JP4664363B2 - ペプチドバソプレッシン受容体アゴニスト - Google Patents
ペプチドバソプレッシン受容体アゴニスト Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/16—Oxytocins; Vasopressins; Related peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Description
Arは芳香族炭素環系、5員又は6員複素芳香族環系及び二環式複素芳香族環系から選択されるアリール基であり;
mは1、2及び3から選択され;
nは0、1、2、3及び4から選択され;
pは2、3及び4から選択され;
R1、R2及びR3は独立してH、OH、アルキル、O−アルキル及びOC(O)−アルキルから選択され;
アルキルはC1−6直鎖及びC4−8分岐鎖アルキルから選択され、場合により少なくとも1個のヒドロキシル置換基をもち;
n=0のとき、R1とR2は場合により一緒になって炭素原子数2〜5の含窒素環構造を形成し;
但し、Arがフェニル(アミノ酸番号2がPhe)であり、m=2、n=0、R1=R2=H(アミノ酸番号4がGln)であり、pが3又は4であるとき、R3はH以外のものである]により表される化合物とその溶媒和物及び医薬的に許容可能な塩に関する。
Abu 2−アミノ酪酸
Boc tert−ブトキシカルボニル
BOP ヘキサフルオロリン酸ベンゾトリアゾール−1−イルオキシトリスジメチルアミノホスホニウム
Dbu 2,4−ジアミノ酪酸
DCC N,N’−ジシクロヘキシルカルボジイミド
DCHA ジシクロヘキシルアミン
DCM ジクロロメタン
DIAD ジアゾジカルボン酸ジイソプロピル
DIC N,N’−ジイソプロピルカルボジイミド
DIEA N,N−ジイソプロピル−N−エチルアミン
DMF N,N−ジメチルホルムアミド
Fm 9−フルオレニルメチル
Fmoc 9−フルオレニルメトキシカルボニル
Hgn ホモグルタミン
Hmp 2−ヒドロキシ−3−メルカプトプロピオン酸
HOBt 1−ヒドロキシベンゾトリアゾール
HPLC 高性能液体クロマトグラフィー
i イソ
Mmt 4−メトキシトリチル
Mob p−メトキシベンジル
MS 質量分析
Orn オルニチン
Ph フェニル
Pr プロピル
PyBOP ヘキサフルオロリン酸ベンゾトリアゾール−1−イルオキシトリスピロリジンホスホニウム
o−NBS−Cl 塩化2−ニトロベンゼンスルホニル
OT オキシトシン
Rt 保持時間
TFA トリフルオロ酢酸
TIS トリイソプロピルシラン
TMOF オルトギ酸トリメチル
TPP トリフェニルホスフィン
Trt トリチル
VT バソトシン,[Ile3]バソプレッシン。
アミノ酸誘導体及び樹脂は商業的供給業者(Novabiochem,Bachem Peptide International及びPepTech Corporation)から購入した。Fmoc−Hgn−OHは文献(Wisniewski,K.,Kolodziejczyk,A.S.Org.Prep.Proced.Int.1997,29,338−341)に従って合成した。他の薬品及び溶媒はSigma−Aldrich、Fisher Scientific及びVWRから購入した。
Kates,S.A.,Albericio,F.編,Solid Phase Synthesis.A Practical Guide,Marcel Dekker,New York,Basel,2000;
Stewart,J.M.,Young,J.D.Solid Phase Synthesis,Pierce Chemical Company,1984;
Biselloら,J.Biol.Chem.1998,273,22498−22505;及び
Merrifield,J.Am.Chem.Soc.1963,85,2149−2154。
Fmoc法によりペプチドを合成した。8位のジアミノ酸残基にメトキシトリチル(Mmt;Barlos,K.ら, Peptides 1992,Schneider,CH.,Eberle,A.N.編,ESCOM Science Publishers B.V.,1993,pp 283−284参照)等の酸レービル(即ち1−2%TFA溶液で除去可能な)保護基を導入した。樹脂に結合したペプチドをDCM/TIS/TFA 93/5/2(v/v/v)溶液で処理し、Mmt基を除去した。アセトン/NaBH(OAc)3で還元アルキル化し、N−イソプロピルペプチドを得た。
Boc法によりペプチドを合成した。4位の残基をBoc−Asp(OFm)−OHとして配列に導入した。ペプチド合成の完了後、DMF中30%ピペリジンで側鎖保護基を除去した。得られた遊離カルボン酸基をPyBOP又はBOP/DIEAにより適切なアミンとカップリングすることにより所望アミドに変換した。次にN末端Boc基を除去した後にHF開裂、環化及びHPLC精製した。
使用したアミノ酸誘導体はBoc−Cys(Trt)−OH、Fmoc−Phe−OH、Fmoc−Ile−OH、Fmoc−Hgn−OH、Fmoc−Asn(Trt)−OH、Fmoc−Cys(Trt)−OH、Fmoc−Pro−OH、Fmoc−Orn(Mmt)−OH及びFmoc−Gly−OHとした。Fmoc−Hgn−OHは上記のように合成した。分析用HPLCは流速2ml/分でVydac C18,5μ 4.6×250mmカラムを使用してWaters 600 Liquid Chromatographで実施した。分取HPLCは流速100ml/分でPrepak 47×300mmカートリッジを使用してWaters 2000 Liquid Chromatographで実施した。最終化合物分析は流速0.3ml/分でVydac C18,5μ 2.1×250mmカラムを使用して1100 Agilent Liquid Chromatographで実施した。質量スペクトルはFinnigan MATスペクトロメーターで記録した。
使用したアミノ酸誘導体はBoc−Cys(Mob)−OH、Boc−Phe−OH、Boc−Ile−OH、Boc−Asp(OFm)−OH、Boc−Asn−OH、Boc−Pro−OH、Boc−Dbu(ベンジルオキシカルボニル)−OH DCHA塩及びBoc−Gly−OHとし、いずれもNovabiochemとBachemから購入した。HPLC及びMS操作は化合物1の合成と同様に実施した。
In vitro受容体アッセイ:
ホタルルシフェラーゼの発現を調節する細胞内カルシウム応答性プロモーターエレメントを含むレポーターDNAと共にhV1a受容体発現DNAをHEK−293細胞に一過的にトランスフェクトすることによりhV1a受容体に対する化合物のアゴニスト活性を測定した。このアッセイの詳細な手引きについてはBoss,V.,Talpade,D.J.,Murphy,T.J.J.Biol.Chem.1996,May 3;271(18),10429−10432参照。用量当たり10倍に希釈した化合物の連続希釈液に細胞を5時間暴露した後、細胞を溶解させ、ルシフェラーゼ活性を測定し、化合物効力とEC50値を非線形回帰により測定した。アルギニン−バソプレッシン(AVP)を各実験で内部対照として使用し、少なくとも3回の独立した実験で化合物を試験した。選択性を測定するために、ヒトオキシトシン(hOT)受容体を発現するルシフェラーゼ転写レポーターアッセイで化合物を試験した。他の受容体(hV2,hV1b,ラットV1a及びラットV2)のアッセイも実施した。
AVPの標準用量に対する相対値として化合物のin vivo作用時間を試験した。麻酔したSprague−Dawley雄ラット(体重270−300g)の頸静脈と頸動脈にカテーテルを挿入して血圧測定を実施した。カテーテルを挿入した頸動脈を使用して血圧を連続的にモニターし、頸静脈を使用して試験化合物を投与した。V1a受容体アゴニストに対する応答性を強化するためにラットに投与前にジベナミンを静脈内注射した(Dekanski,J.,Br.J.Pharmacol.1952,7,567−572参照)。投与手順は生理的食塩水の静脈内注射後に標準用量のAVP(0.1nmol/kg,〜ED70)を2回続けて注射し、AVPの標準用量と少なくとも同等の応答が得られるように選択した漸増用量の所与化合物を3〜5回注射した。投与間隔は血圧が安定な基線まで低下する時間として設定した。
Claims (6)
- 下式(記載順に夫々配列番号1〜6):
- 構造式(配列番号7):
- 医薬用としての請求項1または2に記載の化合物。
- 医薬的に許容可能なアジュバント、希釈剤又はキャリヤーと共に活性成分として請求項1または2に記載の化合物を含有する医薬組成物。
- 循環血液減少性又は血管拡張性ショック、出血性食道静脈瘤、肝腎症候群、心肺蘇生、麻酔による血圧低下、起立性低血圧、穿刺による循環機能障害、術中出血又は熱傷デブリドマンに伴う出血及び鼻出血の治療、並びに流涙/涙液生成の増加による各種眼病の治療用医薬の製造における請求項1または2に記載の化合物の使用。
- 循環血液減少性又は血管拡張性ショック、出血性食道静脈瘤、肝腎症候群、心肺蘇生、麻酔による血圧低下、起立性低血圧、穿刺による循環機能障害、術中出血又は熱傷デブリドマンに伴う出血及び鼻出血の治療、並びに流涙/涙液生成の増加による各種眼病を治療するための、請求項4に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US60037704P | 2004-08-11 | 2004-08-11 | |
EP04019029 | 2004-08-11 | ||
PCT/US2005/027772 WO2006020491A1 (en) | 2004-08-11 | 2005-08-03 | Peptidic vasopressin receptor agonists |
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JP2008509221A JP2008509221A (ja) | 2008-03-27 |
JP4664363B2 true JP4664363B2 (ja) | 2011-04-06 |
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JP2007525670A Active JP4664363B2 (ja) | 2004-08-11 | 2005-08-03 | ペプチドバソプレッシン受容体アゴニスト |
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Country | Link |
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US (2) | US8148319B2 (ja) |
EP (1) | EP1776133B1 (ja) |
JP (1) | JP4664363B2 (ja) |
KR (1) | KR100884323B1 (ja) |
CN (1) | CN1964732B (ja) |
AR (1) | AR050914A1 (ja) |
AT (1) | ATE509944T1 (ja) |
AU (1) | AU2005274070B2 (ja) |
BR (1) | BRPI0511466B8 (ja) |
CA (1) | CA2567797C (ja) |
DK (1) | DK1776133T3 (ja) |
ES (1) | ES2366702T3 (ja) |
HK (1) | HK1100280A1 (ja) |
IL (1) | IL178690A (ja) |
JO (1) | JO2937B1 (ja) |
MX (1) | MX2007001396A (ja) |
NO (1) | NO342449B1 (ja) |
NZ (1) | NZ550707A (ja) |
PL (1) | PL1776133T3 (ja) |
PT (1) | PT1776133E (ja) |
RU (1) | RU2355701C2 (ja) |
SA (1) | SA05260254B1 (ja) |
SI (1) | SI1776133T1 (ja) |
TW (1) | TWI364291B (ja) |
WO (1) | WO2006020491A1 (ja) |
ZA (1) | ZA200700772B (ja) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
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JO2937B1 (en) * | 2004-08-11 | 2016-03-15 | فيرينغ.بي.في | Tight muscles of the peptide vascular tensioner receptor |
CA2641959C (en) * | 2006-02-10 | 2016-12-20 | Ferring B.V. | Novel compounds |
ES2566143T3 (es) | 2006-02-13 | 2016-04-11 | Ferring B.V. | Uso de agonistas peptídicos de receptor de vasopresina |
US9050286B2 (en) | 2007-08-14 | 2015-06-09 | Ferring B.V. | Use of peptidic vasopression receptor agonists |
JP5623406B2 (ja) | 2008-09-17 | 2014-11-12 | キアズマ インコーポレイテッド | 医薬組成物および関連する送達方法 |
JO3109B1 (ar) | 2012-05-10 | 2017-09-20 | Ferring Bv | منبهات لمستقبلات v1a |
US9388214B2 (en) | 2014-11-05 | 2016-07-12 | Ferring B.V. | V1A receptor agonists |
RU2634272C1 (ru) * | 2016-08-10 | 2017-10-24 | Закрытое акционерное общество "Санкт-Петербургский институт фармации" | Композиция с дезамино-аргинин-вазотоцином для парентерального введения и способ её получения |
AU2017345720B2 (en) | 2016-10-21 | 2023-07-27 | Chiasma, Inc. | Terlipressin compositions and their methods of use |
US11033601B2 (en) | 2017-09-14 | 2021-06-15 | The Regents Of The University Of Colorado, A Body Corporate | Selective inhibition of V1b for treating fatty liver |
CN109748950B (zh) * | 2017-11-02 | 2020-10-30 | 深圳翰宇药业股份有限公司 | 一种固相合成血管升压素受体肽激动剂selepressin的方法 |
DK3517543T3 (da) * | 2018-01-30 | 2020-12-07 | Bachem Ag | Fremstilling af glucagonpeptider |
CA3119792A1 (en) | 2018-11-15 | 2020-05-22 | Ferring B.V. | Compounds, compositions and methods for treating sepsis |
WO2024073445A1 (en) * | 2022-09-30 | 2024-04-04 | Ocelot Bio, Inc. | Mixed vasopressin receptor agonist-antagonist for modulating mean arterial pressure |
Citations (2)
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US3352843A (en) * | 1963-08-30 | 1967-11-14 | Sandoz Ltd | Phe2-orn8-oxytocin |
WO2003082334A1 (fr) * | 2002-03-29 | 2003-10-09 | Wakamoto Pharmaceutical Co.,Ltd. | Medicaments pour augmenter la quantite de fluide lacrymal |
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BE651400A (ja) | 1963-04-05 | 1965-02-04 | ||
CS235151B1 (cs) | 1982-08-26 | 1985-05-15 | Michal Lebl | Způsob dělení Dal isomerů analogů oxytocinu |
US4829051A (en) | 1983-04-05 | 1989-05-09 | Vega Laboratories, Inc. | N-substituted derivatives of 1-desaminovasopressin |
US4483794A (en) * | 1983-05-10 | 1984-11-20 | Ceskoslovenska Akademie Ved | Analogs of neurohypophysial hormones |
CS242062B1 (cs) | 1984-08-23 | 1986-04-17 | Milan Zaoral | Vasopresinová a vasotocinová analoga a způsob jejich přípravy |
SE457055B (sv) | 1986-08-18 | 1988-11-28 | Ferring Ab | Topisk straalskyddsgel foer mukosa innehaallande kaerlsammandragande substanser |
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