JP6715830B2 - 過敏性腸症候群および末梢神経系の他の病気の治療のための末梢限局性gabaポジティブアロステリックモジュレーター - Google Patents
過敏性腸症候群および末梢神経系の他の病気の治療のための末梢限局性gabaポジティブアロステリックモジュレーター Download PDFInfo
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- JP6715830B2 JP6715830B2 JP2017520752A JP2017520752A JP6715830B2 JP 6715830 B2 JP6715830 B2 JP 6715830B2 JP 2017520752 A JP2017520752 A JP 2017520752A JP 2017520752 A JP2017520752 A JP 2017520752A JP 6715830 B2 JP6715830 B2 JP 6715830B2
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Classifications
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- 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
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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- A—HUMAN NECESSITIES
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
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Description
であって、A1、A2、およびA3は、独立してCまたはNから選択され、A1、A2、またはA3の少なくとも1つは非置換の、もしくはアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、-COOR10、-COR10、-OR10、-SR10、-NR10R11、および-CONR10R11からなる基で置換されたCであり;
R10およびR11のそれぞれは、独立してH、任意に1つ以上のアミジニル、グアニジニル、リン酸、硫酸、テトラゾール、3-ヒドロキシイソオキサゾール、尿素、第一級アミド、スルホンアミド、スルホニル尿素、アシルアミジン、アシルグアニジン、もしくは-NR12R13基を含む第四級アンモニウム塩で置換されたアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり;R12およびR13のそれぞれは、独立してH、-CONH2、-SOONH2、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり;
XはOであり;
Yは、H、OH、OQ、およびCO2Qから選択され、Qは、Y=HまたはY=OHを遊離させるプロドラッグであり;Zは、酸素および孤立電子対から選択され;
R1は、任意に1つ以上のハロ、CF3、CN、NO2、COOH、C1-4アルキル、C2-4アルケニル、C1-4アルキニル、OH、OR(ORは、C1-4アルキルもしくはC1-4フルオロアルキル)、SO2R(Rは、C1-4アルキルもしくはC1-4フルオロアルキル)で置換されたアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリールであり;
R5は、任意に1つ以上のハロ、CF3、CN、NO2、C1-4アルキル、C2-4アルケニル、C1-4アルキニル、OH、OR(ORは、C1-4アルキルもしくはC1-4フルオロアルキル)、およびSO2R(Rは、C1-4アルキルもしくはC1-4フルオロアルキル)で置換されたアリール、ヘテロアリール、またはシクロアルケニル基からなる群より選択され;ならびに
R6、R7、R8、R9は、それぞれ独立してH、ハロ、CF3、CN、NO2、C1-4アルキル、C2-4アルケニル、C1-4アルキニル、OH、OR(ORは、C1-4アルキルもしくはC1-4フルオロアルキル)、およびSO2R(Rは、C1-4アルキルもしくはC1-4フルオロアルキル)化合物からなる群より選択される化合物を提供する。
一実施形態によれば、本発明は、内臓痛の治療方法を提供し、IBSにより引き起こされるような被験体における腸運動を、腸神経系のGABA-A受容体を正に調節することにより、GABAモジュレーションの通常のCNS副作用なしに調節することが提供される。本明細書に記載される方法は、IBSだけでなく、他の病気により生じる内臓痛を治療するのに有効であると考えられる。本発明の方法により治療することができる非IBS関連の病気には、例えば、機能性腹痛、機能性特発性下痢、炎症性腸疾患、薬物誘導性疼痛、胆汁酸塩吸収不良、ラクターゼまたは他の炭水化物不耐症が挙げられる。膜透過性などの物理的性質の調節と血液脳関門輸送体による認識を向上させることが知られている官能基の組み込みとを介して、本発明において使用されるGABA-A受容体ポジティブアロステリックモジュレーターはCNSから制限されているが、それは、それらが鎮静などの望ましくない副作用を生じさせずに、それでも腸神経系に有益な薬理学的効果を発揮できるようにするためである。
であって、A1、A2、およびA3は、独立してCまたはNから選択され、A1、A2、またはA3の少なくとも1つは非置換の、もしくはアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、-COOR10、-COR10、-OR10、-SR10、-NR10R11、および-CONR10R11からなる基で置換されたCであり;
R10およびR11のそれぞれは、独立してH、任意に1つ以上のアミジニル、グアニジニル、リン酸、硫酸、テトラゾール、3-ヒドロキシイソオキサゾール、尿素、第一級アミド、スルホンアミド、スルホニル尿素、アシルアミジン、アシルグアニジン、もしくは-NR12R13基を含む第四級アンモニウム塩で置換されたアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり;R12およびR13のそれぞれは、独立してH、-CONH2、-SOONH2、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり;
XはOであり;
Yは、H、OH、OQ、およびCO2Qから選択され、Qは、Y=HまたはY=OHを遊離させるプロドラッグであり;Zは、酸素および孤立電子対から選択され;
R1は、任意に1つ以上のハロ、CF3、CN、NO2、COOH、C1-4アルキル、C2-4アルケニル、C1-4アルキニル、OH、OR(ORは、C1-4アルキルもしくはC1-4フルオロアルキル)、SO2R(Rは、C1-4アルキルもしくはC1-4フルオロアルキル)で置換されたアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリールであり;
R5は、任意に1つ以上のハロ、CF3、CN、NO2、C1-4アルキル、C2-4アルケニル、C1-4アルキニル、OH、OR(ORは、C1-4アルキルもしくはC1-4フルオロアルキル)、およびSO2R(Rは、C1-4アルキルもしくはC1-4フルオロアルキル)で置換されたアリール、ヘテロアリール、またはシクロアルケニル基からなる群より選択され;ならびに
R6、R7、R8、R9は、それぞれ独立してH、ハロ、CF3、CN、NO2、C1-4アルキル、C2-4アルケニル、C1-4アルキニル、OH、OR(ORは、C1-4アルキルもしくはC1-4フルオロアルキル)、およびSO2R(Rは、C1-4アルキルもしくはC1-4フルオロアルキル)化合物からなる群より選択される化合物を提供する。
本明細書で使用されるように、上記で使用される化学用語は、標準的な化学的専門用語である。そのような化学置換基のサンプル定義は、その全体が参照により本明細書に組み込まれる特許文献2で見られる。
IBSの症状には、例えば、腹痛、腹部不快感、便秘、下痢、粘液性便、腹部膨満感、または上記の任意の組合せを挙げることができる。直近の3ヶ月間で少なくとも1ヶ月に3回、腹部に痛みや不快感があり、その痛みを説明し得る他の疾患または損傷がない場合に、IBSと診断され得る。
IBSの痛みや不快感は、排便回数または便の硬さの変化に伴って発生したり、または腸運動により緩和されたりする。IBSは、被験体の通常の便の硬さに基づいて、4つのサブタイプに分類することができる。IBSの4つのサブタイプは:便秘型IBS(IBS-C)、下痢型IBS(IBS-D)、混合型IBS(IBS-M)、および分類不能型IBS(IBS-U)である。IBS-Cの被験体では、少なくとも25%の場合で硬いもしくは塊状の便である可能性があり、または25%未満の場合で軟らかいもしくは水っぽい便であるか、またはこれら2つの組み合わせである可能性がある。IBS-Dの被験体では、少なくとも25%の場合で軟らかいもしくは水っぽい便であり、または25%未満の場合で硬いもしくは塊状の便であるか、またはこれら2つの組み合わせである可能性がある。IBS-Mの被験体では、少なくとも25%の場合で硬いもしくは塊状の便であり、少なくとも25%の場合で軟らかいもしくは水っぽい便である可能性がある。IBS-Uの被験体では、25%未満の場合で硬いもしくは塊状の便であり、25%未満の場合で軟らかいもしくは水っぽい便であるか、またはこれら2つの組み合わせである可能性がある。IBSに伴う便秘は、胃運動の減速または遅延に起因し得る。いくつかの実施形態にでは、IBSの被験体は、便秘を経験している。IBSは、当該技術分野で知られているか、そうでなければ本明細書に記載の任意の方法により、被験体において診断することができる。例えば、IBSは、医療供給者により診断され得る。医療供給者は、身体検査を実施してもよく、被験体の病歴を聴取してもよい。被験体は、1つ以上のIBSの症状を少なくとも3、4、5、または6ヶ月間示し、1つ以上の症状が直近の3ヶ月間で少なくとも1ヶ月に3回発現した場合、IBSと診断され得る。IBSの診断に有用であり得る追加の試験には、便検査、下部消化管造影、軟性S状結腸鏡検査または結腸鏡検査が挙げられるが、これらに限定されない。
したがって、開示された化合物の互変異性体形態、鏡像異性体、立体異性体、およびジアステレオ異性体を含む異性体形態、ならびに薬学的に許容されるそれらの塩は、本発明の化合物の内に含まれる。
本明細書に記載の医薬組成物に関して、薬学的に許容される担体は、従来使用されているもののいずれであってもよく、溶解性および活性化合物(単数および複数)との反応性の欠如などの物理化学的考察によって、ならびに投与経路によってのみ制限される。本明細書に記載の薬学的に許容される担体は、例えば、運搬体、アジュバント、賦形剤、および希釈剤であって、当業者によく知られており、容易に一般に利用可能である。薬学的に許容される担体の例には、生理学的に許容可能な既知緩衝液(例えば、リン酸緩衝液)などの可溶性担体、ならびに固体担体またはラテックスビーズなどの固体組成物が挙げられる。薬学的に許容される担体は、活性薬剤(単数または複数)に対して化学的に不活性であるもの、および使用条件下で有害な副作用または毒性がほとんどまたは全くないものであることが好ましい。
本明細書に記載される医薬組成物の投与は、化合物の作用部位への送達を可能にする任意の方法により行うことができる。組成物は、経口、非経口、経腸、腹腔内、局所、経皮、経眼、鼻腔内、局所、非経口、スプレー、皮下、静脈内、扁桃内、筋肉内、口腔内、舌下、直腸内、動脈内に、注入により、または髄腔内に投与され得る。いくつかの実施形態では、組成物は経口投与される。いくつかの例では、経口投与は、本明細書に記載されるように任意の経口剤形の投与を含んでもよい。いくつかの例では、本明細書に記載の組成物は舌下投与される。いくつかの例では、本明細書に記載の組成物は、例えば経皮パッチを介して、経皮的に投与される。投与される化合物の有効量は、治療される被験体、疾患または状態の重症度、投与速度、化合物の性質および処方する医師の裁量によって決まるであろう。
有効量の化合物を含む医薬組成物は、経口投与用に製剤化することができる。いくつかの実施形態では、経口投与用の化合物の有効量を含む医薬組成物は、固体医薬組成物である。いくつかの実施形態では、固体医薬組成物は、個別の(例えば、単位)の経口投与剤形として提供することができる。個別の経口投与剤形の非限定的な例には、錠剤、カプセル剤、カプレット剤、ゼラチンカプセル剤、徐放製剤、トローチ剤、薄膜、ロリポップ、チューインガムが挙げられる。いくつかの実施形態では、個別の経口投与剤形は、口腔内崩壊錠などの口腔内崩壊型経口投与剤形である。
非経口運搬体(皮下、静脈内、動脈内、または筋肉内注射用)には、例えば、塩化ナトリウム溶液、リンゲルデキストロース、デキストロースおよび塩化ナトリウム、乳酸リンゲルならびに固定油が挙げられる。非経口投与に適した製剤には、例えば、抗酸化剤、緩衝剤、静菌剤、および溶質を含むことができ、製剤を、対象とするレシピエントの血液と等張にする水性および非水性等張滅菌注射溶液と、懸濁化剤、可溶化剤、増粘剤、安定化剤、および防腐剤を含み得る水性および非水性滅菌懸濁液とが挙げられる。
あるいは、化合物が投与された体内で放出される様式が、体内での時間および場所に関して制御されるように、本発明の化合物をデポー形態に変更することができる(例えば、特許文献3を参照)。化合物のデポー形態は、例えば、化合物およびポリマーなどの多孔性または非多孔性材料を含み、化合物が、その材料によりもしくはその材料を通じてカプセル化または拡散されるおよび/または非多孔質材料の分解を通じて拡散される、移植可能な組成物であり得る。デポーは、その後体内の所望の場所に移植され、化合物は、移植片から所定の速度で放出される。
本発明の目的上、上述したように、投与される式Iの化合物のいずれかの化合物、塩、溶媒和物、もしくは立体異性体の量または投与量は、被験体において妥当な時間枠にわたって、例えば治療または予防応答をたらすのに十分なものであるべきである。投与量は、特定の化合物の有効性およびヒトの状態、ならびに治療されるヒトの体重により決定される。
8-クロロ-6-(2-フルオロフェニル)-4H-[1,2,4]トリアゾロ[1,5-a][1,4]ベンゾジアゼピン-2-カルボン酸
MS (ES+) m/z 252.0 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 - 1.39 (m, 6 H) 4.10 - 4.17 (m, 2 H) 4.24 - 4.39 (m, 4 H) 5.16 (d, J=6.82 Hz, 1 H)
MS (ES+) m/z 534.0 [M+Na]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24 - 1.36 (m, 6 H) , 3.87 (s, 2 H) , 4.21 -4.36 (m, 4 H) , 7.49 - 7.80 (m, 7 H)
MS (ES+) m/z 394.0 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ ppm 4.87 (s, 2 H), 7.15 - 7.26 (m, 2 H) 7.49 (td, J=7.52, 1.89 Hz, 1 H) 7.55 - 7.66 (m, 1 H) 7.83 - 7.94 (m, 2 H) 8.00 (dd, J=8.46, 2.40 Hz, 1 H)
MS (ES+) m/z 357.0 [M+H]+1H NMR (400 MHz, DMSO-d6) δ ppm 13.76 (br. s., 1H), 7.95 - 8.06 (m, 1H), 7.91 (dd, J = 8.8, 2.3 Hz, 1H), 7.51 - 7.67 (m, 2H), 7.33 - 7.39 (m, 2H), 7.17 - 7.29 (m, 1H), 4.85 (br s, 2H)
6-(2-フルオロフェニル)-8-(トリフルオロメチル)-4H-[1,2,4]トリアゾロ[1,5-a][1,4]ベンゾジアゼピン-2-カルボン酸:
MS (ES+) m/z 568.0 [M+Na]+. 1H NMR (CHLOROFORM-d) δ: 7.77 - 7.88 (m, 2H), 7.56 - 7.71 (m, 1H), 7.29 - 7.35 (m, 1H), 7.09 (ddd, J = 10.9, 8.3, 1.0 Hz, 3H), 4.23 - 4.40 (m, 4H), 4.10 - 4.17 (m, 1H), 3.88 (s, 1H), 2.09 - 2.14 (m, 5H), 2.04 -2.09 (m, 2H), 1.24 - 1.33 (m, 6H)
MS (ES+) m/z 428.0 [M+H]+ 1H NMR (CHLOROFORM-d) δ: 8.00 - 8.08 (m, 2H), 7.87 (d, J = 8.1 Hz, 1H), 7.65 (td, J = 7.6, 1.8 Hz, 1H), 7.21 - 7.27 (m, 1H), 7.06 (dd, J = 10.7, 8.5 Hz, 1H), 4.71 (s, 2H)
MS (ES+) m/z 391.0 [M+H]+ . 1H NMR (DMSO-d6) δ: 8.19 - 8.27 (m, 2H), 7.64 - 7.72 (m, 2H), 7.54 - 7.62 (m, 1H), 7.36 (td, J = 7.6, 1.0 Hz, 1H), 7.24 (dd, J = 1 1.1, 8.3 Hz, 1H), 4.97 (br. s., 2H)
8-フルオロ-6-(2-フルオロフェニル)-4H-[1,2,4]トリアゾロ[1,5-a][1,4]ベンゾジアゼピン-2-カルボン酸:
1H NMR (400 MHz, DMSO-i/6) δ ppm 8.03 (dd, J=8.72, 4.93 Hz, 1 H) 7.71 (td, J=8.46, 2.78 Hz, 1 H) 7.52 - 7.65 (m, 2 H) 7.34 (td, J=7.3, 1.3Hz, 1 H) 7.23 (dd, J=8.3, 9.4 Hz, 1 H); 7.18 (dd, J=9.1, 2.8 1H); 4.88 (br s, 2H).
8-ブロモ-6-(2-フルオロフェニル)-4H-[1,2,4]トリアゾロ[1,5-a][1,4]ベンゾジアゼピン-2-カルボン酸:
MS (ES+) m/z 400.9 [M+H, Br=81]+ 1H NMR (DMSO-d6) δ: 7.98 - 8.08 (m, 1H), 7.89 - 7.97 (m, 1H), 7.54 - 7.68 (m, 2H), 7.50 (d, J = 2.0 Hz, 1H), 7.31 - 7.41 (m, 1H), 7.19 - 7.31 (m, 1H), 4.92 (br. s., 1H)
8-クロロ-6-(2,6-ジフルオロフェニル)-4H-[1,2,4]トリアゾロ[1,5-a][1,4]ベンゾジアゼピン-2-カルボン酸:
MS (ES+) m/z 375 [M+H]+ 1H NMR (DMSO-d6) δ: 7.99 - 8.07 (m, 1H), 7.92 (dd, J = 8.7, 2.4 Hz, 1H), 7.55 -7.66 (m, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.22 (t, J = 8.5 Hz, 2H), 5.02 (s, 2H)
8-クロロ-6-(2-フルオロフェニル)-N-(2-ウレイドエチル)-4H-[1,2,4]トリアゾロ[1,5-a][1,4]ベンゾジアゼピン-2-カルボキサミド:
(化合物6)
1H NMR (DMSO-d6) δ: 8.76 - 8.83 (m, 4H), 8.02 (d, J = 8.8 Hz, 1H), 7.88 - 7.96 (m, 1H), 7.54 - 7.67 (m, 2H), 7.31 - 7.41 (m, 2H), 7.19 - 7.29 (m, 1H), 3.97 (s, 2H), 3.25 - 3.35 (m, 2H), 3.17 (s, 4H).
8-クロロ-N-[2-(ジメチルアミノ)エチル]-6-(2-フルオロフェニル)-4H-[1,2,4]トリアゾロ[1,5-a][1,4]ベンゾジアゼピン-2-カルボキサミド:
MS (ES+) m/z 427.1 [M+H]+ 1H NMR (400 MHz, DMSO-i/6) δ ppm: 9.34 (br. s., 1 H), 8.98 - 9.08 (m, 1 H), 7.98 - 8.08 (m, 1 H), 7.90 -7.97 (m, 1 H), 7.54 - 7.69 (m, 2 H), 7.32 - 7.47 (m, 2 H), 7.19 - 7.30 (m, 1 H), 4.94 (br. s., 2 H), 3.63 (q, J=5.81 Hz, 2 H), 3.28 (d, J=5.81 Hz, 2 H), 2.76 - 2.95 (m, 6 H)
2-[[8-クロロ-6-(2-フルオロフェニル)-4H-[1,2,4]トリアゾロ[1,5-a][1,4]ベンゾジアゼピン-2-カルボニル]アミノ]エチル-トリメチル-アンモニウムトリフルオロ酢酸塩:
MS (ES+) m/z 441.0 [M+]+ IH NMR (400 MHz, DMSO-i/6) δ ppm: 9.17 (t, J=5.94 Hz, 1 H), 8.69 (br. s., 1 H), 7.98 - 8.07 (m, 1 H), 7.90 - 7.97 (m, 1 H), 7.54 - 7.67 (m, 2 H), 7.32 - 7.43 (m, 2 H), 7.19 - 7.31 (m, 1 H), 4.94 (br. s., 2 H), 3.71 (d, J=6.57 Hz, 2 H), 3.48 - 3.57 (m, 2 H), 3.05 - 3.19 (m, 9 H)
8-クロロ-6-(2-フルオロフェニル)-N-[2-(スルファモイルアミノ)エチル]-4H-[1,2,4]トリアゾロ[1,5-a][1,4]ベンゾジアゼピン-2-カルボキサミド:
MS (ES+) m/z 513.1 [M+H]+ IH NMR (400 MHz, DMSO-d6) δ ppm 1.13 - 1.26 (m, 7 H) 1.99 (s, 1 H) 2.86 - 2.95 (m, 7 H) 2.98 - 3.08 (m, 2 H) 3.28 - 3.48 (m, 32 H) 4.03 (q, J=7.07 Hz, 2 H) 4.57 (s, 1 H) 4.92 (br. s., 4 H) 7.24 (dd, J=10.74, 8.46 Hz, 3 H) 7.31 - 7.42 (m, 7 H) 7.53 - 7.68 (m, 2 H) 7.89 - 7.96 (m, 3 H) 7.98 - 8.08 (m, 1 H) 8.92 (q, j=5.64 Hz, 2 H)
N-(2-アミノエチル)-8-クロロ-6-(2-フルオロフェニル)-4H-[1,2,4]トリアゾロ[1,5-a][1,4]ベンゾジアゼピン-2-カルボキサミド:
1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 (t, J=6.19 Hz, 2 H) 3.26 (q, J=6.48 Hz, 16 H) 4.92 (br. s., 9 H) 7.24 (dd, J=10.48, 8.46 Hz, 8 H) 7.31 - 7.42 (m, 15 H) 7.52 - 7.67 (m, 16 H) 7.88 - 7.96 (m, 7 H) 7.99 - 8.09 (m, 8 H) 8.69 (t, J=5.56 Hz, 6 H).
8-クロロ-6-(3-フルオロ-2-ピリジル)-4H-[1,2,4]トリアゾロ[1,5-a][1,4]ベンゾジアゼピン-2-カルボン酸:
MS (ES+) m/z 367.1 [M+H]+ . 1H NMR (CHLOROFORM-d) d: 7.30 - 7.41 (m, 5H), 5.12 - 5.20 (m, 3H), 4.21 - 4.35 (m, 4H), 4.00 (d, J = 5.6 Hz, 2H), 1.26 - 1.36 (m, 6H)
残留物を逆相クロマトグラフィー(C18カラム、0.5%水性TFA中、5%AcNから95%AcNへのリニアグラジエント)により精製し、表題化合物を無色油として得た(383mg)。
MS (ES+) m/z 628.1 [M+H]+ . 1H NMR (Chloroform-d) d: 8.37 (d, J = 4.5 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.51 - 7.65 (m, 2H), 7.46 (d, J = 3.5 Hz, 1H), 7.31 - 7.41 (m,4H), 5.52 (br. s., 1H), 5.17 (s, 2H), 4.18 - 4.36 (m, 4H), 3.90 (d, J = 5.6 Hz, 1H), 1.20 - 1.34 (m, 6H)
MS (ES+) m/z 510.1 [M+H]+
MS (ES+) m/z 358.0 [M+H]+. 1H NMR (DMSO-d6) d: 8.39 (dt, J = 4.5, 1.4 Hz, 1H), 8.32 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.85 - 7.94 (m, 2H), 7.61 (dt, J = 8.7, 4.1 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 5.00 (s, 2H)
8-クロロ-6-(2-フルオロフェニル)-4H-イミダゾ[1,2-a][1,4]ベンゾジアゼピン-2-カルボン酸:
MS (ES+) m/z 305.0 [M+H]+. 1H NMR (CHLOROFORM-d) δ: 8.05 - 8.16 (m, 1H), 7.58 - 7.67 (m, 1H), 7.45 - 7.54 (m, 2H), 7.21 -7.31 (m, 2H), 7.16 (d, J = 8.6 Hz, 1H), 6.99 -7.12 (m, 2H), 4.81 (br. s., 6H), 3.87 - 3.93 (m,2H)
MS (ES+) m/z 319.0 [M+H]+. 1H NMR (CHLOROFORM-d) δ: 7.51 - 7.58 (m, 1H), 7.41 - 7.49 (m, 2H), 7.30 - 7.35 (m, 1H), 7.18 - 7.27 (m, 2H), 7.05 - 7.13 (m, 1H), 2.52 (s, 2H), 1.60 (s, 3H)
残留物をシリカゲルクロマトグラフィーにより精製し、メタノール/ジクロロメタン(0-15%)で溶出し、表題化合物をわずかに着色した固体として得た(330mg)。
MS (ES+) m/z 390.0 [M+H]+. 1H NMR (DMSO-d6) δ: 8.1 1 (d, J = 7.6 Hz, 1H), 7.46 -7.64 (m, 2H), 7.40 (dd, J = 8.6, 2.5 Hz, 1H), 7.31 (td, J = 7.6, 1.0 Hz, 1H), 7.24 (dd, J =10.6, 8.3 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 5.12 (t, J = 5.6 Hz, 1H), 4.52 (br. s., 1H), 3.59 - 3.80 (m, 6H), 1.91 (s, 2H)
MS (ES+) m/z 370.0 [M+H]+. 1H NMR (Chloroform-d) δ: 8.10 (s, 1H), 7.61 - 7.70 (m, 1H), 7.44 - 7.56 (m, 2H), 7.33 - 7.38 (m, 1H), 7.20 - 7.26 (m, 1H), 7.01 - 7.09 (m, lH), 5.32 (s, 1H), 4.39 (s, 1H), 3.95 (s, 3H)
MS (ES+) m/z 356.0 [M+H]+ . 1H NMR (DMSO-d6) δ: 8.55 (s, 1H), 8.32 (s, 1H), 7.91 - 7.96 (m, 1H), 7.84 (dd, J = 8.8, 2.5 Hz, 1H), 7.53 - 7.66 (m, 3H), 7.30 - 7.37 (m, 3H), 7.20- 7.28 (m, 1H)
本発明の化合物および方法の全消化管通過時間に対する効果
50%プロピレングリコール中の化合物1(0、1、3および10mg/kg)を、強制飼養(5ml/kg)によりC57B/6マウスに投与し、その後0.2mlカルミンレッド溶液(0.5%メチルセルロース中6%カルミンレッド)の強制飼養が続く。次いで、マウスを白ダンボール箱に入れ、その時間を時間0として記録した。赤色染料が便中に現れるまで、便の色を、10分ごとに観察した。最初の赤い便が現れた時間を、終了時間として記録した。終了時間と時間0との差を用いて、WGTT(分)を提示する。図1に示すように、化合物1は、WGTTを、統計的に有意に、1,3および10mg/kgの化合物1の全てで用量依存的に増加した。これらのデータは、化合物1の経口投与は、胃腸系における移行を遅らせることを示唆している。
遠位結腸通過時間に対する効果
便組成に対する効果
IBSマウスモデルにおける疼痛感受性
脳および血漿レベルの測定
GABA-A結合の測定
Transcription and translation of two glutamate decarboxylase genes in the ileum of rat, mouse and guinea pig. Journal of the Autonomic Nervous System 1995;55: 18-28.
Maintaining Good Oral Absorption. Acs Medicinal Chemistry Letters 2012;3 :948-950.
Claims (3)
- 被験体における腸運動を抑制するための、化合物1又は薬学的に許容されるその塩
- 被験体における過敏性腸症候群の治療のための、化合物1又は薬学的に許容されるその塩
- 被験体における機能性腹痛、機能性特発性下痢、炎症性腸疾患、薬物誘導性疼痛、胆汁酸塩吸収不良、ラクターゼまたは他の炭水化物不耐症の治療のための、化合物1又は薬学的に許容されるその塩
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WO2015200766A3 (en) | 2016-05-19 |
JP2017522371A (ja) | 2017-08-10 |
JP2021100951A (ja) | 2021-07-08 |
US10266534B2 (en) | 2019-04-23 |
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