JP6089104B2 - アリールエチニル誘導体 - Google Patents
アリールエチニル誘導体 Download PDFInfo
- Publication number
- JP6089104B2 JP6089104B2 JP2015521004A JP2015521004A JP6089104B2 JP 6089104 B2 JP6089104 B2 JP 6089104B2 JP 2015521004 A JP2015521004 A JP 2015521004A JP 2015521004 A JP2015521004 A JP 2015521004A JP 6089104 B2 JP6089104 B2 JP 6089104B2
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- JP
- Japan
- Prior art keywords
- formula
- compound
- pharmaceutically acceptable
- pyrrol
- ethynyl
- Prior art date
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- 108010038421 metabotropic glutamate receptor 2 Proteins 0.000 description 1
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 125000006239 protecting group Chemical group 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
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- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/28—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
[式中、
R1は、フッ素又は塩素から選択される1〜2個のハロゲン原子によって場合により置換されているフェニルである]
で表される、式Iに示すような絶対配置を有するエナンチオピュアな形態のエチニル誘導体又は薬学的に許容しうる酸付加塩に関する。
先行技術の構造的に類似する化合物は、国際公開公報第2011/128279号(=参照文献1、Hoffmann-La Roche)に開示されており、この特許の構造的に最も類似する化合物(実施例13、40及び59)を比較のために示す。
本発明の化合物は全て、参照化合物と比較して類似した効力を有する。その上、これらは全て、参照化合物のずっと高い値(80%を超える)と比較して60%をはるかに下回る有効度を示す(この有効度は、mGluR5陽性アロステリックモジュレーターの耐容性の問題に関する基準である)。60%を超える高い有効値を有する化合物は、所望の治療効果が観察される用量に近い用量(低治療濃度域)での経口投与後、重度のCNS関連副作用(発作)を示す。60%未満の有効度を有する化合物は、それらの所望の治療効果を維持しながら、その治療用量の30〜1000倍より高くなりうる用量で十分に許容される。一般的に言えば、それ故、本発明の化合物は、重度のCNS副作用への易罹病性の不在に相関する60%未満の有効値のため、先行技術の構造的に類似する化合物と比較して薬物安全性に関して明らかな利点を有する。
[式中、
R1は、1〜2個のフッ素原子によって場合により置換されているフェニルである]
で表される、式Iに示すような絶対配置を有するエナンチオピュアな形態の化合物又は薬学的に許容しうる酸付加塩である。
(3aR,6aR)−1−(5−(フェニルエチニル)ピリジン−2−イル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン
(3aR,6aR)−1−(5−((3−フルオロフェニル)エチニル)ピリジン−2−イル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン
(3aR,6aR)−1−(5−((4−フルオロフェニル)エチニル)ピリジン−2−イル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン、又は
(3aR,6aR)−1−(5−((2,5−ジフルオロフェニル)エチニル)ピリジン−2−イル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン。
a)式II:
[式中、Xは、臭素又はヨウ素から選択されるハロゲン原子であり、そして、ここで、式IIの化合物は、ラセミ混合物であるか又はエナンチオピュアな形態である]
で表される化合物を、式III:
で表される適切なアリール−アセチレンと反応させて、式I:
[式中、置換基は、上に記載される]
で表される化合物を形成するか、又は所望であれば、得られた化合物を薬学的に許容しうる酸付加塩に変換すること、あるいは
b)式:
で表される化合物を、式:
で表される化合物と反応させて、式:
[式中、置換基は、請求項1に記載される]
で表される化合物とするか、又は所望であれば、得られた化合物を薬学的に許容しうる酸付加塩に変換すること。
細胞内Ca2+動員アッセイ
ヒトmGlu5a受容体をコードするcDNAで安定的にトランスフェクトされたモノクローナルHEK−293細胞株を生成した;mGlu5陽性アロステリックモジュレーター(PAM)を用いた作業のために、低い受容体発現レベル及び低い構成的受容体活性を有する細胞株を選択して、アゴニストの対PAM活性の識別を可能にした。細胞を、標準プロトコル(Freshney, 2000)に従って、1mMグルタミン、10%(体積/体積)加熱不活性化仔ウシ血清、ペニシリン/ストレプトマイシン、50μg/mlハイグロマイシン及び15μg/mlブラストサイジンを補充した高グルコースのダルベッコ変法イーグル培地中で培養した(Invitrogen, Basel, Switzerland社製の全ての細胞培養試薬及び抗生物質)。
以下の組成の錠剤を常法により製造する:
mg/錠
活性成分 100
粉末乳糖 95
白色トウモロコシデンプン 35
ポリビニルピロリドン 8
カルボキシメチルスターチNa 10
ステアリン酸マグネシウム 2
錠剤重量 250
(3aR,6aR)−1−(5−(フェニルエチニル)ピリジン−2−イル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン
工程1:(1S,5aR)−(R)−3−フェニル−ヘキサヒドロ−1−オキサ−3a−アザ−シクロペンタ[c]ペンタレン−4−オン:
20mlの密封管中、(rac)−2−(2−オキソシクロペンチル)酢酸(1030mg、7.25mmol)及び(R)−2−アミノ−2−フェニルエタノール(994mg、7.25mmol)の混合物を130℃で3時間加熱し、室温まで放冷した。残渣を50mlのジクロロメタンに取った。有機相を10mlの1N HCl溶液で1回、10mlの飽和NaHCO3溶液で1回洗浄した。硫酸マグネシウムで乾燥し、真空下で濃縮した後、ほぼ純粋な標記化合物1.6g(91%)を明褐色の油状物として得て、これをそのまま次の工程に使用した、MS:m/e=244.0(M+H+)。
ジクロロメタン(10ml)中の(1S,5aR)−(R)−3−フェニル−ヘキサヒドロ−1−オキサ−3a−アザ−シクロペンタ[c]ペンタレン−4−オン(1.6g、6.58mmol)の溶液に、三フッ化ホウ素エーテラート(5.6g、5.00ml、39.5mmol、6.0当量)及びトリエチルシラン(1.53g、2.1ml、13.2mmol、2.0当量)を加えた。50℃で20時間撹拌した後、反応物を室温まで放温し、5%NaHCO3溶液を加えてpHを7に調整した。ジクロロメタン、水で抽出し、乾燥して、真空下で濃縮した後、ほぼ純粋な標記化合物(1.6g、99%)を明褐色の油状物として得て、これをそのまま次の工程に使用した、MS:m/e=246.2(M+H+)。
ジクロロメタン(10ml)中の(3aR,6aR)−1−((R)−2−ヒドロキシ−1−フェニルエチル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン(1.6g、6.52mmol)の溶液に、ピリジン(929mg、950μl、11.7mmol)を加えた。次に、溶液を0℃まで冷却し、p−トルエンスルホニルクロリド(1.49g、7.83mmol、1.2当量)を5分間かけて少しずつ加えた。5℃で30分間撹拌した後、反応物を室温まで放温し、さらに20分間撹拌した。ジクロロメタン/水で抽出し、標準的な後処理をして、真空下で濃縮した後、1.59gの粗物質を得て、次に、これを約15gのシリカゲルを加えた50mlのジクロロメタンに溶解した。5分間撹拌した後、溶媒を蒸発させた。残留物をジクロロメタンに懸濁した。固体を濾別し、20mlのジクロロメタンと酢酸エチルの1:1混合物で3回洗浄した。濾液を真空下で濃縮して、ほぼ純粋な標記化合物1.45g(84%)を明褐色の油状物として産し、これをそのまま次の工程に使用した、MS:m/e=264.1、266.2(M+H+)。
20mlのトルエン中の(R)−1−((R)−クロロ−1−(R)−フェネチル)−ヘキサヒドロ−シクロペンタ[b]ピロール−2−オン(1.4g、5.31mmol)の溶液をDBU(1.01g、1.00ml、6.63mmol、1.25当量)で処理した。反応物を2時間還流し、真空下で濃縮し、酢酸エチル/水で抽出し、乾燥させ、真空下で濃縮して、標記化合物1.19g(99%)を明褐色の油状物として産し(MS:m/e=228.3(M+H+))、これをそのまま次の工程に使用した。
5mlのメタノール中の(3aR,6aR)−1−(1−フェニルビニル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン(1.2g、5.28mmol)の溶液に4M HCl溶液(7.92ml、31.7mmol、6.0当量)を加え、反応物を室温で1時間撹拌した。4M NaOH溶液(約8ml)を加えて反応物のpHを7に調整し、エーテル(20ml)を加え、水相を塩化ナトリウムで飽和し、酢酸エチルで2回抽出した。硫酸マグネシウムで乾燥し、真空下で濃縮した後、生成物及びアセトフェノンを含有する1.0gの明黄色の油状物を得た。ヘプタン中20%〜100%酢酸エチルの傾斜を使用し、続いて、酢酸エチル中2%MeOHで溶離させるシリカゲル(20g)フラッシュクロマトグラフィーで精製した後、標記化合物0.66g(53%)を明黄色の固体として産し、そのNMRデータは文献に報告されているものと正確に一致した。その物質をそのまま次の工程に使用した。
トルエン(1.1ml)中の(3aR,6aR)−ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン(210mg、1.68mmol)及び2−フルオロ−5−ヨードピリジン(412mg、1.85mmol、1.1当量)の溶液に、Cs2CO3(656mg、2.01mmol、1.2当量)を加えた。反応物を105℃で16時間撹拌した。残渣を酢酸エチルに取り、固体を濾別し、酢酸エチルで洗浄した。濾液を真空下で濃縮して、残留物を、ヘプタン中0%〜60%酢酸エチルの傾斜を使用したフラッシュクロマトグラフィー(SiO2、20g)によって精製した。標記化合物(300mg、55%)を無色の油状物として得た、MS:m/e=329.4(M+H+)。
10mlのPyrex管中、(3aR,6aR)−1−(5−ヨードピリジン−2−イル)ヘキサヒドロ−シクロペンタ[b]ピロール−2(1H)−オン(107mg、326μmol)を2mlのTHFに溶解した。溶液にアルゴンをバブルした。エチニルベンゼン(59.9mg、64.5μl、587μmol、1.8当量)、トリエチルアミン(99.0mg、136μl、978μmol、3.0当量)、ビス(トリフェニルホスフィン)パラジウム(II)クロリド(13.7mg、19.6μmol、0.06当量)、トリフェニルホスフィン(1.71mg、6.52μmol、0.02当量)、及びヨウ化銅(I)(1.86mg、9.78μmol、0.03当量)を加えた。暗褐色の溶液を50℃で2時間撹拌した。残渣を酢酸エチルに取り、固体を濾別し、酢酸エチルで洗浄した。濾液を真空下で濃縮し、残留物を、ヘプタン中0%〜60%酢酸エチルの傾斜を使用したフラッシュクロマトグラフィー(SiO2、20g)によって精製した。標記化合物95mg(96%)を粘性の黄色の油状物として得た、MS:m/e=303.2(M+H+)。
(3aR,6aR)−1−(5−((3−フルオロフェニル)エチニル)ピリジン−2−イル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン
標記化合物を、(3aR,6aR)−1−(5−ヨードピリジン−2−イル)ヘキサヒドロ−シクロペンタ[b]ピロール−2(1H)−オン(107mg、0.326mmol)(実施例1、工程6)及び1−エチニル−3−フルオロベンゼンを使用して、実施例1、工程7の一般的な方法に従って調製して、標記化合物100mg(96%)を粘性の黄色の油状物として産した;MS:m/e=321.2(M+H+)。
(3aR,6aR)−1−(5−((4−フルオロフェニル)エチニル)ピリジン−2−イル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン
標記化合物を、(3aR,6aR)−1−(5−ヨードピリジン−2−イル)ヘキサヒドロ−シクロペンタ[b]ピロール−2(1H)−オン(100mg、0.305mmol)(実施例1、工程6)及び1−エチニル−4−フルオロベンゼンを使用して、実施例1、工程7の一般的な方法に従って調製して、標記化合物75mg(77%)を粘性の黄色の油状物として産した;MS:m/e=321.2(M+H+)。
Claims (11)
- 化合物が以下である、請求項1又は2のいずれか一項に記載の式I又はI−Aの化合物:
(3aR,6aR)−1−(5−(フェニルエチニル)ピリジン−2−イル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン
(3aR,6aR)−1−(5−((3−フルオロフェニル)エチニル)ピリジン−2−イル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン
(3aR,6aR)−1−(5−((4−フルオロフェニル)エチニル)ピリジン−2−イル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン、又は
(3aR,6aR)−1−(5−((2,5−ジフルオロフェニル)エチニル)ピリジン−2−イル)ヘキサヒドロシクロペンタ[b]ピロール−2(1H)−オン。 - 治療活性物質として使用するための、請求項1〜3のいずれか一項に記載の化合物。
- 請求項1〜3のいずれか一項に記載の化合物又はその薬学的に許容しうる塩の少なくとも1つを含む、医薬組成物。
- 医薬として使用するための、エナンチオマーもしくはジアステレオマーの混合物として、又はエナンチオピュアな形態にて適用可能である場合の請求項1〜3のいずれか一項に記載の化合物;又はその薬学的に許容しうる塩。
- 統合失調症、認知疾患、脆弱性X症候群又は自閉症の治療又は予防のための医薬の製造のための、請求項1〜3のいずれか一項に記載の化合物又はその薬学的に許容しうる塩の使用。
- 統合失調症、認知疾患、脆弱性X症候群又は自閉症の治療又は予防のための、請求項1〜3のいずれか一項に記載の化合物。
- 統合失調症、認知疾患、脆弱性X症候群又は自閉症の処置のための請求項7に記載の医薬組成物。
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