JP2021529778A - Hcn1アンタゴニストとしての置換アルキルフェノール - Google Patents
Hcn1アンタゴニストとしての置換アルキルフェノール Download PDFInfo
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- JP2021529778A JP2021529778A JP2020573346A JP2020573346A JP2021529778A JP 2021529778 A JP2021529778 A JP 2021529778A JP 2020573346 A JP2020573346 A JP 2020573346A JP 2020573346 A JP2020573346 A JP 2020573346A JP 2021529778 A JP2021529778 A JP 2021529778A
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical class [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
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Abstract
Description
本出願は、2018年6月27日に出願された米国仮出願(USSN)第62/690,778号、および2019年2月8日に出願された米国仮出願(USSN)第62/803,109号に対する米国特許法第119条(e)に基づく優先権を主張し、これらの各々は、参照によりその全体が本明細書に組み込まれる。
またはその薬学的に許容される塩であって、
式中、
R1が、非置換アルキルであり、
R2が、非置換アルキルであり、
Xが、ハロゲン、−OP、−N(RA)2、−NRAN(RA)2、−SP、または−NCOであり、
Pが、水素、酸素保護基、硫黄保護基、または置換もしくは非置換ヘテロシクリルであり、
L1が、−(C=O)−、−CH2−、−CH=CH−、−C≡C−、−O−、−S−、または−NRA−であり、
L2が、置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、置換もしくは非置換アルキニレン、置換もしくは非置換ヘテロアルキレン、置換もしくは非置換ヘテロアルケニレン、または置換もしくは非置換ヘテロアルキニレンであり、L2が、L1に対するその接続点からTに対するその接続点までの少なくとも8個の連続した非水素原子の鎖を含み、
Tが、置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換ヘテロアルキル、−ORC、−N(RA)2、−SRA、−CO2H、ハロゲン、−OS(O2)RB、−O(C=O)RC、−(C=O)ORC、−O(C=O)ORC、−(C=O)N(RA)2、−O(C=O)N(RA)2、−NRA(C=O)N(RA)2、−CN、−CHO、−N3、−N=C=S、
Qが、SまたはOであり、
各RAが、独立して、水素、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換アシル、置換もしくは非置換ヘテロシクリル、窒素保護基、または硫黄保護基であり、
RBが、置換もしくは非置換アルキル、または置換もしくは非置換アリールであり、
RCが、置換もしくは非置換アルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロシクリル、置換もしくは非置換ヘテロアリール、または酸素保護基であり、
RDが、ハロゲンまたは−OS(O2)RBであり、
REが、水素、置換もしくは非置換アルキル、置換もしくは非置換カルボシクリル、置換もしくは非置換ヘテロシクリル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、または酸素保護基であり、
RFが、水素、置換もしくは非置換アルキル、または窒素保護基であり、
ただし、化合物は、
R1が、−CH(OH)CH2(OH)、−CH(X1)CH3、CH2CH3、−CH=CH2、−CH=CH(R2)、または−CH2CH2(R3)であり、
R2が、−(CH2)mCH(OH)CH2(OH)、−(CH2)pCH(X2)CH3、−(CH2)tCH=CH2、または−(CH2)vCH2CH3であり、
R3が、−(CH2)wCH(OH)CH2(OH)、−(CH2)xCH(X3)CH3、(CH2)yCH=CH2、または−(CH2)zCH2CH3であり、
X1、X2、およびX3が各々独立して、ClまたはFであり、
nが、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
mが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
pが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
tが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
vが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
wが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
xが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
yが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
zが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15である、化合物またはその薬学的に許容される塩および/もしくは溶媒和物が提供される。
化学的定義
特定の官能基および化学用語の定義は、以下でより詳細に記載される。化学元素は、Periodic Table of the Elements、CAS version、Handbook of Chemistry and Physics、75th Ed.(カバー内側)に従って特定され、特定の官能基は、一般に、その中に記載されるように定義される。加えて、有機化学の一般原理、ならびに特定の機能性部分および反応性は、Organic Chemistry,Thomas Sorrell,University Science Books,Sausalito,1999、Smith and March,March’s Advanced Organic Chemistry,5th Edition,John Wiley & Sons,Inc.,New York,2001、Larock,Comprehensive Organic Transformations,VCH Publishers,Inc.,New York,1989、およびCarruthers,Some Modern Methods of Organic Synthesis,3rd Edition,Cambridge University Press,Cambridge,1987に記載されている。
または炭素原子上の2個のジェミナル水素が、=O、=S、=NN(Rbb)2、=NNRbbC(=O)Raa、=NNRbbC(=O)ORaa、=NNRbbS(=O)2Raa、=NRbb、または=NORccといった基で置き換えられ、
Raaの各々の場合は、独立して、C1−10アルキル、C1−10ペルハロアルキル、C2−10アルケニル、C2−10アルキニル、ヘテロC1−10アルキル、ヘテロC2−10アルケニル、ヘテロC2−10アルキニル、C3−10カルボシクリル、3〜14員環ヘテロシクリル、C6−14アリール、および5〜14員環ヘテロアリールから選択されるか、または2個のRaa基が接続して、3〜14員環のヘテロシクリルまたは5〜14員環ヘテロアリール環を形成し、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRdd基で置換されており、
Rbbの各々の場合は、独立して、水素、−OH、−ORaa、−N(Rcc)2、−CN、−C(=O)Raa、−C(=O)N(Rcc)2、−CO2Raa、−SO2Raa、−C(=NRcc)ORaa、−C(=NRcc)N(Rcc)2、−SO2N(Rcc)2、−SO2Rcc、−SO2ORcc、−SORaa、−C(=S)N(Rcc)2、−C(=O)SRcc、−C(=S)SRcc、−P(=O)(Raa)2、−P(=O)(ORcc)2、−P(=O)(N(Rcc)2)2、C1−10アルキル、C1−10ペルハロアルキル、C2−10アルケニル、C2−10アルキニル、ヘテロC1−10アルキル、ヘテロC2−10アルケニル、ヘテロC2−10アルキニル、C3−10カルボシクリル、3〜14員環ヘテロシクリル、C6−14アリール、および5〜14員環ヘテロアリールから選択されるか、または2個のRbb基が接続して、3〜14員環のヘテロシクリルまたは5〜14員環ヘテロアリール環を形成し、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRdd基で置換されており、X−は、対イオンであり、
Rccの各々の場合は、独立して、水素、C1−10アルキル、C1−10ペルハロアルキル、C2−10アルケニル、C2−10アルキニル、ヘテロC1−10アルキル、ヘテロC2−10アルケニル、ヘテロC2−10アルキニル、C3−10カルボシクリル、3〜14員環ヘテロシクリル、C6−14アリール、および5〜14員環ヘテロアリールから選択されるか、または2個のRcc基が接続して、3〜14員環のヘテロシクリルまたは5〜14員環ヘテロアリール環を形成し、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRdd基で置換されており、
Rddの各々の場合は、独立して、ハロゲン、−CN、−NO2、−N3、−SO2H、−SO3H、−OH、−ORee、−ON(Rff)2、−N(Rff)2、−N(Rff)3 +X−、−N(ORee)Rff、−SH、−SRee、−SSRee、−C(=O)Ree、−CO2H、−CO2Ree、−OC(=O)Ree、−OCO2Ree、−C(=O)N(Rff)2、−OC(=O)N(Rff)2、−NRffC(=O)Ree、−NRffCO2Ree、−NRffC(=O)N(Rff)2、−C(=NRff)ORee、−OC(=NRff)Ree、−OC(=NRff)ORee、−C(=NRff)N(Rff)2、−OC(=NRff)N(Rff)2、−NRffC(=NRff)N(Rff)2、−NRffSO2Ree、−SO2N(Rff)2、−SO2Ree、−SO2ORee、−OSO2Ree、−S(=O)Ree、−Si(Ree)3、−OSi(Ree)3、−C(=S)N(Rff)2、−C(=O)SRee、−C(=S)SRee、−SC(=S)SRee、−P(=O)(ORee)2、−P(=O)(Ree)2、−OP(=O)(Ree)2、−OP(=O)(ORee)2、C1−6アルキル、C1−6ペルハロアルキル、C2−6アルケニル、C2−6アルキニル、ヘテロC1−6アルキル、ヘテロC2−6アルケニル、ヘテロC2−6アルキニル、C3−10カルボシクリル、3〜10員環ヘテロシクリル、C6−10アリール、5〜10員環ヘテロアリールから選択され、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRgg基で置換されているか、または2個のジェミナルRdd置換基が接続して、=Oまたは=Sを形成することができ、X−は、対イオンであり、
Reeの各々の場合は、独立して、C1−6アルキル、C1−6ペルハロアルキル、C2−6アルケニル、C2−6アルキニル、ヘテロC1−6アルキル、ヘテロC2−6アルケニル、ヘテロC2−6アルキニル、C3−10カルボシクリル、C6−10アリール、3〜10員環ヘテロシクリル、および3〜10員環ヘテロアリールから選択され、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRgg基で置換されており、
Rffの各々の場合は、独立して、水素、C1−6アルキル、C1−6ペルハロアルキル、C2−6アルケニル、C2−6アルキニル、ヘテロC1−6アルキル、ヘテロC2−6アルケニル、ヘテロC2−6アルキニル、C3−10カルボシクリル、3〜10員環ヘテロシクリル、C6−10アリール、および5〜10員環ヘテロアリールから選択されるか、または2個のRff基が接続して、3〜10員環のヘテロシクリルまたは5〜10員環ヘテロアリール環を形成し、各アルキル、アルケニル、アルキニル、ヘテロアルキル、ヘテロアルケニル、ヘテロアルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRgg基で置換されており、
Rggの各々の場合は、独立して、ハロゲン、−CN、−NO2、−N3、−SO2H、−SO3H、−OH、−OC1−6アルキル、−ON(C1−6アルキル)2、−N(C1−6アルキル)2、−N(C1−6アルキル)3 +X−、−NH(C1−6アルキル)2 +X−、−NH2(C1−6アルキル)+X−、−NH3 +X−、−N(OC1−6アルキル)(C1−6アルキル)、−N(OH)(C1−6アルキル)、−NH(OH)、−SH、−SC1−6アルキル、−SS(C1−6アルキル)、−C(=O)(C1−6アルキル)、−CO2H、−CO2(C1−6アルキル)、−OC(=O)(C1−6アルキル)、−OCO2(C1−6アルキル)、−C(=O)NH2、−C(=O)N(C1−6アルキル)2、−OC(=O)NH(C1−6アルキル)、−NHC(=O)(C1−6アルキル)、−N(C1−6アルキル)C(=O)(C1−6アルキル)、−NHCO2(C1−6アルキル)、−NHC(=O)N(C1−6アルキル)2、−NHC(=O)NH(C1−6アルキル)、−NHC(=O)NH2、−C(=NH)O(C1−6アルキル)、−OC(=NH)(C1−6アルキル)、−OC(=NH)OC1−6アルキル、−C(=NH)N(C1−6アルキル)2、−C(=NH)NH(C1−6アルキル)、−C(=NH)NH2、−OC(=NH)N(C1−6アルキル)2、−OC(=NH)NH(C1−6アルキル)、−OC(=NH)NH2、−NHC(=NH)N(C1−6アルキル)2、−NHC(=NH)NH2、−NHSO2(C1−6アルキル)、−SO2N(C1−6アルキル)2、−SO2NH(C1−6アルキル)、−SO2NH2、−SO2(C1−6アルキル)、−SO2O(C1−6アルキル)、−OSO2(C1−6アルキル)、−SO(C1−6アルキル)、−Si(C1−6アルキル)3、−OSi(C1−6アルキル)3−C(=S)N(C1−6アルキル)2、C(=S)NH(C1−6アルキル)、C(=S)NH2、−C(=O)S(C1−6アルキル)、−C(=S)SC1−6アルキル、−SC(=S)SC1−6アルキル、−P(=O)(OC1−6アルキル)2、−P(=O)(C1−6アルキル)2、−OP(=O)(C1−6アルキル)2、−OP(=O)(OC1−6アルキル)2、C1−6アルキル、C1−6ペルハロアルキル、C2−6アルケニル、C2−6アルキニル、ヘテロC1−6アルキル、ヘテロC2−6アルケニル、ヘテロC2−6アルキニル、C3−10カルボシクリル、C6−10アリール、3〜10員環ヘテロシクリル、5〜10員環ヘテロアリールであるか、または2個のジェミナルRgg置換基が接続して、=Oまたは=Sを形成することができ、X−は、対イオンである。
「アンタゴニスト」という用語は、(i)別の薬剤の1つ以上の効果を減少または抑制する、および/または(ii)1つ以上の生物学的事象を減少または抑制する薬剤を指す。いくつかの実施形態では、アンタゴニストは、レベルおよび/または活性を減少させ得るか、または標的とする1つ以上の薬剤を減少させ得る。アンタゴニストは、直接的であってもよく(この場合、その標的に直接的にその影響を発揮する)、または間接的であってもよい(この場合、その標的に対する結合以外によって、例えば、標的の調節因子と相互作用することによって、その影響を発揮し、例えば、その結果、標的のレベルまたは活性が変化する)。いくつかの実施形態では、アンタゴニストは、受容体アンタゴニスト、例えば、アゴニストのように受容体を活性化するのではなく、受容体に結合し、遮断することによって、生物学的応答を遮断するか、または減衰させる受容体リガンドまたは薬物であってもよい。特定の実施形態では、式(I)の化合物は、HCN(例えば、HCN1)のアンタゴニストである。特定の実施形態では、式(II)の化合物は、HCN(例えば、HCN1)のアンタゴニストである。特定の実施形態では、式(I)の化合物は、HCN(例えば、HCN1)チャネルゲーティングを阻害する。特定の実施形態では、式(II)の化合物は、HCN(例えば、HCN1)チャネルゲーティングを阻害する。
心臓、中枢神経系(CNS)および末梢神経系(PNS)の細胞を含む、励起可能な細胞の形質膜中の非選択的な電位依存性カチオンチャネルとして機能する膜間タンパク質であるHCNチャネルを調節する、新規な化合物(例えば、式(I)および式(II)の化合物)が本明細書で提供される。特定の実施形態では、化合物は、HCNアイソフォームHCN1の選択的なアンタゴニストおよび/または阻害剤であり、疼痛(例えば、慢性疼痛)の治療に有用であり得る。化合物は、化合物または薬学的に許容される塩として、本明細書に記載の任意の組成物、キット、または方法で使用するために提供され得る。
式中、
R1が、非置換アルキルであり、
R2が、非置換アルキルであり、
Xが、ハロゲン、−OP、−N(RA)2、−NRAN(RA)2、−SP、または−NCOであり、
Pが、水素、酸素保護基、硫黄保護基、または置換もしくは非置換ヘテロシクリルであり、
L1が、−(C=O)−、−CH2−、−CH=CH−、−C≡C−、−O−、−S−、または−NRA−であり、
L2が、置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、置換もしくは非置換アルキニレン、置換もしくは非置換ヘテロアルキレン、置換もしくは非置換ヘテロアルケニレン、または置換もしくは非置換ヘテロアルキニレンであり、L2が、L1に対するその接続点からTに対するその接続点までの少なくとも8個の連続した非水素原子の鎖を含み、
Tが、置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換ヘテロアルキル、−ORC、−N(RA)2、−SRA、−CO2H、ハロゲン、−OS(O2)RB、−O(C=O)RC、−(C=O)ORC、−O(C=O)ORC、−(C=O)N(RA)2、−O(C=O)N(RA)2、−NRA(C=O)N(RA)2、−CN、−CHO、−N3、−N=C=S、
Qが、SまたはOであり、
各RAが、独立して、水素、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換アシル、置換もしくは非置換ヘテロシクリル、窒素保護基、または硫黄保護基であり、
RBが、置換もしくは非置換アルキル、または置換もしくは非置換アリールであり、
RCが、置換もしくは非置換アルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロシクリル、置換もしくは非置換ヘテロアリール、または酸素保護基であり、
RDが、ハロゲンまたは−OS(O2)RBであり、
REが、水素、置換もしくは非置換アルキル、置換もしくは非置換カルボシクリル、置換もしくは非置換ヘテロシクリル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、または酸素保護基であり、
RFが、水素、置換もしくは非置換アルキル、または窒素保護基であり、ただし、化合物は、
本明細書に記載される場合、R1は、非置換アルキルである。特定の実施形態では、R1は、非置換C1−6アルキルである。特定の実施形態では、R1は、非置換C1−4アルキルである。特定の実施形態では、R1は、ネオペンチル、tert−ブチル、sec−ブチル、イソブチル、n−ブチル、イソプロピル、n−プロピル、エチル、またはメチルである。特定の実施形態では、R1は、tert−ブチル、sec−ブチル、イソブチル、n−ブチル、イソプロピル、n−プロピル、エチル、またはメチルである。特定の実施形態では、R1は、tert−ブチル、イソブチル、イソプロピル、エチル、またはメチルである。特定の実施形態では、R1は、tert−ブチル、イソブチル、イソプロピル、エチル、またはメチルである。特定の実施形態では、R1は、tert−ブチル、イソブチル、イソプロピル、またはエチルである。特定の実施形態では、R1は、tert−ブチル、イソブチル、またはイソプロピルである。特定の実施形態では、R1は、tert−ブチルまたはイソプロピルである。特定の実施形態では、R1は、イソプロピルである。特定の実施形態では、R1は、tert−ブチルである。
本明細書に記載される場合、Xは、ハロゲン、−OP、−N(RA)2、−NRAN(RA)2、−SP、または−NCOであり、Pは、水素、酸素保護基、硫黄保護基、または置換もしくは非置換ヘテロシクリルであり、各RAは、独立して、水素、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換アシル、置換もしくは非置換ヘテロシクリル、窒素保護基、または硫黄保護基である。特定の実施形態では、Xは、ハロゲン、−OP、−N(RA)2、−SP、または−NCOであり、Pは、水素、酸素保護基、または硫黄保護基であり、各RAは、独立して、水素、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換アシル、または窒素保護基である。特定の実施形態では、Xは、ハロゲン、−OP、−SP、または−NCOであり、Pは、水素、酸素保護基、または硫黄保護基である。特定の実施形態では、Xは、ハロゲン、−OH、−SH、または−NCOである。特定の実施形態では、Xは、−F、−Cl、−Br、−I、−OH、−SH、または−NCOである。特定の実施形態では、Xは、−F、−Cl、−OH、−SH、または−NCOである。特定の実施形態では、Xが、−F、−OH、−SH、または−NCOである。特定の実施形態では、Xは、−F、−OH、または−SHである。特定の実施形態では、Xは、−OHまたは−SHである。特定の実施形態では、Xは、−Fまたは−OHである。特定の実施形態では、Xは、−Fである。特定の実施形態では、X−Cl。特定の実施形態では、Xは、−Brである。特定の実施形態では、Xは、−Iである。特定の実施形態では、Xは、−OHである。特定の実施形態では、Xは、−OPであり、Pは、酸素保護基である。特定の実施形態では、Xは、−SHである。特定の実施形態では、Xは、−SPであり、Pは、硫黄保護基である。特定の実施形態では、Xは、−NCOである。
本明細書に記載される場合、L1は、−(C=O)−、−CH2−、−CH=CH−、−C≡C−、−O−、−S−、または−NRA−である。特定の実施形態では、L1は、−(C=O)−、−CH=CH−、または−C≡C−である。特定の実施形態では、L1は、−CH2−である。特定の実施形態では、L1は、−CH=CH−である。特定の実施形態では、L1は、−C≡C−である。特定の実施形態では、L1は、−O−である。特定の実施形態では、L1は、−S−である。特定の実施形態では、L1は、−NRA−であり、RAは、水素、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、または窒素保護基である。特定の実施形態では、L1は、−(C=O)−である。
本明細書に記載される場合、L2は、置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、置換もしくは非置換アルキニレン、置換もしくは非置換ヘテロアルキレン、置換もしくは非置換ヘテロアルケニレン、または置換もしくは非置換ヘテロアルキニレンであり、L2は、L1に対するその接続点からTに対するその接続点までの少なくとも8個の連続した非水素原子の鎖を含む。特定の実施形態では、L2は、置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、置換もしくは非置換ヘテロアルキレン、または置換もしくは非置換ヘテロアルケニレンであり、L2は、L1に対するその接続点からTに対するその接続点までの少なくとも8個の連続した非水素原子の鎖を含む。特定の実施形態では、L2は、置換もしくは非置換C8−30アルキレン、置換もしくは非置換C8−30アルケニレン、置換もしくは非置換C4−30ヘテロアルキレン、または置換もしくは非置換C4−30ヘテロアルケニレンである。特定の実施形態では、L2は、置換もしくは非置換C8−20アルキレン、置換もしくは非置換C8−20アルケニレン、置換もしくは非置換C4−20ヘテロアルキレン、または置換もしくは非置換C4−20ヘテロアルケニレンである。特定の実施形態では、L2は、置換もしくは非置換C15−20アルキレン、置換もしくは非置換C15−20アルケニレン、置換もしくは非置換C8−20ヘテロアルキレン、または置換もしくは非置換C8−20ヘテロアルケニレンである。特定の実施形態では、L2は、置換もしくは非置換C8−16アルキレン、置換もしくは非置換C8−16アルケニレン、置換もしくは非置換C4−16ヘテロアルキレン、または置換もしくは非置換C4−16ヘテロアルケニレンである。特定の実施形態では、L2は、置換もしくは非置換C8−12アルキレン、置換もしくは非置換C8−12アルケニレン、置換もしくは非置換C4−12ヘテロアルキレン、または置換もしくは非置換C4−12ヘテロアルケニレンである。
アンカー部分(「T」)は、様々な機能を果たす。いくつかの実施形態では、アンカー部分は、化合物を周囲および細胞外空間に制限する。いくつかの実施形態では、アンカーは、末梢感覚ニューロン(例えば、末梢HCN1チャネル)に対してファーマコフォアを標的化するように機能する。いくつかの実施形態では、アンカー部分は、アンカー部分から別のアンカー部分への変換を促進するように機能し得る反応性基(例えば、求電子性)である。
特定の実施形態では、−L1−L2−Tは、
本開示は、疼痛(例えば、慢性疼痛)の治療を必要とする対象においてそれを行う方法であって、有効量の式(I)、式(II)のいずれかの化合物、またはその薬学的に許容される塩を投与することを含む、方法を提供する。特定の実施形態では、慢性疼痛は、持続的な負の感覚認識、痛覚過敏、異痛、灼熱感、および異常な侵害受容デスクリプターからなる群から選択される1つ以上の症状によって特徴付けられる神経障害性疼痛である。
本開示はまた、本明細書に記載の化合物と、任意選択的に薬学的に許容される賦形剤と、を含む、薬学的組成物を提供する。特定の実施形態では、本明細書に記載の化合物は、式(I)、式(II)の化合物、またはその薬学的に許容される塩、および薬学的に許容される賦形剤である。
図3は、仮想のアンカー−テザーが付けられた2,6−DTBPに関して、BP4C−11:0:1およびBP4L−10:0:1を示す。図4は、HCN1−ΔNvΔCvを発現する3つの別個の細胞由来の記録を示す。各細胞を、0.04% DMSO単独、または示される10μMのBP4C−11:0:1またはBP4L−10:0:1と共に含む記録溶液中、20分間かけてプレインキュベートした。電流−電圧の関係(IV)を、3秒間および5秒間の活性化ステップで収集した(ここでは、各場合に示される5秒のスイープ)。2つのプロトコルによって報告されるV1/2には体系的な差はなく、このことは、全ての薬物およびビヒクル条件下で、両方の場合において活性化が各電圧で平衡化されていることを示す(図示せず)。−65mVでの活性化に応答してスイープおよびテールが、黒色で強調されている。Boltzmann関数にフィッティングしたテール電流活性化曲線を、図4に示す3つの細胞について示す(図5)。BP4C−11:0:1についてのデータは、9つの細胞に由来する(10μMでwtHCN1を発現する3つの細胞、10μMでHCN1−ΔNvΔCvを発現する3つの細胞、100μMでwtHCN1、100μMで1 HCN1−ΔNvΔCvを発現する2つの細胞)。BP4L−10:0:1についてのデータは、6つの細胞に由来する(10μMでHCN1−ΔNvΔCvを発現する3つの細胞および100μMでwt HCN1を発現する3つの細胞)。滑らかな線は、2,6−DTBPデータに対するHill関数のフィッティング、および示されるようなその右にシフトした態様である。
HCN1〜4チャネルのV1/2に対するプロポフォールおよび2,6−DTBPの効果。*は、対照と統計的に異なる応答を示す(図7)。HCN1チャネルのV1/2に対する2,6−(左)または2,4−(右)ジ−ブチルフェノールの効果。実線および示されるパラメータ値は、2,6−DTBP関係に対するHill関数のフィッティングに由来する。破線は、それぞれ、2,4−DTBP、2,6−DSBP、および2,4−DSBPについて、2倍、15倍、および23倍による2,6−DTBPフィットオフセットである。V1/2におけるシフトは、DTBPでは≧1μM、DSBPでは20μMで有意であった(図8)。
図12は、PW,同側およびPW,対側(神経結紮に対して同側および対側の足の逃避の確率)および刺激線維強度の関数としての示される2,6−DTBPの累積腹腔内用量の効果を示す(図12)。図13Aおよび図13Bは、低(15%)および高(30%)刺激強度での累積腹腔内2,6−DTBP用量の関数としてのHPWL(後足逃避潜時)を示す。
ファーマコフォアとしての2,6−DTBPを保持し、脂質膜を通る貫通(最終的にはCNS内への貫通)を防止しつつ、HCN1の選択的阻害を防止する目的で「テザー−アンカー」に焦点を当てた改変を行った、新規な化学エンティティ(NCE)を合成した。これらの化合物のうちの1つであるBP4L−18:1:1は、いくつかの所望な特性を有する。
図18は、CR、CAおよびOが、閉じた休止状態、閉じた活性化状態、および開状態を表し、KVおよびLが、活性化および開放を説明する平衡定数を表し、IおよびHが、逆アゴニストおよび部分逆アゴニストであり、pおよびqが、IおよびHの結合事象の数を表し、KCおよびKOが、適切な上付き文字によって示されるIおよびHに関し、閉チャネルおよび開チャネルに対するIおよびHの会合定数を表すことを示す。単純化のために、リガンドが結合していない状態間の活性化と開放の遷移のみが示されているが、全てのCR−CAおよびCA−O遷移が許容される。HおよびIが共通部位(複数可)と会合する場合、このモデルは、平面当たり3状態、合計で9状態(N=1)、および平面当たり15状態、合計で45状態(N=4)を含む。HおよびIが別の部位(複数可)と会合する場合、このモデルは、平面当たり4状態、合計で12状態(N=1)、および平面当たり25状態、合計で75状態(N=4)を含む。重要なことに、平衡定数は唯一の自由パラメータであり、平衡定数の数は状態の数の拡大とは無関係であるため、これらのモデルの各々がデータを同等に記述することができるかどうかを同等に十分に決定する必要がある。
図19Aは、10μMの示した試薬の不存在下または存在下で20分間インキュベートした後のHCN1電流(左)の代表的な電圧クランプの記録を示す。テール電流(右)は、拡張された時間スケールで示されている。各場合において、黒色のトレースは、−75mVの活性化電位で記録される電流である。全ての記録は、同じ日に単一のドナーカエル由来の別個の卵母細胞から得たものであった。スケールバーは、2μAおよび1s(左)、ならびに200nAおよび50ms(右)である。図19Bは、2,6−ジ−イソ−プロピルベンゼンの化学的表現を示す。1位での置換(凡例に従う)は、図19Aおよび図19Cで効果が記録される分子を記載する。図19Cは、図19Aに示す記録から構築された、正規化された定常状態活性化曲線を示す。滑らかな線は、Boltzmann関数にフィッティングしたものである。記号は、図19Bに記載される分子を表す。
図20は、示される各リガンドの濃度の関数としてのV1/2のシフトを示す。各パネルにおいて、太い黒い線は、2,6−DTBPに対するHill式のフィッティングである。薄い灰色の線は、存在する場合には、EC50のみの調整によって濃度軸上で翻訳された2,6−DTBP Hillフィッティングであり、太い灰色の線は、そのパネルにおける濃度応答に対するHill式のフィッティングであり、2,6−DIPPおよび2,6−DTBPパネルにおける破線の灰色の線は、シクロヘキサノールフィッティング線がΔV1/2最大フェノール/ΔV1/2最大シクロヘキサノール比に従って縮尺が変えられ、シクロヘキサノールフィッティングの他の項は調整されないようにフィッティングの最大応答のみが変更された2,6−DIPCHおよび2,6−DTBCHデータに対するHill式のフィッティングである。全てのデータは、平均値±SEMであり、1点当たり6以上の判定を有する。
図21Aは、計算された分子体積の関数としての観察された水性EC50をプロットする。完全(2,6−DIPP、2,6−DTBP)および部分的(2,6−DEP、2,6−DEIC、2,6−DIPCH、2,6−DTBCH、2,6−DSBP)な有効性が明らかであったリガンドについて、図20に示されるデータに対するHill式のフィッティングからEC50を決定した。最大有効性が十分に定義されず、Hill関数フィッティングが可能ではなかったリガンド(2,6−DMBT、2,6−DIPBT、2,6−DIPFB、2,6−DECH)については、シフトした2,6−DTBP Hillフィッティング(図20の薄い灰色の線)からEC50を推定した。図20の濃度応答曲線では屈曲部が観察できなかった場合、補正したEC50を100mMに設定した。図21Aおよび図21Bの両方において、破線の楕円形は、試薬のイソ−プロピルファミリーについてのデータを囲んだものである。図21Bにおいて、蓄積補正EC50(Aで記載されるように決定される水性EC50に、計算された蓄積比cPを掛け算したもの)のプロットを、計算された分子体積の関数としてプロットする。明確にするために、2,6−DMP(▲)、2,6−DMIC(▲)、2,6−DMCH(▲)、2,6−DECH(■)および2,6−DSBCH(▼)の値は省略されている。)
図22Aおよび図22Bは、イソ−プロピル(図22A)およびtert−ブチル(図22B)フェノールおよびシクロヘキサノールの濃度の関数としてのΔV1/2を示す。データは、図20から再現される。黒色の実線は、これら2つのパネルにおけるデータに対する共通部位モデル(N=4)の同時フィッティングであり、パネル図22C〜図22Eにおけるデータに対する同時フィッティングである。図22C〜図22Eは、3μMの2,6−DTBP存在下での2,6−DIPCH(図22C)、2,6−DTBCH(図22D)または2,6−DIPP(図22E)の濃度の関数としてのΔV1/2を示す。黒色の実線は、パネル図22Aおよび図22Bに定義される通りである。黒色の破線は、共通部位モデルのフィッティングから決定された会合定数を用いた、N=4での別部位モデルの予想挙動である。灰色の線は、各々の相加条件について、対になった対照において3μMの2,6−DTBPによって誘発されるΔV1/2(実線)およびSEM(破線)の平均値を報告する。図22Fは、−(RT)LnKに従って自由エネルギーの項に変換されたN=4の共通部位モデル(図22A〜図22Eに従う)のフィッティングから決定された会合定数を示す。開放平衡定数(L)の報告値は、この同じフィッティングからの値である。
図23は、3μMの2,6−DTBP非存在下(図23A)および存在下(図23B)での2,6−DSBPの濃度の関数としてのΔV1/2を示す。黒色の実線は、これら2つのパネルにおけるデータに対する共通部位モデル(N=4)の同時フィッティングであり、JoIおよびJcI以外の全ての定数は、図23で決定された値と同じままであった。これらのフィッティングから決定されたJoIおよびJcIは、それぞれ、881±1,801および3,696±2,948であった。図23Bの黒色の破線は、上述のパラメータを有するN=4での別部位モデルの予想挙動である。この4モデルの別個のフィッティングによって、それぞれ、1〜4に等しいNで、600および128(共通部位)、ならびに165および167(別部位)のχ2値が得られた。図23Aの記号および灰色の線は、2,6−DSBPについての観察されたΔV1/2、および図20の2,6−DSBPパネルから再現されたEC50調整した2,6−DTBPフィッティング線(370μMに設定されたEC50)である。図23Bにおいて、灰色の線は、対になった対照において3μMの2,6−DTBPによって誘発されるΔV1/2(実線)およびSEM(破線)の平均値を報告する。
2,6−DTBPは、可動性が高く、脂質二重層の疎水性コアの体積全体を探索し、完全にランダムな配向をとる(図27)。加えて、ジオールアンカーが付けられた分子は、遊離2,6−DTBPのようには挙動しない。全体的にさらに疎水性であるにもかかわらず、ジオールアンカーが付けられた分子は、脂質相に自由に分布せず、脂質内を自由に移動しない。シミュレーション軌道の目視での検査は、アンカーがほぼ設計に従って機能していることを示す。したがって、両分子(BP4L−18:1:1およびBP4L−10:0:1)において、ジオールは、極性環境を強く好み、ジオールは、水和された頭部基相に固定され、疎水性コア中、または水相から遠く離れて存在する時間はほとんどない。
BP4C−11:0:1の合成
200μLのLCMSグレードのアセトニトリルを、1mLのエッペンドルフチューブ中の200μLの血液に添加し、10秒間ボルテックス混合し、次いで、2400×gで15分間遠心分離した。200μLを上清から除去し、新しい1mLのエッペンドルフチューブに入れ、5300×gで15分間遠心分離した。最後に、100μLの上清を除去し、0.2μm修飾ナイロン遠心フィルターを通過させ、任意のタンパク質残渣を除去した。得られた上清を、さらなる修飾なしでLCMS分析に使用した。
例示的な化合物BP4L−18:1:1(化合物6)の薬物動態特性をラットで評価した(図29)。特に、経口投与後30時間にわたって全血試料中のBP4L−18:1:1の濃度を決定した。その結果は、化合物が吸収されたことを示し、このことは、バイオアベイラビリティを示している。
請求項において、「1つの(a)」、「1つの(an)」、および「その(the)」などの冠詞は、矛盾する内容が示されていない限り、または文脈から明らかでない限り、1または2以上を意味し得る。ある群の1つ以上のメンバーの間に「または」を含む請求項または説明は、矛盾する内容が示されていない限り、または文脈から明らかでない限り、その群のメンバーの1つ、1つより多く、または全てが、所与の生成物またはプロセスに存在するか、使用されるか、または他の方法で関連する場合に満足すると考えられる。本開示は、その群のたった1つのメンバーが所与の生成物またはプロセスに存在するか、使用されるか、または他の方法で関連する実施形態を含む。本開示は、その群のメンバーの1つより多く、または全てが所与の生成物またはプロセスに存在するか、使用されるか、または他の方法で関連する実施形態を含む。
Claims (37)
- 式(I)の化合物、
R1が、非置換アルキルであり、
R2が、非置換アルキルであり、
Xが、ハロゲン、−OP、−N(RA)2、−NRAN(RA)2、−SP、または−NCOであり、
Pが、水素、酸素保護基、硫黄保護基、または置換もしくは非置換ヘテロシクリルであり、
L1が、−(C=O)−、−CH2−、−CH=CH−、−C≡C−、−O−、−S−、または−NRA−であり、
L2が、置換もしくは非置換アルキレン、置換もしくは非置換アルケニレン、置換もしくは非置換アルキニレン、置換もしくは非置換ヘテロアルキレン、置換もしくは非置換ヘテロアルケニレン、または置換もしくは非置換ヘテロアルキニレンであり、L2が、L1に対するその接続点からTに対するその接続点までの少なくとも8個の連続した非水素原子の鎖を含み、
Tが、置換アルキル、置換もしくは非置換アルケニル、置換もしくは非置換アルキニル、置換もしくは非置換ヘテロアルキル、−ORC、−N(RA)2、−SRA、−CO2H、ハロゲン、−OS(O2)RB、−O(C=O)RC、−(C=O)ORC、−O(C=O)ORC、−(C=O)N(RA)2、−O(C=O)N(RA)2、−NRA(C=O)N(RA)2、−CN、−CHO、−N3、−N=C=S、
Qが、SまたはOであり、
各RAが、独立して、水素、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換アシル、置換もしくは非置換ヘテロシクリル、窒素保護基、または硫黄保護基であり、
RBが、置換もしくは非置換アルキル、または置換もしくは非置換アリールであり、
RCが、置換もしくは非置換アルキル、置換もしくは非置換アリール、置換もしくは非置換ヘテロシクリル、置換もしくは非置換ヘテロアリール、または酸素保護基であり、
RDが、ハロゲンまたは−OS(O2)RBであり、
REが、水素、置換もしくは非置換アルキル、置換もしくは非置換カルボシクリル、置換もしくは非置換ヘテロシクリル、置換もしくは非置換アリール、置換もしくは非置換ヘテロアリール、または酸素保護基であり、
RFが、水素、置換もしくは非置換アルキル、または窒素保護基であり、ただし、前記化合物は、
- 式中、
R1が、非置換C1−4アルキルであり、
R2が、非置換C1−4アルキルである、請求項1に記載の化合物またはその薬学的に許容される塩。 - 式中、
R1が、tert−ブチルまたはイソプロピルであり、
R2が、tert−ブチルまたはイソプロピルである、請求項1または2に記載の化合物またはその薬学的に許容される塩。 - 式中、
R1が、tert−ブチルであり、
R2が、tert−ブチルである、請求項1〜3のいずれかに記載の化合物またはその薬学的に許容される塩。 - 式中、
Xが、F、−OH、−SH、または−NCOである、請求項1〜4のいずれかに記載の化合物またはその薬学的に許容される塩。 - 式中、
Xが、−OHである、請求項1〜5のいずれかに記載の化合物またはその薬学的に許容される塩。 - 式中、
L1が、−(C=O)−、−CH=CH−、または−C≡C−である、請求項1〜6のいずれかに記載の化合物またはその薬学的に許容される塩。 - 式中、
L1が、−(C=O)−である、請求項1〜7のいずれかに記載の化合物またはその薬学的に許容される塩。 - 式中、
L2が、置換または非置換アルキレンである、請求項1〜8のいずれかに記載の化合物またはその薬学的に許容される塩。 - 式中、
Tが、置換もしくは非置換アルケニル、置換アルキル、−OH、ハロゲン、−CO2H、または−(C=O)ORCであり、RCが、置換または非置換ヘテロシクリルである、請求項1〜9のいずれかに記載の化合物またはその薬学的に許容される塩。 - 請求項1〜18のいずれかに記載の化合物、またはその薬学的に許容される塩と、薬学的に許容される担体と、を含む、薬学的組成物。
- 疼痛の治療を必要とする対象においてそれを行う方法であって、有効量の請求項1〜18のいずれかに記載の化合物、もしくはその薬学的に許容される塩、または請求項19に記載の薬学的組成物を投与することを含む、方法。
- 前記疼痛が、慢性疼痛である、請求項20に記載の方法。
- 前記慢性疼痛が、持続的な負の感覚認識、痛覚過敏、異痛、灼熱感、および異常な侵害受容デスクリプターからなる群から選択される1つ以上の症状によって特徴付けられる神経障害性疼痛である、請求項21に記載の方法。
- HCNチャネルゲーティングを調節する方法であって、HCNチャネルを有効量の請求項1〜18のいずれかに記載の化合物、またはその薬学的に許容される塩と接触させることを含む、方法。
- HCNチャネルゲーティングを阻害することを含む、請求項23に記載の方法。
- 前記HCNチャネルが、HCN1チャネルである、請求項23または24に記載の方法。
- ガンマ−アミノ酪酸−A(GABA−A)受容体を増強することなくHCN1チャネルを阻害する方法であって、HCN1チャネルを、有効量の請求項1〜18のいずれかに記載の化合物、またはその薬学的に許容される塩と接触させることを含む、方法。
- 式(II)の化合物、
R1が、−CH(OH)CH2(OH)、−CH(X1)CH3、CH2CH3、−CH=CH2、−CH=CH(R2)、または−CH2CH2(R3)であり、
R2が、−(CH2)mCH(OH)CH2(OH)、−(CH2)pCH(X2)CH3、−(CH2)tCH=CH2、または−(CH2)vCH2CH3であり、
R3が、−(CH2)wCH(OH)CH2(OH)、−(CH2)xCH(X3)CH3、(CH2)yCH=CH2、または−(CH2)zCH2CH3であり、
X1、X2、およびX3が各々独立して、ClまたはFであり、
nが、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
mが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
pが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
tが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
vが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
wが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
xが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
yが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15であり、
zが、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、または15である、化合物またはその薬学的に許容される塩および/もしくは溶媒和物。 - R1が、−CH(X1)CH3、CH2CH3、−CH=CH2、−CH=CH(R2)、または−CH2CH2(R3)である、請求項27に記載の化合物。
- 請求項27〜33のいずれか一項に記載の化合物と、薬学的に許容される担体と、を含む、組成物。
- 慢性疼痛を管理または治療する方法であって、それを必要とする患者に有効量の請求項27〜33のいずれか一項に記載の化合物のうちの1つ以上を投与することを含む、方法。
- HCNチャネルゲーティングを調節する方法であって、有効量の請求項27〜33のいずれか一項に記載の化合物のうちの1つ以上をHCNチャネルに提供することを含む、方法。
- γ−アミノ酪酸−A(GABA−A)受容体を増強することなく、HCN1チャネルを阻害する方法であって、有効量の請求項27〜33のいずれか一項に記載の化合物のうちの1つ以上をHCNチャネルに提供することを含む、方法。
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US201862690778P | 2018-06-27 | 2018-06-27 | |
US62/690,778 | 2018-06-27 | ||
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EP0761652A1 (en) | 1995-08-01 | 1997-03-12 | Mochida Pharmaceutical Co., Ltd. | Acridinium compound having a plurality of luminescent groups and binding groups, and conjugate thereof |
US6218437B1 (en) | 1996-09-30 | 2001-04-17 | The Regents Of The University Of California | Treatment and prevention of hepatic disorders |
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