JP2015145351A - 新規なペプチド誘導体及びこれを含有する医薬 - Google Patents
新規なペプチド誘導体及びこれを含有する医薬 Download PDFInfo
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- JP2015145351A JP2015145351A JP2014019236A JP2014019236A JP2015145351A JP 2015145351 A JP2015145351 A JP 2015145351A JP 2014019236 A JP2014019236 A JP 2014019236A JP 2014019236 A JP2014019236 A JP 2014019236A JP 2015145351 A JP2015145351 A JP 2015145351A
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- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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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- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical class SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
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- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
(1)(a)Tyr−Asn−Trp−Asn−Ser(COR)−Phe−Gly−Leu−Arg−Tyr−NH2(化合物番号1);(b)Ser(COR)−Phe−Gly−Leu−Arg−Tyr−NH2(化合物番号2);(ただし、上記Rは炭素数1−20の置換又は非置換の直鎖状若しくは分枝状のアルキル基である)から選択されるペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
(2)Rが、n−ペンチル基、n−ヘキシル基、n−ヘプチル基、n−オクチル基及びn−ノニル基から選ばれるアルキル基である上記(1)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
(3)上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする医薬。
(4)上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする性腺刺激ホルモン放出ホルモン及び黄体形成ホルモン分泌促進剤。
(5)上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする家畜用繁殖制御剤。
(6)上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする、若年性更年期障害、月経異常、排卵障害、不妊症、生殖機能異常、子宮内膜症、癌転移、ホルモン感受性癌の予防及び/又は治療剤。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の、医薬を調製のための使用。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の、性腺刺激ホルモン放出ホルモン及び黄体形成ホルモン分泌促進剤を調製のための使用。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の、家畜用繁殖制御剤を調製のための使用。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の、若年性更年期障害、月経異常、排卵障害、不妊症、生殖機能異常、子宮内膜症、癌転移、ホルモン感受性癌の予防及び/又は治療剤を調製のための使用。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の有効量を対象に投与する疾病の治療方法。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の有効量を対象に投与する性腺刺激ホルモン放出ホルモン及び黄体形成ホルモンの分泌促進方法。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の有効量を家畜に投与する繁殖制御方法。
上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物の有効量を対象に投与する若年性更年期障害、月経異常、排卵障害、不妊症、生殖機能異常、子宮内膜症、癌転移、ホルモン感受性癌の予防及び/又は治療方法。
疾病の治療に用いるための上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
性腺刺激ホルモン放出ホルモン及び黄体形成ホルモンの分泌促進に用いるための上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
家畜の繁殖制御に用いるための上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
若年性更年期障害、月経異常、排卵障害、不妊症、生殖機能異常、子宮内膜症、癌転移、ホルモン感受性癌の予防及び/又は治療に用いるための上記(1)又は(2)記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
Rの置換基としては、フッ素、塩素、臭素、ヨウ素等のハロゲン、ヒドロキシル基、チオール基、アミノ基、ニトロ基、シアノ基、R1Oで表すことのできるアルコキシ基、R2COで表すことのできるアシル基、R3CO2で表すことのできるアシルオキシ基、R4Sで表すことのできるアルキルチオ基、R5SOで表すことのできるアルキルスルフィニル基、R6SO2で表すことのできるアルキルスルホニル基、R7SO3で表すことのできるアルキルスルホニルオキシ基、R8NHで表すことのできるアルキルアミノ基、R8R9Nで表すことのできるジアルキルアミノ基が挙げられる。ここでR1〜R9としては、上記Rと同様のアルキル基を用いることができる。R1〜R9として、好ましくは炭素数1〜3のアルキル基、さらに好ましくはメチル基である。
また、反応後は通常の精製法、たとえば、溶媒抽出・蒸留・カラムクロマトグラフィー・液体クロマトグラフィー・再結晶などの精製法を組み合わせて本発明のペプチドを精製単離することができる。上記方法で得られるペプチドが遊離体である場合は公知の方法によって適当な塩に変換することができ、逆に塩で得られた場合は、公知の方法によって遊離体に変換することができる。
Fmoc−Tyrが導入された担体を反応溶媒で膨潤させ、2級アミンを添加することによりFmoc基を除去することができる。反応の進行は、Fmoc基の除去により発生する二酸化炭素の泡で確認することができる。前記反応溶媒としてはDMFを用いることが好ましい。また、前記2級アミンとしては、通常ピペリジンが用いられるが、ピロリジン、ジエチルアミン、ジブチルアミン、ジイソプロピルアミン等を用いることもできる。上記反応は、0℃〜溶媒の沸点までの反応温度で行うことができ、室温で反応させることが好ましい。反応後の担体は、ろ過等により溶媒中から取り出すことができる。
上記で得たFmocを除去したTyrが導入された担体を再度DMFに膨潤し、Fmoc−Arg−OH、縮合剤、ヒューニッヒ塩基を添加し、ペプチド鎖の伸長を行う。前記縮合剤としては、O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスフェート(HBTU)、O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボラート(TBTU)、O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボラート(TBTU)、1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−オキシド ヘキサフルオロホスフェート(HATU)、1−ヒドロキシベンゾトリアゾール(HOBt)、1−ヒドロキシ−7−アザベンゾトリアゾール(HOAt)等を単独で又は混合して用いることができる。上記反応は、0℃〜溶媒の沸点までの反応温度で行うことができ、室温で反応させることが好ましい。ペプチド鎖の伸長は、Kaiser試験により確認することができ、反応後の担体は、ろ過等により溶媒中から取り出すことができる。
ペプチドをレジンから切り出した後に、ペプチドのC末端のカルボン酸の第1級アミド化を行う。前記アミド化は、公知の方法で行うことができるが、例えば、4−(4,6−ジメトキシ−1,3,5−トリアジン−2−イル)−4−メチルモルホリニウム 塩酸塩 n−水和物とアンモニアの溶液を用いる方法が挙げられる。前記、アンモニアの溶液としては、第1級アミドが製造される限り、いかなるアンモニア溶液を用いても構わないが、アンモニアのアルコール溶液を用いることが好ましい。
前記C末端のカルボン酸の第1級アミド化後に、必要であればペプチド中の各アミノ酸の保護基の除去を行う。前記保護基の除去については、Green&Wuts, “PROTECTIVE GROUPS in ORGANIC SYNTHESIS” 3rd ed. John Wiley&Sons, Inc.を参照し、用いることができる。
本発明の医薬の適当な投与経路としては特に限定されず、経口、直腸内、経粘膜、または腸内、または筋肉内、皮下、骨髄内、鞘内、直接心室内、静脈内、硝子体内、腹腔内、鼻腔内、または眼内注射が含まれる。投与経路は、患者/患畜の年齢や病状、併用する他の薬剤などを考慮して適宜選択することができる。
ウシ脳下垂体前葉は、黒毛和牛雌(26か月齢)より、2011年9月から2012年7月の期間に得た。ウシ脳下垂体前葉組織を酵素法により単一細胞化し、単一化した細胞の生細胞率は、トリパンブルー染色により90%以上であることを確認してその後の実験に用いた。単一化した細胞は、1%非必須アミノ酸(100×; Gibco, Grand Island, NY, USA)、100 IU/mLペニシリン、50 μg/mLストレプトマイシン、10%ウマ血清(Gibco, Grand Island, NY, USA)、2.5%ウシ胎児血清(Gibco, Grand Island, NY, USA)を加えたダルベッコ改変イーグル培地(DMEM; Gibco, Grand Island, NY, USA)に懸濁した。2.5×105細胞/mLの濃度に調製した細胞を、24ウェルプレート(MS-80240;住友ベークイライト、東京、日本)上で、37℃、5%二酸化炭素、湿潤条件下において82時間培養した。
化合物番号9及び化合物番号10で表されるペプチド誘導体は、P. Robberecht et. al. Mol. Phrmacol. 42, 347-355 (1992)に記載の方法を参考に合成した。
すなわち、AMレジンの一つである4−(2’,4’−ジメトキシフェニル−Fmoc−アミノメチル)−フェノキシレジンを固相担体とし、ペプチドの合成を行った。まず、前記固相担体にFmoc-Tyr−OHを結合し、順次Focの除去、ペプチド伸長を繰り返し、Arg、Leu、Gly、Phe、Ser、Asn、Trp、Asn、Tyrをペプチド鎖に組み込みながら伸長し、Tyr−Asn−Trp−Asn−Ser−Phe−Gly−Leu−Arg−Tyrからなるペプチドを合成した。ペプチド伸長は、HOBt及びHBTUを用いた。続いて、ペプチド中の各アミノ酸の側鎖の保護基のうち、Ser側鎖の水酸基の保護基であるトリフェニルメチル基(トリチル基)を、1%トリフルオロ酢酸を用いて除去した。前記保護基の除去後のSer側鎖の水酸基に、オクタン酸及びWSCIを作用させることで、選択的にアシル化を行った。アシル化後のペプチドはトリフルオロメタンスルホン酸を用いて担体から切り出され、C末端のカルボン酸を第1級アミドへと変換した後に、HPLCで生成を行った。得られた化合物番号9で表されるペプチド誘導体は、質量分析において1445(M+1)+のピークを示し、その計算値と一致した。
上記手法と同様の方法により、化合物番号10で表されるペプチド誘導体を合成した、得られたペプチド誘導体は、質量分析において868(M+1)+のピークを示し、その計算値と一致した。
黒毛和牛雌(n=16)より得た脳下垂体前葉細胞を82時間培養後、リン酸緩衝生理食塩水(PBS)にて2度洗浄した。その後、0.1%ウシ血清アルブミン(BSA; protease-free grade, 01862-87;ナカライテスク、京都、日本)加DMEMのみ、10nM(1x10−8M)GnRH(株式会社ペプチド研究所、大阪、日本)を含む0.1%BSA加DMEM、10nM(1x10−8M)、100nM(1x10−7M)、1000nM(1x10−6M)、10,000nM(1x10−5M)の各濃度の、KP10(化合物番号3)、[dY]KP10(化合物番号5)、[dS]KP6(化合物番号6)、Ac−KP10(化合物番号7)、Ac−KP6(化合物番号8)、オクタン酸側鎖付KP10(化合物番号9)、オクタン酸側鎖付KP6(化合物番号10)をそれぞれ含む0.1%BSA加DMEMで、脳下垂体前葉細胞の培養液を交換した。前記キスペプチン誘導体は、上記方法により合成され(株式会社スクラム、東京、日本)、高速液体クロマトグラフィー及び質量分析法で確認された高純度ものを使用した。各化合物との刺激開始から2時間後、培養液を回収し、ウシLH濃度測定まで‐30℃で保管した。
上記で回収した培養液中のLH濃度は、125I標識ウシLH及び抗ヒツジLH抗血清 (AFP11743B,AFP192279; National Hormone and Pituitary Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, CA, USA)を用いた二抗体ラジオイムノアッセイにて二重測定した。検出限界値は0.40ng/mLであった。また、2.04ng/mLにおいて、測定内変動係数は3.6%、測定間変動係数は6.2%であった。培養液のみを下垂体前葉細胞に添加したControl培養液中LH濃度に対する、各化合物を添加した培養液中LH濃度の比率を求めたところ、オクタン酸側鎖付KP10(化合物番号9)及びオクタン酸側鎖付KP6(化合物番号10)の添加による刺激では、添加濃度の差がLH濃度の比率差に現れず(図1)、また、KP10のLH濃度比率に対し、約2倍のLH分泌を誘導することが明らかとなった。
Claims (6)
- (a)Tyr−Asn−Trp−Asn−Ser(COR)−Phe−Gly−Leu−Arg−Tyr−NH2(化合物番号1);
(b)Ser(COR)−Phe−Gly−Leu−Arg−Tyr−NH2(化合物番号2);
(ただし、上記Rは炭素数1−20の置換又は非置換の直鎖状若しくは分枝状のアルキル基である)
から選択されるペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。 - Rが、n−ペンチル基、n−ヘキシル基、n−ヘプチル基、n−オクチル基及びn−ノニル基から選ばれるアルキル基である請求項1記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物。
- 請求項1又は2記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする医薬。
- 請求項1又は2記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする性腺刺激ホルモン放出ホルモン及び黄体形成ホルモン分泌促進剤。
- 請求項1又は2記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする家畜用繁殖制御剤。
- 請求項1又は2記載のペプチド誘導体、若しくはその塩、又はそれらの溶媒和物を有効成分とする、若年性更年期障害、月経異常、排卵障害、不妊症、生殖機能異常、子宮内膜症、癌転移、ホルモン感受性癌の予防及び/又は治療剤。
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