JP6793859B2 - 同位体濃縮3−アミノ−1−プロパンスルホン酸誘導体及びその使用 - Google Patents
同位体濃縮3−アミノ−1−プロパンスルホン酸誘導体及びその使用 Download PDFInfo
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- JP6793859B2 JP6793859B2 JP2019562256A JP2019562256A JP6793859B2 JP 6793859 B2 JP6793859 B2 JP 6793859B2 JP 2019562256 A JP2019562256 A JP 2019562256A JP 2019562256 A JP2019562256 A JP 2019562256A JP 6793859 B2 JP6793859 B2 JP 6793859B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- 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
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
- C07C309/15—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton the nitrogen atom of at least one of the amino groups being part of any of the groups, X being a hetero atom, Y being any atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/57—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
- C07C309/59—Nitrogen analogues of carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
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Description
本出願は、2017年3月21日に出願された中国特許出願第201710168819.2号、2017年3月31日に出願された米国特許出願第62/479,875号、及び2017年3月31日に出願された米国特許出願第15/476,255号に対する優先権の利益を主張し、そのそれぞれの内容全体は、参照により本明細書に組み込まれる。
ェニル、トリアジニル、1,2,3-トリアゾリル、1,2,4-トリアゾリル、1,2,5-トリアゾリル、1,3,4-トリアゾリル、キサンテニル等を含むが、それらに限定されない。ヘテロ環という用語は、非置換ヘテロ環式基及び置換ヘテロ環式基の両方を含む。
(1)無機酸、例えば塩酸、臭化水素酸、ヨウ化水素酸、硫酸、スルファミン酸、硝酸、リン酸、カルボネート形成剤を添加することにより、塩基性若しくは正に荷電した官能基上で形成される酸付加塩等、又は、有機酸、例えば酢酸、プロピオン酸、乳酸、シュウ酸、グリコール酸、ピバル酸、t-ブチル酢酸、β-ヒドロキシ酪酸、吉草酸、ヘキサン酸、シクロペンタンプロピオン酸、ピルビン酸、マロン酸、コハク酸、リンゴ酸、マレイン酸、フマル酸、酒石酸、クエン酸、安息香酸、3-(4-ヒドロキシベンゾイル)安息香酸、ケイ皮酸、マンデル酸、メタンスルホン酸、エタンスルホン酸、1,2-エタンジスルホン酸、2-ヒドロキシエタンスルホン酸、シクロヘキシルアミノスルホン酸、ベンゼンスルホン酸、スルファニル酸、4-クロロベンゼンスルホン酸、2-ナプタレンスルホン酸、4-トルエンスルホン酸、カンファースルホン酸、3-フェニルプロピオン酸、ラウリルスルホン酸、ラウリル硫酸、オレイン酸、パルミチン酸、ステアリン酸、ラウリン酸、エンボン(パモ)酸、パルモイック酸、パントテン酸、ラクトビオン酸、アルギン酸、ガラクタル酸、ガラクツロン酸、グルコン酸、グルコヘプトン酸、グルタミン酸、ナフトエ酸、ヒドロキシナフトエ酸、サリチル酸、アスコルビン酸、ステアリン酸、ムコン酸等と形成される酸付加塩、
(2)酸性プロトンが未変化体に存在する場合に形成される塩基付加塩は、アルカリ金属イオン(例えば、リチウム、ナトリウム、カリウム)、アルカリ土類イオン(例えば、マグネシウム、カルシウム、バリウム)若しくは他の金属イオン、例えばアルミニウム、亜鉛、鉄等を含む金属イオンにより置き換えられる、又は、有機塩基、例えばアンモニア、エチルアミン、ジエチルアミン、エチレンジアミン、N,N'-ジベンジルエチレンジアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、トロメタミン、N-メチルグルカミン、ピペラジン、クロロプロカイン、プロカイン、コリン、リジン等に配位する。
同位体濃縮は、所定の元素の同位体の相対的存在比が変わり、ひいては、ある特定の同位体として、濃縮した(すなわち増加した)元素のある形態が生成され、他の同位体の形態として、減少又は激減することによるプロセスである。本明細書で使用されている「同位体濃縮」化合物又は誘導体は、1つ又は複数の特定の同位体形態が増加した、すなわち、1つ又は複数の特定の同位体として、1つ又は複数の元素が濃縮した(すなわち、増加した)化合物を指す。一般的に、同位体濃縮化合物又は誘導体では、化合物の特定の位置で、元素の特定の同位体形態が増加する。しかし、化合物において同位体形態の2つ以上の元素が増加し得ることは、理解されるべきである。更に、同位体濃縮化合物は、特定の同位体1つ超、元素1つ超、又はその両方について濃縮した同位体濃縮形態の混合物であり得る。
ある実施形態では、本発明の化合物、例えば、式(I)〜(VI)のいずれか1つの化合物、又は薬学的に許容されるその塩、エステル、もしく溶媒和物、及び薬学的に許容される担体を含む医薬組成物が提供される。ある実施形態では、Table 1〜4(表1〜4)のいずれか1つの化合物、又は薬学的に許容されるその塩、及び薬学的に許容される担体を含む医薬組成物が提供される。別の実施形態では、式(I)〜(VI)のいずれか1つの化合物、若しくはTable 1〜4(表1〜4)のいずれか1つの化合物、又は薬学的に許容されるその塩、及び薬学的に許容される担体を含むが、但し、化合物がN-アセチル-3-アミノ-1-プロパンスルホン酸ではないことが条件である医薬組成物が提供される。
別の態様では、本明細書に記載されている有効量の化合物又は組成物を投与することにより、対象においてアミロイド-β関連疾患を防止又は処置するための方法が提供される。関連した態様では、本明細書に記載されている有効量の化合物又は組成物を投与することにより、それを必要とする対象において、アミロイド-β関連疾患を防止又は処置するための方法が提供される。
本明細書で提供される化合物及び組成物は、任意選択で、容器(例えばパッケージング、箱、バイアル等)を含むキットの一部としてパッケージされ得る。キットは、本明細書に記載されている方法に従って、商業的に使用され得、そのような方法での使用説明書を含み得る。追加のキット成分は、酸、塩基、緩衝剤、無機塩、溶媒、抗酸化剤、防腐剤又は金属キレート剤を含み得る。追加のキット成分は、純粋組成物として、又は、1つ若しくは複数の追加のキット成分を組み込む水性若しくは有機溶液として提示され得る。キット成分のいずれか又はすべては、任意選択で、緩衝液を更に含む。
一般的方法A.3-アミノ-1-プロパンスルホン酸(3APS)ナトリウム塩の調製及び使用。
天然存在比又は同位体濃縮3APSを水に溶解し、続いて1モル等量の水酸化ナトリウムを添加した。混合物を室温(r.t.)にて10min.保持し、濃縮乾固し、真空下で更に乾燥させた。固体残渣は、3APSのナトリウム塩であり、これを以下の合成で精製せずに使用した。
塩化ナトリウム又は臭化ナトリウム(例えば、2mmol)を含有する粗生成物を、水(例えば5mL)中に溶解し、続いて、Amberlite IR-120(H-form)(2mL)を添加した。混合物を3min.撹拌し、濾過した。樹脂を水(例えば、2mL×3)で洗浄した。濾液及び洗浄液を合わせ、樹脂でもう1回処理した。溶液に残った塩化物又は臭化物イオンがあれば、樹脂を用いて3回目の処理を任意で行った。このようにして得られた水溶液を濃縮乾固し(ロータリーエバポレーター)、更に乾燥させて、無塩生成物を得た。
3-アミノ-3,3-二重水素-1-プロパンスルホン酸(1)及びナトリウム3-アミノ-3,3-二重水素-1-プロパンスルホネート(1s)の合成。
3-ヒドロキシプロパンニトリル(26.0g、366mmol、1.0eq.)を乾燥THF(50mL)中に溶解した。溶液を、乾燥THF(200mL)中のLiAlD4(10.0g、238mmol、0.65eq.)の撹拌懸濁剤に滴下添加した。終夜加熱還流した後で、続いて水(4.8mL)、15%NaOH溶液(4.8mL)及び水(14.4mL)をゆっくり添加することにより、反応混合物をr.t.にて加水分解した。混合物を2時間(h)撹拌し、減圧下で濾過した。有機相を濾過により蒸発乾固し、赤色油状物質を得、これを、精製せずに次のステップで使用した。
3-((L-アラニル)アミノ)-3,3-二重水素-1-プロパンスルホン酸(2)の合成。
化合物1s(0.30g、1.80mmol、1.0eq.)及びN-Boc-L-アラニン(0.37g、2.0mmol、1.1eq.)を、乾燥DMF(10mL)中で混合し、0℃に冷却し、続いて、0℃にて、DCC(0.56g、2.7mmol、1.5eq.)及びHOBt(0.24g、1.80mmol、1.0eq.)を添加した。混合物をr.t.にて終夜撹拌し、続いて、水(2mL)を添加し、更に1時間撹拌した。不溶性物質を濾過により除去し、濾液の有機相を蒸発乾固した。残留物を20mL水中に溶解し、酢酸エチル(2×20mL)で洗浄した。水性層を蒸発乾固した。残渣は、10〜30%MeOH-CH2Cl2を溶離液として使用して、シリカゲル上でカラムクロマトグラフィーにより精製して、ナトリウム3-((N-Boc-L-アラニル)アミノ)-3,3-二重水素-1-プロパンスルホン酸(0.50g、81.3%)を白色固体として得た。この白色固体(0.50g、1.5mmol、1.0eq.)を、1N HCl(10mL)に添加し、混合物を50℃にて2h撹拌し、蒸発乾固した。イオン交換樹脂を使用することにより、塩を除去した(上の一般的方法Bに記載されているように)。粗物質を、再結晶化(MeOH及び酢酸エチル)により精製した。固体生成物を濾取し、減圧下で乾燥させ、表題化合物(2)(277mg、87.3%)を白色固体として得た。1H NMR (500 MHz, D2O): δ ppm 1.49 (d, J = 7.0 Hz, 3H), 1.92 (t, J = 8.0 Hz, 2H), 2.90 (t, J = 8.0 Hz, 2H), 3.97-4.07 (m, 1H), 8.34 (s, 1H); 13C NMR (125 MHz, D2O): δ ppm 16.47, 23.71, 48.30, 49.10, 170.69; m/z (ES-) 210.8 (M-H).
3-(L-セリルアミノ)-3,3,-二重水素-1-プロパンスルホン酸(3)の合成。
化合物1s(806mg、5.0mmol、1.0eq.)及びN-Boc-L-セリン(1.03g、5.0mmol、1.0eq)を、DMF(5mL)中で混合し、続いて、ジフェニルホスホリルアジド(DPPA)(1.51g、5.0mmol、1.0eq)及びEt3N(0.77mL)を添加した。混合物をr.t.にて終夜撹拌し、減圧下で濃縮した。残渣を、フラッシュカラムクロマトグラフィー(MeOH/DCM、1:4)により精製し、ナトリウム3-((N-Boc-L-セリル)アミノ)-3,3,-二重水素-1-プロパンスルホン酸(800mg、58.0%)を白色固体として得た。固体物質(250mg、0.71mmol、1.0eq.)を、1N HCl水溶液(10mL)中に添加し、混合物をr.t.にて1h撹拌し、減圧下で濃縮した。イオン交換樹脂を使用することにより、塩を除去した(上の一般的方法Bに記載されているように)。生成物を真空下で乾燥させ、表題化合物(3)(150mg、92.6%)を白色固体として得た。1H NMR (500 MHz, D2O) δ ppm 1.84-1.94 (m, 2H), 2.78-2.94 (m, 2H), 3.83-3.98 (m, 2H), 4.08-4.14 (m, 1H); 13C NMR (125 MHz, D2O) δ ppm 23.70, 37.80, 48.30, 54.57, 60.16, 167.59; m/z (ES+) 228.9 (M+H).
3-((L-バリル)アミノ)-3,3-二重水素-1-プロパンスルホン酸(4)の合成。
化合物1s(1.63g、10.0mmol、1.0eq。化合物1及び水酸化ナトリウムから調製した)及びN-Boc-L-バリン(2.60g、12.0mmol、1.2eq.)を、乾燥DMF(20mL)中で溶解し、続いて、0℃にて、N,N'-ジシクロヘキシルカルボジイミド(DCC、2.47g、12.0mmol、1.2eq.)及びヒドロキシベンゾトリアゾール(HOBt、1.35g、10.0mmol、1.0eq.)を添加した。混合物をr.t.にて終夜撹拌し、続いて、水(2mL)を添加し、更に1時間撹拌した。不溶性物質を濾過により除去した。濾液の有機相を蒸発乾固した。残留物を水(20mL)中に溶解し、酢酸エチル(2×20mL)で洗浄した。水性相を蒸発乾固し、残渣は、溶離液として10〜30%MeOH-CH2Cl2を使用して、シリカゲル上でカラムクロマトグラフィーにより精製し、ナトリウム3-((N-Boc-L-バリル)アミノ)-3,3-二重水素-1-プロパンスルホン酸を白色固体(3.2g、88.3%)として得た。
3-((L-フェニルアラニル)アミノ)-3,3-二重水素-1-プロパンスルホン酸(5)の合成。
化合物1s(815mg、5.0mmol、1.0eq.)及びN-Boc-L-フェニルアラニン(1.59g、6.0mmol、1.2eq.)を、乾燥DMF(20mL)中で混合した。混合物を0℃に冷却し、続いて、0℃にて、DCC(1.24g、6.0mmol、1.2eq.)及びHOBt(675mg、5.0mmol、1.0eq.)を添加した。反応混合物をr.t.にて終夜撹拌し、続いて、水(2mL)を添加し、次いで1時間撹拌した。固体物質を濾過により除去し、濾液の有機相を蒸発乾固した。残留物を水(20mL)中に溶解し、水溶液を、酢酸エチル(2×20mL)で洗浄した。水性相を分離し、蒸発乾固した。残留物を、シリカゲル(溶離液、CH2Cl2中メタノール、10から30%)上でカラムクロマトグラフィーにより精製し、ナトリウム3-((N-Boc-L-フェニルアラニル)アミノ)-3,3-二重水素-1-プロパンスルホン酸(1.80g、87.7%)を白色固体として得た。この白色固体(1.80g、4.39mmol、1.0eq.)を、1M HBr(20mL)で50℃にて2h処理し、次いで、溶媒を蒸発乾固した。残留物を、再結晶化(EtOH及び酢酸エチル)により精製した。固体を濾取し、減圧下で乾燥させ、表題化合物5(1.07g、84.5%)を白色固体として得た。1H NMR (500 MHz, D2O): δ ppm 1.67-1.80 (m, 2H), 2.54-2.68 (m, 2H), 3.05-3.28 (m, 2H), 4.14 (t, J = 6.5 Hz, 1H), 7.28 (d, J = 9.0 Hz, 2H), 7.34-7.47 (m, 3H); 13C NMR (125 MHz, D2O): δ ppm 23.44, 36.87, 37.5 (m, CD2), 48.18, 54.64, 128.04, 129.17, 129.27, 133.86, 168.81; m/z (ES-) 287.0 (M-H).
3-((L-ヒスチジル)アミノ)-3,3-二重水素-1-プロパンスルホン酸塩酸塩(6)の合成。
化合物1s(0.93g、5.74mmol、1.0eq.)及びN-Boc-L-ヒスチジン(1.47g、5.74mmol、1.0eq.)を、DMF(10mL)中で混合し、続いて、DPPA(1.74g、1.1eq.)及びEt3N(0.88mL、1.1eq.)を添加した。混合物をr.t.にて終夜撹拌した。溶媒を減圧下で除去した後で、残留物を、フラッシュカラムクロマトグラフィー(MeOH/DCM、1:3)により精製し、ナトリウム3-((N-Boc-L-ヒスチジル)アミノ)-3,3-二重水素-1-プロパンスルホン酸(1.4g、60.9%)を白色固体として得た。固体を1N HBr水溶液(10mL)中に添加した。混合物をr.t.にて1h撹拌し、減圧下で濃縮した。残留物を、再結晶化(EtOH及びH2O)により精製した。固体を濾取し、減圧下で乾燥させ、表題化合物(6)(1.25g、99.0%)を白色固体として得た。1H NMR (500 MHz, D2O) δ ppm 1.82 (d, J = 6.8 Hz, 2H), 2.78 (t, J = 7.0 Hz, 2H) , 3.37 (s, 2H) , 4.21 (d, J = 6.0 Hz, 1H) , 7.44 (s, 1H), 8.71 (s, 1H); 13C NMR (125 MHz, D2O) δ ppm 23.55, 25.99, 48.21, 52.30, 118.30, 125.91, 134.32, 167.69; m/z (ES+) 278.9 (M+H).
3-(15N-アミノ)-1-プロパンスルホン酸(7)の合成。
封管中のMeOH(10mL)中の1,3-プロパンスルトン(0.61g、5.0mmol、1.0eq.)の溶液に、15N-標識硫酸アンモニウム(1.0g、7.5mmol、1.5eq.)及びNaOH(0.5g、12.5mmol、2.5eq.)を添加した。混合物を70℃にて終夜撹拌し、続いて、NaHCO3(0.63g、7.5mmol、1.5eq.)及び二炭酸ジ-(tert-ブチル)(1.64g、7.5mmol、1.5eq.)を添加した。3h加熱還流した後で、反応混合物を蒸発乾固した。残留物をMeOHで処理し、不溶性物質を濾過により除去した。濾液を蒸発乾固し、残留物を、シリカゲル(溶離液、30%MeOH-DCM)上でフラッシュカラムクロマトグラフィーにより精製して、ワックス状固体を得た。この物質を、1N HBr(20mL)で処理し、混合物を50℃にて2h撹拌した。混合物を蒸発乾固し、残留物を、再結晶化(EtOH及びH2O)により精製した。固体を濾取し、減圧下で乾燥させ、3-(15N-アミノ)-1-プロパンスルホン酸(7)(398mg、56.8%)を白色固体として得た。1H NMR (500 MHz, D2O): δ ppm 2.06-2.16 (m, 2H), 3.01 (t, J = 7.5 Hz, 2H), 3.15 (t, J = 7.5 Hz, 2H); 13C NMR (125 MHz, D2O): δ ppm 22.23, 38.17 (d, J = 5.0 Hz), 47.82; m/z (ES+) 140.8 (M+H).
3-(L-バリル-(15N-アミノ))-1-プロパンスルホン酸(10)の合成。
封管中の20mL MeOH/H2O(1:1)中の1,3-プロパンスルトン(1.22g、10.0mmol、1.0eq.)の溶液に、15N-標識硫酸アンモニウム(2.0g、15.0mmol、1.5eq.)及びNaOH(1.0g、25mmol、2.5eq.)を添加した。混合物を70℃にて終夜撹拌し、続いて、トリエチルアミン(1.51g、15.0mmol、1.5eq.)及び二炭酸ジ-tert-ブチル(3.27g、15.0mmol、1.5eq.)を添加した。3h加熱還流した後で、反応混合物を蒸発乾固した。残留物をMeOHで処理し、不溶性物質を濾過により除去した。濾液を蒸発乾固し、残留物を、シリカゲル(溶離液、30%MeOH-DCM)上でフラッシュカラムクロマトグラフィーにより精製して、ワックス状固体を得た。この物質を1N HCl(30mL)で処理し、混合物を50℃にて2h撹拌した。混合物を蒸発乾固し、残留物3-(15N-アミノ)-1-プロパンスルホン酸(7)は、更なる精製をせずに次のステップで使用した。
3-((18O-L-アラニル)アミノ)-1-プロパンスルホン酸(13)の合成。
L-アラニン(0.91g、10.2mmol、1eq.)を、ジオキサン(5.2mL、20.8mmol、2eq.)中の4M HCl溶液に添加し、続いて、H2 18O(1.8mL、18O-濃縮、98%)を添加した。封管中の混合物を100℃にて24h撹拌し、r.t.に冷却し、蒸発乾固した。残留物を、ジオキサン(2.6mL、10.2mmol、1eq.)中の4M HCl溶液中に取り込み、続いて、H2 18O(1.6mL、18O-濃縮、98%)を添加した。封管中の混合物を100℃にて24h撹拌し、r.t.に冷却し、減圧下で蒸発乾固し、L-アラニン-18O2・HCl(1.32g、100%、18O-濃縮、92%)を白色固体として得た。MeOH(50mL)中のL-アラニン-18O2・HCl(1.32g、10.2mmol、1eq.)1の溶液に、N,N-ジイソプロピルエチルアミン(DIPEA)(4.07mL、22.5mmol、2.2eq.)を添加し、続いて、Boc2O(2.55g、11.2mmol、1.1eq.)を添加した。混合物を50℃にて1h撹拌し(混合物は、この時点で透明になる)、r.t.に冷却し、減圧下で濃縮乾固し、N-Boc-L-アラニン-18O2 DIPEA塩を白色固体として得、これを、更なる精製をせずに次のステップに使用した。DIPEA塩(1eq.、上のステップから得た)を、DMF(40mL)中のp-ニトロフェノール(1.59g、11.22mmol、1.1eq.)の溶液に添加し、続いて、DCC(3.21g、15.3mmol、1.5eq.)を添加した。混合物をr.t.にて終夜撹拌した。反応混合物を濾過し、濾液を減圧下で濃縮した。残渣を、フラッシュカラムクロマトグラフィー(酢酸エチル/pet-エーテル、1:10)により精製して、対応するp-ニトロフェニルエステルを白色固体として得た。このようにして得られた固体を、DMF(30mL)中に溶解し、続いて、ナトリウム3-アミノ-1-プロパンスルホネート(1.72g、10.2mmol、1.0eq.)を添加した。混合物を35℃にて終夜撹拌し、次いで減圧下で濃縮した。残渣を、フラッシュカラムクロマトグラフィー(溶離液、MeOH/DCM、1:8)により精製し、ナトリウム3-((N-Boc-L-18O-アラニル)アミノ)-1-プロパンスルホン酸(1.5g、4.49mmol、上のステップでの全収率、44%)を白色固体として得た。ナトリウム3-((N-Boc-L-18O-アラニル)アミノ)-1-プロパンスルホン酸(1.5g、4.49mmol)を、1N HCl水溶液(20mL)中に溶解した。混合物をr.t.にて1h撹拌し、蒸発乾固した。イオン交換樹脂を使用することにより、塩を除去した(一般的方法B)。生成物を真空下で乾燥させ、表題化合物(13)(0.78g、82.0%)を白色固体として得た。18O-濃縮、92%、1H NMR (D2O, 500 MHz) δ ppm 1.46-1.51 (m, 2 H), 1.88-1.97 (m, 2 H), 2.86-2.92 (m, 2H), 3.30-3.37 (m, 2H), 4.20 (q, 1H, J = 5 Hz); 13C NMR (D2O, 125 MHz) δ ppm 16.45, 23.88, 38.05, 48.33, 49.08, 170.62; m/z (ES-) 211.0 (M-H).
3-((18O-L-バリル)アミノ)-1-プロパンスルホン酸(15)の合成。
18O-水(1.5g、75.0mmol、98原子%の18O)中のL-バリン(1.2g、10.2mmol)の溶液に、1,4-ジオキサン(5.1mL、20.4mmol)中の4N HClをゆっくり添加した。混合物は、ストッパーで封をし、100℃にて24h加熱し、次いでr.t.に冷却し、蒸発させて(60℃の浴温まで)乾燥させた。上のプロセスをもう1回繰り返し、18O-L-バリン塩酸塩を黄色固体(1.57g、100%、91.4原子%の18O)として得、これを、次のステップに直接使用した。
3-((18O-L-フェニルアラニル)アミノ)-1-プロパンスルホン酸(16)の合成。
L-フェニルアラニン(1.0g、6.05mmol、1.0eq.)及び18O-水(1.3mL、98原子%の18O)の混合物に、1,4-ジオキサン(3.0mL、12.0mmol、2.0eq.)中の飽和塩酸塩(HCl)溶液を添加した。混合物を100℃にて24h撹拌し、次いでr.t.に冷却し、減圧下で蒸発乾固した。残留物に、18O-水(1.5mL、98原子%の18O)を添加し、続いて、1,4-ジオキサン(1.6mL)中のHCl溶液を添加した。混合物を100℃にて24h撹拌し、次いでr.t.に冷却し、減圧下で蒸発乾固し、18O-L-フェニルアラニンを白色固体(1.0g、100%、96%の18O-濃縮)として得た。
3-((18O-L-ヒスチジル)アミノ)-1-プロパンスルホン酸臭化水素酸塩(17)の合成。
L-ヒスチジン(1.55g、10mmol、1.0eq.)を、ジオキサン(7.5mL、30mmol、3.0eq.)中の4M HClの溶液に添加し、続いて、H2 18O(2.0g、98%18O-濃縮)を添加した。封管中の混合物を100℃にて24h撹拌した。反応混合物をr.t.に冷却し、真空下で乾燥させた。残渣に、ジオキサン(2.5mL、10mmol、1.0eq.)中の4M HClを添加し、続いて、H2 18O(2.0g、18O-濃縮、98%)を添加した。封管中の混合物を100℃にて24h撹拌した。反応混合物をr.t.に冷却し、蒸発乾固し、更に真空下で乾燥させて、L-His-18O2・2HCl(2.32g、100%、93.8%の18O-濃縮を有する)をオフホワイト固体として得た。18O-濃縮L-ヒスチジン二塩酸塩(2.32g、10mmol、1.0eq.)を、MeOH(50mL)中に溶解し、続いて、Et3N(4.55g、45mmol、4.5eq.)及びBoc2O(5.45g、25mmol、2.5eq.)を添加した。混合物を50℃にて1h撹拌し(混合物は、この時点で透明になる)、次いでこれをr.t.に冷却し、減圧下で濃縮して、対応するTEA塩を薄黄色固体として得た。この薄黄色物質(1.0eq.)を、DCM(40mL)中のp-ニトロフェノール(1.39g、10mmol、1.0eq.)の溶液に添加し、続いて、DCC(2.27g、11mmol、1.1eq.)を添加した。混合物をr.t.にて終夜撹拌した。不溶性物質を濾過により除去し、濾液を減圧下で濃縮した。残留物を、フラッシュカラムクロマトグラフィー(溶離液、DCM/EA/PE、2:1:7)により精製して、対応する4-ニトロフェニルエステル(3.0g、63.0%)を白色固体として得た。エステル(3.0g、6.27mmol、1.0eq.)をDMF(30mL)中に溶解し、続いて、ナトリウム3-アミノプロパン-1-スルホネート(1.0g、6.27mmol、1.0eq.)を添加した。混合物をr.t.にて終夜撹拌した。反応混合物を減圧下で濃縮し、残留物を、フラッシュカラムクロマトグラフィー(溶離液、MeOH/DCM、1:8)により精製して、ナトリウム3-((N,1-ビスBoc-(18O-L-ヒスチジル))アミノ)-1-プロパンスルホン酸(2.27g、72.3%)を白色固体として得た。白色固体(2.27g、4.7mmol)を、1N HBr水溶液(20mL)中に取り込んだ。混合物をr.t.にて1h撹拌し、減圧下で濃縮し、真空下で乾燥させた。残留物を、再結晶化(EtOH及びH2O)により精製した。固体を濾取し、減圧下で乾燥させ、表題化合物(17)(1.5g、92.0%)を白色固体として得た。18O-濃縮、93.7%、1H NMR (D2O, 500 MHz) δ ppm 1.77-1.94 (m, 2 H), 2.72-2.88 (m, 2H), 3.22-3.32 (m, 1H), 3.32-3.46 (m, 3H), 4.18-4.28 (m, 1H), 7.47 (s, 1H), 8.74 (s, 1H); 13C NMR (D2O, 125 MHz) δ ppm 23.75, 25.98, 38.17, 48.26, 52.33, 118.30, 125.95, 134.34, 167.68; m/z (ES+) 279.0 (M+H).
3-((1-13C-L-バリル)アミノ)-1-プロパンスルホン酸(25)の合成。
ナトリウム3-アミノ-1-プロパンスルホン酸(1.10g、6.8mmol、1.5eq.)及びN-Boc-L-バリン-1-13C(1.0g、4.61mmol、1.0eq.)を、乾燥DMF(10mL)中に溶解し、続いて、0℃にて、N,N'-ジシクロヘキシルカルボジイミド(DCC、1.4g、6.8mmol、1.5eq.)及びヒドロキシベンゾトリアゾール(HOBt、0.62g、4.61mmol、1.0eq.)を添加した。混合物をr.t.にて終夜撹拌し、続いて、水(2mL)を添加し、更に1時間撹拌した。不溶性物質を濾過により除去した。濾液の有機相を蒸発乾固した。残留物を水(20mL)中に溶解し、酢酸エチル(2×20mL)で洗浄した。水性相を蒸発乾固し、残渣を、シリカゲル(溶離液、MeOH-CH2Cl2、10〜30%)上でカラムクロマトグラフィーにより精製し、ナトリウム3-((N-Boc-1-13C-L-バリル)アミノ)-1-プロパンスルホン酸を白色固体(1.2g、72.0%)として得た。
3-((18O-L-バリル)アミノ)-3,3-二重水素-1-プロパンスルホン酸(29)の合成。
化合物1s(250mg、1.53mmol、1.0eq.)及びN-Boc-L-(1,1-ジ-18O)-バリン4-ニトロフェニルエステル(624mg、1.84mmol、1.2eq.)を、乾燥DMF(20mL)中で混合した。混合物をr.t.にて終夜撹拌し、続いて減圧下で蒸発乾固した。残留物を、シリカゲル(溶離液、CH2Cl2中のMeOH、10から30%)上でカラムクロマトグラフィーにより精製し、ナトリウム3-((N-Boc-18O-L-バリル)アミノ)-3,3-二重水素-1-プロパンスルホン酸(400mg、71.7%)を白色固体として得た。この固体物質を、1N HCl(30mL)と混合し、混合物を50℃にて2h撹拌した。混合物を蒸発乾固した。イオン交換樹脂を使用することにより、塩を除去した(一般的方法B)。残留物を、再結晶化(EtOH及びH2O)により精製した。固体を濾取し、減圧下で乾燥させ、表題化合物29(283mg、89.8%)を白色固体として得た。1H NMR (500 MHz, D2O): δ ppm 1.00-1.08 (m, 6H), 1.97 (t, J = 7.5 Hz, 2H), 2.16-2.26 (m, 1H), 2.94 (t, J = 8.0 Hz, 2H), 3.75 (d, J = 6.0 Hz, 1H), 8.48 (s, 1H); 13C NMR (125 MHz, D2O): δ ppm 17.03, 17.59, 23.75, 29.81, 37.59 (m, CD2), 48.42, 58.79, 169.16; m/z (ES-) 240.9 (M-H).
3-((L-システイニル)アミノ-)-3,3-二重水素-1-プロパンスルホン酸(33)の合成。
化合物1s(0.7g、4.3mmol、1.0eq.)及びN-Boc-L-システイン(1.4g、4.3mmol、1.0eq.)を、乾燥DMF(15mL)中に溶解し、続いて、0℃にDCC(1.4g、6.5mmol、1.5eq.)及びHOBt(0.6g、4.6mmol、1.1eq.)を添加した。混合物をr.t.にて終夜撹拌し、続いて、水(2mL)を添加し、更に1時間撹拌した。不溶性物質を濾過により除去した。濾液の有機相を蒸発乾固した。残留物を水(20mL)中に溶解し、酢酸エチル(2×20mL)で洗浄した。水性相を蒸発乾固し、残渣を、シリカゲル(溶離液、MeOH-CH2Cl2、10〜30%)上でカラムクロマトグラフィーにより精製し、ナトリウムN-Boc-3-((L-システイニル)アミノ-)-3,3-二重水素-1-プロパンスルホン酸を白色固体(1.2g、59.8%)として得た。上で得られたBoc-保護化合物(1.2g、2.57mmol、1.0eq.)を、1N HCl(30mL)中で50℃にて2h撹拌した。混合物を蒸発乾固した。イオン交換樹脂を使用することにより、塩を除去した(一般的方法B)。残留物を再結晶化(EtOH及びH2O)により精製した。結晶性固体を濾取し、減圧下で乾燥させ、表題化合物(33)(0.57g、83.3%)を白色固体として得た。1H NMR (500 MHz, D2O): δ ppm 1.97 (t, J = 7.5 Hz, 2H), 2.95 (t, J = 6.0 Hz, 2H), 3.01-3.13 (m, 2H), 4.16 (t, J = 6.0 Hz, 1H); 13C NMR (125 MHz, D2O): δ ppm 23.70, 24.73, 48.34, 54.55, 167.83; m/z (ES+) 244.9 (M+H).
同位体濃縮3-((N-置換)アミノ)-1-プロパンスルホン酸及びその塩の合成の一般的な例。
実施例1から15に記載されている実験手順を用いて、当業界で一般的な合成技術を使用した妥当な変更の有無を問わず、式IからVIにより表される他の化合物を合成できる。そのような化合物の例は、3-(アシルアミノ)-3,3-二重水素-1-プロパンスルホン酸及び3-(アシル(15N-アミノ))-1-プロパンスルホン酸を含むが、それらに限定されず、アシル基は、アルギニル、アスパルチル、アスパラギル、シスチル、システイニル、グルタミル、グルタミニル、グリシル、イソロイシル、ロイシル、リジル、メチオニル、プロリル、セレノシスチル、トレオニル、トリプトファニル、チロシル及び4-ヒドロキシイソロイシルから選択される。同様に、式I及びVIによる3-((1-13C-アシル)アミノ)-1-プロパンスルホン酸、3-((1-18O-アシル)アミノ)-1-プロパンスルホン酸及び3-((1-17O-アシル)アミノ)-1-プロパンスルホン酸は、同一のアシル基のセットで調製できる。アシル基は、医薬品に有用な他の天然アミノ酸及び/又はカルボン酸も含み得る。化合物は、一般的な合成技術を使用して、塩及びエステル形態でも調製できる。
模擬胃液(SGF)中での化合物安定性の評価。
化合物を、模擬胃液(SGF)中での安定性について評価した。SGF(400μg/mL)中の化合物の溶液を、37℃にて4hインキュベートした。試料のアリコートは、時間0及び時間4hにおいて、LC-MS/MS機器での濃度分析のために抜き取った。化合物の初期濃度(時間0で)を、1とみなし、4h時点における残りの化合物の濃度を計算し、初期濃度の割合として表現した。化合物1、4、5、15、16及び17に対する模範的な結果は、Table 5(表5)で示されている。
マウス全血中の化合物安定性の評価。
化合物を、マウス全血中における安定性についても評価した。新鮮なマウス血液中におけるテスト化合物の試料(1.44μMの濃度で)を、37℃にて4hインキュベートした。試料のアリコートは、標準的な試料の調製手順を用いた血液試料の分析試料への変換後に、LC-MS/MS機器で濃度分析するために、時間5min及び時間4hで抜き取った。化合物の具体的な回収は、念入りに評価せず、最適化した。試料を、未変化体及び治療化合物について分析した。Table 6(表6)は、化合物1、2、4、5、15、16、17及び29についての模範的な結果を示し、テスト化合物及び化合物1を、5min、及び/又は4hで分析した。
本発明の化合物の薬物動態学的研究の一般的方法。
本発明による化合物は、化合物が投与される特定の動物に望ましい用量及び投与体積により決定した濃度で水中に溶解する。計算された体積の投与溶液が、動物に投与される(PO、SQ、IP又はIV)。血液試料は、化合物を投与した後に、特定の時点(例えば10min.、30min.、1h、2h、4h、8h及び12h)で収集する。血液試料を、標準的技術を使用して血漿試料に変換する。脳試料も、完全に灌流した後で収集する。血漿及び/又は脳試料を分析して、関連化合物(例えば、投与化合物、治療化合物(例えば、薬物)及び代謝産物を含む)の濃度を決定した。
ICRマウスにおける本発明の化合物の薬物動態学的研究。
体重19から21gの雄ICRマウス42匹を、7群に無作為化する。動物に、強制経口投与によりテスト化合物水溶液を投与する。血液試料は、投与した後の時間0.167、0.5、1、2、4、8及び12hで、ヘパリン抗凝固剤を予め充填した管内に収集する。血液試料を遠心分離し、テスト化合物(投与される化合物、代謝産物及び/又はプロドラッグを含む)を分析するために、血漿試料を単離する。各動物から400μL血液試料を収集し、次いで動物をバルビツレート麻酔で眠らせ、生理食塩水を用いて、5mL/min.の速度で6min.灌流を行う(心臓の主要な静脈を介して)。脳を収集し、-40℃にて試料が分析されるまで保持する。血漿中のタンパク質を沈殿させ、分析試料をAB4000-Q-Trap UPLC-MS/MS機器で分析する。
Sprague-Dawley(SD)ラットでの3APS(天然存在比)、化合物1及び化合物4の薬物動態学的研究。
薬物動態学的研究は、Sprague-Dawley(SD)ラットで行った。実験は、実施例21に記載されている同一のプロトコールを使用して行い、動物18匹を3群(各群に6匹、3APS(天然存在比)に1群、化合物1に1群、及び化合物4に他の群)に分けた。研究の主要なPKパラメータ及び結果は、Table 7(表7)で要約されている。
C57Bl6マウスでの化合物の薬物動態学的研究。
薬物動態学的研究をC57Bl6マウスで行った。実験は、実施例20に記載されているものと同一のプロトコールを使用して行った。各化合物に対して、動物42匹を使用した(時点ごとに動物6匹、時点を10min、0.5、1、2、4、8及び12hの7時点に振り分けた)。研究の主要なPKパラメータ及び結果は、Table 8(表8)で要約されている。
アルツハイマー病の動物モデルにおける本発明の化合物の効能。
APP/PS1トランスジェニックマウス(7ヶ月齢、雄及び雌の両方)100匹を、モデル対照、陽性対照、並びに、低、中及び高用量テスト群の5群(各群に20匹)に無作為化した。野生型C57BL/6Jマウス(7ヶ月齢、雄及び雌の両方)20匹の1群も、正常対照として使用した。研究室の環境に5日間適応させた後で、動物を、強制経口投与により1日1回、週に6日、3ヶ月連続して、ビヒクル、対照化合物又はテスト化合物でそれぞれ処置した。処置の終わりに、動物に、Y迷路テスト、Morris水迷路テスト、並びに、短期間及び長期間の記憶を測定するように設計されている他のテストを含む行動評価を施す。最終的に、動物を屠殺し、様々な生化学的及び分子的評価、例えばAβ(1〜40及び1〜42を含む、可溶性、プラーク及び全体)、P-タウ、GSK-3β、SYP、PSD95、NMDAR2B、p-NMDAR2B、CaMKII、p-CaMKII等、並びに、炎症及び関連した生理学的条件についての様々なパラメータを施す。
APP/PS1マウスの動物脳アミロイドプラークの画像解析。
二重トランスジェニックAPP/PS1マウス(詳細な説明、C57BL/6JNjuバックグラウンドのB6/JNju-Tg(APPswe、PSEN1dE9)/Nju)、4ヶ月齢を群に無作為化した。動物は、生理食塩水又は化合物4を用いて、170mg/kg(低用量)又は340mg/kg(高用量)の用量で、皮下注入により1日1回処置した。処置の持続時間は3ヶ月であった。研究の終わりに、動物に、400〜800mL/分のガス流量で1〜2%イソフルランを用いてMatrx小動物麻酔器(VIP 3000(登録商標)、MIDMARK社、USA)で麻酔をかけた。麻酔をかけた動物は、小動物用のPET/CTベッドに置き、イソフルランを供給し続けた。18F-AV45は、必要に応じて生理食塩水で希釈し、希釈した18F-AV45溶液を、尾静脈注入を介してテスト動物に投与した。各動物に、100±20μCiの用量で18F-AV45を与えた。PET/CTダイナミックスキャンは、注入の直後に記録し、スキャニングエネルギーウィンドウを350〜650Kevにセットして30min続けた。収集した生データを加工し、画像の再構成を行った、再構成アルゴリズム、OSEM 3D、反復数2回。次いで、画像及びデータをPMODソフトウェアで加工した。脳領域に対する加工した画像は、写真として提示し(図3)、%ID/g(グラム当たりの放射能取り込み速度)について計算したデータをグラフとして示した(図4)。
Claims (25)
- 式(II)
Xは、天然存在比の窒素同位体若しくは 15 N、又は 15 Nが富化された窒素同位体であり、
Rが、天然存在比の水素同位体、重水素(D)、又は重水素が富化された水素同位体であり、
式(II)のC、H、S、及びOはそれぞれ天然存在比の炭素、水素、硫黄、及び酸素の同位体を表し、
但し、X及びRの少なくとも1つが、天然存在比ではない同位体からなることを条件とする)、
又は薬学的に許容されるその塩。 - Rが、天然存在比の水素同位体である、請求項1に記載の同位体異性体又はその薬学的に許容される塩。
- RがD(重水素)である、請求項1に記載の同位体異性体又はその薬学的に許容される塩。
- 式(IV)
R4が、天然アミノ酸の側鎖であり、
Xは、天然存在比の窒素同位体若しくは 15 N、又は 15 Nが富化された窒素同位体であり、
O*が、天然存在比の酸素同位体、18O、17O又はそれらの組合せであり、
C*が、天然存在比の炭素同位体、13C又はそれらの組合せであり、
式(IV)のN,C、H、S、及びOはそれぞれ天然存在比の窒素、炭素、水素、硫黄、及び酸素の同位体を表す)
又は薬学的に許容されるその塩。 - 式(V)
R4が、天然アミノ酸の側鎖であり、
O*が、天然存在比の酸素同位体、18O、17O又はそれらの組合せであり、
C*が、天然存在比の炭素同位体、13C又はそれらの組合せであり、
式(V)のN,C、H、S、及びOはそれぞれ天然存在比の窒素、炭素、水素、硫黄、及び酸素の同位体を表す)
又は薬学的に許容されるその塩。 - 式(VI)
R4が、天然アミノ酸の側鎖であり、
O#が、天然存在比の酸素同位体、18O、17O又はそれらの組合せであり
C#が、天然存在比の炭素同位体、13C又はそれらの組合せであり、
式(VI)のN,C、H、S、及びOはそれぞれ天然存在比の窒素、炭素、水素、硫黄、及び酸素の同位体を表し、
但し、O#及びC#の少なくとも1つが、同位体濃縮原子であることを条件とする)、又は薬学的に許容されるその塩。 - 3-(15N-アミノ)-1-プロパンスルホン酸、又は薬学的に許容されるその塩。
-
-
-
- 3-アミノ-3,3-二重水素-1-プロパンスルホン酸
- 天然存在比ではない同位体を有する同位体異性体における同位体濃縮のレベルが、2%以上、5%以上、10%以上、20%以上、50%以上、75%以上、90%以上、95%以上、又は100%である、請求項1から6のいずれか一項に記載の同位体異性体。
- 請求項1から6及び12のいずれか一項に記載の同位体異性体若しくは薬学的に許容されるその塩又は請求項7から11のいずれか一項に記載の化合物若しくは薬学的に許容されるその塩、及び薬学的に許容される担体を含む、医薬組成物。
- 経口投与に適している、請求項13に記載の医薬組成物。
- ハードシェルゼラチンカプセル剤、ソフトシェルゼラチンカプセル剤、カシェ剤、丸剤、錠剤、ロゼンジ剤、散剤、粒剤、ペレット剤、トローチ剤又は糖衣錠剤の形態である、請求項13又は14に記載の医薬組成物。
- 液剤、水性液体懸濁剤、非水性液体懸濁剤、水中油液体エマルション剤、油中水液体エマルション剤、エリキシル剤、又はシロップ剤の形態である、請求項13又は14に記載の医薬組成物。
- 腸溶性コーティングされている、請求項14又は15に記載の医薬組成物。
- 制御放出のために配合されている、請求項13〜15及び17のいずれか一項に記載の医薬組成物。
- アミロイド-β関連疾患の防止又は処置を必要とする対象において、当該疾患を防止又は処置するための、請求項13〜18のいずれか一項に記載の医薬組成物。
- アミロイド-β関連疾患が、アルツハイマー病、軽度認知欠陥(MCI)、ダウン症候群、オランダ型アミロイドーシスを伴う遺伝性脳出血、脳アミロイド血管症、変性認知症、血管及び変性原因が混在する認知症、パーキンソン病に関連する認知症、進行性核上性麻痺に関連する認知症、大脳皮質基底核変性症に関連する認知症又はびまん性レビー小体型アルツハイマー病に関連する認知症である、請求項19に記載の医薬組成物。
- アミロイド-β関連疾患が、アルツハイマー病、軽度認知欠陥、脳アミロイド血管症又は変性認知症である、請求項19に記載の医薬組成物。
- アミロイド-β関連疾患が、アルツハイマー病である、請求項19に記載の医薬組成物。
- 対象が、ApoE4陽性である、請求項19から22のいずれか一項に記載の医薬組成物。
- 対象において、アルツハイマー病を防止又は処置するための医薬組成物であって、治療有効量の3-アミノ3,3-二重水素-1-プロパンスルホン酸
- 対象において、アルツハイマー病を防止又は処置するための医薬組成物であって、治療有効量の3-(15N-アミノ)-1-プロパンスルホン酸、又は薬学的に許容されるその塩を含む医薬組成物。
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