JP2021513518A - 新規使用 - Google Patents
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- JP2021513518A JP2021513518A JP2020541880A JP2020541880A JP2021513518A JP 2021513518 A JP2021513518 A JP 2021513518A JP 2020541880 A JP2020541880 A JP 2020541880A JP 2020541880 A JP2020541880 A JP 2020541880A JP 2021513518 A JP2021513518 A JP 2021513518A
- Authority
- JP
- Japan
- Prior art keywords
- adenosine
- alkyl
- receptor
- pde1
- agents
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
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- 229940075582 sorbic acid Drugs 0.000 description 1
- 206010062261 spinal cord neoplasm Diseases 0.000 description 1
- 201000002245 spindle cell lipoma Diseases 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 150000008143 steroidal glycosides Chemical class 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000001300 stimulation of adenylate cyclase Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- XMFCOYRWYYXZMY-UHFFFAOYSA-N sulmazole Chemical compound COC1=CC(S(C)=O)=CC=C1C1=NC2=NC=CC=C2N1 XMFCOYRWYYXZMY-UHFFFAOYSA-N 0.000 description 1
- 229950006153 sulmazole Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940106719 tambocor Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940065385 tenex Drugs 0.000 description 1
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- 229960000195 terbutaline Drugs 0.000 description 1
- WUBVEMGCQRSBBT-UHFFFAOYSA-N tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)C(F)(F)F)=CC1 WUBVEMGCQRSBBT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
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- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- WRCITXQNXAIKLR-UHFFFAOYSA-N tiadenol Chemical compound OCCSCCCCCCCCCCSCCO WRCITXQNXAIKLR-UHFFFAOYSA-N 0.000 description 1
- 229960000822 tiadenol Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229960002872 tocainide Drugs 0.000 description 1
- 229950001089 todralazine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 229940108522 trandate Drugs 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 208000010556 transitional cell papilloma Diseases 0.000 description 1
- 201000004420 transitional papilloma Diseases 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- CHQOEHPMXSHGCL-UHFFFAOYSA-N trimethaphan Chemical compound C12C[S+]3CCCC3C2N(CC=2C=CC=CC=2)C(=O)N1CC1=CC=CC=C1 CHQOEHPMXSHGCL-UHFFFAOYSA-N 0.000 description 1
- 229940035742 trimethaphan Drugs 0.000 description 1
- 229950004678 tripamide Drugs 0.000 description 1
- UHLOVGKIEARANS-QZHINBJYSA-N tripamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)NN2C[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3C2)=C1 UHLOVGKIEARANS-QZHINBJYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000013706 tumor of meninges Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229960001130 urapidil Drugs 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 208000024523 vestibulocochlear nerve neoplasm Diseases 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
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- 229940046010 vitamin k Drugs 0.000 description 1
- 208000022752 well-differentiated liposarcoma Diseases 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 229940072358 xylocaine Drugs 0.000 description 1
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Abstract
Description
本開示の方法で使用するための化合物
特定に実施態様では、本開示は、本明細書に記載の治療および予防の方法で使用するためのPDE1阻害剤が、下記の本出願人自身の公開公報に記載されているPDE1阻害剤から選択されることを提供する:US2008−0188492A1、US2010−0173878A1、US2010−0273754A1、US2010−0273753A1、WO2010/065153、WO2010/065151、WO2010/065151、WO2010/065149、WO2010/065147、WO2010/065152、WO2011/153129、WO2011/133224、WO2011/153135、WO2011/153136、WO2011/153138、WO2012/171016、WO2013/192556、WO2014/151409、WO2015/196186、WO2016/022825、WO2016022836、WO2016/022893、WO2016/044667、US9546175(それぞれの内容全体は出典明示によりその全体が本明細書の一部とされる)。
(i)R1は、HまたはC1-4アルキル(例えば、メチル)であり;
(ii)R4は、HまたはC1-4アルキルであり、R2およびR3は、独立して、HまたはC1-4アルキル(例えば、R2およびR3は共にメチルであるか、またはR2はHであり、R3はイソプロピルである)、アリール、ヘテロアリール、(場合によってはヘテロ)アリールアルコキシ、または(場合によってはヘテロ)アリールアルキルであるか;または
R2はHであり、R3およびR4は一緒になってジ−、トリ−またはテトラメチレン架橋を形成し(好ましくはR3およびR4が一緒になってシス配置を有しており、例えば、R3およびR4を担持する炭素はそれぞれR配置およびS配置を有する);
(iii)R5は、例えばハロアルキルで置換されている、置換ヘテロアリールアルキルであるか;または
R5は、式Iのピラゾロ部分の窒素の1つに結合しており、式A:
で示される部分であり;
(iv)R6は、H、アルキル、アリール、ヘテロアリール、アリールアルキル(例えば、ベンジル)、アリールアミノ(例えば、フェニルアミノ)、ヘテロアリールアミノ、N,N−ジアルキルアミノ、N,N−ジアリールアミノ、またはN−アリール−N−(アリールアルキル)アミノ(例えば、N−フェニル−N−(1,1'−ビフェン−4−イルメチル)アミノ)であり;
(v)nは0または1であり;
(vi)nが1である場合、Aは、−C(R13R14)−であり、
ここで、R13およびR14は、独立して、HまたはC1-4アルキル、アリール、ヘテロアリール、(場合によってはヘテロ)アリールアルコキシまたは(場合によってはヘテロ)アリールアルキルである]
で示される化合物であることを提供する。
(i)Xは、C1-6アルキレン(例えば、メチレン、エチレンまたはプロパ−2−イン−1−イレン)であり;
(ii)Yは、単結合、アルキニレン(例えば、−C≡C−)、アリーレン(例えば、フェニレン)またはヘテロアリーレン(例えば、ピリジレン)であり;
(iii)Zは、H、アリール(例えば、フェニル)、ヘテロアリール(例えば、ピリジル、例えば、ピリダ−2−イル)、ハロ(例えば、F、Br、Cl)、ハロC1-6アルキル(例えば、トリフルオロメチル)、−C(O)−R1、−N(R2)(R3)、またはNもしくはOからなる群から選択される少なくとも1個の原子を含有していてもよいC3-7シクロアルキル(例えば、シクロペンチル、シクロヘキシル、テトラヒドロ−2H−ピラン−4−イル、またはモルホリニル)であり;
(iv)R1は、C1-6アルキル、ハロC1-6アルキル、−OHまたは−OC1-6アルキル(例えば、−OCH3)であり;
(v)R2およびR3は、独立して、HまたはC1-6アルキルであり;
(vi)R4およびR5は、独立して、H、C1-6アルキルまたはアリール(例えば、フェニル)(これは、1個以上の、ハロで置換されていてもよい(例えば、フルオロフェニル、例えば、4−フルオロフェニル)、ヒドロキシで置換されていてもよい(例えば、ヒドロキシフェニル、例えば、4−ヒドロキシフェニルまたは2−ヒドロキシフェニル)またはC1-6アルコキシで置換されていてもよい)であり;
(vii)ここで、X、YおよびZは、独立して、1個以上の、ハロ(例えば、F、ClまたはBr)、C1-6アルキル(例えば、メチル)、ハロC1-6アルキル(例えば、トリフルオロメチル)で置換されていてもよく、例えば、Zは、1個以上の、ハロ(例えば、6−フルオロピリダ−2−イル、5−フルオロピリダ−2−イル、6−フルオロピリダ−2−イル、3−フルオロピリダ−2−イル、4−フルオロピリダ−2−イル、4,6−ジクロロピリダ−2−イル)、ハロC1-6アルキル(例えば、5−トリフルオロメチルピリダ−2−イル)またはC1-6−アルキル(例えば、5−メチルピリダ−2−イル)で置換されている、ヘテロアリール、例えばピリジルであるか、またはZは、1個以上のハロ(例えば、4−フルオロフェニル)で置換されている、アリール、例えばフェニルである]
で示される化合物であることを提供する。
(i)R1は、HまたはC1-4アルキル(例えば、メチルまたはエチル)であり;
(ii)R2およびR3は、独立して、HまたはC1-6アルキル(例えば、メチルまたはエチル)であり;
(iii)R4は、HまたはC1-4アルキル(例えば、メチルまたはエチル)であり;
(iv)R5は、独立して、−C(=O)−C1-6アルキル(例えば、−C(=O)−CH3)およびC1-6−ヒドロキシアルキル(例えば、1−ヒドロキシエチル)から選択される1個以上の基で置換されていてもよいアリール(例えば、フェニル)であり;
(v)R6およびR7は、独立して、H、または独立してC1-6アルキル(例えば、メチルまたはエチル)およびハロゲン(例えば、FまたはCl)から選択される1個以上の基で置換されていてもよいアリール(例えば、フェニル)であり、例えば、非置換フェニル、または1個以上のハロゲン(例えば、F)で置換されているフェニル、または1個以上のC1-6アルキルおよび1個以上のハロゲンで置換されているフェニル、または1個のC1-6アルキルおよび1個のハロゲンで置換されているフェニル、例えば4−フルオロフェニルまたは3,4−ジフルオロフェニルまたは4−フルオロ−3−メチルフェニルであり;
(vi)nは、1、2、3または4である]
であることを提供する。
(i)R1は、C1-4アルキル(例えば、メチルまたはエチル)、または−NH(R2)であり、ここで、R2は、ハロ(例えば、フルオロ)で置換されていてもよいフェニル、例えば4−フルオロフェニルであり;
(ii)X、YおよびZは、独立して、NまたはCであり;
(iii)R3、R4およびR5は、独立して、HまたはC1-4アルキル(例えば、メチル)であるか;またはR3はHであり、R4およびR5は一緒になってトリメチレン橋を形成し(好ましくはR4およびR5が一緒になってシス配置を有しており、例えば、R4およびR5を担持する炭素はそれぞれR配置およびS配置を有する)、
(iv)R6、R7およびR8は、独立して、
H、
C1-4アルキル(例えば、メチル)、
ヒドロキシで置換されているピリダ−2−イル、または
−S(O)2−NH2であり;
(v)ただし、X、Yおよび/またはZがNである場合、それぞれ、R6、R7および/またはR8は存在せず;また、X、YおよびZが全てCである場合、R6、R7またはR8のうち少なくとも1つは、−S(O)2−NH2、またはヒドロキシで置換されているピリダ−2−イルである]
であることを提供する。
本開示化合物およびそれらの薬学的に許容される塩は、本明細書に記載および例示された方法およびそれに類似する方法、ならびに化学技術分野で知られている方法によって製造され得る。このような方法としては以下のものが挙げられるが、これらに限定されない。市販されていない場合、これらのプロセスのための出発物質は、既知化合物の合成と同様または類似の技術をもしいて化学技術から選択される手順によって製造することができる。本開示化合物の製造の出発物質および方法は上記の出典明示により引用され本明細書の一部とされる特許出願に記載されている。
BuLi = n−ブチルリチウム
ButOH = tert−ブチルアルコール、
CAN = 硝酸アンモニウムセリウム(IV)、
DIPEA = ジイソプロピルエチルアミン、
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、
equiv.= 当量、
h = 時間、
HPLC =高速液体クロマトグラフィー、
LDA = リチウムジイソプロピルアミド
MeOH = メタノール、
NBS = N−ブロモスクシンイミド
NCS = N−クロロスクシンイミド
NaHCO3 = 重炭酸ナトリウム、
NH4OH = 水酸化アンモニウム、
Pd2(dba)3 = トリス[ジベンジリデンアセトン]ジパラジウム(0)
PMB = p−メトキシベンジル、
POCl3 = オキシ塩化リン、
SOCl2 = 塩化チオニル、
TFA = トリフルオロ酢酸、
TFMSA = トリフルオロメタンスルホン酸
THF = テトラヒドロフラン。
本開示化合物は、例えばドーパミンおよび一酸化窒素(NO)のような環状ヌクレオチド合成の誘導剤の阻害またはレベル減少に起因するPDE1の発現の増加またはcGMP/PKGまたはcAMP/PKA活性の発現の低下の結果としての、cGMP/PKGおよび/またはcAMP/PKAシグナル伝達媒介経路の破壊または損傷によって特徴づけられる疾患の治療に有用である。この作用は、例えばPDE1を阻害することにより、cGMP/PKGまたはcAMP/PKAシグナル伝達の減衰を逆転または防止し得る(例えば、それぞれcGMPまたはcAMPを増強し得る)と考えられる。したがって、本明細書に記載されているような好ましいPDE1阻害剤、例えば上記されているPDE1阻害剤の投与または使用は、様々な心血管疾患および障害の治療を提供するための潜在的な手段を提供し得る。
a. 遊離形態または薬学的に許容される塩形態、例えば一リン酸塩形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン;
b. 遊離形態または薬学的に許容される塩形態の7,8−ジヒドロ−2−(4−アセチルベンジル)−3−(4−フルオロフェニルアミノ)−5,7,7−トリメチル−[2H]−イミダゾ−[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン;および
c. 遊離形態または薬学的に許容される塩形態の3−((4−フルオロフェニル)アミノ)−5,7,7−トリメチル−2−((2−メチルピリミジン−5−イル)メチル)−7,8−ジヒドロ−2H−イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン
から選択される、上記方法のいずれか。
a. 遊離形態または薬学的に許容される塩形態、例えば一リン酸塩形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン;
b. 遊離形態または薬学的に許容される塩形態の7,8−ジヒドロ−2−(4−アセチルベンジル)−3−(4−フルオロフェニルアミノ)−5,7,7−トリメチル−[2H]−イミダゾ−[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン;および
c. 3−((4−フルオロフェニル)アミノ)−5,7,7−トリメチル−2−((2−メチルピリミジン−5−イル)メチル)−7,8−ジヒドロ−2H−イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン
から選択される、上記方法のいずれか。
a. 遊離形態または薬学的に許容される塩形態、例えば一リン酸塩形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン;
b. 遊離形態または薬学的に許容される塩形態の7,8−ジヒドロ−2−(4−アセチルベンジル)−3−(4−フルオロフェニルアミノ)−5,7,7−トリメチル−[2H]−イミダゾ−[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン;および
c. 3−((4−フルオロフェニル)アミノ)−5,7,7−トリメチル−2−((2−メチルピリミジン−5−イル)メチル)−7,8−ジヒドロ−2H−イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン
から選択される、上記方法のいずれか。
a. 遊離形態または薬学的に許容される塩形態、例えば一リン酸塩形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン;
b. 遊離形態または薬学的に許容される塩形態の7,8−ジヒドロ−2−(4−アセチルベンジル)−3−(4−フルオロフェニルアミノ)−5,7,7−トリメチル−[2H]−イミダゾ−[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン;および
c. 3−((4−フルオロフェニル)アミノ)−5,7,7−トリメチル−2−((2−メチルピリミジン−5−イル)メチル)−7,8−ジヒドロ−2H−イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン
から選択される、いずれもの上記方法。
いくつかの実施態様では、PDE1阻害剤は、他の治療様式と組み合わせて投与される。したがって、上記の治療法に加えて、より多くの薬剤による心臓治療法を患者に提供することもできる。他の治療法の例としては、降圧薬、強心薬、抗血栓薬、血管拡張薬、ホルモン拮抗薬、変力薬(inotropes)、利尿剤、エンドセリン拮抗薬、カルシウムチャネル遮断薬、ホスホジエステラーゼ阻害薬、ACE阻害剤、アンジオテンシン受容体2型拮抗薬およびサイトカイン遮断薬/阻害剤、およびHDAC阻害剤が挙げられるが、これらに限定されない。併用療法の特定の形態には、PDE1阻害剤の使用が含まれる。
a. 遊離形態または薬学的に許容される塩形態、例えば一リン酸塩形態の、(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン;
b. 遊離形態または薬学的に許容される塩形態の7,8−ジヒドロ−2−(4−アセチルベンジル)−3−(4−フルオロフェニルアミノ)−5,7,7−トリメチル−[2H]−イミダゾ−[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン;および
c. 3−((4−フルオロフェニル)アミノ)−5,7,7−トリメチル−2−((2−メチルピリミジン−5−イル)メチル)−7,8−ジヒドロ−2H−イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン
から選択される、上記の組合せのいずれか。
a. 遊離形態または薬学的に許容される塩形態、例えば一リン酸塩形態の、(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン;
b. 遊離形態または薬学的に許容される塩形態の7,8−ジヒドロ−2−(4−アセチルベンジル)−3−(4−フルオロフェニルアミノ)−5,7,7−トリメチル−[2H]−イミダゾ−[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン;および
c. 3−((4−フルオロフェニル)アミノ)−5,7,7−トリメチル−2−((2−メチルピリミジン−5−イル)メチル)−7,8−ジヒドロ−2H−イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン
から選択される、上記の組合せのいずれか。
心筋で主にPDE1Cを発現する哺乳動物で実験モデルを確立するために、ヒト、イヌ、ウサギ、ラットおよびマウスでタンパク質および遺伝子発現を調べる。安楽死させた成体C57BL/6Jマウス、Sprague Dawleyラット、雑種犬、ニュージーランド白ウサギから心臓組織を迅速に切除し、洗浄した後、液体窒素中で凍結する。ヒト心筋組織はUniversity of Pennsylvaniaの組織バンクから、ドナー対照心臓および末期心筋症心臓(摘出)から得た。心臓は、氷冷心筋保護液を用いて管理された外科的処置の下で採取され、氷上で輸送され、その後まもなく液体窒素中でスナップ冷凍された。次に、組織を、種特異的プライマーおよび抗体を用いて、PDE1A、1Bおよび1CのmRNA発現およびタンパク質発現について分析する。
PDE1Cを発現する2匹の哺乳動物、イヌおよびウサギにおける強力なPDE1阻害剤(化合物1)の効果を正常心臓および不全心の両方で試験する研究が行われ、その結果をβアドレナリン調節と対比させた。これらの動物は、心筋組織のmRNAおよびタンパク質レベルでPDE1C>>PDE1Aを発現するので、選択された。
意識下圧力−容積血行動態解析のために、成犬雑種(25〜30kg;n=6)に左室ソノマイクロメーター、マイクロメーター、下大静脈カフオクルダー、ならびに動脈および静脈留置カテーテルを慢性的に装着する。犬は、200bpmで2週間タキペーシング(tachypacing)によって拡張型心筋症を誘発する前と後の意識下状態で研究される。これらの犬は、経口および静脈内化合物1の効果、およびβ1アドレナリン刺激との相互作用を決定するために、別々の日に研究される。
急性PDE1阻害の効果を評価するために、健常または不全心の無傷のイヌにおいて、圧力−容積関係の試験を行い、化合物1(10mg/kg)の経口投与のベースラインおよびその2時間後の血行動態および心臓力学を解析した。対照イヌおよび心不全(HF)イヌの両方において、LV予圧(拡張末期容積)または収縮期血圧にはほとんど変化がなく、収縮力の増加(収縮末期エラスタンスの上昇)があった。正常イヌでは、化合物1は収縮期血圧を変化させることなく、心拍数を増加させ、全身の血管抵抗を減少させ、心拍出量を増加させた。収縮力の負荷不感応指標(dP/dtmax/IPおよびPRSW)が増加した。圧力低下ピーク率(dP/dtmin)および弛緩時定数(tau)に反映される弛緩も改善した。同様の薬効が、特に収縮力と血管拡張において、HFイヌでも観察された。心拍数の増加は、HF動物では鈍化した(2−way ANOVAによる相互作用ではp=0.07)。このように、化合物1の正味の効果は、全身の血圧を変化させることなく、対照群では心拍出量を50%(HF群では32%)増加させることであった。
化合物1の急性心血管効果は、cGMP関連の反応ではなくcAMP関連の反応を示唆している。これは、その正味の影響がβアドレナリン経路のドブタミンとの共活性化と重複しているかまたは増幅されているかどうかの疑問を提起した。10μg/kg/分のドブタミンを、10mg/kg化合物1を用いてまたは用いずにイヌに投与した。ドブタミンは、PVループ面積を増加させ(脳卒中ワークを示している)、各ループの上隅を左にシフトさせた(収縮力の増加を示している);化合物1を追加すると、両方がさらに強化された。これらの効果は相加的であることが観察された。これは、2−way ANOVAから交互作用項を評価することによって定量化された。同様の結果が、対照および不全心で得られた。
サイクリックAMPは、主に刺激性Gタンパク質(Gs)を介して活性化された膜貫通型アデニルシクラーゼによって生成され、心筋細胞ではβアドレナリン、アデノシン(主にA2B)、グルカゴン、プロスタノイド、ヒスタミン、セロトニンのすべてがGsと結合している。本研究では、βアドレナリン受容体とアデノシン受容体に焦点を当て、後者については、cAMP依存性の収縮力を直接刺激することが報告されているA2B受容体に焦点を当てた。麻酔したウサギに、選択的β1遮断薬エスモロールまたはアデノシンA2BR遮断薬MRS−1754による前治療を伴ってまたは伴わずに、ボーラス静脈内化合物1を0.1mg/kg(イヌの結果に基づく用量)で投与する。イヌの場合と同様に、急性PDE1阻害のみでは、収縮力の上昇(収縮期末期エラスターンスおよび負荷前リクルート可能な脳卒中ワークが50%上昇)に起因して心拍出量が増加し、心拍数が緩やかに上昇し、全身抵抗が低下したが、収縮期血圧には変化はなかった。リラクゼーションの変化は控えめであり、LV予圧(拡張末期および容積)に変化はなかった;しかしながら、血管拡張薬と強心薬を組み合わせた反応は、心室/動脈結合比、Ees/Eaを2倍に増加させた。
in vivoウサギ研究法
ニュージーランド白ウサギ(雄、2〜3kg)を35mg/kgのケタミンと5mg/kgのキシラジンで鎮静化し、挿管および換気(Model 683、Harvard Apparatus, Holliston, MA)を行い、イソフルラン吸入(1〜2%)で麻酔を維持する。圧力−容積カテーテル(SPR−894、Millar, Inc., Houston, TX)を総頸動脈を介して挿入し、LVの頂点まで進め、2−Frペーシングカテーテルを右頸静脈を介して右心房に配置し、心房ペーシングを提供する。4−Frバーマンバルーンカテーテル(AI−07134、Teleflex, Wayne, PA)を、静脈還流を一時的に閉塞し、プレロードの変動を防ぐために、大腿静脈を介して下大静脈(IVC)に配置する。平行コンダクタンスは、高張性生理食塩水注入法によって決定される。ウサギに、動脈圧を安定化させるために処置中に生理食塩水中6%のヘタスターチを注入する。すべての医薬品を静脈内投与する: A)化合物1(0.1mg/kg)を、β1受容体アンタゴニストエスモロール(0.5mg/kgボーラス注入後、0.05mg/kg/分の連続注入)の事前注入を伴うかまたは伴わずに、1〜2分間にわたってボーラス注入として投与する。これらの用量はまた、βアドレナリン受容体遮断の有効性を実証するために、10μg/kg/分のドブタミンに対して試験される。B)アデノシンA2B受容体アンタゴニストMRS1754(1mg/kg iv)のボーラス注射を伴うかまたは伴わない、化合物1(0.1mg/kg)。
PDE1阻害が心筋細胞の収縮およびカルシウムトランジェントに直接影響を与えるかどうかを試験するために、正常な成体ウサギ筋細胞を用いて研究を行う。対照として、イソプロテレノール(Iso、50nM)を投与し、これは、サルコメア短縮およびピークCa2+の両方を増加させ、両方の崩壊時間を加速する。対照的に、化合物1は1mMでも効果がない。広範囲のPDE阻害剤(IBMX、100μM)の添加は、短縮および収縮/カルシウム崩壊速度を増加させたが、ピークカルシウムトランジェントを変化させなかった。PDE1は、影響を与えるために十分なcAMPおよびCa2+を必要とするので、アデニル酸シクラーゼ活性化剤であるフォルスコリン(FSK)に対して用量反応を行い、控えめではあるが有意なイノトロピック効果をもたらす最低用量(1μM)を決定した。この用量を最初に適用すると、化合物1の添加は、短縮およびリラクゼーション/カルシウム崩壊速度を有意に増加させる。ピークカルシウムトランジェントは依然として変化しない。
化合物1は無傷のマウスでは急性心血管系への影響はない。
イヌ、ウサギおよびマウスの間のアイソフォームの不一致により、cAMPのPDE1Aの調節がPDE1Cと比較してはるかに少ないので、マウスが急性化合物1に類似した反応をしないかもしれないことが予測された。これを試験するために、マウスにイヌおよびウサギで使用されているものと同じかそれ以上の用量(0.1、0.5mg/kg)の静脈内ボーラスを投与し、ウサギと同様の調製物を用いて試験した。その結果により、高用量でも、PDE1Aを優勢に発現するマウスの心臓が有意な血行動態や心臓の変化を示さなかったことが示された。
実施例1〜3の試験は、我々の実験モデルでは、ヒトに存在する条件であるLV心筋におけるPDE1Cの顕著な発現を必要とする、高度に選択的なPDE1阻害剤(化合物1)からの強力な心血管効果を明らかにした。主にPDE1Aを発現するマウスでは無視できる反応が観察された。これは、大型哺乳動物におけるPDE1阻害による心血管効果についての初めての報告であり、この結果はトランスレーショナルな関連性があると考えられる。化合物1は、全身の血管拡張はあるが、最小限の静脈拡張を伴い、収縮力およびルシトロピー(10μg/kg/分のドブタミンと同様)を増加させることが判明した。その結果、動脈収縮期血圧を変化させることなく、心拍出量が純増する。in vivoでのβAR刺激とは異なり、PDE1阻害は血漿cAMPを上昇させず、その効果はβAR遮断によって抑制されるのではなく、A2BR阻害によって阻止される。これらの変化は心拍数の高速化と関連しているが、心不全によって心拍数の変化が鈍化し、エスモロールまたは定速ペーシングによって遮断されるため、それによって駆動されるものではないが、イノトロピック/血管拡張薬作用は持続する。ウサギの筋細胞のデータは、PDE1がAC刺激されたcAMPを制御して収縮およびカルシウムトランジェント崩壊の速度を変更することを示しているが、ピークカルシウムを変更しない;後者はまた、βAR刺激とは異なる。以上のことから、化合物1のプロファイルおよびHFモデルにおけるその有効性は、臨床的な可能性を持つ新規のメカニズムを示している。
ウサギの筋細胞を単離して、心筋細胞の収縮および全細胞のCa2+トランジェントに対するPDE1阻害の効果を決定し、PDE3阻害剤シロスタミド(Cil、1μM)との結果を比較した。Cilで処理した細胞では、サルコメアの短縮率およびピークCa2+トランジェントが上昇し、それらの崩壊速度が加速されましたが、これは化合物1(1μM)では観察されなかった。
Claims (23)
- イノトロピックおよび/またはルシトロピック機能不全によって特徴づけられる疾患または状態の治療、緩和または予防においてアデノシンA2受容体アゴニストの効果を増強する方法および/またはアデノシンA2受容体機能障害によって特徴づけられる疾患または状態の治療、緩和または予防においてアデノシンA2受容体機能を増強する方法であって、これを必要とする患者にPDE1阻害剤の有効量を投与することを含む、方法。
- PDE1阻害剤が、
A) エナンチオマー、ジアステレオ異性体およびラセミ体を含む、遊離形態、塩形態またはプロドラッグ形態の、式I':
(i)R1は、HまたはC1-4アルキル(例えば、メチル)であり;
(ii)R4は、HまたはC1-4アルキルであり、R2およびR3は、独立して、HまたはC1-4アルキル(例えば、R2およびR3は共にメチルであるか、またはR2はHであり、R3はイソプロピルである)、アリール、ヘテロアリール、(場合によってはヘテロ)アリールアルコキシ、または(場合によってはヘテロ)アリールアルキルであるか;または
R2はHであり、R3およびR4は一緒になってジ−、トリ−またはテトラメチレン架橋を形成し(好ましくはR3およびR4が一緒になってシス配置を有しており、例えば、R3およびR4を担持する炭素はそれぞれR配置およびS配置を有する);
(iii)R5は、例えばハロアルキルで置換されている、置換ヘテロアリールアルキルであるか;または
R5は、式Iのピラゾロ部分の窒素の1つに結合しており、式A:
で示される部分であり;
(iv)R6は、H、アルキル、アリール、ヘテロアリール、アリールアルキル(例えば、ベンジル)、アリールアミノ(例えば、フェニルアミノ)、ヘテロアリールアミノ、N,N−ジアルキルアミノ、N,N−ジアリールアミノ、またはN−アリール−N−(アリールアルキル)アミノ(例えば、N−フェニル−N−(1,1'−ビフェン−4−イルメチル)アミノ)であり;
(v)nは0または1であり;
(vi)nが1である場合、Aは、−C(R13R14)−であり、
ここで、R13およびR14は、独立して、HまたはC1-4アルキル、アリール、ヘテロアリール、(場合によってはヘテロ)アリールアルコキシまたは(場合によってはヘテロ)アリールアルキルである]
で示される化合物;
B) 遊離形態、塩形態またはプロドラッグ形態の、式II':
(i)Xは、C1-6アルキレン(例えば、メチレン、エチレンまたはプロパ−2−イン−1−イレン)であり;
(ii)Yは、単結合、アルキニレン(例えば、−C≡C−)、アリーレン(例えば、フェニレン)またはヘテロアリーレン(例えば、ピリジレン)であり;
(iii)Zは、H、アリール(例えば、フェニル)、ヘテロアリール(例えば、ピリジル、例えば、ピリダ−2−イル)、ハロ(例えば、F、Br、Cl)、ハロC1-6アルキル(例えば、トリフルオロメチル)、−C(O)−R1、−N(R2)(R3)、またはNもしくはOからなる群から選択される少なくとも1個の原子を含有していてもよいC3-7シクロアルキル(例えば、シクロペンチル、シクロヘキシル、テトラヒドロ−2H−ピラン−4−イル、またはモルホリニル)であり;
(iv)R1は、C1-6アルキル、ハロC1-6アルキル、−OHまたは−OC1-6アルキル(例えば、−OCH3)であり;
(v)R2およびR3は、独立して、HまたはC1-6アルキルであり;
(vi)R4およびR5は、独立して、H、C1-6アルキルまたはアリール(例えば、フェニル)(これは、1個以上の、ハロで置換されていてもよい(例えば、フルオロフェニル、例えば、4−フルオロフェニル)、ヒドロキシで置換されていてもよい(例えば、ヒドロキシフェニル、例えば、4−ヒドロキシフェニルまたは2−ヒドロキシフェニル)またはC1-6アルコキシで置換されていてもよい)であり;
(vii)ここで、X、YおよびZは、独立して、1個以上の、ハロ(例えば、F、ClまたはBr)、C1-6アルキル(例えば、メチル)、ハロC1-6アルキル(例えば、トリフルオロメチル)で置換されていてもよく、例えば、Zは、1個以上の、ハロ(例えば、6−フルオロピリダ−2−イル、5−フルオロピリダ−2−イル、6−フルオロピリダ−2−イル、3−フルオロピリダ−2−イル、4−フルオロピリダ−2−イル、4,6−ジクロロピリダ−2−イル)、ハロC1-6アルキル(例えば、5−トリフルオロメチルピリダ−2−イル)またはC1-6−アルキル(例えば、5−メチルピリダ−2−イル)で置換されている、ヘテロアリール、例えばピリジルであるか、またはZは、1個以上のハロ(例えば、4−フルオロフェニル)で置換されている、アリール、例えばフェニルである]
で示される化合物;
C) 遊離形態または塩形態の、式III':
(i)R1は、HまたはC1-4アルキル(例えば、メチルまたはエチル)であり;
(ii)R2およびR3は、独立して、HまたはC1-6アルキル(例えば、メチルまたはエチル)であり;
(iii)R4は、HまたはC1-4アルキル(例えば、メチルまたはエチル)であり;
(iv)R5は、独立して、−C(=O)−C1-6アルキル(例えば、−C(=O)−CH3)およびC1-6−ヒドロキシアルキル(例えば、1−ヒドロキシエチル)から選択される1個以上の基で置換されていてもよいアリール(例えば、フェニル)であり;
(v)R6およびR7は、独立して、H、または独立してC1-6アルキル(例えば、メチルまたはエチル)およびハロゲン(例えば、FまたはCl)から選択される1個以上の基で置換されていてもよいアリール(例えば、フェニル)であり、例えば、非置換フェニル、または1個以上のハロゲン(例えば、F)で置換されているフェニル、または1個以上のC1-6アルキルおよび1個以上のハロゲンで置換されているフェニル、または1個のC1-6アルキルおよび1個のハロゲンで置換されているフェニル、例えば4−フルオロフェニルまたは3,4−ジフルオロフェニルまたは4−フルオロ−3−メチルフェニルであり;
(vi)nは、1、2、3または4である]
で示される化合物;または
D) 遊離形態または塩形態の、式IV':
(vi)R1は、C1-4アルキル(例えば、メチルまたはエチル)、または−NH(R2)であり、ここで、R2は、ハロ(例えば、フルオロ)で置換されていてもよいフェニル、例えば4−フルオロフェニルであり;
(vii)X、YおよびZは、独立して、NまたはCであり;
(viii)R3、R4およびR5は、独立して、HまたはC1-4アルキル(例えば、メチル)であるか;またはR3はHであり、R4およびR5は一緒になってトリメチレン橋を形成し(好ましくはR4およびR5が一緒になってシス配置を有しており、例えば、R4およびR5を担持する炭素はそれぞれR配置およびS配置を有する)、
(ix)R6、R7およびR8は、独立して、
H、
C1-4アルキル(例えば、メチル)、
ヒドロキシで置換されているピリダ−2−イル、または
−S(O)2−NH2であり;
ただし、X、Yおよび/またはZがNである場合、それぞれ、R6、R7および/またはR8は存在せず;また、X、YおよびZが全てCである場合、R6、R7またはR8のうち少なくとも1つは、−S(O)2−NH2、またはヒドロキシで置換されているピリダ−2−イルである]
で示される化合物
のうちの1つである、請求項1記載の方法。 - PDE1阻害剤が、
a) 遊離形態または薬学的に許容される塩形態、例えば一リン酸塩形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン;
b) 遊離形態または薬学的に許容される塩形態の7,8−ジヒドロ−2−(4−アセチルベンジル)−3−(4−フルオロフェニルアミノ)−5,7,7−トリメチル−[2H]−イミダゾ−[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン;および
c) 遊離形態または薬学的に許容される塩形態の3−((4−フルオロフェニル)アミノ)−5,7,7−トリメチル−2−((2−メチルピリミジン−5−イル)メチル)−7,8−ジヒドロ−2H−イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン
から選択される、請求項1または2記載の方法。 - 疾患または状態が、狭心症、脳卒中、腎不全、本態性高血圧症、肺高血圧症、二次性高血圧症、孤立性収縮期高血圧症、糖尿病関連高血圧症、アテローム性動脈硬化症関連高血圧症、腎血管性高血圧症、うっ血性心不全、炎症性疾患または障害、線維症、心肥大、血管リモデリング、結合組織疾患または障害(例えば、マルファン症候群)、慢性心不全、心筋虚血、心筋低酸素症、再灌流傷害、左室機能不全(例えば、心筋梗塞、心室拡張)、血管漏出(すなわち、低酸素症の結果として生じる))、筋ジストロフィー(例えば、デュシェンヌ型筋ジストロフィー)、または筋萎縮性側索硬化症、慢性心不全、心筋炎症、線維症、心筋虚血、心筋低酸素症、再灌流傷害、左室機能不全(例えば、心筋梗塞、心室拡張)、血管漏出(すなわち、低酸素症の結果として生じる)、急性血管炎症(すなわち、血管損傷の結果として生じる)、または心肥大である、いずれかの上記請求項に記載の方法。
- 治療されるべき疾患または状態が心不全である、いずれかの上記請求項に記載の方法。
- PDE1阻害剤が、アデノシンA2アゴニスト、βアドレナリン受容体アンタゴニスト(すなわち、β遮断薬);ACE阻害剤;ネプリライシン阻害剤;抗高リポタンパク血症薬(例えば、アリールオキシアルカン酸/フィブリン酸誘導体、レジン/胆汁酸捕捉剤、HMG−CoA還元酵素阻害剤、ニコチン酸誘導体、甲状腺ホルモンまたは甲状腺ホルモンアナログまたはそれらの組合せ);抗動脈硬化症薬(例えば、ピリジノールカルバメート);グアニル酸シクラーゼ活性化薬;抗血栓薬および/または線維素溶解薬(例えば、抗凝固薬、抗凝固薬アンタゴニスト、血小板凝集阻害薬、血栓溶解薬、血栓溶解薬アンタゴニスト);血液凝固薬(例えば、血栓溶解薬アンタゴニストおよび抗凝固薬アンタゴニスト);抗不整脈薬(例えば、ナトリウムチャネル遮断薬、再分極延長薬、カルシウムチャネル遮断薬);抗高血圧薬(例えば、交感神経遮断薬、α/β遮断薬、α遮断薬、抗アンジオテンシンII薬、β遮断薬、カルシウムチャネル遮断薬、血管拡張薬);アリールエタノールアミン誘導体;ベンゾチアジアジン誘導体;N−カルボキシアルキル(ペプチド/ラクタム)誘導体;ジヒドロピリジン誘導体;グアニジン誘導体;ヒドラジン/フタラジン;イミダゾール誘導体;四級アンモニウム化合物;レセルピン誘導体;スルホンアミド誘導体;血管収縮剤;利尿剤;強心薬;抗狭心症薬またはそれらの組合せから選択される別の治療薬と組み合わせて投与される、上記方法のいずれか。
- イノトロピックおよび/またはルシトロピック機能不全によって特徴づけられる疾患または状態の治療、緩和または予防においてアデノシンA2受容体アゴニストの効果を増強する方法を含み、アデノシンA2受容体アゴニストが、アデノシンA2B受容体アゴニストであり、該効果が、PDE1によるcAMPの分解を阻害することによって環状ヌクレオチドのアデノシンA2媒介上昇を増強または延長することである、上記方法のいずれか。
- アデノシンA2受容体アゴニストが内在性アデノシンを含む、請求項7記載の方法。
- アデノシンA2受容体機能障害によって特徴づけられる疾患または状態の治療、緩和または予防においてアデノシンA2受容体機能を増強することを含み、該アデノシンA2受容体機能障害が、(i)内在性アデノシンに対するアデノシンA2B受容体の反応性の低下および/または(ii)心臓損傷または心不全に応答した内在性アデノシンの放出および/または産生の低下によって特徴づけられる、いずれかの上記請求項に記載の方法。
- PDE1阻害剤が、0.01mg/kg〜10mg/kgの濃度で投与される、いずれかの上記請求項に記載の方法。
- 患者がヒトであり、PDE1阻害剤が経口一日量1〜10mgで投与される、いずれかの上記請求項に記載の方法。
- 患者がヒトであり、PDE1阻害剤が経口一日量0.5〜20mg、例えば1〜10mgで投与され、PDE1阻害剤が、
a) 遊離形態または薬学的に許容される塩形態、例えば一リン酸塩形態の(6aR,9aS)−5,6a,7,8,9,9a−ヘキサヒドロ−5−メチル−3−(フェニルアミノ)−2−((4−(6−フルオロピリジン−2−イル)フェニル)メチル)−シクロペント[4,5]イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(2H)−オン;
b) 遊離形態または薬学的に許容される塩形態の7,8−ジヒドロ−2−(4−アセチルベンジル)−3−(4−フルオロフェニルアミノ)−5,7,7−トリメチル−[2H]−イミダゾ−[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン;および
c) 遊離形態または薬学的に許容される塩形態の3−((4−フルオロフェニル)アミノ)−5,7,7−トリメチル−2−((2−メチルピリミジン−5−イル)メチル)−7,8−ジヒドロ−2H−イミダゾ[1,2−a]ピラゾロ[4,3−e]ピリミジン−4(5H)−オン
から選択される、請求項11記載の方法。 - イノトロピックおよび/またはルシトロピック機能不全によって特徴づけられる疾患または状態の治療、緩和または予防におけるアデノシンA2受容体アゴニストの効果の増強、および/またはアデノシンA2受容体機能障害によって特徴づけられる疾患または状態の治療、緩和または予防におけるアデノシンA2受容体機能の増強において用いるための、単独の活性薬剤としての、または1つ以上のさらなる治療薬との医薬組合せにおける、PDE1阻害剤。
- 方法1以降よび方法2以降から選択される方法、ならびに組合せ1以降から選択される医薬組合せを包含する、特に実施例を参照する、本明細書の先に記載の全ての方法およびプロダクト。
- 心毒性を治療、緩和または予防する方法であって、これを必要とする患者にPDE1阻害剤の有効量を投与することを含む、方法。
- PDE1阻害剤の投与が、アデノシンA2シグナル伝達を増強するのに有効な量で投与される、請求項15記載の方法。
- PDE1阻害剤の投与が、アデノシンA2AまたはアデノシンA2Bの発現の増加を誘発する、請求項16記載の方法。
- 心毒性が、心毒性治療または薬の投与の結果として生じる、請求項15〜17のいずれかに記載の方法。
- 心毒性治療または薬が、放射線療法および/または化学療法剤である、請求項18記載の方法。
- 心毒性治療が化学療法剤である、請求項19記載の方法。
- 化学療法剤が、ダウノルビシン、ドキソルビシン、エピルビシン、イダルビシン、バルルビシン、シクロホスファミド、イホスファミド、シスプラチン、カルムスチン、ブスルファン、クロルメチン、マイトマイシン、パクリタキセル、エトポシド、テニポシド、ビンカアルカロイド、フルオロウラシル、シタラビン、アムサクリン、クラドリビン、アスパラギナーゼ、トレチノインおよび/またはペントスタチンである、請求項20記載の方法。
- 心毒性治療が放射線療法である、請求項18記載の方法。
- 心毒性の治療、緩和または予防のための医薬組合せであって、PDE1阻害剤の有効量と、例えばアンジオテンシン変換酵素(ACE)阻害剤、アンジオテンシン受容体遮断薬(ARB)、β遮断薬(例えば、カルベジロールまたはネビボロール)、および鉄キレート剤(例えば、デクスラゾキサン)から選択される、1つ以上のさらなる心保護薬を含む医薬組合せ。
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CN113244395A (zh) * | 2020-02-10 | 2021-08-13 | 广州市妇女儿童医疗中心 | 纤维化疾病机制及其治疗药物 |
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US20210205307A1 (en) | 2021-07-08 |
JP7401442B2 (ja) | 2023-12-19 |
US11839614B2 (en) | 2023-12-12 |
EP3746081A1 (en) | 2020-12-09 |
US20200289519A1 (en) | 2020-09-17 |
US20240091232A1 (en) | 2024-03-21 |
WO2019152697A1 (en) | 2019-08-08 |
US11759465B2 (en) | 2023-09-19 |
US20230338385A1 (en) | 2023-10-26 |
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