ガンマ配位子、ロサグリタゾン、ピオグリタゾン、GW−1929、スルホニル尿素、グリパジド、グリブリドおよびクロルプロパミドからなる群から選択される、化合物;および
薬学的に受容可能なキャリア。
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