JP5946192B2 - 肥満症及び糖尿病を含む代謝性疾患の処置に有用なカンナビノイド受容体拮抗薬/逆作動薬 - Google Patents
肥満症及び糖尿病を含む代謝性疾患の処置に有用なカンナビノイド受容体拮抗薬/逆作動薬 Download PDFInfo
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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Description
本願は、35U.S.C.§119(e)の下で、2010年11月18日出願の米国特許仮出願第61/415,051号明細書の優先権による利益を主張するものである。この出願の開示は、参照により本明細書に組み込まれる。
式中、
X、Y、X’、Y’、X”及びY”は、H、C1〜6アルキル、ハロゲン、CF3、O−C1〜6アルキル、NO2、NR2、O(CH2)nCO2R、O(CH2)nCN、OCH2CH=CHCO2R、CH2O(CH2)nCO2R、CH2OCH2CH=CHCO2R、O(CH2)nPO(OR)2、CH2O(CH2)nPO(OR)2、NRa(CH2)nCO2R、NRa(CH2)nPO(OR)2、NRaCH2CH=CHCO2R、NRaSO2R、NRaCO(CH2)nCO2R、NRaCO(CH2)nCONRa 2、O(CH2)nC6H4CO2R、O(CH2)nC6H4(CH2)nCO2R、CH2O(CH2)nC6H4CO2R、O(CH2)nC6H4CONRa 2、O(CH2)nC6H4(CH2)nCONRa 2、O(CH2)nC6H4−テトラゾール、CH2O(CH2)nC6H4CONRa 2、CH2O(CH2)nC6H4−テトラゾール、O(CH2)nC6H4(CH2)n−テトラゾール、NRa(CH2)nC6H4CO2R、CH2NRa(CH2)nC6H4CO2R、NRa(CH2)nC6H4(CH2)nCO2R、NRa(CH2)nC6H4CONRa 2、CH2NRa(CH2)nC6H4CONRa 2、NRa(CH2)nC6H4(CH2)nCONRa 2、NRa(CH2)nC6H4−テトラゾール、CH2NRa(CH2)nC6H4−テトラゾール、NRa(CH2)nC6H4(CH2)n−テトラゾール、CONHOH、C(NH)NRa 2、(CH2)nC(NH)NRa 2、O(CH2)nCONRa 2、O(CH2)nC(NH)NRa 2、O(CH2)nC(NOH)NRa 2、CH2O(CH2)nCONRa 2、NRa(CH2)nCONRa 2、OCH2CH=CHCONRa 2、CH2OCH2CH=CHCONRa 2、NRaCH2CH=CHCONRa 2、(CH2)m−テトラゾール、O(CH2)n−テトラゾール、O(CH2CH2O)pR、NRa(CH2CH2O)pR及びSO2NHCH3から独立して選択され;
Zは、H、C1〜6アルキル、OH、O−C1〜6アルキル、O(CH2CH2O)pR、OC(O)−C1〜6アルキル、O(CH2)nCO2R、OCH2CH=CHCO2R、O(CH2)nPO(OR)2、O(CH2)nCONRa 2、O(CH2)nC(NH)NH2、O(CH2)nC(NOH)NRa 2、OCH2CH=CHCONRa 2、O(CH2)n−フェニル−(CH2)mCO2R及びO(CH2)n−フェニル−(CH2)m−テトラゾールから選択され;
Z’は、H、CO2R及びCONRa 2から選択され;
Qは、(CH2)nCHA(CH2)mC(O)NR2、(CH2)mCAA”(CH2)mC(O)NR2、(CH2)nCHA(CH2)mCO2R、(CH2)mCAA”(CH2)mCO2R、(CH2)mCHA(CH2)mSO2NR2、(CH2)mCHA(CH2)mSO3R、(CH2)mCHA(CH2)mC(NH)NH2、(CH2)mCHA(CH2)mC(NOH)NH2、(CH2)mCHA(CH2)mCONHCHA(CH2)mCO2R、(CH2)mCAA”(CH2)mCONHCHA(CH2)mCO2R、(CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCO2R、(CH2)mCHA(CH2)mCONHCHA(CH2)mCONRa 2、(CH2)mCAA”(CH2)mCONHCHA(CH2)mCONRa 2、(CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCONRa 2、C3−C6−環状アミノ−(CH2)mCO2R、C3−C6−環状アミノ−(CH2)mCONRa 2、C3−C6−シクロアルキレン−(CH2)mCO2R、C3−C6−シクロアルキレン−(CH2)mCONRa 2、(CH2)nCH=CHCO2R、(CH2)nCH=CHCONRa 2、(CH2)mCHA(CH2)mCONHCHA(CH2)mSO2NRa 2、(CH2)mCAA”(CH2)mCONHCHA(CH2)mSO2NRa 2、(CH2)mCHA(CH2)mCONHCAA”(CH2)mSO2NRa 2、(CH2)mCAA”(CH2)mCONHCAA”(CH2)mSO2NRa 2、(CH2)m−アリール−(CH2)mCO2R、(CH2)m−アリール−(CH2)mCONRa 2、ヘテロアリール−(CH2)mCO2R、ヘテロアリール−(CH2)mCONRa 2、(CH2)mCHA(CH2)mPO3R2、(CH2)mCAA”(CH2)mPO3R2、(CH2)mCHA(CH2)mPO(OR)NRa、(CH2)mCAA”(CH2)mPO(OR)NRa、(CH2)mCAA”(CH2)mPONRa 2、及び(CH2)mCHA(CH2)mPONRa 2から選択され;
Aは、H、C1〜6アルキル、(CH2)mC3〜6−シクロアルキル、OH、CH2OH、CH(CH3)OH、C(CH3)2OH、(CH2)nCO2Rb、(CH2)nC(O)NRb 2及び(CH2)m−フェニルであり、ここでフェニルは、H、C1〜4アルキル、ハロゲン、CF3、O−C1〜4アルキル、NO2、CONRC2、CO2R、NR2、OR、NHSO2CH3、NHCONH2及びSONHRから選択される0〜3個の基で置換され;
A”は、C1〜6アルキルであり;
代替的に、CAA”基は、C3〜6スピロシクロアルキル環又は4〜6員のスピロシクロアルキルアミン環を形成し;
Mは、C=O又はSO2であり;
Rは、H、(CH2)m(CHRb)n(CH2)mOH、CH(CH2OH)2、C1〜6アルキル、C2〜6アルケニル及びC2〜6アルキニルから独立して選択され;
Raは、H、(CH2)m(CHR)n(CH2)mOH、C1〜6アルキル、C2〜6アルケニル及びC2〜6アルキニルから独立して選択され;
Rbは、H、C1〜6アルキル、C2〜6アルケニル及びC2〜6アルキニルから独立して選択され;
pは、2、3、4、5、6、7、8、9、10、11及び12から選択され;
mは、0、1、2、3及び4から選択され;
nは、1、2、3及び4から選択され;
但し、(a)〜(c)のうちの少なくとも一つが、満たされることを条件とする:
(a)Qは、(CH2)nCH=CHCO2R、(CH2)nCH=CHCONRa 2、(CH2)mCHA(CH2)mCONHCHA(CH2)mSO2NRa 2、(CH2)mCAA”(CH2)mCONHCHA(CH2)mSO2NRa 2、(CH2)mCHA(CH2)mCONHCAA”(CH2)mSO2NRa 2、(CH2)mCAA”(CH2)mCONHCAA”(CH2)mSO2NRa 2、(CH2)m−アリール−(CH2)mCO2R、(CH2)m−アリール−(CH2)mCONRa 2、ヘテロアリール−(CH2)mCO2R、ヘテロアリール−(CH2)mCONRa 2、(CH2)mCHA(CH2)mPO3R2、(CH2)mCAA”(CH2)mPO3R2、(CH2)mCHA(CH2)mPO(OR)NRa、(CH2)mCAA”(CH2)mPO(OR)NRa、(CH2)mCAA”(CH2)mPONRa 2及び(CH2)mCHA(CH2)mPONRa 2から選択され;
b)CAA”基は、C3〜6スピロシクロアルキル環又は4〜6員のスピロシクロアルキルアミン環を形成し;
(c)Aは、(CH2)m−フェニルであり、ここでフェニルは、CONRc 2、CO2R、NR2、OR、NHSO2CH3、NHCONH2及びSONHRから選択される一つの基で置換され、かつH、C1〜4アルキル、ハロゲン、CF3、O−C1〜4アルキル、NO2、CONRc 2、CO2R、NR2、OR、NHSO2CH3、NHCONH2及びSONHRから選択される0〜2個の基で置換される。
式中、
X、Y、X’、Y’、X”及びY”は、以下から個々に選択され、H、C1〜4アルキル、ハロゲン、CF3、O−C1〜4アルキル、NO2、O(CH2CH2O)pR、NRa(CH2CH2O)pR及びNR2;
Zは、H、C1〜4アルキル、OH、O−C1〜4アルキル、アセチルオキシ及びプロピニルオキシから選択され;
Qは、(CH2)nCHA(CH2)mC(O)NR2、(CH2)mCAA”(CH2)mC(O)NR2、(CH2)nCHA(CH2)mCO2R、(CH2)mCAA”(CH2)mCO2R、(CH2)mCHA(CH2)mSO2NR2、(CH2)mCHA(CH2)mCONHCHA(CH2)mCO2R、(CH2)mCAA”(CH2)mCONHCHA(CH2)mCO2R、(CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCO2R、(CH2)mCHA(CH2)mCONHCHA(CH2)mCONRa 2、(CH2)mCAA”(CH2)mCONHCHA(CH2)mCONRa 2、(CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCONRa 2、C3−C6−環状アミノ−(CH2)mCO2R、C3−C6−環状アミノ−(CH2)mCONRa 2、C3−C6−シクロアルキレン−(CH2)mCO2R、C3−C6−シクロアルキレン−(CH2)mCONRa 2、(CH2)nCH=CHCO2R、(CH2)nCH=CHCONRa 2、(CH2)mCHA(CH2)mCONHCHA(CH2)mSO2NRa 2、(CH2)mCAA”(CH2)mCONHCHA(CH2)mSO2NRa 2、(CH2)mCHA(CH2)mCONHCAA”(CH2)mSO2NRa 2、(CH2)mCAA”(CH2)mCONHCAA”(CH2)mSO2NRa 2、(CH2)m−アリール−(CH2)mCO2R、(CH2)m−アリール−(CH2)mCONRa 2、ヘテロアリール−(CH2)mCO2R、ヘテロアリール−(CH2)mCONRa 2、(CH2)mCHA(CH2)mPO3R2、(CH2)mCAA”(CH2)mPO3R2、(CH2)mCHA(CH2)mPO(OR)NRa、(CH2)mCAA”(CH2)mPO(OR)NRa、(CH2)mCAA”(CH2)mPONRa 2、及び(CH2)mCHA(CH2)mPONRa 2から選択され;
Aは、H、C1〜4アルキル、(CH2)mC3〜6−シクロアルキル、OH、CH2OH、CH(CH3)OH、C(CH3)2OH、(CH2)nCO2Rb、(CH2)nC(O)NRb 2及び(CH2)m−フェニルから選択され、ここでフェニルは、H、C1〜4アルキル、ハロゲン、CF3、O−C1〜4アルキル、NO2、CONRC2、CO2R、NR2、OR、NHSO2CH3、NHCONH2及びSONHRから選択される0〜3個の基で置換され;
代替的に、CAA”基は、C3〜6スピロシクロアルキル環又は4〜6員のスピロシクロアルキルアミン環を形成し;
Rは、H、C1〜6アルキル、C2〜6アルケニル及びC2〜6アルキニルから独立して選択され;
Rbは、H、C1〜6アルキル、C2〜6アルケニル及びC2〜6アルキニルから独立して選択され;
pは、2、3、4、5、6、7及び8から選択され;
mは、0、1、2及び3から独立して選択され;
nは、1、2及び3から独立して選択される。
Qは、(CH2)nCHA(CH2)mC(O)NR2、(CH2)mCAA”(CH2)mC(O)NR2、(CH2)mCHA(CH2)mSO2NR2、(CH2)mCHA(CH2)mCONHCHA(CH2)mCONRa 2、(CH2)mCAA”(CH2)mCONHCHA(CH2)mCONRa 2、(CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCONRa 2、C3−C6−環状アミノ−(CH2)mCO2R、C3−C6−環状アミノ−(CH2)mCONRa 2、C3−C6−シクロアルキレン−(CH2)mCONRa 2、(CH2)nCH=CHCONRa 2、(CH2)mCHA(CH2)mCONHCHA(CH2)mSO2NRa 2、(CH2)mCAA”(CH2)mCONHCHA(CH2)mSO2NRa 2、(CH2)mCHA(CH2)mCONHCAA”(CH2)mSO2NRa 2、(CH2)mCAA”(CH2)mCONHCAA”(CH2)mSO2NRa 2、(CH2)m−アリール−(CH2)mCONRa 2、ヘテロアリール−(CH2)mCO2R、ヘテロアリール−(CH2)mCONRa 2、(CH2)mCHA(CH2)mPO3R2、(CH2)mCAA”(CH2)mPO3R2、(CH2)mCHA(CH2)mPO(OR)NRa、(CH2)mCAA”(CH2)mPO(OR)NRa、(CH2)mCAA”(CH2)mPONRa 2、及び(CH2)mCHA(CH2)mPONRa 2から選択され;
Mは、SO2であり;
代替的に、CAA”基は、C3〜6スピロシクロアルキル環又は4〜6員のスピロシクロアルキルアミン環を形成し;
Rは、H及びC1〜4アルキルから独立して選択され;
Rbは、H及びC1〜4アルキルから独立して選択され;
mは、0、1及び2から独立して選択され;
nは、独立して1及び2から選択される。
本願に提示された定義に提供する例は、特に指摘しない限り、非包括的である。それらの定義は、引用された例を含むが、それらに限定されない。
化合物AAにおいて、X、Y、X’、Y’、X”、Y、Z、Z’又はQのうちの一つは、化合物AAのCNS活性を低減又は限定することが可能な基である。この低減又は限定されたCNS活性は、X、Y、X’、Y’、X”、Y、Z、Z’及びQのうちの少なくとも一つが、BBBを交差する化合物AAの能力をSLV319と比較して限定するか、又はSLV319と比較して化合物AAが脳から能動的に除去される速度を速めることが可能であることにより生じる。脳内に存在する化合物AAの量の例としては、同一の量で投与された際、(a)SLV319と比較して50、55、60、65、70、75、80、85、90、91、92、93、94、95、96、97、98、99から100%低い量、(b)SLV3199と比較して90、91、92、93、94、95、96、97、98、99から100%低い量、及び(c)SLV319と比較して98、99から100%低い量が挙げられる。
本発明において、本発明の化合物は、任意の都合のよい方法(例えば経腸又は非経口)で投与することができる。投与方法の例には、経口及び経皮が挙げられる。当業者は、本発明の化合物の投与経路が、相当様々であり得ることに気付くであろう。他の経口投与に加えて、持続放出組成物が好まれ得る。他の許容され得る経路には、注射(例えば静脈内、筋内、皮下及び腹腔内);皮下インプラント;並びに、頬内、舌下、局所、直腸、経膣及び鼻腔内投与を挙げることができる。生体内侵食性、非生体内侵食性、生分解性及び非生分解性の投与システムも使用され得る。経口製剤の例には、錠剤、被覆錠剤、硬及び軟ゼラチンカプセル剤、液剤、乳剤及び縣濁剤が挙げられる。
本発明の化合物は、有機合成の当業者に既知の多数の方法で調製することができる(例えば、米国特許第6,476,060B2号明細書、J Med Chem 2004,47,627参照)。本発明の化合物は、下記に記載する方法を、合成有機化学の当業者に既知の合成方法と共に用いて合成することができ、又は当業者が認識し得る該合成方法の変形により合成することができる。好ましい方法としては、下記に記載する方法が挙げられるが、これらに限定されない。反応は、使用する試薬及び材料に適し、かつ達成される変換に好適な溶媒中で行われる。有機合成の当業者は、分子上に存在する官能基が、提案される変換に一致するものでなければならないことを理解するであろう。このことは、時には合成ステップの順序を変更する判断を必要とし、又は、特定の一つの工程スキームを他の工程スキームに優先して選択して、本発明の所望の化合物を得る必要があるであろう。また、この分野において任意の合成経路の計画の他の主な考慮事項は、本発明に記載する化合物中に存在する反応性官能基の保護のための保護基の賢明な選択であることが認識されるであろう。熟練した専門家に多数の代替物を記載している権威ある説明書は、Greene及びWuts(Protective Groups In Organic Synthesis,Wiley and Sons,1991)である。本明細書に引用する全ての参考文献は、それらの全体が参照により本明細書に組み込まれる。
スキーム1は、2’−、3’−又は4’−(カルボ−t−ブトキシメトキシ)−2−フェニルアセトフェノンをどのように変換するかを示し、2’−、3’−又は4’−(カルボ−t−ブトキシメトキシ)−2−フェニルアセトフェノンは、商業的に入手可能な2’−、3’−又は4’−メトキシ−2−フェニルアセトフェノンから、HBr/HOAc又はBBr3/CH2Cl2を使用してO−脱メチル化し、得られたフェノールを、ピペリジンを含有する37%ホルムアルデヒド水溶液中、塩基の存在下、還流下でt−ブチルブロモアセテートで対応するアクリロフェノンにアルキル化して調製される(ステップa)。アクリロフェノンをエタノール中にてヒドラジン水和物で処理すると、3,4−ジアリールピラゾリンを生成することができる(ステップb)。ジアリールピラゾリンを更に、溶媒(例えばアセトニトリル)中、トリエチルアミンの存在下、対応するアリールスルホンアミド、CS2及びMeIから調製されたアリールスルホニルジチオイミド炭酸メチルエステル(J.Med Chem.,47,627(2004);Chem.Ber.1966,99,2885参照)で還流下にて処理して、ピラゾール−1−カルボキシイミドチオ酸メチルエステルを得ることができる(ステップc)。これらのイミノチオエーテルを更に、メチルアミン及び塩化メチレンの水溶液に室温で暴露することにより、ピラゾリン−1−カルボキサミジンを得るであろう(ステップd)。TFA/CH2Cl2を使用したエステルの加水分解は、カルボン酸を生成するであろう(ステップe)。
スキーム2は、2−(2’−、3’−又は4’−カルボ−t−ブトキシメトキシフェニル)アセトフェノン(スキーム1と同様に調製)が、対応するアクリロフェノンをどのように提供するかを記載する(ステップa)。アクリロフェノンをエタノール中にてヒドラジン水和物で処理すると、3,4−ジアリールピラゾリンを生成することができる(ステップb)。ジアリールピラゾリンを更に、アセトニトリルのような溶媒中、トリエチルアミンの存在下、還流下にてアリールスルホニルジチオイミド炭酸メチルエステルで処理して、ピラゾール−1−カルボキシイミドチオ酸メチルエステルを得ることができる(ステップc)。これらのイミノチオエーテルを更に、メチルアミン及び塩化メチレンの水溶液に室温で暴露することにより、ピラゾリン−1−カルボキサミジンを得るであろう(ステップd)。TFA/CH2Cl2を使用したエステルの加水分解は、カルボン酸を生成するであろう(ステップe)。
スキーム3は、ピペリジン及び酢酸を含む37%ホルマリン水溶液及びMeOH中、還流下での4’−クロロ−2−フェニルアセトフェノンの転換を示し、該転換によりアクリロフェノンを得るであろう(J.Agric.Food Chem.1979,27(2),406)(ステップa)。アクリロフェノンをエタノール中にてヒドラジン水和物で処理して、3,4−ジアリールピラゾリンを生成することができる(ステップb)。ジアリールピラゾリンを更に、アセトニトリルのような溶媒中、トリエチルアミンの存在下、還流下にてアリールスルホニルジチオイミド炭酸メチルエステルで処理して、ピラゾール−1−カルボキシイミドチオ酸メチルエステルを得ることができる(ステップc)。これらのイミノチオエーテルを更に、トリエチルアミンを含むエタノール及び塩化メチレン中のβ−アラニンt−ブチルエステルに暴露することにより、ピラゾリン−エステルを得るであろう(ステップd)。TFA/CH2Cl2を使用したエステルの加水分解は、カルボン酸を生成するであろう(ステップe)。エステルをメタノール中の無水アンモニアで約0°〜室温にて処理することにより、カルボキサミド化合物を得ることができる(ステップf)。代替的に、イミノチオエーテルを他のアミノ酸エステルと結合させて付加物を与えてもよく(ステップg)、該付加物をカルボン酸に加水分解してもよい(ステップh)。これらの酸は、ジクロロエタン中、塩化オキサリルを使用し、その後無水アンモニアを使用して、又はピリジン/THF中のBoc2Oを使用し、その後無水アンモニアを使用して、カルボキサミドに転換されてもよい(ステップi)。
スキーム4は、塩化メチレン中でm−クロロペル安息香酸を用いた4’−クロロ−2−フェニルアクリロフェノンの酸化がどのようにエポキシドを提供するかを示し(ステップa)、このエポキシドを、エタノール溶液中にてヒドラジン水和物を用いて約35〜40℃で処理することにより、3,4−ジアリールピラゾリンアルコールを与えることができる(ステップb)。ピラゾリンは、塩基の存在下、ジ−t−ブチル−ジカーボネート(t−Boc無水物)を使用して保護されてN−t−BOC−ピラゾリンを与えてもよい(ステップc)。次いで、カルバメートアルコールをDMFのような溶媒中にて水素化ナトリウムを用いて脱プロトン化し、その後エチル4−ブロモクロトネートを用いてアルキル化して、エステルを得ることができる(ステップd)。t−BOC基の除去は、TFAを用いた処理により達成することができる(ステップe)。次いで、ピラゾリンをアセトニトリルのような溶媒中、トリエチルアミンの存在下、還流下にてアリールスルホニルジチオイミド炭酸メチルエステルと反応させて、ピラゾール−1−カルボキシイミドチオ酸メチルエーテルを得ることができる(ステップf)。これらのイミノチオエーテルを更に、メチルアミン及び塩化メチレンの水溶液に室温で暴露することにより、ピラゾリン−1−カルボキサミジンを得ることができ(ステップg)、またTHF水溶液中でLiOHを使用してエステルを加水分解することによりカルボン酸を生成することができる(ステップh)。カルボキサミドは、エステルをアルコール中にて−20℃〜周囲温度で無水アンモニアで処理することにより調製することができる(ステップi)。
スキーム5は、3,4−ジアリールピラゾリン及びS−メチルイソチオウレアのピリジン溶液の加熱がどのようにピラゾリン−1−カルボキサミジンを形成し得るかを示す(ステップa)。このアミジンをアセトニトリル中、N.N−ジメチル−4−アミノピリジン及びトリエチルアミンの存在下、t4−シアノベンゼンスルホニルクロリドで処理して、カルボキサミジン−結合スルホンアミド誘導体を与えることができる(ステップb)。ニトリルのフェニルカルボキサミジンへの転換は、MeOH中、0℃〜室温でHCl(気体)を使用し、次いでMeOH中、約0℃〜室温で炭酸アンモニウム又は無水アンモニアを使用して達成することができる(ステップc)。
スキーム6は、4−クロロベンゾイルクロリド及びアンモニウムイソシアナートから作製された4−クロロベンゾイルイソチオシアナート(J Heterocycl.Chem.1991,28,1645参照)の新たに調製された無水アセトニトリル溶液と、冷所中で撹拌されている3,4−ジアリールピラゾリンとの反応が、どのようにピラゾリン付加物を与え得るかを記載する(ステップa)。このチオカルボキサミドを、HgCl2の存在下、エチルβ−アラニン等のアミノ化合物で処理して、ベンゾイルグアニジンを生成することができる(ステップb)。エステルをTHF水溶液中でLiOHを使用して加水分解して、カルボン酸を生成することができる(ステップc)。酸から酸塩化物への更なる転換、その後の無水アンモニアを用いた処理により、カルボキサミドを得るであろう(ステップd)。
スキーム7は、ピペリジン及び酢酸を含む37%ホルマリン水溶液及びMeOH中の4’−ニトロ−2−フェニルアセトフェノンの溶液の濃縮が、加熱還流後、どのように対応するアクリロフェノンを与えるかを示す(ステップa)。アクリロフェノンをエタノール中にてヒドラジン水和物で処理して、3,4−ジアリールピラゾリンを生成することができる(ステップb)。次いで、ピラゾリンを、アセトニトリルのような溶媒中、トリエチルアミンの存在下、還流下にてアリールスルホニルジチオイミド炭酸メチルエステルと反応させて、対応するピラゾール−1−カルボキシイミドチオ酸メチルエステルを得ることができる(ステップc)。ニトロ基を塩基水溶液中で亜ジチオン酸ナトリウムを使用して還元して、アニリン化合物を生成することができる(ステップd)。塩基の存在下でエチルマロニルクロリドを用いてアニリンをアシル化すると、アミドを生成するであろう(ステップe)。アミドエステルをメタノール又は塩化メチレン等の溶媒中、メチルアミン又は無水アンモニア等のアミンを用いて0度〜室温にて処理すると、末端カルボキサミド基を有するピラゾール−1−カルボキサミジンを与えるであろう(ステップf)。代替的に、アニリン化合物を塩化メタンスルホニルで処理してスルホンアミドを与えてもよく(ステップg)、該スルホンアミドは室温でメチルアミン及び塩化メチレンの水溶液に暴露された後、ピラゾリン−1−カルボキサミジンを与えるであろう(ステップh)。
スキーム8は、エタノール中でのヒドラジン水和物を用いた4’−シアノ−2−フェニルアクリロフェノンの処理が、どのように3,4−ジアリールピラゾリンを生成するかを示す(ステップa)。次いで、ピラゾリンを一当量のアジ化ナトリウムと一当量のトリ−n−ブチルすずクロリドとの反応によりインサイチューで都合よく調製されたトリ−n−ブチルすずアジドと(J.Med.Chem.1991,56,2395参照)、還流トルエン又はキシレン中で反応させて、トリ−n−ブチルすず−テトラゾール付加物を得ることができる(ステップb)。トリ−n−ブチルすず−付加物を、一当量の水酸化ナトリウム水溶液及び一当量のトリチルクロリドを用いて室温で処理することにより、トリチル−テトラゾール付加物に転換することができる(ステップc)。この付加物をアセトニトリルのような溶媒中、トリエチルアミンの存在下、還流下にてアリールスルホニルジチオイミド炭酸メチルエステルと反応させると、ピラゾール−1−カルボキシイミドチオ酸メチルエステルを得るであろう(ステップd)。イミノチオエーテルをメチルアミン及び塩化メチレン水溶液を用いて室温で処理することにより、ピラゾール−1−カルボキサミジンを得るであろう(ステップe)。室温にてTHF中でTFA水溶液を用いてトリチル基を除去することにより、非保護テトラゾールを得るであろう(ステップf)。
スキーム9は、商業的に入手可能な2’−、3’−又は4’−メトキシ−2−フェニルアセトフェノンから、HBr/HOAc又はBBr3/CH2Cl2を使用したO−脱メチル化と、得られたフェノールのアルキルキャップ化又はTBDMSキャップ化ハロゲン化物(Nuclear Medicine and Biology,32,799(2005)に記載されているように調製)によるアルキル化とを介して調製された、2−フェニルアセトフェノンの2’−、3’−又は4’−ポリエトキシル化類似体をどのように転換するかを示す。これらのポリエーテルケトンを、ピペリジンを含む37%ホルムアルデヒド水溶液中、還流下で処理すると、対応するアクリロフェノンを与えるであろう(ステップa)。このアクリロフェノンを、エタノール中にてヒドラジン水和物を用いて処理して、3,4−ジアリールピラゾリンを生成することができる(ステップb)。ジアリールピラゾリンを更に、溶媒(例えば、アセトニトリル)中、トリエチルアミンの存在下、対応するアリールスルホンアミド、CS2及びMeIから調製したアリールスルホニルジチオイミド炭酸メチルエステル(J.Med Chem.,47,627(2004);Chem.Ber.1966,99,2885参照)で還流下にて処理して、ピラゾール−1−カルボキシイミドチオ酸メチルエステルを得ることができる(ステップc)。これらのイミノチオエーテルを更に、メチルアミン及び塩化メチレンの水溶液に室温で暴露することにより、ピラゾリン−1−カルボキサミジンを得ることができる(ステップd)。THF中、無水テトラブチルアンモニウムフロリドを使用してTBDMS−キャップ基を除去すると、ヒドロキシル−PEG類似体が生成されるであろう(ステップe)。
以下の実施例は、本願にて好ましい化合物の調製に使用される手順の代表である。
MeOH−メタノール
DCM−ジクロロメタン
EtO Ac−酢酸エチル
HCl−塩酸
PE−石油エーテル
NMM−N−メチルモルホリン
IBCF−イソ−ブチルクロロホルメート
TEA−トリエチルアミン
実施例1
20mLのDCM中に懸濁された10mモルのイミドイルクロリドに、12mmolのグリシンメチルエステル塩酸塩及び25mモルのTEAの50mL DCM中の冷却溶液に滴加し、滴加後、反応混合物を周囲温度に暖まらせた。約1時間撹拌した後、溶媒を真空下で除去し、水(50mL)を加え、混合物をEtOAcで抽出した。一緒にした抽出物をブラインで洗浄した後、無水Na2SO4上で乾燥した。溶媒を真空下で除去した後、残留物をシリカゲルカラム(PE/EtOAc:2/1)により精製して、カルボキサミジン(収率50〜80%)を得た。
THF(50mL)及び水(16mL)中の水酸化リチウム一水和物(10mモル)及び5mモルのカルボキサミジンエステルを室温で5〜7時間撹拌した。次いで、1N HC1溶液を加えることにより溶液のpHを約1〜2に調整し、溶媒を減圧下で除去した。残留物に水(15mL)を加え、次いでこれをEtOAcで抽出した。一緒にした抽出物をブラインで洗浄し、無水Na2SO4上で乾燥した。溶媒を真空下で蒸発させることにより、カルボン酸生成物(収率70〜95%)を得た。
NMM(3mmol)を含む40mLの乾燥DCM中の、エステルから実施例2に記載した手順により得られたカルボン酸(1mmol)を、塩氷浴を用いて約−15℃に冷却した。IBCF(1.1mmol)の乾燥DCM(20mL)溶液を、5分間にわたって滴加し、氷−ブライン浴内で20分間撹拌した後、乾燥アンモニア/THF溶液を一部で加え、次いで反応混合物をゆっくり室温に暖まらせ、室温にて混合物を20分間撹拌した。溶媒を蒸発により除去し、残留物を20mLの水で希釈し、EtOAcで抽出した。一緒にした抽出物を15mLの1N HC1溶液及び30mLのブラインで洗浄した後、無水Na2SO4上で乾燥した。溶液の濾過と、溶媒の真空下での除去後、残留物をシリカゲルクロマトグラフィーにより精製して、カルボキサミド付加物(収率60〜80%)を与えた。
+ 1000〜10,000nM
++ 100〜1,000nM
+++ <100nM
Claims (20)
- 化合物2、4−6、8−17、19、又は21−29:
から選択されることを特徴とする化合物、若しくは立体異性体、又は薬学的に許容され得るそれらの塩。 - 請求項1に記載の化合物において、前記化合物が化合物2である、又は、化合物2の立体異性体又は薬学的に許容され得るそれらの塩。
- 請求項1に記載の化合物において、前記化合物が化合物4である、又は、化合物4の立体異性体又は薬学的に許容され得るそれらの塩。
- 請求項1に記載の化合物において、その化合物が化合物5である、又は、化合物5の立体異性体又は薬学的に許容され得るそれらの塩。
- 請求項1に記載の化合物において、その化合物が化合物6である、又は、化合物6の立体異性体又は薬学的に許容され得るそれらの塩。
- 請求項1に記載の化合物において、その化合物が化合物8である、又は、化合物8の立体異性体又は薬学的に許容され得るそれらの塩。
- 請求項1に記載の化合物において、その化合物が化合物9である、又は、化合物9の立体異性体又は薬学的に許容され得るそれらの塩。
- 請求項1に記載の化合物において、その化合物が化合物10である、又は、化合物10の立体異性体又は薬学的に許容され得るそれらの塩。
- 請求項1に記載の化合物において、その化合物が化合物11である、又は、化合物11の立体異性体又は薬学的に許容され得るそれらの塩。
- 請求項1に記載の化合物において、その化合物が化合物12である、又は、化合物12の立体異性体又は薬学的に許容され得るそれらの塩。
- 請求項1に記載の化合物の治療的に有効な量と、薬学的に許容され得る担体とを含有することを特徴とする医薬組成物。
- 請求項2に記載の化合物の治療的に有効な量と、薬学的に許容され得る担体とを含有することを特徴とする医薬組成物。
- 請求項3に記載の化合物の治療的に有効な量と、薬学的に許容され得る担体とを含有することを特徴とする医薬組成物。
- 請求項4に記載の化合物の治療的に有効な量と、薬学的に許容され得る担体とを含有することを特徴とする医薬組成物。
- 請求項5に記載の化合物の治療的に有効な量と、薬学的に許容され得る担体とを含有することを特徴とする医薬組成物。
- 請求項6に記載の化合物の治療的に有効な量と、薬学的に許容され得る担体とを含有することを特徴とする医薬組成物。
- 請求項7に記載の化合物の治療的に有効な量と、薬学的に許容され得る担体とを含有することを特徴とする医薬組成物。
- 請求項8に記載の化合物の治療的に有効な量と、薬学的に許容され得る担体とを含有することを特徴とする医薬組成物。
- 請求項9に記載の化合物の治療的に有効な量と、薬学的に許容され得る担体とを含有することを特徴とする医薬組成物。
- 請求項10に記載の化合物の治療的に有効な量と、薬学的に許容され得る担体とを含有することを特徴とする医薬組成物。
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US41505110P | 2010-11-18 | 2010-11-18 | |
US61/415,051 | 2010-11-18 | ||
PCT/US2011/061508 WO2012068529A2 (en) | 2010-11-18 | 2011-11-18 | Cannabinoid receptor antagonists-inverse agonists useful for treating metabolic disorders, including obesity and diabetes |
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JP5946192B2 true JP5946192B2 (ja) | 2016-07-05 |
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US (1) | US8580768B2 (ja) |
EP (1) | EP2640381A4 (ja) |
JP (1) | JP5946192B2 (ja) |
CN (1) | CN103547263B (ja) |
AU (1) | AU2011329636B2 (ja) |
CA (1) | CA2818198A1 (ja) |
IL (1) | IL226370A (ja) |
WO (1) | WO2012068529A2 (ja) |
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US8680131B2 (en) | 2012-07-25 | 2014-03-25 | Jenrin Discovery, Inc. | Cannabinoid receptor antagonists/inverse agonists useful for treating disease conditions, including metabolic disorders and cancers |
IN2015DN03733A (ja) * | 2012-11-13 | 2015-09-18 | Us Health | |
US11155521B2 (en) | 2012-11-13 | 2021-10-26 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Cannabinoid receptor mediating compounds |
CN104918935B (zh) * | 2012-11-16 | 2017-07-28 | 百时美施贵宝公司 | 二氢吡唑gpr40调节剂 |
AU2013344604B2 (en) * | 2012-11-16 | 2017-07-27 | Bristol-Myers Squibb Company | Dihydropyrazole GPR40 modulators |
JP2016504282A (ja) | 2012-11-16 | 2016-02-12 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | ジヒドロピラゾールgpr40モジュレーター |
US10329259B2 (en) | 2014-05-09 | 2019-06-25 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Pyrazole derivatives and their use as cannabinoid receptor mediators |
US20180273485A1 (en) * | 2015-06-04 | 2018-09-27 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Serv | Cannabinoid receptor mediating compounds |
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US20080255093A1 (en) * | 1999-06-14 | 2008-10-16 | Tam Peter Y | Compositions and methods for treating obesity and related disorders |
DZ3335A1 (fr) | 2000-03-23 | 2001-09-27 | Solvay Pharm Bv | Derives de 4,5-dihydro-1h-pyrazole ayant une activite antagoniste de cb1 |
PL368441A1 (en) * | 2001-09-21 | 2005-03-21 | Solvay Pharmaceuticals B.V. | Novel 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity |
HUP0402113A3 (en) | 2001-09-21 | 2012-05-29 | Solvay Pharm Bv | 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity, preparation and use thereof |
EP2012775A1 (en) * | 2006-04-27 | 2009-01-14 | Solvay Pharmaceuticals GmbH | Use of cbx cannabinoid receptor modulators as potassium channel modulators |
CA2651385C (en) | 2006-05-05 | 2015-02-03 | John F. Mcelroy | Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes |
EP2111394A1 (en) * | 2007-01-10 | 2009-10-28 | Solvay Pharmaceuticals B.V. | Compounds with a combination of cannabinoid-cb1 antagonism and serotonin reuptake inhibition |
SA08280759B1 (ar) * | 2007-01-10 | 2011-05-04 | سولفاي فارماسوتيكالز بي . في | مركبات من عوامل مضادة لشبيه القنب – cb1 ومكونات هيكلية من مثبطات إعادة إمتصاص السيروتونين بأندلابين أو فلوكسامين |
US7655685B2 (en) | 2007-11-02 | 2010-02-02 | Jenrin Discovery, Inc. | Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes |
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US8580768B2 (en) | 2013-11-12 |
US20120157414A1 (en) | 2012-06-21 |
EP2640381A4 (en) | 2014-05-21 |
IL226370A0 (en) | 2013-07-31 |
JP2014505665A (ja) | 2014-03-06 |
AU2011329636B2 (en) | 2016-05-19 |
CN103547263B (zh) | 2015-12-09 |
WO2012068529A2 (en) | 2012-05-24 |
WO2012068529A3 (en) | 2013-11-21 |
EP2640381A2 (en) | 2013-09-25 |
AU2011329636A1 (en) | 2013-05-30 |
CN103547263A (zh) | 2014-01-29 |
IL226370A (en) | 2015-07-30 |
CA2818198A1 (en) | 2012-05-24 |
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