JP6814814B2 - Taarのアゴニストとしての活性を有する5−エチル−4−メチル−ピラゾール−3−カルボキサミド誘導体 - Google Patents
Taarのアゴニストとしての活性を有する5−エチル−4−メチル−ピラゾール−3−カルボキサミド誘導体 Download PDFInfo
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- JP6814814B2 JP6814814B2 JP2018545336A JP2018545336A JP6814814B2 JP 6814814 B2 JP6814814 B2 JP 6814814B2 JP 2018545336 A JP2018545336 A JP 2018545336A JP 2018545336 A JP2018545336 A JP 2018545336A JP 6814814 B2 JP6814814 B2 JP 6814814B2
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- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940125425 inverse agonist Drugs 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
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- 239000008101 lactose Substances 0.000 description 1
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- 238000012417 linear regression Methods 0.000 description 1
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- 230000007774 longterm Effects 0.000 description 1
- 238000003819 low-pressure liquid chromatography Methods 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 229960002510 mandelic acid Drugs 0.000 description 1
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- 230000028161 membrane depolarization Effects 0.000 description 1
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- SYHGEUNFJIGTRX-UHFFFAOYSA-N methylenedioxypyrovalerone Chemical compound C=1C=C2OCOC2=CC=1C(=O)C(CCC)N1CCCC1 SYHGEUNFJIGTRX-UHFFFAOYSA-N 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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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
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- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 208000019116 sleep disease Diseases 0.000 description 1
- ZNJHFNUEQDVFCJ-UHFFFAOYSA-M sodium;2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid;hydroxide Chemical compound [OH-].[Na+].OCCN1CCN(CCS(O)(=O)=O)CC1 ZNJHFNUEQDVFCJ-UHFFFAOYSA-M 0.000 description 1
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- RYLFTAZSKDUPAA-UHFFFAOYSA-N tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCOC1C1=CC=C(N)C=C1 RYLFTAZSKDUPAA-UHFFFAOYSA-N 0.000 description 1
- JDDPITNKUXPLSB-UHFFFAOYSA-N tert-butyl morpholine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCOCC1 JDDPITNKUXPLSB-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description
−ヒトTAAR1受容体における強力なアゴニスト活性、
−ドーパミントランスポーター(DAT)に対する選択性、
−hERGイオンチャネルに対する選択性、
−低い両親媒性ベクトルであり、そのため、薬物誘導性リン脂質症(DIPL)を引き起こすリスクが低いこと(下記参照)。
a)式:
[式中、PGは、−C(O)O−tert−ブチル(BOC)から選択されるN保護基である]
で示される化合物にすること、及び
所望により、得られた化合物を薬学的に許容し得る酸付加塩に変換すること
を含む、プロセスによって調製することができる。
本明細書中に記載の化合物及び中間体の単離及び精製は、所望により、例えば、濾過、抽出、結晶化、カラムクロマトグラフィー、薄層クロマトグラフィー、厚層クロマトグラフィー、分取の低圧若しくは高圧液体クロマトグラフィー、又はこれらの手順の組合せのような任意の好適な分離又は精製手順によって達成することができる。好適な分離及び単離手順の具体的な説明は、本明細書中で後述する調製例及び実施例を参照すれば分かる。しかしながら、他の等価の分離又は単離手順も当然使用することができよう。式Iで示されるキラル化合物のラセミ混合物は、キラルHPLCを用いて分離することができる。キラル合成中間体のラセミ混合物もまた、キラルHPLCを用いて分離されよう。
式Iで示される化合物は塩基性であり、そして、対応する酸付加塩に変換してもよい。変換は、少なくとも化学量論量の適切な酸(例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸など)及び有機酸(例えば、酢酸、プロピオン酸、グリコール酸、ピルビン酸、シュウ酸、リンゴ酸、マロン酸、コハク酸、マレイン酸、フマル酸、酒石酸、クエン酸、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、p−トルエンスルホン酸、サリチル酸など)との処理によって達成される。典型的には、遊離塩基をジエチルエーテル、酢酸エチル、クロロホルム、エタノール又はメタノールなどのような不活性有機溶媒中に溶解し、そして、酸を同様の溶媒中で加える。温度は0℃〜50℃の間に維持される。得られた塩は自然に沈殿するか、又はより極性の低い溶媒を用いて溶液から取り出してもよい。
5−エチル−4−メチル−N−[4−[(2S)−モルホリン−2−イル]フェニル]−1H−ピラゾール−3−カルボキサミド
(2S)−2−(4−アミノフェニル)モルホリン−4−カルボン酸tert−ブチル(CAS RN: 1260220-43-6、350mg、1.26mmol、1.00当量)及び5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸(CAS RN: 957129-38-3、245mg、1.51mmol、1.20当量)のTHF(8ml)中の撹拌溶液に、TBTU(807mg、2.51mmol、2.00当量)及びN−メチルモルホリン(509mg、553μl、5.03mmol、4.00当量)を加えた。反応混合物を50℃で15時間撹拌した。t=15hでのTLCは、反応が完了したことを示した。反応混合物を減圧濃縮した。粗物質をフラッシュクロマトグラフィー(シリカゲル、溶離剤:ヘプタン中 0%〜100% EtOAc)により精製して、(2S)−2−[4−[(5−エチル−4−メチル−1H−ピラゾール−3−カルボニル)アミノ]フェニル]モルホリン−4−カルボン酸tert−ブチル(501mg、96%)をオフホワイト色の固体として得た。MS(ISP):413.7([M−H]−)。
トリフルオロ酢酸(1.37g、918μl、12.0mmol、10当量)の水(8ml)中の撹拌溶液に、(2S)−2−[4−[(5−エチル−4−メチル−1H−ピラゾール−3−カルボニル)アミノ]フェニル]モルホリン−4−カルボン酸tert−ブチル(497mg、1.2mmol、1.00当量)のアセトニトリル(4ml)中懸濁液を加えた。反応混合物を80℃で3時間撹拌した。t=3hでのMSは、反応が完了したことを示した。反応混合物を1M NaOH水溶液に注ぎ入れ、EtOAcで2回抽出した。有機層をNa2SO4で乾燥させ、減圧濃縮した。粗物質をフラッシュカラムクロマトグラフィー(SiliaSep(商標)アミンカートリッジ、溶離剤:ヘプタン中 0%〜100% EtOAc、次に、EtOAc中 0%〜10% MeOH)により精製して、5−エチル−4−メチル−N−[4−[(2S)−モルホリン−2−イル]フェニル]−1H−ピラゾール−3−カルボキサミド(327mg、87%)をオフホワイト色の固体として得た。MS(ISP):315.7([M+H]+)。
(比較例)
5−エチル−4−メチル−N−[4−[(2R)−モルホリン−2−イル]フェニル]−1H−ピラゾール−3−カルボキサミド
工程(a)において(2S)−2−(4−アミノフェニル)モルホリン−4−カルボン酸エステルの代わりに(2R)−2−(4−アミノフェニル)モルホリン−4−カルボン酸エステル(CASRN:1260220-42-5)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):315.6([M+H]+)。
(比較例)
N−[4−[(2S)−モルホリン−2−イル]フェニル]−6−(2,2,2−トリフルオロエトキシ)ピリジン−3−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに6−(2,2,2−トリフルオロエトキシ)ニコチン酸(CAS RN: 159783-29-6)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):382.1([M+H]+)。
(比較例)
6−クロロ−N−[4−[(2S)−モルホリン−2−イル]フェニル]ピリジン−3−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに6−クロロ−ニコチン酸(CAS RN: 5326-23-8)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):320.1([{37Cl}M+H]+)、318.2([{35Cl}M+H]+)。
(比較例)
2−クロロ−N−[4−[(2S)−モルホリン−2−イル]フェニル]ピリジン−4−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに2−クロロ−イソニコチン酸(CAS RN: 6313-54-8)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):320.1([{37Cl}M+H]+)、318.1([{35Cl}M+H]+)。
(比較例)
N−[4−[(2S)−モルホリン−2−イル]フェニル]−2−フェニル−1,3−チアゾール−5−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに2−フェニルチアゾール−5−カルボン酸(CAS RN: 10058-38-5)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):366.1([M+H]+)。
(比較例)
2,6−ジクロロ−N−[4−[(2S)−モルホリン−2−イル]フェニル]ピリジン−4−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに2,6−ジクロロ−イソニコチン酸(CAS RN: 5398-44-7)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):356.1([{37Cl}M+H]+)、354.1([{37Cl35Cl}M+H]+)、352.1([{35Cl}M+H]+)。
(比較例)
4−メチル−N−[4−[(2S)−モルホリン−2−イル]フェニル]−5−フェニル−1H−ピラゾール−3−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに4−メチル−5−フェニル−1H−ピラゾール−3−カルボン酸(CAS RN: 879770-33-9)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):363.2([M+H]+)。
(比較例)
5,6−ジクロロ−N−[4−[(2S)−モルホリン−2−イル]フェニル]ピリジン−3−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに5,6−ジクロロ−ニコチン酸(CAS RN: 41667-95-2)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):356.1([{37Cl35Cl}M+H]+)、354.1([{37Cl}M+H]+)、352.1([{35Cl}M+H]+)。
(比較例)
6−シアノ−N−[4−[(2S)−モルホリン−2−イル]フェニル]ピリジン−3−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに6−シアノ−ニコチン酸(CAS RN: 70165-31-0)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):309.1([M+H]+)。
(比較例)
N−[4−[(2S)−モルホリン−2−イル]フェニル]−6−(トリフルオロメチル)ピリジン−3−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに6−(トリフルオロメチル)ニコチン酸(CAS RN: 158063-66-2)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):352.2([M+H]+)。
(比較例)
5−クロロ−N−[4−[(2S)−モルホリン−2−イル]フェニル]ピリジン−2−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに5−クロロ−ピコリン酸(CAS RN: 86873-60-1)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):320.1([{37Cl}M+H]+)、318.2([{35Cl}M+H]+)。
(比較例)
5−クロロ−N−[4−[(2S)−モルホリン−2−イル]フェニル]ピリジン−3−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに5−クロロ−ニコチン酸(CAS RN: 22620-27-5)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):320.1([{37Cl}M+H]+)、318.1([{35Cl}M+H]+)。
(比較例)
2−クロロ−6−メチル−N−[4−[(2S)−モルホリン−2−イル]フェニル]ピリジン−4−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに2−クロロ−6−メチルピリジン−4−カルボン酸(CAS RN: 25462-85-5)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):334.1([{37Cl}M+H]+)、332.1([{35Cl}M+H]+)。
(比較例)
N−[4−[(2S)−モルホリン−2−イル]フェニル]−2−フェニル−1,3−オキサゾール−4−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに2−フェニルオキサゾール−4−カルボン酸(CAS RN: 23012-16-0)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):350.2([M+H]+)。
(比較例)
N−[4−[(2S)−モルホリン−2−イル]フェニル]−2−フェニル−1,3−チアゾール−4−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに2−フェニルチアゾール−4−カルボン酸(CAS RN: 7113-10-2)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):366.1([M+H]+)。
(比較例)
2−メチル−N−[4−[(2S)−モルホリン−2−イル]フェニル]ピリジン−4−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに2−メチル−イソニコチン酸(CAS RN: 4021-11-8)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):298.2([M+H]+)。
(比較例)
2,6−ジメチル−N−[4−[(2S)−モルホリン−2−イル]フェニル]ピリジン−4−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに2,6−ジメチル−イソニコチン酸(CAS RN: 54221-93-1)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):312.2([M+H]+)。
(比較例)
N−[4−[(2S)−モルホリン−2−イル]フェニル]−2−メチル−1,3−チアゾール−4−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに2−メチルチアゾール−4−カルボン酸(CAS RN: 35272-15-2)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):304.1([M+H]+)。
(比較例)
N−[4−[(2S)−モルホリン−2−イル]フェニル]−1−フェニルピラゾール−3−カルボキサミド
工程(a)において5−エチル−4−メチル−1H−ピラゾール−3−カルボン酸の代わりに1−フェニル−1H−ピラゾール−3−カルボン酸(CAS RN: 4747-46-0)を用いて、実施例1と同様に標題化合物を得た。白色固体。MS(ISP):349.2([M+H]+)。
齧歯類TAAR1とヒトTAAR1との間のリガンド−受容体相互作用において、顕著に種差があるとの証拠がある[1]。したがって、TAAR1関連疾患を処置するためのヒト治療薬として使用するための化合物を選択する場合、ヒト型TAAR1受容体(hTAAR1)でのそれらの機能活性の効力に基づいた候補化合物の優先順位付けが重要である。hTAAR1はGタンパク質共役膜貫通受容体(GPCR)であり、そこでは、リガンドは、受容体のアンタゴニスト、アゴニスト、部分アゴニスト又はインバースアゴニストとして機能し得る。式Iで示される化合物及び比較例は、hTAAR1での機能活性についてインビトロで試験され、そこでは、式Iで示される化合物は、hTAAR1の部分アゴニストであることが見出された。式Iで示される化合物及び選択された比較例についての実験的に決定されたhTAAR1 EC50値を表1に示す(下記参照)。これにより、実施例1の化合物は、特に、インビトロでhTAAR1の強力な部分アゴニストであることが見出された。
ドーパミントランスポーター(DAT)の薬理は、とりわけ、コカイン及びMDPVのような特定の精神刺激薬の精神刺激効果に、並びに乱用傾向及び中毒メカニズムに関係している[1〜3]。したがって、ヒトでの使用を意図した新しい治療薬については、乱用傾向又は中毒に対する潜在性のリスクを最小限に抑えるために、ドーパミントランスポーターDATの阻害又はこれとの相互作用を回避することが望ましい。
薬物誘発性の心臓副作用を引き起こす見込みを最小化することは、ヒトでの安全な使用を意図した治療剤、特に長期処置レジメンに使用されることが意図された薬物には非常に望ましい。近年、規制当局は、心臓QT間隔を延長する治療剤の承認を遅延させるか又はその使用に制限を課すか、そして、その承認を拒絶するか又は市場から排除さえしている。QT間隔は、心電図(ECG)のQRS群の開始からT波の終わりまでの時間であり、心室脱分極及び再分極の期間の尺度である。QT間隔を延長する薬物は、トルサード・ド・ポワント(Torsades de Pointes)(TdP)と呼ばれる多形性心室頻拍と関連している。この不整脈は、重篤な心血管転帰を引き起こし得、不可逆的な心室細動及び死に進行し得る。ICH S7B規制ガイドライン[1]は、インビトロのIKrアッセイ[ヒト エーテルアゴーゴー(ether-a-go-go)関連遺伝子(hERG)によって伝導されるカリウム電流]を含む新規分子実体(NME)の心血管リスクを評価するための全体的な非臨床の方策を推奨している。hERGの阻害は、QT延長についての主要な機序として同定された[2]。したがって、推奨される最小限の非臨床QT間隔のリスク回避方策は、インビトロhERGアッセイにおいて所与の化学系列からの代表化合物を試験することである[3]。目標は、治療活性の有効なインビトロ(又は利用可能であればインビボ)濃度より少なくとも30倍低い濃度で、20%以下のhERG阻害を引き起こす化合物を選択することである。TAAR1アゴニストの場合には、hTAAR1 EC50を、治療活性を予測する妥当なインビトロ濃度として考えることができる(上記参照)。したがって、hERG IC20/hTAAR1 EC50比が少なくとも30倍である、TAAR1アゴニストを選択することが望ましい。
リン脂質症(PLD)は、組織におけるリン脂質の過剰蓄積を特徴とするリソソーム貯蔵障害である[1][2][3]。抗鬱剤、抗狭心症剤、抗マラリア剤及びコレステロール低下剤を含む多くのカチオン性両親媒性薬物は、動物及びヒトにおいて薬物誘導性リン脂質症(DIPL)を引き起こすことが報告されている。DIPLの機序は、患部細胞のリソソーム及び酸性小胞内へのDIPL薬物の捕捉又は選択的取り込みを伴う。薬物捕捉の後に、内部のリソソーム膜内に薬物−リン脂質複合体が徐々に蓄積される。未消化物質の増加は、組織中の多層体(ミエロイド小体)の異常な蓄積をもたらす。リン脂質症は主として貯蔵障害であると考えられているが、幾つかの化合物では、貯蔵障害は、炎症及び壊死と関連しており、患部組織の機能障害につながることが知られている。したがって、治療薬は、DIPLを引き起こすリスクを生じないことが非常に望ましい。これは、長期使用を意図した医薬(例えば、統合失調症、双極性障害又は鬱病のような慢性精神障害の処置を意図した薬物)、又は糖尿病のような慢性代謝障害の処置を意図した薬物の場合に特に当てはまる。
両親媒性ベクトル>−5.0kJ/mol、及びBPKA1≦5.60 陰性DIPLが予測される;
−7.0kJ/mol<両親媒性ベクトル<−5.0kJ/mol、及び/又は7.0>BPKA1>5.60 境界DIPLが予測される;
両親媒性ベクトル<−7.0kJ/mol、及びBPKA1≧7.00 陽性DIPLが予測される。
ヒトTAAR1
発現プラスミドの構築のために、ヒトTAAR1のコード配列を、本質的にLindemann et al.により記載[14]されたとおりゲノムDNAから増幅した。1.5mM Mg2+を含むExpand High Fidelity PCRシステム(Roche Diagnostics)を使用して、精製PCR産物を、製造者の取扱説明書に従いpCR2.1−TOPOクローニングベクター(Invitrogen)にクローニングした。PCR産物をpIRESneo2ベクター(BD Clontech, Palo Alto, California)にサブクローニングし、細胞株に導入する前に発現ベクターの配列検証を行った。
インビトロでのドーパミントランスポーター(DAT)への結合。ヒトDATで安定にトランスフェクトされたヒト胎児腎臓(HEK)293細胞(Invitrogen, Zug, Switzerland)を培養した。細胞を収集し、リン酸緩衝食塩水(PBS)で3回洗浄した。ペレットを−80℃で凍結させた。次に、ペレットを4℃で10mM EDTAを含む20mM HEPES−NaOH(pH7.4)(400ml)中に再懸濁した。Polytron(Kinematica, Lucerne, Switzerland)を用いて10000回転/分(rpm)で15秒間ホモジナイズした後、ホモジネートを4℃で30分間、48000×gで遠心分離した。膜ストックのアリコートを−80℃で凍結させた。全てのアッセイを少なくとも3回実施した。試験化合物を結合緩衝液(252mM NaCl、5.4mM KCl、20mM Na2HPO4、3.52mM KH2PO4、pH7.4)(20ml)中に希釈して、10点希釈曲線を作成し、96ウェル白色ポリスチレンアッセイプレート(Sigma-Aldrich, Buchs, Switzerland)に移した。[3H]−WIN35,428(〜86Ci/mmol;Perkin-Elmer)は、DATアッセイ用の放射性リガンドであり、12nMのKdを有した。[3H]−WIN35,428(〜40nM濃度) 50μlをhDATアッセイプレートの各ウェルに加え、[3H]−WIN35,428の最終濃度10nMを目標とした。アッセイプレート中の結合緩衝液(20μl)単独で全結合が規定され、一方で、10μM インダトラリンの存在下の結合では非特異的結合が規定された。凍結したDAT膜ストックを解凍し、ポリトロン組織ホモジナイザーを用いて約0.04mgタンパク質/ml結合緩衝液(H2O中 1:1希釈)の濃度に再懸濁した。次に、膜ホモジネート(40μg/ml)を、ポリビニルトルエン(PCT)コムギ胚芽凝集素被覆シンチレーション近接アッセイ(WGASPA;Amersham Biosciences)ビーズ(7.7mgビーズ/mlホモジネート)と共に、5〜30分間軽く混合した。アッセイを開始するために、放射性リガンド及び試験化合物を含有するアッセイプレートの各ウェルに膜/ビーズ混合物 130μlを添加し(各ウェル中の最終容量 200μl)、これを撹拌しながら室温で約2時間インキュベートした。次に、アッセイプレートをPackard TopcountのPVT SPA計数モードで計数した。[3H]−WIN35428ストック 50μlを、Packard 1900CA液体シンチレーションカウンターでReadySafeシンチレーションカクテル(Beckman Industries) 5ml中で計数して、それぞれのアッセイに加えた総カウントを決定した。非線形回帰を利用して、データをシグモイド曲線にフィッティングし、結合及び取り込みについてのIC50値を決定した。結合及び取り込みについてのKi値は、以下のCheng−Prusoff式:Ki=IC50/(1+[S]/Km)を用いて算出された。
ホールセル・パッチクランプ技法を用いて、安定にトランスフェクトされたCHO細胞における、生理的温度(36±1℃)付近のhERG(human-ether-a-go-go関連遺伝子)カリウムチャネルに及ぼす試験品目の効果を調べた。hERGチャネルを安定に発現する少なくとも3つのCHO細胞において、4濃度(0.3−3−30−300μM)でhERG K+電流パラメーターに及ぼす化合物の効果を評価した。電気生理学的測定のために、ハイグロマイシンBを含まない培地 2mlを含む35mmの滅菌培養皿に細胞を播種した。単一細胞(隣接細胞との、視認できる接続が無い)が測定できる密度で細胞を培養した。5% CO2(相対湿度 約95%)の加湿雰囲気中、37℃で細胞をインキュベートした。10%ウシ胎仔血清及び10%ペニシリン/ストレプトマイシン溶液を補充した栄養混合物F−12(L−グルタミンを含むDMEM/F−12)を含む滅菌培養フラスコ中で細胞を継続的に維持し継代した。方法の正確さを確保するために、毎日、少なくとも3つの細胞を選択的IKrブロッカー(E−4031、参照物質)で処理した。単一細胞が記録できる密度で細胞を播種した35mm培養皿を顕微鏡のディッシュホルダー上に載せ、生理的温度(36±1℃)付近で浴液(塩化ナトリウム 150mM、塩化カリウム 4mM、塩化カルシウム 1.2mM、塩化マグネシウム 1mM、HEPES 10mM、pH(NaOH)7.4)を用いて継続的に灌流した(約1ml/分で)。パッチ電極と個々のhERGを安定にトランスフェクトされたCHO細胞(ピペット抵抗範囲:2.0MΩ〜7.0MΩ;シール抵抗範囲:>1GΩ)との間のギガシールの形成後、ピペット先端を横切る細胞膜が破れて、細胞内部への電気的アクセスが確保された(ホールセル・パッチ構成)。シールの質が不充分な場合には、異なる細胞及び新しいピペットを用いてシール形成プロセスを繰り返した。安定なシールが確立されるとすぐに、−80mVの保持電位から−40mVへの細胞膜の脱分極時に50ms、次に、+20mV(チャネルの活性化)で500ms、そして、続く−40mVへの再分極時に500ms、外向きのhERGテール電流を測定した。この電圧プロトコルを、10秒間隔で少なくとも10回実行した。電流密度が測定には低すぎると判断された場合、別の細胞を記録した。対照の記録が達成されたら、試験品目を含む浴液を用いて細胞を継続的に灌流した。試験品目の洗い流し中に、定常状態レベルの遮断に達するまで、上記の電圧プロトコルを10秒間隔で継続的に再度実行した。化合物の4つの試験品目濃度を累積的に3つの細胞に順次適用した。hERGテール電流が試験品目により阻害されると、濃度−応答曲線が作成され、IC50値が算出された。IC50値に基づいてIC20を推定した。試験品目の各濃度を3回の実験(n=3)で分析した。
式Iで示される化合物及び比較化合物についての分子構造式から、公開アルゴリズム(Fischer, H.; Kansy, M.; Bur, D.;“CAFCA: a novel tool for the calculation of amphiphilic properties of charged drug molecules”. Chimia 2000, 54, 640-645; Fischer, H.; Atzpodien, E. A.; Csato, M; Doessegger, L.; Lenz, B.; Schmitt, G.; Singer, T.;“In silico assay for assessing phospholipidosis potential of small drug like molecules: training, validation and refinement using several datasets.”J. Med. Chem. 2012, 55, 126-139)により、両親媒性ベクトル(ΔΔGam)及びインシリコDIPL予測をコンピュータ上で決定した。
項目 成分 mg/錠
1.式Iで示される化合物 5 25 100 500
2.乳糖無水物DTG 125 105 30 150
3.Sta−Rx 1500 6 6 6 30
4.微結晶性セルロース 30 30 30 150
5.ステアリン酸マグネシウム 1 1 1 1
合計 167 167 167 831
1.項目1、2、3及び4を混合し、精製水と共に造粒する。
2.顆粒を50℃で乾燥させる。
3.顆粒を好適な粉砕機器を通過させる。
4.項目5を加えて3分間混合し;好適な打錠機(press)で圧縮する。
項目 成分 mg/カプセル
1.式Iで示される化合物 5 25 100 500
2.乳糖水和物 159 123 148 −−−
3.トウモロコシデンプン 25 35 40 70
4.タルク 10 15 10 25
5.ステアリン酸マグネシウム 1 2 2 5
合計 200 200 300 600
1.項目1、2及び3を好適なミキサーで30分間混合する。
2.項目4及び5を加えて3分間混合する。
3.好適なカプセルに充填する。
Claims (14)
- 請求項1〜3のいずれか1項に記載の化合物と薬学的に許容し得る賦形剤とを含む医薬組成物。
- 鬱病、不安障害、双極性障害、注意欠陥多動性障害(ADHD)、ストレス関連障害、統合失調症、パーキンソン病、アルツハイマー病、てんかん、片頭痛、高血圧、薬物乱用、中毒、摂食障害、糖尿病、糖尿病合併症、肥満、脂質異常症、エネルギーの消費及び同化の障害、体温恒常性の障害及び機能不全、睡眠及び概日リズムの障害、並びに心血管障害を処置するための請求項5に記載の医薬組成物。
- 鬱病を処置するための請求項5に記載の医薬組成物。
- 双極性障害を処置するための請求項5に記載の医薬組成物。
- 統合失調症を処置するための請求項5に記載の医薬組成物。
- 薬物乱用を処置するための請求項5に記載の医薬組成物。
- 中毒を処置するための請求項5に記載の医薬組成物。
- 摂食障害を処置するための請求項5に記載の医薬組成物。
- 糖尿病を処置するための請求項5に記載の医薬組成物。
- 請求項1〜3のいずれか1項に記載の化合物を含む経口医薬製剤であって、錠剤、コーティング錠、糖衣錠、硬及び軟ゼラチンカプセル剤、液剤、乳剤ならびに懸濁剤からなる群より選択される形態である経口医薬製剤。
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