JP6787926B2 - 肺高血圧症の治療方法 - Google Patents
肺高血圧症の治療方法 Download PDFInfo
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- JP6787926B2 JP6787926B2 JP2017555438A JP2017555438A JP6787926B2 JP 6787926 B2 JP6787926 B2 JP 6787926B2 JP 2017555438 A JP2017555438 A JP 2017555438A JP 2017555438 A JP2017555438 A JP 2017555438A JP 6787926 B2 JP6787926 B2 JP 6787926B2
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- 239000010452 phosphate Substances 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- IENZFHBNCRQMNP-UHFFFAOYSA-N prx-08066 Chemical compound C1=C(C#N)C(F)=CC=C1CN1CCC(NC=2C=3C=C(Cl)SC=3N=CN=2)CC1 IENZFHBNCRQMNP-UHFFFAOYSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 210000003492 pulmonary vein Anatomy 0.000 description 1
- 230000010349 pulsation Effects 0.000 description 1
- 150000003218 pyrazolidines Chemical class 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000008584 quinuclidines Chemical class 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- WEMQMWWWCBYPOV-UHFFFAOYSA-N s-indacene Chemical compound C=1C2=CC=CC2=CC2=CC=CC2=1 WEMQMWWWCBYPOV-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000013275 serotonin uptake Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000008117 stearic acid Chemical group 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960004558 terguride Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 230000009424 thromboembolic effect Effects 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
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 229960005032 treprostinil Drugs 0.000 description 1
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
「アルキル」または「アルカニル」は、親アルカンの単一炭素原子からの1個の水素原子の除去によって誘導された飽和、分枝もしくは直鎖、または環式一価炭化水素ラジカルを指す。典型的なアルキル基には、メチル;エチル;プロパン−1−イル、プロパン−2イル、シクロプロパン−1−イル等のプロピル;ブタン−1−イル、ブタン−2−イル、2−メチル−プロパン−1−イル、2−メチル−プロパン−2−イル、シクロブタン−1−イル等のブチル等が含まれるが、これらに限定されない。好ましくは、アルキル基は、1〜20個の炭素原子、より好ましくは、1〜10個、または1〜6個、または1〜4個の炭素原子を含む。
式(I)の化合物は、本発明に有用である。
Aは、−(CH2)n−、−O−(CH2)n−、−S−(CH2)n−、−S(O)(O)−(CH2)n−、−NH−(CH2)n−、
−CH2−O−(CH2)n−、−(CH2)n−O−CH2−CH2−、−CH2−S−(CH2)n−、−(CH2)n−S−CH2−CH2−、
−CH2−S(O)(O)−(CH2)n−、−(CH2)n−S(O)(O)−CH2−CH2−、−O−C(O)−(CH2)n−、
−S−C(O)−(CH2)n−、−NH−C(O)−(CH2)n−、−CH2−C(O)−O−(CH2)n−、
−CH2−C(O)−NH−(CH2)n−、−CH2−C(O)−S−(CH2)n−、−(CH2)n−C(O)−O−CH2−CH2−、
−(CH2)n−C(O)−NH−CH2−CH2−、−(CH2)n−C(O)−S−CH2−CH2−、
−CH2−O−C(O)−(CH2)n−、−CH2−NH−C(O)−(CH2)n−、−CH2−S−C(O)−(CH2)n−、
−(CH2)n−O−C(O)−CH2−CH2−、(CH2)n−NH−C(O)−CH2−CH2−、または
(CH2)n−S−C(O)−CH2−CH2−であり、式中、nは、1〜7の整数であり、好ましくは、nは、2〜5であり、例えば、nは、4であり、
Bは、O、S、S(O)(O)、またはNR5であり、
R1、R2、R3、R4、R5、R6、R7、及びR8の各々は、独立して、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル、置換シクロヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、置換ヘテロアリールアルキル、アシルアルキルオキシカルボニル、アシルオキシアルキルオキシカルボニル、アシルアルキルオキシカルボニルアミノ、アシルオキシアルキルオキシカルボニルアミノ、アルコキシ、アルコキシカルボニル、アルコキシカルボニルアルコキシ、アルコキシカルボニルアルキルアミノ、アルキルスルフィニル、アルキルスルホニル、アルキルチオ、アミノ、アルキルアミノ、アリールアルキルアミノ、ジアルキルアミノ、アリールアルコキシ、アリールアルコキシカルボニルアルコキシ、アリールアルコキシカルボニルアルキルアミノ、アリールオキシカルボニル、アリールオキシカルボニルアルコキシ、アリールオキシカルボニルアルキルアミノ、カルボキシ、カルバモイル、カルバメート、カーボネート、シアノ、ハロ、ヘテロアリールオキシカルボニル、ヒドロキシ、ホスフェート、ホスホネート、サルフェート、スルホネート、もしくはスルホンアミド(式中、R1、R2、R3、R4、R5、R6、R7、及びR8、ならびにAは、任意に、2H(重水素)、3H(トリチウム)、13C、36Cl、18F、15N、17O、18O、31P、32P、及び35Sが含まれるが、これらに限定されない同位体で置換され得、2H(重水素)が好ましい)、
またはその薬学的に許容される塩、ラセミ体、もしくはジアステレオマー混合物である。
本発明は、肺高血圧症(肺内の高い血圧)の治療方法を対象とする。本方法は、有効量の式Iの化合物を、肺高血圧症に罹患している患者に投与するステップを含む。式Iの化合物は、患者の肺動脈(心臓から肺につながる血管)内の血圧を低下させ、肺動脈高血圧症を治療することができる。この治療はまた、息切れ、疼痛危機、肺炎等の疾患合併症を低減し、生存率を高めることができる。
本発明は、肺高血圧症を治療するための薬学的製剤を対象とする。薬学的製剤は、治療上有効な量の式Iの1つ以上の化合物を、好ましくは精製形態で、好適な量の薬学的に許容されるビヒクルと一緒に含有する。患者に投与される場合、薬学的製剤は、好ましくは無菌である。水は、本発明の化合物が静脈内投与される場合に好ましいビヒクルである。生理食塩水、及び水性デキストロース、及びグリセロール溶液は、液体ビヒクルとして、特に注射液に用いることもできる。好適な薬学的ビヒクルはまた、デンプン、グルコース、ラクトース、スクロース、ゼラチン、麦芽、米、小麦粉、チョーク、シリカゲル、ステアリン酸ナトリウム、モノステアリン酸グリセロール、タルク、塩化ナトリウム、乾燥脱脂乳、グリセロール、プロピレン、グリコール、水、エタノール等の賦形剤も含む。本薬剤またはpH緩衝剤。加えて、補助剤、安定剤、増粘剤、湿潤剤、及び着色剤が使用されてもよい。
投与される式Iの化合物の量は、他の因子の中で、治療される対象、及び対象の体重、病気の重症度、投与方法、及び処方する医師の判断に依存する。例えば、投薬量は、薬学的組成物中で、単回投与によって、複数適用または制御放出によって送達され得る。一実施形態において、本発明の化合物は、経口徐放投与によって送達される。一実施形態において、本発明の化合物は、1日2回、好ましくは1日1回投与される。投薬は、断続的に繰り返されてもよく、単独で、または他の薬物との複合で提供されてもよく、また病状もしくは障害の有効な治療に必要な限り長く継続してもよい。
本発明のある特定の実施形態において、本発明の化合物は、少なくとも1つの他の治療剤との複合療法で使用され得る。式Iの化合物及び治療剤は、付加的または相乗的に作用し得る。一実施形態において、式Iの化合物は、式Iの化合物の同じ組成物の一部であり得る、別の治療剤の投与と同時に投与される。別の実施形態において、本発明の化合物を含む組成物は、別の治療剤の投与前または後に投与される。
式(I)の2つのアリールピペラジン誘導体を、インビトロ薬理学的アッセイにおいて試験して、ドーパミン、D2s、セロトニン、5−HT1A、5−HT2A、5−HT2B、5−HT6、及び5−HT7受容体に対するそれらの活性を評価した。インビトロアッセイプロトコル及び参考文献は、本明細書に記載される。
材料及び方法:
受容体起源: ヒト組み換えD2sを発現した哺乳類細胞
放射性リガンド: [3H]スピペロン(20〜60Ci/mmol)または[3 H]−7−ヒドロキシDPAT、1.0nM
対照化合物: ハロペリドールまたはクロルプロマジン
インキュベーション条件:反応は、120mM NaCl、5mM KCl、5mM MgCl2、1mM EDTAを含有する50mM TRIS−HCl(pH7.4)中、25℃で60分間実行した。ガラスファイバーフィルター上への急速真空濾過によって、反応を終了させた。試験化合物の、クローン化ドーパミン−D2短結合部位との任意の相互作用を確認するために、フィルターの上に捕捉された放射活性を判定し、対照値と比較した(参考文献:Jarvis,K.R.et al.Journal of Receptor Research 1993,13(1−4),573−590、Gundlach,A.L.et al.Life Sciences 1984,35,1981−1988)。
材料及び方法:
受容体起源: ヒト組み換え5−HT1Aを発現した哺乳類細胞
放射性リガンド: [3H]−8−OH−DPAT(221Ci/mmol)
対照化合物: 8−OH−DPAT
インキュベーション条件:反応は、10mM MgSO4、0.5mM EDTA、及び0.1%アスコルビン酸を含有する50mM TRIS−HCl(pH7.4)中、室温で1時間実行した。ガラスファイバーフィルター上への急速真空濾過によって反応を終了させた。試験化合物の、クローン化セロトニン−5HT1A結合部位との任意の相互作用を確認するために、フィルターの上に捕捉された放射活性を判定し、対照値と比較した(参考文献:Hoyer,D.et al.Eur.Journal Pharmacol.1985,118,13−23、Schoeffter,P.and Hoyer,D.Naunyn−Schmiedeberg′s Arch.Pharmac.1989,340,135−138)
材料及び方法:
受容体起源: ヒト皮質またはヒト組み換え5−HT2Aを発現した哺乳類細 胞
放射性リガンド: [3H]−ケタンセリン(60〜90Ci/mmol)
対照化合物: ケタンセリン
インキュベーション条件:反応は、50mM TRIS−HCl(pH7.6)中、室温で90分間実行した。ガラスファイバーフィルター上への急速真空濾過によって反応を終了させた。試験化合物の、セロトニン−5HT2A結合部位との任意の相互作用を確認するために、フィルターの上に捕捉された放射活性を判定し、対照値と比較した(参考文献:Leysen,J.E.et al.Mol.Pharmacol.1982,21,301−314、Martin,G.R.and Humphrey,P.P.A.Neuropharmacol.1994,33(3/4),261−273)。
材料及び方法:
受容体起源: ヒト組み換え5−HT2Bを発現したCHO−K1細胞
放射性リガンド: 1.20nM[3H]リゼルグ酸ジエチルアミド(LSD)
対照化合物: ケタンセリン
インキュベーション条件:反応は、50mM TRIS−HCl(pH7.6)中、室温で90分間実行した。ガラスファイバーフィルター上への急速真空濾過によって反応を終了させた。試験化合物の、セロトニン−5HT2B結合部位との任意の相互作用を確認するために、フィルターの上に捕捉された放射活性を判定し、対照値と比較した。
材料及び方法:
受容体起源: ヒト組み換え5−HT6を発現した哺乳類細胞
放射性リガンド: [125I]SB258585、15nMまたは[3H]
LSD、2nM
対照化合物: メチオテピンまたはセロトニン
インキュベーション条件:反応は、10mM MgSO4、0.5mM EDTA、及び0.1%アスコルビン酸を含有する50mM TRIS−HCl(pH7.4)中、室温で1時間実行した。ガラスファイバーフィルター上への急速真空濾過によって反応を終了させた。試験化合物の、クローン化セロトニン−5HT6結合部位との任意の相互作用を確認するために、フィルターの上に捕捉された放射活性を判定し、対照値と比較した(参考文献:Gonzalo,R.,et al.,Br.J.Pharmacol.,2006(148),1133−1143)
材料及び方法:
受容体起源: ヒト組み換え5−HT7を発現したCHO細胞
放射性リガンド: [3H]リゼルグ酸ジエチルアミド(LSD)、4nM
対照化合物: セロトニン
インキュベーション条件:反応は、50mM TRIS−HCl(pH7.6)中、室温で90分間実行した。ガラスファイバーフィルター上への急速真空濾過によって反応を終了させた。試験化合物の、セロトニン−5HT7結合部位との任意の相互作用を確認するために、フィルターの上に捕捉された放射活性を判定し、対照値と比較した。
化合物 アッセイ Ki
A D2S 0.30nM
A 5−HT1A 0.65nM
A 5−HT2A 118nM
B D2S 0.62nM
B 5−HT1A 1.50nM
B 5−HT2A 2.50nM
B 5−HT2B 0.19nM
B 5−HT6 51nM
B 5−HT7 2.70nM
この研究の目的は、ラットにおけるモノクロタリン誘導型肺動脈高血圧症(PAH)に対する試験物品の効果を評価することであった。アッセイは、単一皮下用量のモノクロタリンによって誘導されたPAHを有する麻酔下のラットにおいて、肺及び全身動脈血圧を測定するように設計した。研究の結果は、疾患の進行及び肺動脈血圧(PAP)に対するその効果、ならびに試験物品または基準化合物による治療を行う場合と行わない場合の、誘導型PAHを有するラットにおける湿臓器重量の定量的測定である。更に、肺血管の組織学に関する詳細な形態計測及び臨床調査を行って、血管リモデリングを、PAHの発症の機能的影響と相関させた。
体重200〜250グラムの間の雄Wistar−Kyotoラット(Charles River Laboratories)(およそ10〜12週齢)を、それらの体重に従い、実験群にわたってランダム化し、末期手術の各日に1つの治療群当たり1匹の動物をスケジューリングすることを狙いとする(可能な場合)。この結果、各治療群からの動物が各手術日に手術されることになった。治療群2〜4からのラットは、0日目にDMSO中のモノクロタリン(MCT)溶液(60mg/kg)の皮下注入を1回受け、ケージに戻された。対照群1からのラットは、0日目にDMSO(モノクロタリンのビヒクル)の皮下注入を1回受け、それぞれのケージに戻された。5%グルコース溶液中の試験物品、化合物B(3mg/kg、10mg/kg)(1日2回)、基準化合物(シルデナフィル、50mg/kg、1日2回)、またはビヒクルでの治療を開始し、スケジュールどおり、表1に記載されるように、0日目に投与を開始した。食餌及び水は自由に与えた。動物の行動及び全般健康状態を毎日観察した。週1回の採血、体重及び体温を測定した。
この研究の目的は、ラットにおけるSugen−低酸素(SuHx)誘導型肺動脈高血圧症(PAH)に対する化合物B(試験物品)の効果を評価することである。アッセイは、低酸素で3週間と組み合わせた単一皮下用量のSugenによって誘導されたPAHを有する麻酔下のラットにおいて、肺動脈血圧を測定するように設計した。動物から採取された組織の巨視的及び形態測定的組織学試験と組み合わせて、の結果は、試験物品、ビヒクル、または基準化合物で治療されたSuHx誘導型PAHラットにおける、全身動脈血圧、肺動脈血圧、ならびに湿臓器重量に関する疾患の進行の定量的測定を提供する。
体重200〜250グラムの間の雄Wistar−Kyotoラット(Charles River Laboratories)(およそ10〜12週齢)を、それらの体重に従い、実験群にわたってランダム化し、末期手術の各日に1つの治療群当たり1匹のラットをスケジューリングすることを狙いとする(可能な場合)。この結果、各治療群からの動物が各手術日に手術されることになった。群2〜4からのラット(表3を参照されたい)は、0日目にDMSO中のsugen(20mg/kg)の単一皮下注入を受け、ケージに戻された。群1からのラットは、0日目にDMSO(sugenのビヒクル)の皮下注入を1回受け、それぞれのケージに戻された。群2〜4を、換気ケージシステムによって制御された窒素及び周囲空気の混合を使用して、0.10(10%)に等しいFiO2を受けるように制御された空気を調整したケージに入れた。ラットをこれらの低酸素条件下で21日間保持した。低酸素下で、ケージを清掃し、48時間毎に変えて、1回の清掃セッション毎に5分未満にわたって動物を周囲酸素レベルに曝露した。次いで、22日目〜35日目に、動物を周囲酸素レベルに曝露した。群1の動物は、周囲酸素レベルに曝露されたケージ内で35日間維持した。行動及び全般健康状態の任意の変化について、動物を毎日観察した。5%グルコース溶液中の試験物品化合物B(10mg/kg、20mg/kg)(1日2回)、基準化合物(シルデナフィル、50mg/kg、1日2回)、またはビヒクルでの治療を開始し、スケジュールどおり、表1に記載されるように、14日目に投与を開始した。食餌及び水は自由に与えた。動物の行動及び全般健康状態を毎日観察した。週1回の採血、及び体重測定を行った。手術の日に、ラットに麻酔をかけ、器具を装着し、血行動態パラメータ(全身動脈血圧、右室血圧、肺動脈血圧、酸素飽和、呼吸抵抗、換気圧、呼吸速度、及び心拍数)を、5分間継続的に、または肺動脈圧シグナルの質の損失まで、いずれか早い方を記録した。これらの記録は、右室腔から肺動脈に戻るまで圧力変換器を動かすことと、カテーテルが動脈に入り、室に引き込まれたときの拡張期圧及び全般圧力波形の非常に明らかな移行を観察することを含んでいた。次いで、ラットを失血させ、肺循環を0.9% NaClで洗い流した。気管支、肺、及び心臓全体を胸腔から除去した。10% NBFで灌流し、10%ホルマリンに浸漬する前に、肺の右葉及び左葉を計量した。肺は、10%ホルマリン中、室温で貯蔵した。心臓を切除し、フルトン指数計算の一部として、右室(RV)及び隔膜を含む左室(LV−S)の湿重量を測定した。
目的:この研究は、本発明の化合物が、肺高血圧症を有する患者において、肺動脈内の血圧を低下させることができるかどうかを調べる。この治療は、息切れ、疼痛危機、肺炎等の疾患合併症を低減し、生存率を高めることができるかどうかを示す。
患者は、少なくとも12歳であり、鎌状赤血球疾患及び肺高血圧症を有する。
1.18〜65歳の男性または女性対象
2.WHOのI群に属する以下の型の肺動脈高血圧症(PAH)を有する患者
○突発性(IPAH)
○遺伝性(HPAH)
○関連性(APAH)
●結合組織疾患
●薬物及び毒素
3.登録時に修正されたNYHA機能クラスIIIまたはIVのPAHを有し、注入可能なエポプロステノールを必要とする患者
4.患者は、注入可能なプロスタノイド治療にナイーブであり、
○新たに診断され、特定のPAH療法で治療されていないか、または
○以下の医薬品のうちの1つ以上で登録前の90日間、及び安定した用量で登録前の30日間にわたって、既存のバックグラウンドPAH療法で現在治療されているかのいずれかでなければならない。
●ボセンタン
●アンブリセンタン
●シルデナフィル
●タダラフィル
5.出産可能な女性は、信頼できる避妊法を使用しなければならない。
1.静脈内エポプロステノール投与または任意の血管収縮性静脈内薬物を含む緊急治療を必要とする、呼吸器及び/または心血管促拍を有する患者
2.既知の肺静脈閉塞性疾患(PVOD)
3.静脈内変力剤の現在の使用
4.120拍/分を超える心拍数を有する頻脈
5.包含基準において特定されるもの以外の任意の条件に関連する肺動脈高血圧症
6.ACT−385781Aの製剤またはその賦形剤のうちのいずれか、及びフロランまたはその賦形剤のうちのいずれかに対する既知の過敏症
7.スクリーニング前の週における吸入型イロプロストまたはトレプロスチニルの使用
8.スクリーニングの6ヶ月以内の心血管事象(例えば、一過性虚血発作または卒中)
9.心筋梗塞の病歴
10.以下のうちのいずれかを含む、左側心疾患の病歴
○血行動態的に重大な大動脈または僧帽弁疾患
○拘束性または充血性心筋症
○マルチゲート放射性ヌクレオチド血管造影図(MUGA)、血管造影法、または心電図による、40%未満の左室駆出分画
○不安定な狭心症
○致命的な心不整脈
11.慢性出血障害
12.調査者の記憶において、エポプロステノールの使用に禁忌を示す過去1ヶ月以内の感染(複数可)
13.妊娠または授乳
14.観察(非介入的)を除く別の臨床治験への参加、またはランダム化前30日以内の調査製品の受領
15.治療コンプライアンス、研究の遂行または結果の解釈に干渉し得る任意の既知の要因または疾患、例えば、薬物もしくはアルコール依存、または精神疾患
16.平均余命が12ヶ月未満のPAH以外の既知の付随する致命的疾患
相A(6週)肺血管抵抗
相B(16週)機能的改善
治療を開始する前に、患者は、出産年齢の女性の妊娠検査、胸部X線、患者が吸入及び吐出することができる空気の量を測定するための肺機能検査、心電図(心超音波)、運動能力を測定するための6分間歩行検査、生活の質アセスメント、及び疼痛インベントリを含むベースライン研究を受ける。患者は、治療を始める前に、高血圧の重症度を評価するために心臓カテーテルを受ける。
治療中、患者は以下について監視される。
●心臓カテーテルのフォローアップ:6週、心電図:6週及び16週。
●6分歩行検査:6週、10週、及び16週。
●体重、血圧、及び心拍数の測定:6週、10週、及び16週。
●出産年齢の女性の妊娠検査:6週、10週、及び16週。
●1日1回1週間にわたる疼痛質問票:6週及び10週。
●生活の質質問票:6週及び16週。
●6週及び16週目の不安症、抑鬱、及び認知機能バッテリー
●サイトカインをインターロイキンとして含む炎症としてのバイオマーカー変化
Claims (6)
- 前記化合物が、塩酸塩の形態を取る、請求項1に記載の薬学的組成物。
- 前記薬学的組成物が、薬学的に許容される担体、賦形剤、または希釈剤を含む、請求項1に記載の薬学的組成物。
- 前記化合物が、経口投与される、請求項1に記載の薬学的組成物。
- 肺動脈高血圧症を治療する、請求項1に記載の薬学的組成物。
- 慢性閉塞性肺疾患(COPD)、鎌状赤血球症(SCD)またはヒト免疫不全ウイルス(HIV)を有する対象における肺高血圧症を治療する、請求項1に記載の薬学的組成物。
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