JP2017524005A - オレキシンレセプターモジュレーターとしてのジフルオロピロリジン - Google Patents
オレキシンレセプターモジュレーターとしてのジフルオロピロリジン Download PDFInfo
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- JP2017524005A JP2017524005A JP2017506968A JP2017506968A JP2017524005A JP 2017524005 A JP2017524005 A JP 2017524005A JP 2017506968 A JP2017506968 A JP 2017506968A JP 2017506968 A JP2017506968 A JP 2017506968A JP 2017524005 A JP2017524005 A JP 2017524005A
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Abstract
Description
本発明は、政府支援を受けて、アメリカ国立衛生研究所によって認められた認可番号1 P01 DA033622および1 U01 NS083614の下で行われた。政府は本発明に一定の権限を有する。
本願は、2014年8月13日に出願された、米国仮出願第62/037,024号に対する優先権を主張する。上に引用した出願の内容は、その全体が本明細書中に参考として援用される。
オレキシンは、種、オレキシンA、またはOR−A、およびオレキシンB、またはOR−Bを含む相同性ペプチドのファミリーである。オレキシンAは、33アミノ酸のペプチドであり、オレキシンBは、28アミノ酸のペプチドである(Sakurai T. et al., Cell (1998), 92, 573−585)。オレキシンは、外側視床下部のニューロンにおいて生成され、少なくとも2種の別個のGプロテイン共役レセプター(OX1レセプターおよびOX2レセプターといわれる)に結合する。OX1レセプターは、OR−Aに対して選択的である一方で、OX2レセプターは、OR−AおよびOR−Bの両方に結合し得る。オレキシンは、食物消費を刺激し、睡眠および覚醒の状態を調節することが見出され、薬物乱用および薬物嗜癖の神経系機構に関与し得る。
一局面において、本出願は、式(I):
ここで
Xは、NR4またはOであり;
R1は、単環式または二環式のヘテロアリール基であり、ここでR1は、置換されていないか、またはアルキル、ハロアルキル、ハロ、−OH、−O−アルキル、−CN、−NRaRb、−N(Ra)C(O)アルキル、−N(Ra)CO2アルキル、−N(Ra)SO2アルキル、−C(O)アルキル、−CO2H、−CO2アルキル、−CONRaRb、−SO2アルキル、および−SO2NRaRbからなる群より独立して選択される1個もしくはこれより多くの置換基で置換されており;
ここでRaおよびRbは、各々独立して、Hまたはアルキルであり;
R2は、フェニルまたは単環式ヘテロアリールであり、ここでR2は、置換されていないか、またはアルキル、ハロアルキル、シクロアルキル、ハロ、−OH、−O−アルキル、−CN、−NRcRd、−N(Ra)C(O)アルキル、−N(Rc)CO2アルキル、−N(Rc)SO2アルキル、−C(O)アルキル、−CO2H、−CO2アルキル、−CONRcRd、−SO2アルキル、および−SO2NRcRdからなる群より独立して選択される1個もしくはこれより多くの置換基で置換されており;
ここでRcおよびRdは、各々独立して、Hまたはアルキルであり;
R3は、フェニルまたは単環式ヘテロアリールであり、ここでR3は、置換されていないか、またはアルキル、ハロアルキル、ハロ、−OH、−O−アルキル、−CN、−NReRf、−N(Re)C(O)アルキル、−N(Re)CO2アルキル、−N(Re)SO2アルキル、−C(O)アルキル、−CO2H、−CO2アルキル、−CONReRf、−SO2アルキル、および−SO2NReRfからなる群より独立して選択される1個もしくはこれより多くの置換基で置換され;
ここでReおよびRfは、各々独立して、Hまたはアルキルであり;そして
R4は、Hまたはアルキルである。
ここで
R10は、Hまたはアルキルであり;
R1aは、置換されていないかまたはアルキル、ハロアルキル、もしくはハロで置換された、6員のヘテロアリールであり;
環系
各R11は、アルキル、シクロアルキル、−CN、ハロ、およびアルコキシからなる群より独立して選択され;
tは、0、1、または2であり;そして
R3aは、置換されていないかまたはアルキル、アルコキシ、ハロ、−CN、および−CF3からなる群より独立して選択される1個もしくは2個の置換基で置換された、フェニルまたは単環式ヘテロアリールである、式(II)、またはその薬学的に受容可能な塩によって表され得る。
一局面において、本出願は、式(I):
ここで
Xは、NR4、またはOであり;
R1は、単環式または二環式のへテロアリールであり、ここでR1は、置換されていないかまたはアルキル(例えば、C1−4アルキル)、ハロアルキル(例えば、C1−4ハロアルキル)、ハロ、−OH、−O−アルキル(例えば、−OC1−4アルキル)、−CN、−NRaRb、−N(Ra)C(O)アルキル(例えば、−N(Ra)C(O)C1−4アルキル)、−N(Ra)CO2アルキル(例えば、−N(Ra)CO2C1−4アルキル)、−N(Ra)SO2C1−4アルキル、−C(O)アルキル(例えば、−C(O)C1−4アルキル)、−CO2H、−CO2アルキル(例えば、−CO2C1−4アルキル)、−CONRaRb、−SO2アルキル(例えば、−SO2C1−4アルキル)、および−SO2NRaRbからなる群より独立して選択される1個もしくはこれより多くの置換基で置換され;ここでRaおよびRbは、各々独立して、Hまたはアルキル(例えば、C1−4アルキル)であり;
R2は、フェニルまたは単環式ヘテロアリールであり、ここでR2は、置換されていないかまたはアルキル(例えば、C1−4アルキル)、シクロアルキル(例えば、シクロプロピル)、ハロアルキル(例えば、C1−4ハロアルキル)、ハロ、−OH、−O−アルキル(例えば、−OC1−4アルキル)、−CN、−NRcRd、−N(Rc)C(O)アルキル(例えば、−N(Rc)C(O)C1−4アルキル)、−N(Rc)CO2アルキル(例えば、−N(Rc)CO2C1−4アルキル)、−N(Rc)SO2アルキル(例えば、−N(Rc)SO2C1−4アルキル)、−C(O)アルキル(例えば、−C(O)C1−4アルキル)、−CO2H、−CO2アルキル(例えば、−CO2C1−4アルキル)、−CONRcRd、−SO2アルキル(例えば、−SO2C1−4アルキル)、および−SO2NRcRdからなる群より独立して選択される1個もしくはこれより多くの置換基で置換され;ここでRcおよびRdは、各々独立して、Hまたはアルキル(例えば、C1−4アルキル)であり;
R3は、フェニルまたは単環式ヘテロアリールであり、ここでR3は、置換されていないかまたはアルキル(例えば、C1−4アルキル)、ハロアルキル(例えば、C1−4ハロアルキル)、ハロ、−OH、−O−アルキル(例えば、−OC1−4アルキル)、−CN、−NReRf、−N(Re)C(O)アルキル(例えば、−N(Re)C(O)C1−4アルキル)、−N(Re)CO2アルキル(例えば、−N(Re)CO2C1−4アルキル)、−N(Re)SO2C1−4アルキル、−C(O)アルキル(例えば、−C(O)C1−4アルキル)、−CO2H、−CO2アルキル(例えば、−CO2C1−4アルキル)、−CONReRf、−SO2アルキル(例えば、−SO2C1−4アルキル)、および−SO2NReRfからなる群より独立して選択される1個もしくはこれより多くの置換基で置換され;ここでReおよびRfは、各々独立して、Hまたはアルキル(例えば、C1−4アルキル)であり;そして
R4は、Hまたはアルキル(例えば、C1−4アルキル)である、
化合物、またはその薬学的に受容可能な塩を提供する。
a)Xは、OまたはNR4であり、ここでR4は、Hであり;
b)R1は、ピリジニル、ピリミジニル、またはベンゾオキサゾリルであり、各々置換されていないかまたはハロアルキル(例えば、−CF3)、もしくはハロ(例えば、−Clもしくは−F)で置換され;
c)R2は、フェニルまたはチアゾリルであり、各々置換されていないかまたはアルキル(例えば、メチル)、およびハロ(例えば、−F)から独立して選択される1個もしくは2個の基(例えば、2個のメチル基、2個のフルオロ基、もしくは1個のフルオロ基および1個のメチル基)で置換され;そして
d)R3は、置換されていないかまたはハロ(例えば、−F)で置換されたフェニルであるか;またはR3は、置換されていないトリアゾリル、ピリミジニル、もしくはピラゾリル(例えば、トリアゾリルもしくはピリミジニル)である、
化合物およびその薬学的に受容可能な塩である。
a)Xは、OまたはNHであり;
b)R1は、ピリジニル、ピリミジニル、ベンゾオキサゾリル、ピラジニル、またはチアジアゾリル(例えば、ピリジニル、ピリミジニル、ベンゾオキサゾリル、もしくはピラジニル)であり、各々置換されていないかまたはハロアルキル(例えば、−CF3)もしくはハロ(例えば、−Clもしくは−F)で置換され;
c)R2は、フェニル、ピリジニル、またはチアゾリルであり、各々置換されていないかまたはアルキル(例えば、メチル)、ハロ(例えば、−Fもしくは−Cl)、ハロアルキル(例えば、CF3)、およびCNから独立して選択される1個もしくは2個の基で置換され;そして
d)R3は、置換されていないかもしくはハロ(例えば、−F)で置換されたフェニルであるか;またはR3は、置換されていないトリアゾリル、ピリミジニル、もしくはピラゾリル(例えば、トリアゾリルもしくはピリミジニル)である、
化合物およびその薬学的に受容可能な塩である。
R10は、Hまたはアルキル(例えば、C1−4アルキル(例えば、メチル))であり;
R1aは、置換されていないかまたはアルキル(例えば、C1−4アルキル)、ハロアルキル(例えば、C1−4ハロアルキル)、もしくはハロ(例えば、−Clもしくは−F)で置換された6員のヘテロアリールであり;
ここで環系
ここで各R11は、アルキル(例えば、C1−4アルキル(例えば、メチル))、シクロアルキル(例えば、シクロプロピル)、−CN、ハロ(例えば、−Clもしくは−F)、およびアルコキシ(例えば、C1−4アルコキシ(例えば、−OCH3))からなる群より独立して選択され;
tは、0、1、または2であり;そして
R3aは、置換されていないかまたはアルキル(例えば、C1−4アルキル)、アルコキシ(例えば、C1−4アルコキシ)、ハロ、−CN、およびハロアルキル(例えば、−CF3)からなる群より独立して選択される1個もしくは2個の置換基で置換された、フェニルまたは単環式ヘテロアリールである;
式(II)またはその薬学的に受容可能な塩によって表され得る。
本記載が、記載される特定の実施形態に限定されず、よって、当然のことながら変動し得ることは、理解されるべきである。本明細書で使用される用語法が特定の実施形態を記載する目的に過ぎず、限定することを意図していないこともまた理解されるべきである。なぜなら本出願の範囲は、添付の特許請求の範囲によってのみ限定されるからである。本出願で示される定義は、本出願全体を通じて使用される用語を明瞭にすることが意図される。
ここでR29およびR30は、独立して、水素もしくはヒドロカルビル(例えば、アルキル)を表すか、またはR29のうちのいずれかの存在がR30および間にある原子と一緒になって、環構造の中に4〜8個の原子を有する複素環を完成させるものによって表され得る。
互変異性
本出願内では、本明細書で記載される化合物またはその塩は、2個の化学化合物が、水素原子を2個の原子(これらのうちのいずれかに、この水素原子が共有結合を形成している)の間で交換することによって、相互変換を容易にし得ることによる互変異性という現象を示し得ることが理解されるべきである。互変異性化合物は、互いに対して移動性の平衡状態で存在するので、それらが同じ化合物の異なる異性形態とみなされ得る。本明細書中の式による図示(formulae drawings)は、可能な互変異性形態のうちの1つのみを表し得ることは、理解されるべきである。しかし、本出願が任意の互変異性形態を包含し、式による図示内で利用されるいずれか1つの互変異性形態にのみ限定されないこともまた、理解されるべきである。本明細書中の式による図示は、可能な互変異性形態のうちの1つのみを表し得、そして本明細書が、本明細書で図示して示すために都合のよかった形態だけでなく、図示された化合物の全ての可能な互変異性形態を包含することは、理解されるべきである。例えば、互変異性は、波線によって示されるように結合されるピラゾリル基によって示され得る。両方の置換基が4−ピラゾリル基と称される一方で、各構造において異なる窒素原子が水素原子を有することは明らかである:
本出願の化合物が1個またはこれより多くのキラル中心を含む場合、その化合物は、純粋なエナンチオマー形態もしくはジアステレオマー形態として、またはラセミ混合物として、存在し得、そして単離され得ることが理解される。本出願は、従って、本出願の化合物の任意の可能なエナンチオマー、ジアステレオマー、ラセミ化合物またはこれらの混合物を包含する。
アミド結合連結の周りでの制限された回転(以下で図示される)の化学特性(すなわち、いくらかの二重結合特性をC−N結合にもたらす共鳴)に起因して、別個の回転異性体種を観察し、そしてさらには、いくらかの状況下では、このような種を単離する(以下を参照のこと)が可能であることは、理解される。ある種の構造的要素(立体的かさ高さまたはアミド窒素上の置換基を含む)が、単一の安定な回転異性体として化合物が単離され得る程度まで無期限に存在し得る程度まで、回転異性体の安定性を増強し得ることは、さらに理解される。本出願は従って、がんまたは他の増殖性疾患状態の処置において生物学的に活性である式(I)の任意の可能な安定な回転異性体を包含する。
本出願の好ましい化合物は、化合物クラスによって示される構造活性関係に関連する、芳香族環上の置換基の特定の空間的配置を有する。しばしば、このような置換の配置は、番号付けシステムによって示される;しかし、番号付けシステムは、異なる環系の間ではしばしば一致しない。6員の芳香族系では、空間的配置は、以下に示されるように、一般的命名法、1,4−置換に関しては「パラ」、1,3−置換に関しては「メタ」、および1,2−置換に関しては「オルト」によって特定される。
本出願の組成物および方法は、その必要性のある被験体(例えば、哺乳動物、例えば、ヒト、または非ヒト哺乳動物)を処置するために利用され得る。動物(例えば、ヒト)に投与される場合、組成物または化合物は、好ましくは、例えば、本出願の化合物および薬学的に受容可能なキャリアを含む薬学的組成物として投与される。
種々の実施形態において、本出願の化合物は、オレキシンレセプターを調節する(例えば、活性化する(アゴニスト)か、またはその活性化を遮断する(アンタゴニスト))ために使用され得る。よって、種々の実施形態において、本出願は、オレキシンレセプターを調節するための方法を提供し、上記方法は、上記レセプターと、有効量または有効濃度の本出願の化合物とを接触させる工程を包含する。オレキシンレセプターは、OX1またはOX2であり得る。種々の実施形態において、本出願の化合物は、オレキシンレセプター(例えば、OX1もしくはOX2、またはその両方)のアンタゴニストであり、一方または他方の選択的インヒビターであり得る。種々の実施形態において、接触させる工程は、患者(例えば、ヒト患者)の組織内で、インビボで行われ得る。種々の実施形態において、本出願の化合物によるオレキシンレセプターの調節(例えば、オレキシン−1の拮抗作用)は、本明細書で記載されるように、患者において疾患、障害または医学的状態を処置するために使用され得る。
本明細書で記載される本発明の化合物は、本明細書で記載される疾患および障害の処置において1またはこれより多くのさらなる活性成分との組み合わせにおいて、薬学的組成物または方法において使用され得る。さらに、さらなる活性成分は、意図された疾患標的に関する治療の有害効果を緩和する他の治療剤または薬剤を含む。このような組み合わせは、効力を増大させるか、他の疾患症状を改善するか、1もしくはこれより多くの副作用を低減するか、または本発明の化合物の必要用量を低減するように働き得る。さらなる活性成分は、本出願の化合物とは別個の薬学的組成物において投与されてもよいし、単一の薬学的組成物において本出願の化合物とともに含まれていてもよい。さらなる活性成分は、本出願の化合物の投与と同時に、その前に、またはその後に投与され得る。薬学的組成物中の活性成分の実際の投与量レベルは、被験体に対して毒性であることなしに、特定の被験体(例えば、患者)、組成物、および投与様式に関して所望の治療応答を達成するために有効である活性成分の量を得るように変動し得る。
本出願の方法において有用な例示的な化学実体は、ここで、以下のそれらの一般的調製のための例示的合成スキームおよび以下に続く具体例を参照することによって記載される。当業者は、本明細書の種々の化合物を得るために、最終的に所望の置換基が、所望の生成物を得るために適切である場合には保護ありまたは保護なしで、反応スキームを通じて保持されるように出発材料が適切に選択され得ることを認識する。あるいは、最終的に所望の置換基の代わりに、反応スキームを通じて保持され得、適切な場合には所望の置換基で置き換えられ得る適切な基を使用することは、必要であり得るかまたは望ましいことであり得る。さらに、当業者は、以下のスキームで示される変換が、特定のペンダント基の官能性と適合性である任意の順序で行われ得ることを認識する。一般的スキームにおいて示される反応の各々は、好ましくは、約0℃から使用される有機溶媒の還流温度までの温度で行われる。別段特定されなければ、変数は、式(I)または式(II)を参照して上記で定義されるとおりである。本明細書で記載されるような同位体標識化合物は、以下で記載される方法に従って、適切に標識された出発材料を使用して調製される。このような材料は、一般に、放射性標識化学試薬の商業的供給者から入手可能である。
ACN アセトニトリル;
aq 水性;
Atm 大気圧;
Boc t−ブトキシカルボニル;
Borax 四ホウ酸二ナトリウムまたはホウ酸ナトリウムまたは四ホウ酸ナトリウム;
Cbz ベンジルオキシカルボニル;
CDI 1,1’−カルボニルジイミダゾール;
dba ジベンジリデンアセトン;
DCM ジクロロメタン;
DEA ジエチルアミン;
DIBAL−H 水素化ジイソブチルアルミニウム;
DIPEA ジイソプロピルエチルアミン;
DME 1,2−ジメトキシエタン;
DMF N,N−ジメチルホルムアミド;
DMSO ジメチルスルホキシド;
Et2O ジエチルエーテル;
EtOAc 酢酸エチル;
EtOH エタノール;
eq.またはequiv. 当量;
h 時間;
HATU 2−(7−アザ−1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェート;
HBTU O−ベンゾトリアゾール−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスフェート
HPLC 高速液体クロマトグラフィー;
LCMS 液体クロマトグラフィー質量分析;
LDA リチウムジイソプロピルアミド;
LiHMDS リチウムビス(トリメチルシリル)アミド;
MeOH メタノール;
min 分;
MS 質量分析;
MW マイクロ波;
NH4OAc 酢酸アンモニウム;
NMR 核磁気共鳴;
ox 酸化;
Psi ポンド/平方インチ;
quant. 定量的;
RCM 閉環メタセシス;
r.t. 室温;
sat. 飽和;
SFC 超臨界流体クロマトグラフィー;
T3P プロピルホスホン酸無水物;
TFA トリフルオロ酢酸;
THF テトラヒドロフラン;
TLC 薄層クロマトグラフィー;
TMEDA テトラメチルエチレンジアミン;
UPLC 超高速液体クロマトグラフィー(ultra performance liquid chromatography)。
化合物(x):3,6−ジフルオロ−2−(2H−1,2,3−トリアゾール−2−イル)安息香酸
全ての実験に関して、ラット(体重250〜300g)を、昼夜逆転の(reversed)12時間明/暗サイクル(午前8時に消灯)の下で温度制御飼育器中、1ケージあたり1〜23群において飼育した。飼料および水は、行動トレーニングが始まるまで自由給餌とした。トレーニングの間、ラットを食餌制限して、彼らの自由給餌のときの体重の約85〜90%を維持する。行動試験を、午前9時〜午後1時の時間の間の上記明/暗サイクルの暗部分(上記サイクルのうちの暗相の早い部分の間)の間に行う。全ての手順は、実験動物の管理と使用に関する米国国立衛生研究所の指針を厳守して行い、The Scripps Research Instituteの実験動物委員会によって承認される。ラットを、酸素中1〜3%のイソフルランの吸入によって麻酔し、シラスティックカテーテルを、頸静脈に挿入する。簡潔には、そのカテーテルは、直角に弯曲し、歯科用アクリル樹脂中に覆われたガイドカニューレ(Plastics One, Wallingford, CT)にはめ込んだ14cm長のシラスティック管系からなる。そのカテーテル管系を、各動物の背中から右頸静脈へと皮下に通し、そのカテーテル先端の1cm長を静脈の中に挿入する。手術の後、カテーテルに、0.1mLのヘパリン化(30USP単位/ml)滅菌生理食塩水溶液を毎日流す。手術回復から7日後、ラットを、彼らの自由給餌のときの体重の85〜90%へと穏やかに食餌制限し、カテーテル埋め込みの前の固定比5、時間切れ20秒(FR5TO20s)の強化スケジュールの下で、飼料ペレット(20mg; TestDiet, Richmond, IN)のためにオペラントチャンバ(Med Associates, St. Albans, VT)の中のレバーを押すようにトレーニングする。安定な応答がいったん達成されたら(>25ペレット/セッション)、ラットに、1時間の毎日のセッション(7日間/週)の間に自己反応形成させることによって、IVニコチン自己投与を獲得させる。ニコチンを、IVカテーテルへとRazelシリンジポンプ(Med Associates)によって、その管系を通して送達する。各ニコチン自己投与セッションを、2つの格納式レバー(1つは活用可能;1つは、活用不能)を使用して行う。活用可能レバーに対する応答基準の完了は、IVニコチン注入物(0.03mg/kg/注入物)の送達を生じる。1週間後、そのニコチン容量を、その後のトレーニングセッションおよび試験セッションを含め、実験の残りの間に、0.1mg/kg/注入物に増大させる。全てのニコチン注入物の送達は、レバーの上に位置した光による合図によって信号が出される、20秒時間切れ(TO)期間の開始と同時に起こる。TO期間の間に、レバーに対する応答を記録するが、予定された結論はない。カテーテルが完全であることを、超短時間作用バルビツレートBrevital(メトヘキシタールナトリウム; Eli Lilly)で実験の最後に試験する。
本発明の具体的実施形態が考察されてきたものの、上記の明細書は例示であって、限定ではない。本発明の多くのバリエーションは、本明細書および以下の特許請求の範囲をみれば、当業者に明らかになる。本発明の全範囲は、均等物のそれらの全範囲とともに特許請求の範囲を、およびこのようなバリエーションとともに本明細書を参照することによって、決定されるものとする。
Claims (71)
- 式(I):
ここで
Xは、NR4またはOであり;
R1は、単環式または二環式のヘテロアリール基であり、ここでR1は、置換されていないか、またはアルキル、ハロアルキル、ハロ、−OH、−O−アルキル、−CN、−NRaRb、−N(Ra)C(O)アルキル、−N(Ra)CO2アルキル、−N(Ra)SO2アルキル、−C(O)アルキル、−CO2H、−CO2アルキル、−CONRaRb、−SO2アルキル、および−SO2NRaRbからなる群より独立して選択される1個もしくはこれより多くの置換基で置換されており;
ここでRaおよびRbは、各々独立して、Hまたはアルキルであり;
R2は、フェニルまたは単環式ヘテロアリールであり、ここでR2は、置換されていないか、またはアルキル、ハロアルキル、シクロアルキル、ハロ、−OH、−O−アルキル、−CN、−NRcRd、−N(Ra)C(O)アルキル、−N(Rc)CO2アルキル、−N(Rc)SO2アルキル、−C(O)アルキル、−CO2H、−CO2アルキル、−CONRcRd、−SO2アルキル、および−SO2NRcRdからなる群より独立して選択される1個もしくはこれより多くの置換基で置換されており;
ここでRcおよびRdは、各々独立して、Hまたはアルキルであり;
R3は、フェニルまたは単環式ヘテロアリールであり、ここでR3は、置換されていないか、またはアルキル、ハロアルキル、ハロ、−OH、−O−アルキル、−CN、−NReRf、−N(Re)C(O)アルキル、−N(Re)CO2アルキル、−N(Re)SO2アルキル、−C(O)アルキル、−CO2H、−CO2アルキル、−CONReRf、−SO2アルキル、および−SO2NReRfからなる群より独立して選択される1個もしくはこれより多くの置換基で置換され;
ここでReおよびRfは、各々独立して、Hまたはアルキルであり;そして
R4は、Hまたはアルキルである、
化合物、またはその薬学的に受容可能な塩。 - Xは、NR4である、請求項1に記載の化合物。
- R4は、Hである、請求項1または2に記載の化合物。
- Xは、Oである、請求項1〜3のいずれかに記載の化合物。
- R1は、単環式ヘテロアリールである、請求項1〜4のいずれかに記載の化合物。
- R1は、二環式へテロアリールである、請求項1〜4のいずれかに記載の化合物。
- R1は、ピリミジニル、ピリジニル、ピラジニル、チアジアゾリル、およびベンゾオキサゾリルからなるリストより選択される、請求項1〜4のいずれかに記載の化合物。
- R1は、ピリミジニルまたはピリジニルである、請求項7に記載の化合物。
- R1は、置換されていない、請求項1〜8のいずれかに記載の化合物。
- R1は、アルキル、ハロアルキル、およびハロからなる群より独立して選択される1個またはこれより多くの置換基で置換されている、請求項1〜8のいずれかに記載の化合物。
- R1は、メチル、−CF3、−F、または−Clからなる群より独立して選択される1個またはこれより多くの置換基で置換されている、請求項10に記載の化合物。
- R1は、−CF3で置換されたピリミジニルである、請求項1〜8のいずれかに記載の化合物。
- R1は、−CF3で置換されたピリジニルである、請求項1〜8のいずれかに記載の化合物。
- R1は、−Clで置換されたピリミジニルである、請求項1〜8のいずれかに記載の化合物。
- R1は、置換されていないか、または−Clもしくは−Fで置換されているベンゾオキサゾリルである、請求項1〜4または6のいずれかに記載の化合物。
- R2は、フェニルである、請求項1〜15のいずれかに記載の化合物。
- R2は、単環式ヘテロアリールである、請求項1〜15のいずれかに記載の化合物。
- R2は、チアゾリルまたはピリジニルである、請求項17に記載の化合物。
- R2は、置換されていない、請求項1〜18のいずれかに記載の化合物。
- R2は、フェニルまたは単環式ヘテロアリールであり、ここでR2は、置換されていないか、またはアルキル、ハロアルキル、ハロ、−OH、−O−アルキル、−CN、−NRcRd、−N(Ra)C(O)アルキル、−N(Rc)CO2アルキル、−N(Rc)SO2アルキル、−C(O)アルキル、−CO2H、−CO2アルキル、−CONRcRd、−SO2アルキル、および−SO2NRcRdからなる群より独立して選択される1個もしくはこれより多くの置換基で置換されている、請求項1〜15のいずれかに記載の化合物。
- R2は、アルキル、ハロアルキル、ハロ、および−CNからなる群より独立して選択される1個またはこれより多くの置換基で置換されている、請求項20に記載の化合物。
- R2は、メチル、−CF3、−F、−Cl、および−CNからなる群より独立して選択される1個またはこれより多くの置換基で置換されている、請求項20または21に記載の化合物。
- R2は、1個または2個のメチル基またはフルオロ基で置換されている、請求項20〜22のいずれかに記載の化合物。
- R2は、メチルで置換されたチアゾリルである、請求項1〜15または17〜18のいずれかに記載の化合物。
- R3は、フェニルである、請求項1〜24のいずれかに記載の化合物。
- R3は、単環式ヘテロアリールである、請求項1〜24のいずれかに記載の化合物。
- R3は、トリアゾリル、ピリミジニル、またはピラゾリルである、請求項26に記載の化合物。
- R3は、置換されていない、請求項1〜27のいずれかに記載の化合物。
- R3は、−アルキル、ハロアルキル、およびハロからなる群より独立して選択される1個またはこれより多くの置換基で置換されている、請求項1〜27のいずれかに記載の化合物。
- R3は、フルオロで置換されている、請求項29に記載の化合物。
- R3は、フルオロで置換されたフェニルである、請求項1〜25のいずれかに記載の化合物。
- R2およびR3のうちの一方がフェニルである場合、他方はフェニルではない、請求項1に記載の化合物。
- R2およびR3のうちの一方がヘテロアリールである場合、他方はヘテロアリールではない、請求項1に記載の化合物。
- 表1に示されるような化合物、およびそれらの薬学的に受容可能な塩からなる群より選択される、請求項1に記載の化合物。
- 式(II)
ここで
R10は、Hまたはアルキルであり;
R1aは、置換されていないかまたはアルキル、ハロアルキル、もしくはハロで置換された6員のヘテロアリールであり;
環系
ここで各R11は、アルキル、シクロアルキル、−CN、ハロ、およびアルコキシからなる群より独立して選択され;
tは、0、1、または2であり;そして
R3aは、置換されていないか、またはアルキル、アルコキシ、ハロ、−CN、および−CF3からなる群より独立して選択される1個もしくは2個の置換基で置換されている、フェニルまたは単環式ヘテロアリールである、
化合物、またはその薬学的に受容可能な塩。 - R10は、Hである、請求項35に記載の化合物。
- R10は、メチルである、請求項35に記載の化合物。
- R1aは、ピリミジニルまたはピリジニルである、請求項35〜37のいずれかに記載の化合物。
- R1aは、−CF3で置換されている、請求項35〜38のいずれかに記載の化合物。
- R11は、アルキル、−CN、ハロ、およびアルコキシからなる群より独立して選択される、請求項35〜45のいずれかに記載の化合物。
- R11は、メチル、クロロ、フルオロ、および−CNからなる群より独立して選択される、請求項46に記載の化合物。
- R11は、クロロまたはフルオロである、請求項35〜47のいずれかに記載の化合物。
- tは、0である、請求項35〜48のいずれかに記載の化合物。
- tは、1である、請求項35〜48のいずれかに記載の化合物。
- tは、2である、請求項35〜48のいずれかに記載の化合物。
- R3aは、必要に応じて置換されたフェニルである、請求項35〜51のいずれかに記載の化合物。
- R3aは、必要に応じて置換された単環式ヘテロアリールである、請求項35〜51のいずれかに記載の化合物。
- R3aは、置換されていない、請求項35〜53のいずれかに記載の化合物。
- R3aは、メチル、エチル、イソプロピル、メトキシ、−F、および−CF3からなる群より独立して選択される置換基で置換されている、請求項35〜53のいずれかに記載の化合物。
- 式(I):
a)Xは、OまたはNHであり;
b)R1は、ピリジニル、ピリミジニル、ベンゾオキサゾリル、チアジアゾリル、またはピラジニルであり、各々置換されていないかまたは−CF3、−Clもしくは−Fで置換されており;
c)R2は、フェニル、ピリジニル、またはチアゾリルであり、各々置換されていないかまたはメチル、−F、−CN、−CF3、もしくは−Clから独立して選択される1個もしくは2個の基で置換されており;そして
d)R3は、置換されていないかもしくは−Fで置換されたフェニルであるか;またはR3は、置換されていないトリアゾリル、ピリミジニル、もしくはピラゾリルである、
化合物、またはその薬学的に受容可能な塩。 - (a)請求項1〜58のいずれかに記載の化合物、および(b)薬学的に受容可能な賦形剤を含む、薬学的組成物。
- 医薬としての使用のための、請求項1〜58のいずれかに記載の化合物。
- オレキシンレセプター活性によって媒介される疾患、障害または医学的状態を処置するための方法であって、該方法は、このような処置の必要性のある被験体に、請求項1〜58のいずれかに記載の少なくとも1種の化合物の有効量を投与する工程を包含する、方法。
- 前記疾患、障害、または医学的状態は、摂食障害、肥満症、アルコール依存症もしくはアルコール関連障害、薬物乱用もしくは薬物嗜癖、睡眠障害、精神障害もしくは神経学的障害における認知機能障害、うつ病、不安、パニック障害、心的外傷後ストレス障害、季節性感情障害、統合失調症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、頭痛、片頭痛、疼痛、消化器疾患、癲癇、炎症、免疫関連疾患、潰瘍、過敏性腸症候群、下痢、胃食道逆流、内分泌関連疾患、がん、高血圧症、行動障害、気分障害、躁うつ病、認知症、性的障害、性心理障害、および腎疾患である、請求項61に記載の方法。
- 前記薬物乱用もしくは薬物嗜癖は、コカイン、オピエート、アンフェタミン、エタノール、大麻/マリファナ、もしくはニコチンの乱用またはこれらに対する嗜癖から選択される、請求項62に記載の方法。
- オレキシンレセプター活性によって調節される疾患、障害、および医学的状態の処置のための医薬の調製における請求項1〜58のいずれかに記載の化合物の使用、ならびにこのような疾患および医学的状態の処置のためのこのような化合物の使用。
- 前記疾患、障害、または医学的状態は、摂食障害、肥満症、アルコール依存症もしくはアルコール関連障害、薬物乱用もしくは薬物嗜癖、睡眠障害、精神障害もしくは神経学的障害における認知機能障害、うつ病、不安、パニック障害、心的外傷後ストレス障害、季節性感情障害、統合失調症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、頭痛、片頭痛、疼痛、消化器疾患、癲癇、炎症、免疫関連疾患、潰瘍、過敏性腸症候群、下痢、胃食道逆流、内分泌関連疾患、がん、高血圧症、行動障害、気分障害、躁うつ病、認知症、性的障害、性心理障害、および腎疾患である、請求項64に記載の使用。
- 前記薬物乱用もしくは薬物嗜癖は、コカイン、オピエート、アンフェタミン、エタノール、大麻/マリファナ、もしくはニコチンの乱用またはこれらに対する嗜癖から選択される、請求項65に記載の使用。
- オレキシンレセプターOX1、OX2、または両方の活性を調節するための方法であって、該方法は、該オレキシンレセプターを含む細胞と、請求項1〜58のいずれかに記載の少なくとも1種の化合物の有効量とを接触させる工程を包含する、方法。
- 前記接触させる工程は、インビトロ、エキソビボ、またはインビボで起こる、請求項67に記載の方法。
- 疾患または障害の処置の必要性のある患者において、疾患または障害を処置するための方法であって、該方法は、請求項1〜58のいずれかに記載の化合物を投与する工程を包含し、ここで該疾患または障害は、摂食障害、肥満症、アルコール依存症もしくはアルコール関連障害、薬物乱用もしくは薬物嗜癖、睡眠障害、精神障害もしくは神経学的障害における認知機能障害、うつ病、不安、パニック障害、心的外傷後ストレス障害、季節性感情障害、統合失調症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、頭痛、片頭痛、疼痛、消化器疾患、癲癇、炎症、免疫関連疾患、潰瘍、過敏性腸症候群、下痢、胃食道逆流、内分泌関連疾患、がん、高血圧症、行動障害、気分障害、躁うつ病、認知症、性的障害、性心理障害、および腎疾患からなる群より選択される、方法。
- 前記疾患または障害は、薬物乱用もしくは薬物嗜癖、パニック障害、不安、心的外傷後ストレス障害、疼痛、うつ病、季節性感情障害、摂食障害、および高血圧症からなる群より選択される、請求項69に記載の方法。
- 前記薬物乱用もしくは薬物嗜癖は、コカイン、オピエート、アンフェタミン、エタノール、大麻/マリファナ、もしくはニコチンの乱用またはこれらに対する嗜癖から選択される、請求項69または70に記載の方法。
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WO2016025669A1 (en) | 2016-02-18 |
AR101558A1 (es) | 2016-12-28 |
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