JP2010001316A - 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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- JP2010001316A JP2010001316A JP2009232046A JP2009232046A JP2010001316A JP 2010001316 A JP2010001316 A JP 2010001316A JP 2009232046 A JP2009232046 A JP 2009232046A JP 2009232046 A JP2009232046 A JP 2009232046A JP 2010001316 A JP2010001316 A JP 2010001316A
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- -1 Aryl compound Chemical class 0.000 title description 60
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- 229940002612 prodrug Drugs 0.000 abstract description 36
- 150000003839 salts Chemical class 0.000 abstract description 33
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 28
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 18
- 239000012453 solvate Substances 0.000 abstract description 11
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 9
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- 102000006953 melanin-concentrating hormone receptor activity proteins Human genes 0.000 abstract 3
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- 229940044551 receptor antagonist Drugs 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 306
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/54—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C311/07—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract
【解決手段】1つの実施形態において、本発明は、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。本明細書では、例証的な本発明の化合物が示されている。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。
【選択図】なし
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。
本願発明の好ましい実施形態によれば、以下の化合物などが提供される。
(項1)
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、互変異性体およびプロドラッグ、ならびに該化合物または該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、Ar 2 は、非置換または置換フェニルであり、ここで、該置換基は、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、NO 2 およびCF 3 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;
R 1 は、同一または異なり得、そして独立して、R;NH 2 ;NHR;N(R) 2 ;N(R) 2 →O;NH(CH 2 ) n OR;N(R)SO 2 R;NH(CH 2 ) n −N(R) 2 ;N(R)SO 2 (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;NH 2 ;
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R 2 は、Hまたはアルキルである、
化合物。
(項2)
Mが、Hである、上記項1に記載の化合物。
(項3)
Ar 1 が、4−フェニルである、上記項1に記載の化合物。
(項4)
Ar 1 が、4−ピリジルである、上記項1に記載の化合物。
(項5)
前記フェニルが、前記環上で、CN、OCF 3 、FおよびClまたはそれらの組合せの少なくとも1個で置換されている、上記項3に記載の化合物。
(項6)
前記置換基が、式Iのベンジル位への前記環の結合に関して、該環上の3位にある、上記項3に記載の化合物。
(項7)
前記ピリジルが、前記環上で、CN、OCF 3 、FおよびClまたはそれらの組合せの少なくとも1個で置換されている、上記項4に記載の化合物。
(項8)
Zが、Ar 2 −NH−COであり、ここで、Ar 2 が、フェニルである、上記項1に記載の化合物。
(項9)
前記フェニルが、0個〜5個の1つ以上の部分で置換され、同一または異なり、そして独立して、F、Cl、Br、I、OCH 3 およびCF 3 からなる群から選択される、上記項8に記載の化合物。
(項10)
Ar 2 上にある前記置換基が、F、ClまたはOCH 3 である、上記項9に記載の化合物。
(項11)
Rが、C 1 〜C 4 直鎖アルキル、C 1 〜C 4 分枝アルキルまたはC 3 〜C 7 シクロアルキルである、上記項1に記載の化合物。
(項12)
Rが、メチル、エチルまたはプロピルである、上記項11に記載の化合物。
(項13)
Rが、イソプロピルである、上記項11に記載の化合物。
(項14)
Rが、シクロブチルである、上記項11に記載の化合物。
(項15)
nが、2〜4である、上記項1に記載の化合物。
(項16)
nが、2である、上記項1に記載の化合物。
(項17)
R 1 が、NH 2 ;NHR;N(R) 2 ;N(R) 2 →O;NH(CH 2 ) n OCH 3 ;N(R)SO 2 R;NH(CH 2 ) n −N(R) 2 ;N(R)SO 2 (R);
(項18)
R 1 が、NHMe;NHEt;NMe 2 ;NH(CH 2 ) n OCH 3 ;NH−シクロプロピル;NH−シクロブチル;NH−シクロペンチル;NH(CH 2 ) 3 NMe 2 ;
(項19)
Yが、NH 2 ;NMe 2 ;NHMe;
(項20)
式II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、互変異性体およびプロドラッグ、ならびに該化合物または該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;
kは、0〜5である;
pは、1〜6である;
nは、0〜6である;
Zは、
ここで、Ar 2 は、非置換または置換フェニルであり、該置換基は、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、NO 2 およびCF 3 からなる群から選択される;R 1 は、同一または異なり得、そして独立して、R;NH 2 ;NHR;N(R) 2 ;N(R) 2 →O;NH(CH 2 ) n OR;N(R)SO 2 R;NH(CH 2 ) n −N(R) 2 ;N(R)SO 2 (R);
ここで、nおよびRは、上で定義されており、そして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;NH 2 ;
ここで、nは、上で定義されており、そしてtは、1〜5である;Xは、同一または異なり得、そして独立して、H、Cl、F、Br、I、R、OR、CF 3 、OCF 3 、メチレンジオキシ、フェニル、
化合物。
(項21)
kが、1〜3の数である、上記項20に記載の化合物。
(項22)
Xが、R、H、Cl、CF 3 およびOCF 3 からなる群から選択され、ここで、Rが、上記項20で定義されている、上記項20に記載の化合物。
(項23)
Mが、Hである、上記項20に記載の化合物。
(項24)
Zが、Ar 2 −NH−COであり、ここで、Ar 2 が、フェニルである、上記項20に記載の化合物。
(項25)
前記フェニルが、0個〜5個の1つ以上の部分で置換され、同一または異なり、そして独立して、F、Cl、Br、I、OCH 3 およびCF 3 からなる群から選択される、上記項24に記載の化合物。
(項26)
Rが、C 1 〜C 4 直鎖アルキルまたはC 1 〜C 4 分枝アルキルである、上記項20に記載の化合物。
(項27)
nが、2である、上記項20に記載の化合物。
(項28)
活性成分として、上記項1または上記項20の少なくとも1種の化合物を含有する、薬学的組成物。
(項29)
MCHレセプターに関連した障害を処置する際に使用する、上記項28に記載の薬学的組成物。
(項30)
さらに、薬学的に受容可能なキャリアを含有する、上記項28に記載の薬学的組成物。
(項31)
MCHレセプターに関連した障害を処置する方法であって、このような処置を必要としている患者に、薬学的組成物を投与する工程を包含し、該薬学的組成物は、処置有効量の上記項1または上記項20に記載の少なくとも1種の化合物を含有する、
方法。
(項32)
前記投与が、経口である、上記項31に記載の方法。
(項33)
前記投与が、皮下投与を経由する、上記項31に記載の方法。
(項34)
MCHレセプターに関連した障害を処置する医薬を製造するための上記項1または上記項20に記載の化合物の使用。
(項35)
MCHレセプターに関連した障害を処置する薬学的組成物を調製する方法であって、上記項1または上記項20に記載の化合物のうち少なくとも1種の化合物および薬学的に受容可能なキャリアを密接に接触させる工程を包含する、方法。
(項36)
MCHモジュレーター活性を示す化合物であって、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、該化合物は、以下で列挙した構造を有する化合物:
の群から選択される、化合物。
(項37)
式III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、互変異性体およびプロドラッグ、ならびに該化合物または該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;
kは、0〜5である;
pは、1〜6である;
nは、0〜6である;
Gは、−CH 2 −、−C(O)−および−C(O)−O−からなる群から選択される部分であり、該−C(O)は、図において、N(R 1 R 2 )に連結されている;
R 1 は、同一または異なり得、そして独立して、R;NH 2 ;NHR;N(R) 2 ;N(R) 2 →O;NH(CH 2 ) n OR;N(R)SO 2 R;NH(CH 2 ) n −N(R) 2 ;N(R)SO 2 (R);
ここで、nおよびRは、上で定義されており、そして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;NH 2 ;
ここで、nは、上で定義されており、そしてtは、1〜5である;
R 2 は、Hまたはアルキルである;
R 3 は、アルキル、アリール、アリールアルキルおよびアルキルアリールからなる群から選択される;そして
Lは、同一または異なり得、そして独立して、H、アリール、アルキル、ハロゲン、アルコキシ、アリールオキシ、アリールアルコキシ、アルキルアリールオキシ、ヒドロキシ、カルボキシ、カルボアルコキシ、シアノ、CF 3 およびNO 2 からなる群から選択される、
化合物。
(項38)
MCHレセプターに関連した障害を処置する薬学的組成物であって、処置有効量の上記項36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。
(項39)
摂食障害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:
処置有効量の上記項1または上記項20に記載の少なくとも1種の化合物、そのプロドラッグ、または該化合物もしくは該プロドラッグ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、β 3 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;および
薬学的に受容可能なキャリア。
(項40)
摂食障害を処置する方法であって、該方法は、このような処置が必要な哺乳動物に、以下を投与する工程を包含する:
(a)処置有効量の上記項1または上記項20に記載の少なくとも1種の化合物、そのプロドラッグ、または該化合物もしくは該プロドラッグの薬学的に受容可能な塩;および
(b)処置有効量の1種以上の化合物であって、該化合物は、β 3 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、ここで、(a)および(b)の量は、該処置がなされる量である、
方法。
(項41)
摂食障害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:
処置有効量の上記項1または上記項20に記載の少なくとも1種の化合物、そのプロドラッグ、または該化合物もしくは該プロドラッグ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、グリバジド、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;および
薬学的に受容可能なキャリア。
Claims (1)
- 本願明細書に記載の発明。
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