JP2009530348A - M1受容体で活性を有するベンズイミダゾールおよび医薬におけるその使用 - Google Patents
M1受容体で活性を有するベンズイミダゾールおよび医薬におけるその使用 Download PDFInfo
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- JP2009530348A JP2009530348A JP2009500854A JP2009500854A JP2009530348A JP 2009530348 A JP2009530348 A JP 2009530348A JP 2009500854 A JP2009500854 A JP 2009500854A JP 2009500854 A JP2009500854 A JP 2009500854A JP 2009530348 A JP2009530348 A JP 2009530348A
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- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Endocrinology (AREA)
- Psychology (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
−R4は、フルオロであり;
−R5は、水素、シアノ、ハロゲン、C1−6アルキル、1個または複数のフッ素原子で置換されるC1−6アルキル、C1−6アルコキシ、および1個または複数のフッ素原子で置換されるC1−6アルコキシから選択され;
−R6は、水素、ハロゲン、シアノ、C1−6アルキル、1個または複数のフッ素原子で置換されるC1−6アルキル、C1−6アルキルスルホニル、C3−6シクロアルキル、1個または複数のフッ素原子で置換されるC3−6シクロアルキル、C1−6アルコキシおよび1個または複数のフッ素原子で置換されるC1−6アルコキシから選択され;
−Rは、C1−6アルキル、C3−6シクロアルキル、C3−6シクロアルキルC1−6アルキルおよびC2−6アルキニル,所望により1個または複数のフッ素原子で置換されていてもよいいずれかのアルキルまたはシクロアルキル基から選択され;および
−Qは水素またはC1−6アルキルである]
で示される化合物またはその塩もしくは溶媒和物を提供する。
−R4は、フルオロであり;
−R5は、水素、ハロゲン、C1−6アルキル、1個または複数のフッ素原子で置換されるC1−6アルキル、C1−6アルコキシ、および1個または複数のフッ素原子で置換されるC1−6アルコキシから選択され;
−R6は、ハロゲン、C1−6アルキル、1個または複数のフッ素原子で置換されるC1−6アルキル、C3−6シクロアルキル、1個または複数のフッ素原子で置換されるC3−6シクロアルキル、C1−6アルコキシおよび1個または複数のフッ素原子で置換されるC1−6アルコキシから選択され;
−Rは、C1−6アルキル、C3−6シクロアルキル、C3−6シクロアルキルC1−6アルキル、所望により1個または複数のフッ素原子で置換されていてもよいいずれかのアルキルまたはシクロアルキル基から選択され;および
−Qは、水素またはC1−6アルキルである]
で示される化合物またはその医薬上許容される塩もしくは溶媒和物を提供する。
1. 4−フルオロ−6−メチル−1−[1−(シス−4−メトキシシクロヘキシル)−4−ピペリジニル]−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
2. 4−フルオロ−6−メチル−1−[1−(トランス−4−メトキシシクロヘキシル)−4−ピペリジニル]−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
ならびにその塩および溶媒和物、例えば、塩酸塩、トリフルオロ酢酸塩またはギ酸塩。
1. 4−フルオロ−6−メチル−1−[1−(トランス−4−エトキシシクロヘキシル)−4−ピペリジニル]−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
2. 4−フルオロ−6−メチル−1−[1−(トランス−4−プロポキシシクロヘキシル)−4−ピペリジニル]−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
3. 4−フルオロ−6−メチル−1−{1−[トランス−1−メチル−4−(プロピルオキシ)シクロヘキシル]−4−ピペリジニル}−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
4. 1−{1−[トランス−4−(エチルオキシ)−1−メチルシクロヘキシル]−4−ピペリジニル}−4−フルオロ−6−メチル−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
5. 1−{1−[トランス−4−(エチルオキシ)−1−メチルシクロヘキシル]−4−ピペリジニル}−4,6−ジフルオロ−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
6. 4−フルオロ−6−メチル−1−{1−[トランス−1−メチル−4−(メチルオキシ)シクロヘキシル]−4−ピペリジニル}−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
7. 4,6−ジフルオロ−1−{1−[トランス−1−メチル−4−(メチルオキシ)シクロヘキシル]−4−ピペリジニル}−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
8. 4−フルオロ−1−{1−[トランス−1−メチル−4−(メチルオキシ)シクロヘキシル]−4−ピペリジニル}−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
9. 1−{1−[トランス−4−(エチルオキシ)−1−メチルシクロヘキシル]−4−ピペリジニル}−4−フルオロ−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
ならびにその塩および溶媒和物、例えば、塩酸塩、トリフルオロ酢酸塩またはギ酸塩。
式(II):
で示される化合物とカップリングさせることを含む方法を提供する。
で示される化合物とカップリングさせることを含む方法を提供する。XおよびYは、同一であっても異なっていてもよく、例としてCl、PhO、EtO、イミダゾールがある。XおよびYが両方ともCl、すわなち、ホスゲンである場合、該試薬は、インサイツ(in situ)、例えば、ジホスゲンまたはトリホスゲンから生じさせられうる。
で示される化合物をパラジウムまたは銅触媒(VII)で処理し、分子内環化をもたらすことを含む方法を提供する。
で示される化合物とカップリングさせることを含む方法を提供する。
で示される化合物をジフェニルホスホリルアジドまたは他の試薬/試薬の組み合わせと反応させ、化合物(X)のクルチウス転位、次いで、分子内環化をもたらす方法を提供する。
で示される化合物とカップリングさせることを含む方法を提供する。
・標準的条件を用いて、2種のアミン(XXXIV)および(XXVII)をホスゲンまたはホスゲン等価物と合すること(ホスゲン等価物には、カルボニルジイミダゾール、ジホスゲン、トリホスゲン、クロロギ酸フェニルが含まれる)
・アミン(XXVII)をイソシアネート(XXXV)と反応させること
・アミン(XXXIV)をイソシアネート(XXXVI)と反応させること
によってスキーム12に示されるように達成されうる。
大うつ病エピソード、躁病エピソード、混合性エピソードおよび軽躁病エピソードを含むうつ病および気分障害;大うつ病性障害、胸腺異常症(300.4)、特定不能のうつ病性障害(311)を含むうつ病性障害;双極性I障害、双極性II障害(軽躁病エピソードを伴う再発性大うつ病エピソード)(296.89)、循環病(301.13)および特定不能の双極性障害(296.80)を含む双極性障害;うつ病の特徴、大うつ様エピソード、躁病の特徴および混合型の特徴を有するサブタイプを含む一般身体疾患による気分障害(293.83)、物質誘発性気分障害(うつ病の特徴、大うつ様エピソード、躁病の特徴および混合型の特徴を有するサブタイプを含む)および特定不能の気分障害(296.90)を含む他の気分障害;
アゴニスト/アンタゴニスト効力を決定するためのM 1 受容体に対するFLIPR試験
アッセイA
本発明の化合物を、FLIPR(蛍光イメージングプレートリーダー)技術を用い、ヒトムスカリン性受容体を安定発現するCHO細胞における細胞内カルシウム経路の活性化能を測定する機能アッセイで特徴付けた。要するに、CHO−M1細胞を播種し(20,000/ウェル)、37℃で一晩増殖させた。培地を除去し、FLIPRカルシウム3色素(Molecular Devices Co.,Sunnyvale,CA)を含有する30μLのローディングバッファー(20mM HEPESを含むHBSS、pH7.4)を製造業者の使用説明書に従って加えた。37℃で45〜60分間インキュベートした後、試験化合物を含有する10μLのアッセイバッファー(20mM HEPESと2.5mMプロベネシドを含むHBSSd、pH7.4)を、FLIPR装置上の各ウェルに加えた。カルシウム応答をモニタリングし、促進作用を測定した。次いで、プレートをさらに30分間インキュベートした後、アゴニスト刺激として、アセチルコリンを含有するアッセイバッファー10μLをEC80で加えた。その後、カルシウム応答を再度モニタリングし、アセチルコリンに対する化合物の拮抗作用を測定した。M1受容体に対する促進作用および拮抗作用の双方の濃度応答曲線を各化合物について作製した。結果をActiveBaseデータ分析スイート(ID Business Slution Inc.,Parsippany,NJ)にインポートし、これらの曲線を非線形曲線の当てはめにより解析し、結果としてのpEC50/pIC50を算出した。アゴニスト化合物の固有活性は、アセチルコリンにより誘発された最大FLIPR応答の割合%として算出した(すなわち、対照としてEC100のアセチルコリンを使用)。
本発明の化合物を、FLIPR(蛍光イメージングプレートリーダー)技術を用い、ヒトムスカリン性受容体を安定発現するCHO細胞における細胞内カルシウム経路の活性化能を測定する機能アッセイで特徴付けた。要するに、CHO−M1細胞を播種し(15,000/ウェル)、37℃で一晩増殖させた。培地を除去し、30μLのローディングバッファー(2.5mMプロベニシド(probenicid)、2μM Fluo−4、500μM ブリリアントブラックを含むHBSS、pH7.4)を加えた。37℃で90分間インキュベートした後、試験化合物を含有する10μLのアッセイバッファー(2.5mMプロベネシドを含むHBSS、pH7.4)を、FLIPR装置上の各ウェルに加えた。カルシウム応答をモニタリングし、促進作用を測定した。次いで、プレートをさらに30分間インキュベートした後、アゴニスト刺激として、アセチルコリンを含有するアッセイバッファー10μLをEC80で加えた。その後、カルシウム応答を再度モニタリングし、アセチルコリンに対する化合物の拮抗作用を測定した。M1受容体に対する促進作用および拮抗作用の双方の濃度応答曲線を各化合物について作製した。結果をActiveBaseデータ分析スイート(ID Business Solution Inc.,Parsippany,NJ)にインポートし、これらの曲線を非線形曲線の当てはめにより解析し、結果としてのpEC50/fpKipを算出した。アゴニスト化合物の固有活性は、同じ化合物プレートに対照として加えたアセチルコリンにより誘発された最大FLIPR応答の割合%として算出し、0と1の間の分数に変換した(すなわち、対照として複数の濃度を含むアセチルコリン標準曲線の当てはめから得られた最大100%応答を用いて算出)。
アッセイA
M1アゴニスト化合物の固有活性を決定するために、本発明の化合物を、ヒトムスカリン性M1受容体を一時的に発現するU2OS細胞におけるFLIPR試験で特徴付けた。要するに、U2OS細胞にM1 BacMamウイルス(Ames,R S;Fornwald,J A;Nuthulaganti,P;Trill,J J;Foley,J J;Buckley,P T;Kost,T A;Wu,ZおよびRomanos,M A.(2004) Use of BacMam recombinant baculoviruses to support G protein−coupled receptor drug discovery.Receptors and Channels 10(3−4):99−109)を、2×10e5/mL細胞懸濁液、0.1%ウイルス/細胞比(v/v)で形質導入した。ウイルスと細胞の比を、部分的アゴニストの固有活性を測定するのに最も適当となるように機能的滴定により別々の試験で決定した。ウイルスを懸濁液と合した後、細胞を播種し(10,000/ウェル)、37℃で一晩増殖させた。次いで、翌日、CHO−M1細胞に関して上記したものと同じプロトコールを用いてFLIPR試験を行った。結果をActiveBaseデータ分析スイートにインポートし、これらの曲線を非線形曲線の当てはめにより解析し、結果としてのpEC50値を算出した。アゴニスト化合物の固有活性は、同じ化合物プレートに対照として加えたアセチルコリンにより誘発された最大FLIPR応答の割合%として算出し、0と1の間の分数に変換した(すなわち、対照として複数の濃度を含むアセチルコリン標準曲線の当てはめから得られた最大100%応答を用いて算出)。
M1アゴニスト化合物の固有活性を決定するために、本発明の化合物を、ヒトムスカリン性M1受容体を一時的に発現するCHO細胞におけるFLIPR試験で特徴付けた。要するに、CHO細胞にM1 BacMamウイルス(Ames,R S;Fornwald,J A;Nuthulaganti,P;Trill,J J;Foley,J J;Buckley,P T;Kost,T A;Wu,ZおよびRomanos,M A.(2004) Use of BacMam recombinant baculoviruses to support G protein−coupled receptor drug discovery.Receptors and Channels 10(3−4):99−109)を、多重感染度6で形質導入した。ウイルスと細胞の比を、部分的アゴニストの固有活性を測定するのに最も適当となるように機能的滴定により別々の試験で決定した。ウイルスを懸濁液と合した後、細胞を播種し(15,000/ウェル)、37℃で一晩増殖させた。あるいは、その後、細胞を1mlバイアル内にて、90%透析ウシ胎児血清、10%ジメチルスルホキシド中、4.8×10e7細胞/mlの濃度で−140℃にて凍結した。次いで、細胞をアッセイ前日に解凍し、播種し(15,000/ウェル)、37℃で一晩増殖させた。播種の翌日、CHO−M1細胞に関して上記したものと同じプロトコールを用いてFLIPR試験を行った。結果をActiveBaseデータ分析スイートにインポートし、これらの曲線を非線形曲線の当てはめにより解析し、結果としてのpEC50値を算出した。アゴニスト化合物の固有活性は、同じ化合物プレートに対照として加えたアセチルコリンにより誘発された最大FLIPR応答の割合%として算出し、0と1の間の分数に変換した(すなわち、対照として複数の濃度を含むアセチルコリン標準曲線の当てはめから得られた最大100%応答を用いて算出)。
アッセイA
他のムスカリン性受容体サブタイプ対する本発明の化合物の選択性を決定するために、化合物を、ヒトムスカリン性受容体M2、M3、M4またはM5を安定発現するCHO細胞におけるFLIPR試験で特徴付けた。M2およびM4受容体の場合、キメラGタンパク質Gqi5はまた同時発現され、カルシウムシグナル伝達経路に受容体を共役させた。要するに、細胞を播種し(20,000/ウェル)、37℃で一晩増殖させた。次いで、翌日、CHO−M1細胞に関して上記したものと同じプロトコールを用いてFLIPR試験を行った。結果をActiveBaseデータ分析スイートにインポートし、これらの曲線を非線形曲線の当てはめにより解析し、結果としてのpEC50/pIC50値を算出した。
他のムスカリン性受容体サブタイプに対する本発明の化合物の選択性を決定するために、化合物を、ヒトムスカリン性受容体M2、M3、M4またはM5を安定発現するCHO細胞におけるFLIPR試験で特徴付けた。M2およびM4受容体の場合、キメラGタンパク質Gqi5はまた同時発現され、カルシウムシグナル伝達経路に受容体を共役させた。要するに、細胞を播種し(15,000/ウェル)、37℃で一晩増殖させた。次いで、翌日、CHO−M1細胞に関して上記したものと同じプロトコールを用いてFLIPR試験を行った。結果をActiveBaseデータ分析スイートにインポートし、これらの曲線を非線形曲線の当てはめにより解析し、結果としてのpEC50/fpKi値を算出した。
1H NMR δ (d6DMSO,400MHz):1.44(4H,m),1.65(4H,m),3.55(1H,d broad),3.83(4H,m),4.48(1H,d)。
1H NMR δ (d6DMSO,400MHz):1.46(2H,m),1.55(2H,m),1.64(2H,m),1.73(2H,m),3.21(3H,s),3.24(1H,m),3.83(4H,m)。
1H NMR δ (d6DMSO,400MHz):1.92(4H,m),2.20(2H,m),2.348(2H,m),3.29(3H,s),3.53(1H,m)
1H NMR δ (CDCl3,400MHz):0.01(6H,m),0.85(9H,s),1.2(3H,m),1.3−1.5(2H,m),1.6(2H,m),1.85−2(3H,m),2.15−2.3(1H,m) 3.5(0.4H,m) 3.86(1H,m) 4.1(1H,m)。
1H NMR δ (CDCl3,400MHz):0.92(3H,t),1.24(3H,s),1.54−1.74(8H,m),1.78−1.88(2H,m),3.33−3.40(3H,m)。1Hはスペクトルから識別できなかった。
1H NMR δ (CDCl3,400MHz):0.91(3H,t),1.36(3H,s),1.50−1.60(4H,m),1.65−1.80(6H,m),3.33(2H,t),3.46−3.52(1H,m)。
1H NMR δ (CDCl3,400MHz):0.91(3H,t),1.47(3H,s),1−45−1.70(4H,m),1.75−2.00(6H,m),3.52(2H,t),3.40−3.48(1H,m),8.38(3H,br s)。
1H NMR δ (CDCl3,400MHz):0.93(3H,s+3H,t),1.48−1.72(8H,m),1.80−1.92(2H,m),2.41(4H,t),2.82(4H,t),3.35−3.45(3H,t+m)。
1H NMR δ (CDCl3,400MHz):0.91(3H,t),1.08(3H,br s),1.32−1.45(2H,m),1.5−1−60(2H,m),1.62−2.60(想定12H,ブロードシグナルの集合),2.70−3.10(1H,br),34.10−3.25(2H,br),3.30−3.45(3H,m),3.40−4.40(2H,v br)。
1H NMR δ (CDCl3,400MHz):0.01(6H,m),0.85(9H,s),1.2(3H,m),1.3−1.5(2H,m),1.6(2H,m),1.85−2(3H,m),2.15−2.3(1H,m) 3.5(0.4H,m) 3.86(1H,m) 4.1(1H,m)。
1H NMR δ (DMSO,400MHz):1.1(3H,m),1.15(3H,m),1.492−3.212(想定10H,ブロードシグナルおよびマルチプレットの集合),3.312(2H,m),4.041(2H,m)。
1H NMR δ (DMSO,400MHz):1.1(3H,m),1.3−3.201(想定10H,ブロードシグナルおよびマルチプレットの集合),3.417(2H,m),12.1(1H,s broad)。
1H NMR δ (DMSO,400MHz):1.086(想定8H,m),1.510(3H,m),1.698(1H,m),1.781(1H,m),2.005(1H,m),3.191(0.5H,m),3.392(2H,m),3.606(0.5H,m),12.2(1H,s br)。
1H NMR δ (DMSO,400MHz):1.076(6H,m),1.505(6H,m),1.693(2H,m),3.331(1H,m),3.394(2H,q),12.1(1H,s br)。
1H NMR δ (DMSO,400MHz):1.092(3H,t),1.330(3H,s),1.487−1.691(8H,m),3.392(2H,q),3.477(1H,m)。
1H NMR δ (DMSO,400MHz):1.084(3H,t),1.256(3H,s),1.378(2H,m),1.619(4H,m),1.847(2H,m),3.243(1H,m),3.424(2H,q),8.090(3H,br s)。
1H NMR δ (DMSO,400MHz):0.855(3H,s),1.099(3H,t),1.421(2H,m),1.544(4H,m),1.793(2H,m),2.297(4H,t),2.726(4H,t),3.377−3.430(3H,t+m)。
1H NMR δ (DMSO,250MHz,352.2Kで):1.091(6H,m br),1.336(2H,m),1.695−1.865(7H,m),2.067(2H,d br),2.531(1H,br),3.187−3.317(想定6H,ブロードシグナルおよびマルチプレットの集合),3.434(2H,q),8.496(2H,s br)。
1H NMR δ (CDCl3,400MHz):0.93(3H,s),1.20−1.23(3H,t),1.44−1.59(4H,m),1.59−1.68(2H,m),1.82−1.87(2H,m),2.00−2.07(2H,m),2.23−2.34(2H,m),3.18(1H,m),3.33−3.38(1H,m),3.45−3.51(2H,m),3.69−3.75(1H,m),3.89(1H,m),6.12−6.22(2H,m)。
1H NMR δ (d6DMSO,400MHz):1.078−2.018(11H,シス/トランス異性体),3.074(1H,m 単一異性体),3.193(3H,s 単一異性体),3.213(3H,s 単一異性体),3.606(1H,s broad,単一異性体),>12.5(1H,s broad,シス/トランス異性体)。
1H NMR δ (d6DMSO,400MHz):1.085(3H,s),1.419(2H,m),1.485(4H,m),1.701(2H,m),3.225(4H,m),3.342(1H,s)。
1H NMR δ (d6DMSO,400MHz):1.327(3H,s),1.61(8H,m),3.197(3H,s) 3.355(1H,m)。
1H NMR δ (d6DMSO,400MHz):1.260(3H,s),1.39(2H,m),1.632(4H,m),1.87(2H,m),3.157(1H,m),3.217(3H,s)。
1H NMR δ (d6DMSO,400MHz) 0.85(3H,s),1.50(8H,m) 1.762(2H,t),2.301(4H,t),2.725(4H,t),3.207(3H,s),3.274(1H,m)。
1HNMR δ (d6DMSO):1.4(2H,m),1.7(2H,m),1.8−2.1(6H,m),2.35(3H,s),2.8(2H,m),3.25(3H,s),3.3−3.8(6H,m),4.6(1H,m),6.7(1H,d,J=11Hz),7.4(1H,s),10.5(1H,br s),11.4(1H,s),MH+362。
1H NMR δ (d6DMSO):1.2(2H,m),1.6(2H,m),1.9(2H,m),2.2(4H,m),2.35(3H,s),2.8(2H,m),3.3(3H,s),3.1−3.6(6H,m),4.6(1H,m),6.75(1H,d,J=11Hz),7.4(1H,s),10.6(1H,br s),11.3(1H,s),MH+362。
1H NMR(HCl塩) δ (d6DMSO):1.1(3H,t),1.2(2H,m),1.55(2H,m),1.9(2H,m),2.15(4H,m),2.35(3H,s),2.8(2H,m),3.2−3.5(12H,m),4.6(1H,m),6.7(1H,d,J=11Hz),7.4(1H,s),10.5(1H,br s),11.35(1H,s),MH+376。
1H NMR(HCl塩) δ (d6DMSO):0.85(3H,t),1.2(2H,m),1.5(4H,m),1.9(2H,m),2.15(4H,m),2.35(3H,s),2.8(2H,m),3.2−3.5(15H,m),4.6(1H,m),6.7(1H,d,J=11Hz),7.4(1H,s),10.2(1H,br s),11.35(1H,s),MH+390。
1H NMR δ (d6DMSO,400MHz):0.87(3H,t),1.20−1.40(5H,s+m),1.41−1.54(2H,m),1.80−2.03(想定6H,m),2.33(3H,s),2.83−3.00(2H,m),3.10−3.26(3H,m),3.30−3.70(想定6H,いくつかのシグナル),4.55−4.67(1H,m),6.73(1H,d),7.53(1H,s),10.4(1H,br s),11.33(1H,s)。
1H NMR(遊離塩基) δ (CDCl3,400MHz):0.95(3H,s),1.19−1.28(3H,m),1.43−1.58(4H,m),1.66−1.72(2H,m),1.80−1.83(2H,m),1.88−1.93(2H,m),2.23−2.36(4H,m),2.39(3H,s),3.14−3.16(2H,m),3.39−3.43(1H,m),3.47−3.53(2H,m),4.22−4.26(1H,m),6.25−6.65(1H,d),6.83(1H,s),7.98(1H,s)。
1H NMR(遊離塩基) δ (CDCl3,400MHz):0.94(3H,s),1.20−1.23(3H,t),1.44−1.59(4H,m),1.64−1.69(2H,m),1.80−1.91(4H,m),1.80−1.91(4H,m),3.14−3.15(2H,d),3.42−3.44(1H,m),3.46−3.53(2H,q),4.25(1H,m),6.56−6.64(1H,m),6.82−6.85(1H,m),8.48(1H,s)。
1H NMR δ (DMSO−d6,400MHz):1.23−1.38(5H,m),1.75−2.07(8H,m),2.33(3H,s),2.79(2H,m),3.06−3.26(3H,m),3.26(3H,s),3.65(2H,m),4.57(1H,m),6.75(1H,d,J11),7.24(1H,s),9.57(1H,m),11.35(1H,s)
1H NMR δ (DMSO−d6,400MHz):1.24−1.38(5H,m),1.77(2H,m),1.90−2.08(6H,m),2.70(2H,m),3.06−3.25(3H,m),3.26(3H,m),3.66(2H,m),4.59(1H,m),6.98(1H,m),7.38(1H,m),9.45(1H,m),11.55(1H,s)。
1H NMR δ (d6DMSO,250MHz):0.95(3H,s),1.15−1.45(5H,m),1.8−2.1(8H,m),2.75−3.0(2H,m),3.0−3.3(約10H,m),3.34(3H,m),3.1−3.25(2H,m),4.6(1H,m),6.9(2H,m) 7.6(1H,d),10.3(1H,m),11.5(1H,s)。
1H NMR δ (d6DMSO,400MHz)(遊離塩基):0.95(3H,s),1.23(3H,t),1.45−1.6(4H,m),1.65−1.8(4H,m),1.85−2.0(4H,m),2.2−2.4(4H,m),3.15(2H,m),3.43(1H,m),3.5(2H,m),4.3(1H,m),6.81(1H,d),6.96(1H,m)9.63(1H,m),7.03(1H,m),9.2(1H,s)。
19F NMR δ (d6DMSO) −134.19ppm
Claims (16)
- 式(I):
−R4は、フルオロであり;
−R5は、水素、シアノ、ハロゲン、C1−6アルキル,1個または複数のフッ素原子で置換されるC1−6アルキル、C1−6アルコキシ、および1個または複数のフッ素原子で置換されるC1−6アルコキシから選択され;
−R6は、水素、ハロゲン、シアノ、C1−6アルキル,1個または複数のフッ素原子で置換されるC1−6アルキル、C1−6アルキルスルホニル、C3−6シクロアルキル,1個または複数のフッ素原子で置換されるC3−6シクロアルキル、C1−6アルコキシおよび1個または複数のフッ素原子で置換されるC1−6アルコキシから選択され;
−Rは、C1−6アルキル、C3−6シクロアルキル、C3−6シクロアルキルC1−6アルキルおよびC2−6アルキニル、1個または複数のフッ素原子で置換されていてもよいいずれかのアルキルまたはシクロアルキル基から選択され;および
−Qは、水素またはC1−6アルキルである]
で示される化合物またはその塩もしくは溶媒和物。 - R5が、水素、シアノ、ハロゲン、C1−2アルキル,1個または複数のフッ素原子で置換されるC1−2アルキル、C1−2アルコキシ、および1個または複数のフッ素原子で置換されるC1−2アルコキシから選択される、請求項1記載の化合物。
- R6が、水素、ハロゲン、シアノ、C1−4アルキル、1個または複数のフッ素原子で置換されるC1−4アルキル、C1−4アルキルスルホニル、C3−6シクロアルキル、1個、2個または3個のフッ素原子で置換されるC3−6シクロアルキル、C1−4アルコキシおよび1個、2個または3個のフッ素原子で置換されるC1−4アルコキシから選択される、請求項1または請求項2記載の化合物。
- Rが、C1−4アルキル、C3−6シクロアルキル、C3−6シクロアルキルC1−4アルキルおよびC2−4アルキニル、1個、2個または3個のフッ素原子で置換されていてもよいいずれかのアルキルまたはシクロアルキル基から選択される、請求項1,2または3記載の化合物。
- Qが、水素およびC1−3アルキルから選択される、請求項1−4のいずれか記載の化合物。
- 1. 4−フルオロ−6−メチル−1−[1−(シス−4−メトキシシクロヘキシル)−4−ピペリジニル]−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
2. 4−フルオロ−6−メチル−1−[1−(トランス−4−メトキシシクロヘキシル)−4−ピペリジニル]−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
3. 4−フルオロ−6−メチル−1−[1−(トランス−4−エトキシシクロヘキシル)−4−ピペリジニル]−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
4. 4−フルオロ−6−メチル−1−[1−(トランス−4−プロポキシシクロヘキシル)−4−ピペリジニル]−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
5. 4−フルオロ−6−メチル−1−{1−[トランス−1−メチル−4−(プロピルオキシ)シクロヘキシル]−4−ピペリジニル}−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
6. 1−{1−[トランス−4−(エチルオキシ)−1−メチルシクロヘキシル]−4−ピペリジニル}−4−フルオロ−6−メチル−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
7. 1−{1−[トランス−4−(エチルオキシ)−1−メチルシクロヘキシル]−4−ピペリジニル}−4,6−ジフルオロ−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
8. 4−フルオロ−6−メチル−1−{1−[トランス−1−メチル−4−(メチルオキシ)シクロヘキシル]−4−ピペリジニル}−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
9. 4,6−ジフルオロ−1−{1−[トランス−1−メチル−4−(メチルオキシ)シクロヘキシル]−4−ピペリジニル}−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
10. 4−フルオロ−1−{1−[トランス−1−メチル−4−(メチルオキシ)シクロヘキシル]−4−ピペリジニル}−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
11. 1−{1−[トランス−4−(エチルオキシ)−1−メチルシクロヘキシル]−4−ピペリジニル}−4−フルオロ−1,3−ジヒドロ−2H−ベンズイミダゾール−2−オン
またはその塩もしくは溶媒和物である、請求項1記載の化合物。 - 請求項1〜6のいずれか1項記載の化合物および医薬上許容される担体を含む医薬組成物。
- 治療に用いるための請求項1〜6のいずれか1項記載の化合物。
- ムスカリン性M1受容体の促進作用を必要とする病態の治療に用いるための請求項1〜6のいずれか1項記載の化合物。
- 精神病性障害または認識機能障害の治療に用いるための請求項1〜6のいずれか1項記載の化合物。
- ムスカリン性M1受容体の促進作用を必要とする病態の治療のための医薬の製造における請求項1〜6のいずれか1項記載の化合物の使用。
- 精神病性障害または認識機能障害の治療のための医薬の製造における請求項1〜6のいずれか1項記載の化合物の使用。
- ムスカリン性M1受容体の促進作用を必要とする病態を治療する方法であって、有効量の請求項1〜6のいずれか1項記載の化合物をそれを必要とする哺乳動物に投与することを含む方法。
- 精神病性障害または認識機能障害を治療する方法であって、有効量の請求項1〜6のいずれか1項記載の化合物をそれを必要とする哺乳動物に投与することを含む方法。
- 方法が、
−還元的アルキル化に適当な条件下、式(II):
とカップリングさせることを含む方法(A1);
−グリニャール試薬に適当な条件下、シアン化物の供給源の存在下において、式(II)の化合物を式(III)の化合物と反応させ、シアノ中間体(XXXX)を形成し、アルキルグリニャール試薬QMgXと反応させ、式(I)の化合物を形成しうることを含む方法(A2):
−塩基の存在下において、加熱しながら、不活性溶媒中で式(IV):
で示される化合物とカップリングさせることを含む方法(B);
−式(VI):
で示される化合物をパラジウムまたは銅触媒(VII)で処理し、分子内環化をもたらすことを含む方法(C);
−不活性溶媒、例えば、キシレン中での加熱、次いで、ピペリジン二重結合の還元によって、式(VIII):
で示される化合物とカップリングさせることを含む方法(D);
−式(X):
で示される化合物を試薬/試薬の組み合わせと反応させ、化合物(X)のクルチウス転位、次いで、分子内環化をもたらすことを含む方法(E);および
−アルキル化または光延反応条件下、式(XI):
で示される化合物とカップリングさせることを含む方法(F)から選択され、その後、上記の方法のいずれかに関して、
−いずれかの保護基を除去してもよく;および/または
−式(I)の化合物またはその塩もしくは溶媒和物を別の式(I)の化合物またはその塩もしくは溶媒和物に変換してもよい、請求項1記載の化合物の調製方法。
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US8841447B2 (en) * | 2009-03-26 | 2014-09-23 | Mapi Pharma Ltd. | Process for the preparation of alogliptin |
CN110368375B (zh) * | 2019-07-02 | 2021-10-01 | 青岛大学附属医院 | 用于抑郁症及相关病症的缓释组合物及其制备方法 |
WO2023114224A1 (en) | 2021-12-13 | 2023-06-22 | Sage Therapeutics, Inc. | Combination of muscarinic receptor positive modulators and nmda positive allosteric modulators |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997016186A1 (en) * | 1995-10-31 | 1997-05-09 | Merck & Co., Inc. | Muscarine agonists |
JP2002515008A (ja) * | 1994-10-27 | 2002-05-21 | メルク エンド カンパニー インコーポレーテッド | ムスカリン・アンタゴニスト |
WO2004089942A2 (en) * | 2001-10-02 | 2004-10-21 | Acadia Pharmaceuticals Inc. | Benzimidazolidinone derivatives as muscarinic agents |
JP2005532361A (ja) * | 2002-06-17 | 2005-10-27 | メルク エンド カムパニー インコーポレーテッド | 高眼圧症の治療用の眼科用組成物 |
JP2009512635A (ja) * | 2005-09-30 | 2009-03-26 | グラクソ グループ リミテッド | M1受容体にて活性を有する化合物および医薬におけるそれらの使用 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5574044A (en) * | 1994-10-27 | 1996-11-12 | Merck & Co., Inc. | Muscarine antagonists |
US5691323A (en) * | 1995-05-12 | 1997-11-25 | Merck & Co., Inc. | Muscarine antagonists |
ATE275141T1 (de) * | 1999-10-13 | 2004-09-15 | Banyu Pharma Co Ltd | Substituierte imidazolin-derivate |
GB0505304D0 (en) * | 2005-03-15 | 2005-04-20 | Ds Smith Plastics Ltd | Tap for liquid containers |
WO2007036711A1 (en) * | 2005-09-30 | 2007-04-05 | Glaxo Group Limited | BENZIMIDAZOLONES WHICH HAVE ACTIVITY AT Ml RECEPTOR |
GB0605786D0 (en) * | 2006-03-22 | 2006-05-03 | Glaxo Group Ltd | Compounds |
GB0605784D0 (en) * | 2006-03-22 | 2006-05-03 | Glaxo Group Ltd | Compounds |
GB0706189D0 (en) * | 2007-03-29 | 2007-05-09 | Glaxo Group Ltd | Compounds |
-
2006
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002515008A (ja) * | 1994-10-27 | 2002-05-21 | メルク エンド カンパニー インコーポレーテッド | ムスカリン・アンタゴニスト |
WO1997016186A1 (en) * | 1995-10-31 | 1997-05-09 | Merck & Co., Inc. | Muscarine agonists |
WO2004089942A2 (en) * | 2001-10-02 | 2004-10-21 | Acadia Pharmaceuticals Inc. | Benzimidazolidinone derivatives as muscarinic agents |
JP2005532361A (ja) * | 2002-06-17 | 2005-10-27 | メルク エンド カムパニー インコーポレーテッド | 高眼圧症の治療用の眼科用組成物 |
JP2009512635A (ja) * | 2005-09-30 | 2009-03-26 | グラクソ グループ リミテッド | M1受容体にて活性を有する化合物および医薬におけるそれらの使用 |
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