JP2018536677A - てんかんおよび疼痛の治療において使用するための、GABA受容体モジュレーターとしての式(I)の4−(ビフェン−3−イル)−1H−ピラゾロ[3,4−c]ピリダジン誘導体 - Google Patents
てんかんおよび疼痛の治療において使用するための、GABA受容体モジュレーターとしての式(I)の4−(ビフェン−3−イル)−1H−ピラゾロ[3,4−c]ピリダジン誘導体 Download PDFInfo
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- PBJUNZJWGZTSKL-MRXNPFEDSA-N tiagabine Chemical compound C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C PBJUNZJWGZTSKL-MRXNPFEDSA-N 0.000 description 1
- 229960001918 tiagabine Drugs 0.000 description 1
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- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 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
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- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
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- 238000002054 transplantation Methods 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
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- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- IRYJRGCIQBGHIV-UHFFFAOYSA-N trimethadione Chemical compound CN1C(=O)OC(C)(C)C1=O IRYJRGCIQBGHIV-UHFFFAOYSA-N 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
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- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 229960004751 varenicline Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 description 1
- 229960005318 vigabatrin Drugs 0.000 description 1
- 229960001255 viloxazine Drugs 0.000 description 1
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- 230000008673 vomiting Effects 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- BPKIMPVREBSLAJ-QTBYCLKRSA-N ziconotide Chemical compound C([C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]2C(=O)N[C@@H]3C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC2)C(N)=O)=O)CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CSSC3)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(N1)=O)CCSC)[C@@H](C)O)C1=CC=C(O)C=C1 BPKIMPVREBSLAJ-QTBYCLKRSA-N 0.000 description 1
- 229960002811 ziconotide Drugs 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229960001360 zolmitriptan Drugs 0.000 description 1
- UTAZCRNOSWWEFR-ZDUSSCGKSA-N zolmitriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1C[C@H]1COC(=O)N1 UTAZCRNOSWWEFR-ZDUSSCGKSA-N 0.000 description 1
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- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
- 210000002517 zygapophyseal joint Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Xは、−S(O)2−および−C(O)−から選択され、
R1は、(C2〜C4)アルキル、(C3〜C5)シクロアルキルおよびメチル置換(C3〜C5)シクロアルキルから選択され、
R2は、H、F、Cl、OCH3およびCNから選択され、
R3は、H、F、CHF2、OCH3およびCNから選択され、
Xが−S(O)2−である場合、
R4は、(C1〜C4)アルキル、(C3〜C5)シクロアルキル、NH2およびNH(C1〜C4)アルキルから選択され、R5は、Hであるか、または
R4およびR5は一緒に、−CH2CH2−または−N(CH3)CH2−であり、
Xが、−C(O)−である場合、
R4は、NH2およびNH(C1〜C4)アルキルから選択され、R5は、Hであるか、または
R4およびR5は一緒に、−N(CH3)CH2−である]
または薬学的に許容できるその塩を提供する。
R1、R2およびR3は、請求項1に定義されているとおりであり、
R4は、(C1〜C4)アルキル、(C3〜C5)シクロアルキル、NH2およびNH(C1〜C4)アルキルから選択され、R5は、Hであるか、または
R4およびR5は一緒に、−CH2CH2−または−N(CH3)CH2−である]
または薬学的に許容できるその塩を提供する。
R1、R2およびR3は、請求項1において定義されるとおりであり、
R4は、NH2およびNH(C1〜C4)アルキルから選択され、R5は、Hであるか、または
R4およびR5は一緒に、−N(CH3)CH2−である]
または薬学的に許容できるその塩を提供する。
4−(4’−エタンスルホニル−6−フルオロ−2’−メトキシビフェニル−3−イル)−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン、
4−(4’−エタンスルホニル−6−フルオロビフェニル−3−イル)−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン、および
5−[5−(1−エチル−1H−ピラゾロ[3,4−c]ピリダジン−4−イル)−2−フルオロフェニル]−6−メトキシ−2−メチル−2,3−ジヒドロイソインドール−1−オン、
ならびに薬学的に許容できるその塩が含まれる。
(i)式(I)の化合物を所望の酸または塩基と反応させることによる方法;
(ii)所望の酸または塩基を使用して、式(I)の化合物の適切な前駆体から、酸または塩基に不安定な保護基を除去することによる方法;または
(iii)適切な酸もしくは塩基と反応させることにより、または適切なイオン交換カラムを用いて、式(I)の化合物のある塩を別の塩に変換することによる方法。
・例えば、以下でさらに検討するとおり、急性疼痛、慢性疼痛、神経障害性疼痛、侵害受容性(炎症性を含む)疼痛、体性疼痛、内臓疼痛、および機能障害性疼痛を含めた疼痛を治療するための、ならびに特に、根底にある機序に脳または脊髄成分が存在する疼痛状態のための鎮痛薬として;
・例えば、Lennox−Gastaut症候群、Dravet病、および熱性発作陽性(GEFS+)の全身てんかんを含めたてんかんおよびてんかん関連障害を治療するための抗痙攣薬として;
・例えば、パニック障害、全般性不安障害、心的外傷後ストレス障害、急性ストレス障害および物質誘発性ストレス障害などのストレス障害、広場恐怖症、社会恐怖症および動物恐怖症などの恐怖症、ならびに強迫性障害を治療するための抗不安薬として;ならびに
・例えば、筋肉痙攣、ジストニア、痙縮(全身および限局性痙縮を含む)および本態性振戦を治療するための筋弛緩薬として使用することができる。
・WO2008/118758に開示されている化合物などの選択的Nav1.3チャネルモジュレーター;
・WO2010/079443に開示されている化合物などの選択的Nav1.7チャネルモジュレーター、例えば、4−[2−(5−アミノ−1H−ピラゾール−4−イル)−4−クロロフェノキシ]−5−クロロ−2−フルオロ−N−1,3−チアゾール−4−イルベンゼンスルホンアミドもしくは4−[2−(3−アミノ−1H−ピラゾール−4−イル)−4−(トリフルオロメチル)フェノキシ]−5−クロロ−2−フルオロ−N−1,3−チアゾール−4−イルベンゼンスルホンアミド、または薬学的に許容できるいずれかの塩;
・選択的なNav1.8チャネルモジュレーター;
・選択的なNav1.9チャネルモジュレーター;
・ブピバカイン、カルバマゼピン、ラモトリジン、リドカイン、メキシレチンまたはフェニトインなどの非選択的モジュレーターを含めた、1種を超えるNavチャネルにおいて活性をモジュレートする化合物;
・NGFに結合して、NGFシグナル伝達により媒介されるNGF生物学的活性および/または下流の経路(複数可)を阻害する薬剤(例えば、タネズマブ)、TrkAアンタゴニストもしくはp75アンタゴニスト、またはNGF刺激TrkAまたはP75シグナル伝達に関する下流のシグナル伝達を阻害する薬剤などの神経成長因子(NGF)シグナル伝達の任意の阻害薬;
・その阻害が、(a)神経成長因子(NGF)(例えば、タネズマブ、ファシヌマブ(fasinumab)またはフルラヌマブ(fulranumab))、脳由来神経栄養因子(BDNF)、ニューロトロフィン−3(NT−3)もしくはニューロトロフィン−4(NT−4)に結合する薬剤、または1種を超える上述のニューロトロフィンに結合する薬剤(例えば、可溶性P75);または(b)オルソステリック部位においてか、アロステリック部位においてか、または受容体(複数可)の触媒活性の阻害により、TrKA、TrKB、TrKCまたはP75の1種または複数において受容体機能を阻害する薬剤により達成される神経栄養経路の阻害薬;
・脂肪酸アミドヒドロラーゼ阻害(FAAH)活性またはモノアシルグリセロールリパーゼ(MAGL)活性を有する化合物などの、エンドカンナビノイドのレベルを上昇させる化合物;
・鎮痛薬、特に、パラセタモール;
・ブプレノルフィン、ブトルファノール、コカイン、コデイン、ジヒドロコデイン、フェンタニール、ヘロイン、ヒドロコドン、ヒドロモルホン、レバロルファン レボルファノール、メペリジン、メタドン、モルヒネ、ナルメフェン、ナロルフィン、ナロキソン、ナルトレキソン、ナルブフィン、オキシコドン、オキシモルホン、プロポキシフェンまたはペンタゾシンなどのオピオイド鎮痛薬;
・TRV130など、ベータアレスチン動員とは対照的に、特異的細胞内経路、例えば、Gタンパク質を優先的に刺激するオピオイド鎮痛薬;ノルアドレナリン(ノルエピネフリン)再取り込み阻害(NRI)活性(例えば、タベンタドール);セロトニンおよびノルエピネフリン再取り込み阻害(SNRI)活性(例えば、トラマドール);またはノシセプチン受容体(NOP)アゴニスト活性(GRT6005など)などの追加の薬理を有するオピオイド鎮痛薬;
・非選択的シクロオキシゲナーゼ(COX)阻害薬などの非ステロイド系抗炎症薬(NSAID)、例えば、アスピリン、ジクロフェナク、ジフルシナル、エトドラク、フェンブフェン、フェノプロフェン、フルフェニサル、フルルビプロフェン、イブプロフェン、インドメタシン、ケトプロフェン、ケトロラック、メクロフェナム酸、メフェナム酸、メロキシカム、ナブメトン、ナプロキセン、ニメスリド、ニトロフルルビプロフェン、オルサラジン、オキサプロジン、フェニルブタゾン、ピロキシカム、スルファサラジン、スリンダク、トルメチンもしくはゾメピラク;またはCOX−2選択的阻害薬、例えば、セレコキシブ、デラコキシブ、エトリコキシブ、マヴァコキシブ(mavacoxib)またはパレコキシブ;
・プロスタグランジンE2サブタイプ4(EP4)アンタゴニスト;
・ミクロソームプロスタグランジンEシンテターゼ1型(mPGES−1)阻害薬;
・グルテチミド、メプロバメート、メタクワロンまたはジクロラールフェナゾンなどの鎮静薬;
・クロルジアゼポキシド、アルプラゾラム、ジアゼパム、ロラゼパム、オキサゼパム、テマゼパム、トリアゾラム、クロナゼパムまたはクロバザムなどの、ベンゾジアゼピン結合部位により媒介される幅広いサブタイプモジュレート効果を有するGABAAモジュレーター;
・TPA023、TPA023B、L−838,417、CTP354またはNSD72などの、有害作用の低減を伴う、ベンゾジアゼピン結合部位により媒介されるサブタイプ選択的モジュレート効果、例えば、鎮静を有するGABAAモジュレーター;
・バルビツレート、例えば、アモバルビタール、アプロバルビタール、ブタビタール(butabital)、メホバルビタール、メトヘキシタール、ペントバルビタール、フェノバルチタール(phenobartital)、セコバルビタール、またはチオペンタールなどの受容体上の代替的結合部位により作用するGABAAモジュレーター;アルファキサロン、アルファドロンまたはガナキソロン(ganaxolone)などの神経ステロイド;エチホキシンなどのβ−サブユニットリガンド;またはガボキサドール(gaboxadol)などのδ−選択的リガンド;
・GlyR3アゴニストまたは陽性アロステリックモジュレーター;
・骨格筋弛緩薬、例えば、バクロフェン、カリソプロドール、クロルゾキサゾン、シクロベンザプリン、メタキソロン(metaxolone)、メトカルバモールまたはオルフレナジン(orphrenadine);
・NMDA受容体アンタゴニストなどのグルタミン酸受容体アンタゴニストまたは陰性アロステリックモジュレーター、例えば、デキストロメトルファン、デキストロルファン、ケタミン、もしくはメマンチン;またはmGluRアンタゴニストもしくはモジュレーター;
・クロニジン、グアンファシンまたはデクスメタトミジン(dexmetatomidine)などのアルファ−アドレナリン作用薬;
・プロプラノロールなどのベータ−アドレナリン作用薬;
・三環系抗うつ薬、例えば、デシプラミン、イミプラミン、アミトリプチリンまたはノルトリプチリン;
・アプレピタントまたはマロピタント(maropitant)などのタキキニン(NK)アンタゴニスト;
・ムスカリン様アンタゴニスト、例えば、オキシブチニン、トルテロジン、プロピベリン、塩化トロプシウム(tropsium chloride)、ダリフェナシン、ソリフェナシン、テミベリンおよびイプラトロピウム;
・イスプロニクリン(TC−1734)、バレニクリンまたはニコチンなどのコリン作動性(ニコチン作動性)鎮痛薬;
・一過性受容体電位V1(TRPV1)受容体アゴニスト(例えば、レシンフェラトキシン(resinferatoxin)またはカプサイシン)またはアンタゴニスト(例えば、カプサゼピンまたはマヴァトラップ(mavatrap));
・一過性受容体電位A1(TRPA1)受容体アゴニスト(例えば、シンナムアルデヒドまたはカラシ油)またはアンタゴニスト(例えば GRC17536またはCB−625);
・一過性受容体電位M8(TRPM8)受容体アゴニスト(例えば、メントールまたはイシリン(icilin))またはアンタゴニスト;
・一過性受容体電位V3(TRPV3)受容体アゴニストまたはアンタゴニスト(例えば、GRC−15300);
・デキサメタゾンなどのコルチコステロイド;
・エレトリプタン、スマトリプタン、ナラトリプタン、ゾルミトリプタンまたはリザトリプタンなどの5−HT受容体アゴニストまたはアンタゴニスト、特に、5−HT1B/1Dアゴニスト;
・5−HT2A受容体アンタゴニスト;
・シルデナフィル、タダラフィルまたはバルデナフィルなどのPDEV阻害薬;
・ガバペンチン、ガバペンチンエナカルビルまたはプレガバリンなどのアルファ−2−デルタリガンド;
・セルトラリン、デメチルセルトラリン、フルオキセチン、ノルフルオキセチン、フルボキサミン、パロキセチン、シタロプラム、デスメチルシタロプラム、エスシタロプラム、d,l−フェンフルラミン、フェモキセチン、イフォキセチン(ifoxetine)、シアノドチエピン、リトキセチン(litoxetine)、ダポキセチン、ネファゾドン、セリクラミン(cericlamine)およびトラゾドンなどのセロトニン再取り込み阻害薬(SRI);
・マプロチリン、ロフェプラミン、ミルタゼピン(mirtazepine)、オキサプロチリン、フェゾラミン(fezolamine)、トモキセチン、ミアンセリン、ブプロプリオン、ブプロプリオン代謝産物ヒドロキシブプロプリオン、ノミフェンシンおよびビロキサジンなどのNRI、特に、レボキセチンなどの選択的ノルアドレナリン再取り込み阻害薬;
・ベンラファキシン、O−デスメチルベンラファキシン、クロミプラミン、デスメチルクロミプラミン、デュロキセチン、ミルナシプランおよびイミプラミンなどのSNRI;
・誘導型酸化窒素シンターゼ(iNOS)阻害薬;
・ロイコトリエンB4アンタゴニスト;
・ジロートンなどの5−リポキシゲナーゼ阻害薬;
・KCNQ/Kv7の開口薬または陽性モジュレーターなどのカリウムチャネル開口薬または陽性モジュレーター(例えば、レチガビンまたはフルピルチン)、サブファミリーA(例えば、Kv1.1)、サブファミリーB(例えば、Kv2.2)またはサブファミリーK(例えば、TASK、TREKまたはTRESK)のメンバーなどのGタンパク質共役型内向き整流性カリウムチャネル(GIRK)、カルシウム活性化カリウムチャネル(Kca)またはカリウム電位開口型チャネル;
・P2X3受容体アンタゴニスト(例えば、AF219)、またはP2X2/3ヘテロマー受容体などの、そのサブユニットの1つとしてP2X3サブユニットを含有する受容体のアンタゴニスト;
・ジコノチドなどのCaV2.2カルシウムチャネル遮断薬(N型);ならびに
・エトスクシミドなどのCaV3.2カルシウムチャネル遮断薬(T型)。
・フェナセミドまたはフェネトライドなどのアセチル尿素;
・ガバペンチンまたはプレガバリンなどのアルファ−2−デルタリガンド;
・バルベキサクロン、エテロバルブ、メホバルビタール、メタルビタールもしくはフェノバルビタールなどのバルビツレート、またはプリミドンなどのデオキシバルビツレート;
・クロバザム、クロナゼパムまたはニトラゼパムなどのベンゾジアゼピン;
・4−アミノ−3−ヒドロキシ酪酸、プロガビド、チアガビンまたはビガバトリンなどのガンマ−アミノ酪酸(GABA)類似体;
・カルバマゼピン、エスリカルバゼピン酢酸塩またはオキスカルバゼピンなどのイミノスチルベン;
・エトトイン、メフェニトイン、フェニトインまたはフェニトインナトリウムなどのヒダントイン;
・エタジオン、パラメタジオン、トロキシドンなどのオキサゾリジンジオン
・エトスクシミド、メスクシミドまたはフェンスクシミドなどのスクシンイミド
・バルプロアートナトリウム、バルプロ酸またはバルプロミドなどのバルプロアート;
・アセタゾラミド;ベクラミド、フェルバメート、ラコサミド、ラモトリジン、レベチラセタム、ミラセミド、ナフィミドン、ペランパネル、ピラセタム、レチガビン、ルフィナミド、スチリペントール、スルチアム、トピラマートまたはゾニサミド。
brは、ブロードであり;
℃は、摂氏温度であり
CDCl3は、重水素−クロロホルムであり;
CD3ODは、ペルジュウテロメタノールであり:
δは、化学シフトであり;
dは、二重線であり;
DCMは、ジクロロメタン;塩化メチレンであり;
ddは、二重−二重線であり;
dddは、二重−二重−二重線であり;
DMFは、N,N−ジメチルホルムアミドであり;
DMSO−d6は、ペルジュウテロ―ジメチルスルホキシドであり;
ELSDは、蒸発光散乱検出器であり;
EtOAcは、酢酸エチルであり;
EtOHは、エタノールであり;
gは、グラムであり;
HPLCは、高圧液体クロマトグラフィーであり;
Lは、リットルであり
LCMSは、液体クロマトグラフィー質量分析法(Rt=保持時間)であり;
mは、多重線であり;
Mは、モル濃度であり;
MeCNは、アセトニトリルであり;
MeOHは、メタノールであり;
mgは、ミリグラムであり;
MHzは、メガヘルツであり;
minは、分であり;
mLは、ミリリットルであり;
mmolは、ミリモルであり;
molは、モルであり;
MS m/zは、質量スペクトルピークであり;
NaHCO3は、炭酸水素ナトリウムであり;
Na2CO3は、炭酸ナトリウムであり;
NMRは、核磁気共鳴であり;
P(2−furyl)3は、トリス(2−フリル)ホスフィンであり
Pd(dba)2は、ビス(ジベンジリデンアセトン)パラジウム(0)であり;
Pd2(dba)3は、トリス(ジベンジリデンアセトン)ジパラジウム(0)であり;
Pd(PPh3)4は、テトラキス(トリフェニルホスフィン)パラジウム(0)であり;
pHは、水素イオン指数であり;
ppmは、百万分率であり;
qは、四重線であり;
sは、一重線であり;
tは、三重線であり;
TEAは、トリメチルアミンであり;
THFは、テトラヒドロフランであり;
TLCは、薄層クロマトグラフィーであり;
μLは、マイクロリットルであり;
μmolは、マイクロモルである。
4−(3−ブロモ−4−フルオロフェニル)−3,6−ジクロロピリダジン
市販用に調製された2,2,6,6−ビス(テトラメチルピペリジン)亜鉛リチウムクロリド錯体の溶液(0.35M、41mL、14.3mmol)を、THF(24mL)中の3,6−ジクロロピリダジン(2g、13mmol)の溶液でゆっくり処理し、混合物を室温で30分間撹拌した。THF(24mL)中のPd(dba)2(225mg、0.39mmol)、P(2−フリル)3(181mg、0.78mmol)、および3−ブロモ−4−フルオロヨードベンゼン(5.1g、16.9mmol)の溶液を添加し、得られた混合物を室温で3時間撹拌した。反応混合物を飽和塩化アンモニウムでクエンチし、水で希釈し、EtOAc(2×)で抽出した。合わせた有機物を硫酸マグネシウム上で脱水し、濾過し、減圧下で濃縮して、薄茶色の固体8.9gを得た。粗製物をメタノール(10mL)中で1時間スラリー化し、次いで、濾過して、表題化合物をベージュ色の固体(1.61g、38%)として得た。
LCMS: AP+ (M+H)+
321.0/323.0 (100% ELSD) Rt = 0.94分 (1.5分の操作時間)
1H NMR
(500 MHz, CD3OD) δ
7.90 - 7.97 (m, 2 H) 7.63 (ddd, J=8.54, 4.51, 2.32 Hz, 1 H) 7.41 (t, J=8.54 Hz,
1 H) ppm
[5−(3−ブロモ−4−フルオロフェニル)−3,6−ジクロロピリダジン−4−イル]メタノール
DCM(75mL)およびMeOH(125mL)中の4−(3−ブロモ−4−フルオロ−フェニル)−3,6−ジクロロ−ピリダジン(調製例1、1g、3.1mmol)の溶液を、水(2.5mL)中の硫酸鉄(II)(1.2g、12.5mmol)の溶液で、続いて、濃硫酸(0.75mL、14mmol)で処理した。混合物を還流するよう加熱し、次いで、過酸化水素水溶液(30%、5.0mL、49.3mmol)で滴下処理した。混合物を2、4、22、および27時間後に、さらなる酸化剤5mLで処理した。合計30時間後に、出発物質が消費されたら、混合物を室温に冷却し、発泡が止まるまで飽和炭酸カリウム水溶液で慎重に処理した。混合物を減圧下で濃縮して、有機溶媒を除去し、DCMに抽出した(3回)。合わせた有機物を硫酸マグネシウム上で脱水し、濾過し、減圧下で濃縮して、薄茶色の油状物1.16gを得、これを、中圧クロマトグラフィー(24gシリカ、0〜30%EtOAc/ヘプタン、12カラム体積)を使用して精製した。生成物画分を減圧下で濃縮して、表題化合物を無色の泡(426mg、39%)として得た。
LCMS: ES+ (M+H)+ 351.0/353.0, Rt
= 0.81分 (1.5分の操作時間)
1H NMR
(500 MHz, CDCl3) δ7.59
(dd, J=6.22, 2.07 Hz, 1 H) 7.23 - 7.39 (m, 2 H) 4.56 (m, 2 H) 3.24 (br. s., 1
H) ppm
5−(3−ブロモ−4−フルオロフェニル)−3,6−ジクロロピリダジン−4−カルバルデヒド
DCM(10mL)中の[5−(3−ブロモ−4−フルオロ−フェニル)−3,6−ジクロロ−ピリダジン−4−イル]−メタノール(調製例2、238mg、0.68mmol)の溶液をデスマーチン試薬(332mg、0.74mmol)で処理し、室温で1時間撹拌した。反応混合物を飽和NaHCO3水溶液および飽和チオ硫酸ナトリウム水溶液(それぞれ6mL)でクエンチし、30分間撹拌した。層を分離し、水性層をDCMでさらに2回抽出した。合わせた有機物を硫酸マグネシウム上で脱水し、濾過し、減圧下で濃縮して、黄色の油状物208mgを得た。粗製の物質を、中圧クロマトグラフィー(12gシリカ、0〜30%EtOAc/ヘプタン、24カラム体積)を使用して精製した。生成物画分を合わせ、減圧下で濃縮して、表題化合物を黄色のフィルム状物(150mg、63%)として得た。
LCMS: AP+ (M+H)+
349.0/351.0, Rt = 0.86/0.91分 (1.5分の操作時間)
1H NMR
(500 MHz, CDCl3) δ10.07
(s, 1 H) 7.52 (dd, J=6.34, 2.20 Hz, 1 H) 7.26 - 7.33 (m, 1 H) 7.21 - 7.26 (m, 1
H) ppm
4−(3−ブロモ−4−フルオロフェニル)−5−クロロ−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン
EtOH(5mL)中の5−(3−ブロモ−4−フルオロ−フェニル)−3,6−ジメトキシ−ピリダジン−4−カルバルデヒド(調製例3、150mg、0.43mmol)、シュウ酸エチルヒドラジン(71mg、0.47mmol)およびTEA(0.2mL、1.4mmol)の溶液を室温で1時間撹拌し、次いで、マイクロ波で10分間、120℃に加熱した。粗製物を、中圧クロマトグラフィー(12gシリカ、0〜25%EtOAc/ヘプタン、25カラム体積)を使用して精製した。生成物画分を合わせ、減圧下で濃縮して、表題化合物を黄色の固体(84mg、収率55%)として得た。
LCMS: ES+ (M+H)+
357.0 (100% ELSD) 0.98分 (1.5分の操作時間)
1H NMR
(500 MHz, CDCl3) δ7.96
(s, 1 H) 7.87 (dd, J=6.34, 2.20 Hz, 1 H) 7.60 (ddd, J=8.48, 4.57, 2.32 Hz, 1 H)
7.35 (t, J=8.29 Hz, 1 H) 4.82 (q, J=7.16 Hz, 2 H) 1.65 (t, J=7.20 Hz, 3 H) ppm
5−クロロ−4−(4’−エタンスルホニル−6−フルオロ−2’−メトキシビフェニル−3−イル)−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン
ジオキサン(4mL)および水(1mL)中の2−(4−エタンスルホニル−2−メトキシ−フェニル)−4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン(44mg、0.14mmol)、4−(3−ブロモ−4−フルオロ−フェニル)−5−クロロ−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン(調製例4、44mg、0.12mmol)、およびNa2CO3(40mg、0.37mmol)の溶液を窒素で脱気し、Pd(PPh3)4(15mg、0.012mmol)で処理し、還流するよう15時間加熱した。混合物を室温に冷却し、減圧下で濃縮して、茶色の油状物184mgを得、これを、中圧クロマトグラフィー(12gシリカ、0〜40%EtOAc/ヘプタン、25カラム体積)を使用して精製した。生成物画分を合わせ、減圧下で濃縮して、表題化合物を無色の固体(39mg、66%)として得た。
LCMS: ES+ (M+H)+
475.2, Rt = 0.92分
(1.5分の操作時間)
1H NMR
(500 MHz, CDCl3) δ8.02
(s, 1 H) 7.69 - 7.76 (m, 2 H) 7.58 - 7.63 (m, 1 H) 7.54 - 7.58 (m, 1 H) 7.53
(d, J=1.71 Hz, 1 H) 7.35 - 7.42 (m, 1 H) 4.81 (q, J=7.32 Hz, 2 H) 3.95 (s, 3 H)
3.19 (q, J=7.32 Hz, 2 H) 1.64 (t, J=7.20 Hz, 3 H) 1.36 (t, J=7.44 Hz, 3 H) ppm
5−クロロ−4−(4’−エタンスルホニル−6−フルオロビフェニル−3−イル)−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン
ジオキサン(4mL)および水(1mL)中の4−(エチルスルホニル)ベンゼンボロン酸(29mg、0.14mmol)、4−(3−ブロモ−4−フルオロ−フェニル)−5−クロロ−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン(調製例4、43mg、0.12mmol)、およびNa2CO3(40mg、0.37mmol)の溶液を窒素で脱気し、Pd(PPh3)4(15mg、0.012mmol)で処理し、15時間、還流するよう加熱した。混合物を室温に冷却し、減圧下で濃縮して、黄色の油状物を得、これを、中圧クロマトグラフィー(12gシリカ、0〜40%EtOAc/ヘプタン、20カラム体積)を使用して精製した。生成物画分を合わせ、減圧下で濃縮して、表題化合物を無色の固体(40mg、74%)として得た。
LCMS: ES+ (M+H)+
445.2 (100% ELSD), Rt = 0.92分 (1.5分の操作時間)
1H NMR
(500 MHz, CDCl3) δ8.03
(d, J=8.54 Hz, 2 H) 7.99 (s, 1 H) 7.81 (dd, J=8.54, 1.46 Hz, 2 H) 7.78 (dd,
J=7.20, 2.32 Hz, 1 H) 7.71 (ddd, J=8.48, 4.57, 2.32 Hz, 1 H) 7.44 (dd, J=10.00,
8.54 Hz, 1 H) 4.82 (q, J=7.16 Hz, 2 H) 3.18 (q, J=7.40 Hz, 2 H) 1.61 - 1.68 (m,
3 H) 1.34 (t, J=7.44 Hz, 3 H) ppm
5−[5−(5−クロロ−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン−4−イル)−2−フルオロフェニル]−6−メトキシ−2−メチル−2,3−ジヒドロイソインドール−1−オン
脱気DMF(1.4mL)中の6−メトキシ−2−メチル−2,3−ジヒドロイソインドール−1−オン5−イルボロン酸(37mg、0.17mmol)、4−(3−ブロモ−4−フルオロ−フェニル)−5−クロロ−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン(調製例4、50mg、0.14mmol)、Pd2(dba)3(6.4mg、0.007mmol)、トリ(tert−ブチル)ホスフィンテトラフルオロボラート(8.2mg、0.028mmol)および新たに摩砕されたフッ化セシウム(85mg、0.56mmol)の溶液を室温、窒素下、密閉バイアル内で24時間撹拌し、次いで、6時間、50℃で、次いで18時間、80℃で、最後に24時間、110℃で加熱し、次いで、室温に冷却し、水で希釈した。固体物質を濾取し、濾液を濃縮し、次いで、再び濾過した。合わせた固体を、カラムクロマトグラフィー(EtOAc)を使用して精製した。生成物画分を合わせ、減圧下で濃縮して、表題化合物を無色の固体(16mg、25%)として得た。
[M+H+] = 452.1 (ES+)
1H NMR (600 MHz, CDCl3) δ8.03 (s, 1H), 7.73 (dd, J = 6.8, 2.3 Hz,
1H), 7.70 (ddd, J = 7.4, 4.5, 2.3 Hz, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.37 (t,
J = 8.9 Hz, 1H), 4.81 (q, J = 7.3 Hz, 2H), 4.38 (s, 2H), 3.93 (s, 3H), 3.23 (s,
3H), 1.64 (t, J = 7.2 Hz, 3H) ppm
4−(4’−エタンスルホニル−6−フルオロ−2’−メトキシビフェニル−3−イル)−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン
LCMS: ES+ (M+H)+
441.3 (100% ELSD) Rt = 0.85分 (1.5分の操作時間)
1H NMR
(500 MHz, CDCl3) δppm
9.25 (s, 1 H) 8.29 (s, 1 H) 7.82 - 7.91 (m, 2 H) 7.60 - 7.66 (m, 1 H) 7.53 -
7.59 (m, 2 H) 7.38 - 7.46 (m, 1 H) 4.87 (q, J=7.24 Hz, 2 H) 3.96 (s, 3 H) 3.21
(q, J=7.56 Hz, 2 H) 1.66 (t, J=7.32 Hz, 3 H) 1.38 (t, J=7.44 Hz, 3 H) ppm
4−(4’−エタンスルホニル−6−フルオロビフェニル−3−イル)−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン
LCMS: ES+ (M+H)+
411.2 (100% ELSD) Rt = 0.85分 (1.5分の操作時間)
1H NMR
(500 MHz, CDCl3) δppm
9.28 (s, 1 H) 8.32 (s, 1 H) 8.06 (d, J=8.54 Hz, 2 H) 7.86 - 7.94 (m, 2 H) 7.83
(dd, J=8.42, 1.34 Hz, 2 H) 7.49 (dd, J=9.76, 8.54 Hz, 1 H) 4.89 (q, J=7.32 Hz,
2 H) 3.20 (q, J=7.32 Hz, 2 H) 1.67 (t, J=7.32 Hz, 3 H) 1.36 (t, J=7.44 Hz, 3
H).
5−[5−(1−エチル−1H−ピラゾロ[3,4−c]ピリダジン−4−イル)−2−フルオロフェニル]−6−メトキシ−2−メチル−2,3−ジヒドロイソインドール−1−オン
[M+H+] = 418.8 (ES+)
1H NMR (600 MHz, DMSO-d6) δ9.47 (s, 1H), 8.66 (s, 1H), 8.14 - 8.07 (m,
1H), 8.06 - 7.99 (m, 1H), 7.68 (s, 1H), 7.56 (t, J = 9.1 Hz, 1H), 7.38 (s, 1H),
4.77 (q, J = 7.2 Hz, 2H), 4.46 (s, 2H), 3.87 (s, 3H), 3.11 (s, 3H), 1.54 (t, J =
7.2 Hz, 3H).
細胞系の構築および維持
ヒト胎児由来腎臓(HEK)細胞に、標準的な技法を使用してGABRA2−GABRB2−GABRG2構築物をトランスフェクトした。GABRA2−GABRB2−GABRG2構築物を安定発現する細胞を、ジェネテシンG−418(320μg/ml)、ハイグロマイシン(160μg/ml)およびゼオシン(40μg/ml)に対するそれらの耐性により同定した。クローンを、BD Pathway 855イメージングシステム(BD Biosciences、Rockville、MD、USA)およびQ Patch自動電気生理プラットフォーム(Sophion、Copenhagen、Denmark)を使用して、発現についてスクリーニングした。
GABRA2−GABRB2−GABRG2を安定的にトランスフェクトしたHEK細胞を、ジェネテシンG−418(320μg/ml)、ハイグロマイシン(160μg/ml)およびゼオシン(40μg/ml)と共にEarle塩、10%FBS、1×L−Glutamax、1% mM非必須アミノ酸(MEM)、および1mMピルビン酸ナトリウムを含むMEM培地中、インキュベーター内、37℃において、5%CO2の加湿雰囲気下で維持した。Q Patch電気生理試験のために、細胞を、酵素的解離によりフラスコから採取し、血清非含有培地に再懸濁させた。細胞を典型的には、分割後24〜72時間以内に、電気生理学的実験のために使用した。
被験化合物の親和性を、既知の化合物[3H]Ro−15−1788(フルマゼニル)(Perkin Elmer、85.4Ci/mmol)、ならびにアルファ2、ベータ2、およびガンマ2サブユニットを含有するヒト組換えGABA A受容体を使用して放射性リガンド競合結合アッセイにより決定した。
GABRA2−GABRB2−GABRG2を発現するHEK細胞を含有する細胞懸濁液を、血清非含有培地中で、Q Patch機器の細胞攪拌機内に設置した。この機器は、細胞外緩衝液を使用して細胞を一度洗浄し、次いで、それらを、3〜4000000/mlの濃度で、Q Plate HT測定プレートに分配した。細胞外溶液は、次の組成からなった:137mM NaCl、1.8mM CaCl2、4mM KCl、1mM MgCl2、10mMグルコース、および10mM HEPES、pH7.4、NaOH含有、300〜310mOsm/kg。Q Plate測定プレートの内側に、次の組成の細胞内溶液を充填した:90mM KCl、50mM KF、1mM MgCl2、10mM HEPES、11mM EGTA、および2mM Mg−ATP、pH7.35、KOH含有、295〜305mOsm/kg。記録はすべて、室温(22〜24℃)において取った。
[((モジュレーター電流振幅のピーク−漏れ)−(GABA電流振幅−漏れ))/(GABA電流振幅−漏れ)]×100
[式中、「漏れ」は、−60mVにおける漏れ電流であり、「モジュレーター電流振幅のピーク」は、ガンマ−アミノ酪酸および被験化合物の同時適用により誘発された電流であり、「GABA電流振幅」は、ガンマ−アミノ酪酸の単独適用により誘発された電流である]。
Claims (24)
- 式(I)の化合物
Xは、−S(O)2−および−C(O)−から選択され、
R1は、(C2〜C4)アルキル、(C3〜C5)シクロアルキルおよびメチル置換(C3〜C5)シクロアルキルから選択され、
R2は、H、F、Cl、OCH3およびCNから選択され、
R3は、H、F、CHF2、OCH3およびCNから選択され、
Xが−S(O)2−である場合、
R4は、(C1〜C4)アルキル、(C3〜C5)シクロアルキル、NH2およびNH(C1〜C4)アルキルから選択され、R5は、Hであるか、または
R4およびR5は一緒に、−CH2CH2−または−N(CH3)CH2−であり、
Xが、−C(O)−である場合、
R4は、NH2およびNH(C1〜C4)アルキルから選択され、R5は、Hであるか、または
R4およびR5は一緒に、−N(CH3)CH2−である]
または薬学的に許容できるその塩。 - R4が、(C1〜C4)アルキルであり、R5が、Hである、請求項2に記載の化合物または薬学的に許容できるその塩。
- R4が、エチルである、請求項3に記載の化合物または薬学的に許容できるその塩。
- R4およびR5が一緒に、−N(CH3)CH2−である、請求項5に記載の化合物または薬学的に許容できるその塩。
- R1が、(C2〜C4)アルキルである、請求項1から6のいずれか一項に記載の化合物または薬学的に許容できるその塩。
- R1が、エチルである、請求項7に記載の化合物または薬学的に許容できるその塩。
- R2が、HおよびFから選択される、請求項1から8のいずれか一項に記載の化合物または薬学的に許容できるその塩。
- R2が、Fである、請求項9に記載の化合物または薬学的に許容できるその塩。
- R3が、HおよびOCH3から選択される、請求項1から10のいずれか一項に記載の化合物または薬学的に許容できるその塩。
- R3が、OCH3である、請求項11に記載の化合物または薬学的に許容できるその塩。
- 4−(4’−エタンスルホニル−6−フルオロ−2’−メトキシビフェニル−3−イル)−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン、
4−(4’−エタンスルホニル−6−フルオロビフェニル−3−イル)−1−エチル−1H−ピラゾロ[3,4−c]ピリダジン、および
5−[5−(1−エチル−1H−ピラゾロ[3,4−c]ピリダジン−4−イル)−2−フルオロフェニル]−6−メトキシ−2−メチル−2,3−ジヒドロイソインドール−1−オン
から選択される、請求項1に記載の化合物または薬学的に許容できるその塩。 - 請求項1から13のいずれか一項に記載の化合物と、薬学的に許容できる添加剤とを含む医薬組成物。
- 医薬として使用するための、請求項1から13のいずれか一項に記載の化合物。
- 疼痛の治療において使用するための、請求項15に記載の化合物。
- てんかんの治療において使用するための、請求項15に記載の化合物。
- 治療を必要とする対象に、有効量の請求項1から13のいずれか一項に記載の化合物を投与することを含む、疼痛を治療する方法。
- 治療を必要とする対象に、有効量の請求項1から13のいずれか一項に記載の化合物を投与することを含む、てんかんを治療する方法。
- 疼痛を治療するための、請求項1から13のいずれか一項に記載の化合物の使用。
- てんかんを治療するための、請求項1から13のいずれか一項に記載の化合物の使用。
- 疼痛を治療するための医薬を製造するための、請求項1から13のいずれか一項に記載の化合物の使用。
- てんかんを治療するための医薬を製造するための、請求項1から13のいずれか一項に記載の化合物の使用。
- 請求項1から6のいずれか一項に記載の化合物と、第2の薬学的活性薬剤とを含む組み合わせ。
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CN116693555A (zh) * | 2022-02-25 | 2023-09-05 | 上海赛默罗生物科技有限公司 | 咪唑并哒嗪类衍生物、其制备方法、药物组合物和用途 |
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JP2002501071A (ja) * | 1998-01-21 | 2002-01-15 | メルク シャープ エンド ドーム リミテッド | Gaba受容体のリガンドとしてのトリアゾロ−ピリダジン誘導体 |
JP2004523584A (ja) * | 2001-03-21 | 2004-08-05 | メルク シャープ エンド ドーム リミテッド | Gaba受容体のためのリガンドとしてのイミダゾ−ピリミジン誘導体 |
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GB9518953D0 (en) | 1995-09-15 | 1995-11-15 | Pfizer Ltd | Pharmaceutical formulations |
WO2000035296A1 (en) | 1996-11-27 | 2000-06-22 | Wm. Wrigley Jr. Company | Improved release of medicament active agents from a chewing gum coating |
GB9711643D0 (en) | 1997-06-05 | 1997-07-30 | Janssen Pharmaceutica Nv | Glass thermoplastic systems |
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BRPI1006128A2 (pt) | 2009-01-12 | 2016-11-01 | Cagen Inc | derivados de sulfonamida |
WO2015189744A1 (en) * | 2014-06-12 | 2015-12-17 | Pfizer Limited | Imidazopyridazine derivatives as modulators of the gabaa receptor activity. |
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JP2002501071A (ja) * | 1998-01-21 | 2002-01-15 | メルク シャープ エンド ドーム リミテッド | Gaba受容体のリガンドとしてのトリアゾロ−ピリダジン誘導体 |
JP2004523584A (ja) * | 2001-03-21 | 2004-08-05 | メルク シャープ エンド ドーム リミテッド | Gaba受容体のためのリガンドとしてのイミダゾ−ピリミジン誘導体 |
JP2005529909A (ja) * | 2002-05-02 | 2005-10-06 | メルク シャープ エンド ドーム リミテッド | Gaba受容体に対するリガンドとしてのイミダゾ−トリアジン誘導体 |
JP2005531582A (ja) * | 2002-05-24 | 2005-10-20 | メルク シャープ エンド ドーム リミテッド | Gaba受容体のリガンドとしてのイミダゾ−ピリジン誘導体 |
US20140171435A1 (en) * | 2012-12-14 | 2014-06-19 | Pfizer Limited | Chemical Compounds |
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CA3007595A1 (en) | 2017-06-15 |
SG11201803489SA (en) | 2018-06-28 |
US20180346470A1 (en) | 2018-12-06 |
US10538523B2 (en) | 2020-01-21 |
EP3386983A1 (en) | 2018-10-17 |
WO2017098367A1 (en) | 2017-06-15 |
CA3007595C (en) | 2020-08-25 |
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