JP5124431B2 - 血管疾病および異種移植におけるラパマイシン誘導体の使用 - Google Patents
血管疾病および異種移植におけるラパマイシン誘導体の使用 Download PDFInfo
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- JP5124431B2 JP5124431B2 JP2008314494A JP2008314494A JP5124431B2 JP 5124431 B2 JP5124431 B2 JP 5124431B2 JP 2008314494 A JP2008314494 A JP 2008314494A JP 2008314494 A JP2008314494 A JP 2008314494A JP 5124431 B2 JP5124431 B2 JP 5124431B2
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- 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
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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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Description
Xは(H,H)またはO;
Yは(H,OH)またはO;
R1およびR2は、独立してH、アルキル、アリールアルキル、ヒドロキシアルキル、ジヒドロキシアルキル、ヒドロキシアルコキシカルボニルアルキル、ヒドロキシアルキルアリールアルキル、ジヒドロキシアルキルアリールアルキル、アシルオキシアルキル、アミノアルキル、アルキルアミノアルキル、アルコキシカルボニルアミノアルキル、アシルアミノアルキル、アリールスルホンアミドアルキル、アリル、ジヒドロキシアルキルアリル、ジオキソラニルアリル、ジアルキル−ジオキソラニルアルキル、ジ(アルコキシカルボニル)−トリアゾリル−アルキルおよびヒドロキシ−アルコキシ−アルキル;ここで、“alk-”または“アルキル”は分枝鎖または直鎖C1−6アルキル;“アリール”はフェニルまたはトリル;およびアシルはカルボン酸由来の残基;そして
R4はメチルまたは
R4とR1が共にC2−6アルキルを形成する;
但し、R1およびR2は両方ともHではない;そしてヒドロキシアルコキシアルキルはヒドロキシアルコキシメチル以外である〕
の式Iの化合物を含む。
1.40−O−ベンジル−ラパマイシン
2.40−O−(4'−ヒドロキシメチル)ベンジル−ラパマイシン
3.40−O−[4'−(1,2−ジヒドロキシエチル)]ベンジル−ラパマイシン
4.40−O−アリル−ラパマイシン
5.40−O−[3'−(2,2−ジメチル−1,3−ジオキソラン−4(S)−イル)−プロプ−2'−エン−1'−イル]−ラパマイシン
6.(2'E,4'S)−40−O−(4',5'−ジヒドロキシペント−2'−エン−1'−イル)−ラパマイシン
7.40−O−(2−ヒドロキシ)エトキシカルボニルメチル−ラパマイシン
8.40−O−(2−ヒドロキシ)エチル−ラパマイシン
9.40−O−(3−ヒドロキシ)プロピル−ラパマイシン
10.40−O−(6−ヒドロキシ)ヘキシル−ラパマイシン
11.40−O−[2−(2−ヒドロキシ)エトキシ]エチル−ラパマイシン
12.40−O−[(3S)−2,2−ジメチルジオキソラン−3−イル]メチル−ラパマイシン
13.40−O−[(2S)−2,3−ジヒドロキシプロプ−1−イル]−ラパマイシン
14.40−O−(2−アセトキシ)エチル−ラパマイシン
15.40−O−(2−ニコチノイルオキシ)エチル−ラパマイシン
16.40−O−[2−(N−モルホリノ)アセトキシ]エチル−ラパマイシン
17.40−O−(2−N−イミダゾリルアセトキシ)エチル−ラパマイシン
18.40−O−[2−(N−メチル−N'−ピペラジニル)アセトキシ]エチル−ラパマイシン
19.39−O−デスメチル−39,40−O,O−エチレン−ラパマイシン
20.(26R)−26−ジヒドロ−40−O−(2−ヒドロキシ)エチル−ラパマイシン
21.28−O−メチル−ラパマイシン
22.40−O−(2−アミノエチル)−ラパマイシン
23.40−O−(2−アセトアミドエチル)−ラパマイシン
24.40−O−(2−ニコチンアミドエチル)−ラパマイシン
25.40−O−(2−(N−メチル−イミダゾ−2'−イルカルボキシアミド)エチル)−ラパマイシン
26.40−O−(2−エトキシカルボニルアミノエチル)−ラパマイシン
27.40−O−(2−トリルスルホンアミドエチル)−ラパマイシン
28.40−O−[2−(4',5'−ジカルボエトキシ−1',2',3'−トリアゾル−1'−イル)−エチル]−ラパマイシン
好ましい化合物は、例えば40−O−(2−ヒドロキシ)エチル−ラパマイシン(以後、化合物Aと称する)である。
1.治療的有効量の式Iの化合物を患者に投与することを含む、処置を必要とする患者の新脈管内膜増殖および肥厚を予防または処置する方法が提供される。
2.1.レシピエントに治療的有効量の式Iの化合物を投与する段階を含む、臓器または組織レシピエントの慢性拒絶の発現を予防しまたはそれを抑制する方法。
2.2.レシピエントに治療的有効量の式Iの化合物を投与する段階を含む、臓器または組織移植片レシピエントの移植片血管疾患、例えば、移植片血管疾病、動脈硬化またはアテローム性動脈硬化の発現を予防しまたはそれを制御する方法。
を提供する。
3.患者に治療的有効量の式Iの化合物を投与することを含む、処置を必要とする患者の血管障害、例えば、血管形成術に続く脈管内膜平滑筋細胞増殖および移動、例えば再狭窄および/または血管閉塞を予防または処置する方法。
を提供する。
4.レシピエントに治療的有効量の式Iの化合物を投与することを含む、臓器または組織異種移植片移植のレシピエントの急性または慢性拒絶を予防するまたはそれを制御する方法。
を提供する。
5.上記1から4で定義の方法に使用するための式Iの化合物;または
6.上記1から4で定義の方法に使用するための医薬組成物の製造における式Iの化合物の使用;または
7.製薬学的に許容される希釈剤または担体と共に、式Iの化合物を含む、上記1から4で定義の方法に使用するための医薬組成物。
も提供する。
雄DA(RT1a)ラットの腎臓を雄Lewis(RT1l)レシピエントに同所移植する。全24匹の動物を移植する。全動物を、移植の日に開始して14日間シクロスポリンA、経口7.5mg/kg/日で処置し、急性細胞性拒絶を予防する。反対側の腎臓摘出は行わない。6匹の動物から成る各実験群を、異なる量の式Iの化合物またはプラセボで処置する。
このラットの大動脈移植モデルにおいて、移植片に対する同種性の反応は移植片を破壊しないが、臨床移植における慢性移植と類似の病理学的変化を起こす。これらは単核細胞(リンパ球、マクロファージ、ある血漿細胞)の外膜への浸出および脈管内膜の肥厚を含む。
血管形成術の実験をバルーンカテーテル傷害のモデルで行う:バルーンカテーテル法を0日に、本質的にPowell et al. (1989)に記載のように行う。イソフルオラン麻酔下に、フォガルティ2Fカテーテルを外部頸動脈を介して左総頚動脈に挿入し、膨らませる(膨張 ≒ 10μl H2O)。膨らませたバルーンを総頚動脈の長さに沿って3回引き、残りの2回は穏やかにねじりながら行い、均質な内皮剥離(de-endothelialization)を行う。次いで、カテーテルを除き、出血を防止するための外部頚動脈の周りの結紮部位および動物を回復させる。
ハムスターからラット異種移植組み合わせは、いわゆる困難な調和の組み合わせである。ラットは、天然抗ハムスター抗体を、通常調和した組み合わせで見られるような即座の超急性拒絶を産生するほど十分な量で有しない:しかしながら、補体と組み合わさった非処理レシピエントでの拒絶が抗体により3−4日以内に起こる。これは血管の組織学的破壊、赤血球の滲出および管外遊出、更に多形核顆粒球の流入により可視化される;ここではしばしば出血および血栓の兆項が見られる。抗体合成の有効な阻害または補体の不活性化によりこの拒絶に一旦打ち勝ったら、細胞性拒絶が次ぎに発現し得る。これは、リンパ球、リンパ芽球、およびマクロファージを含む単核球細胞流入および筋実質組織の破壊により組織学的に可視化される。細胞性拒絶の阻害には、同種移植片のそれよりもより強い免疫抑制を必要とする。先天性(congenitially)無胸腺(rnu/rnu)ラットは補体(胸腺依存性)細胞性免疫システムを欠き、一般に同種移植片を拒絶できない。このような動物はハムスター異種移植片を正常胸腺ラットと同じ形式で拒絶し、(少なくとも一部の)抗ハムスター抗体のラット内の合成が、胸腺非依存的B細胞応答に続いて起こることを示す。このようなレシピエントはハムスター異種移植片が胸腺非依存的抗体介在拒絶により拒絶されることを評価するのに有用である。
8.例えば、同時にまたは連続して、治療的有効量の式Iの化合物および第2の医薬物質(ここで、第2の医薬物質は、上記で示したように免疫抑制性または免疫調節性医薬である)を共投与することを含む、前記で定義の方法。
Claims (2)
- 内皮剥離(de-endothelialization)による血管損傷に続く新脈管内膜増殖および肥厚の処置用医薬の製造のための、40−O−(2−ヒドロキシ)エチル−ラパマイシンの使用。
- 内皮剥離による血管損傷に続く再狭窄および/または血管閉塞の予防もしくは処置用医薬の製造のための、40−O−(2−ヒドロキシ)エチル−ラパマイシンの使用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9606452.2A GB9606452D0 (en) | 1996-03-27 | 1996-03-27 | Organic compounds |
GB9606452.2 | 1996-03-27 |
Related Parent Applications (1)
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JP9532077A Division JP2000507226A (ja) | 1996-03-27 | 1997-03-26 | 血管疾病および異種移植におけるラパマイシン誘導体の使用 |
Publications (4)
Publication Number | Publication Date |
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JP2009102349A JP2009102349A (ja) | 2009-05-14 |
JP2009102349A6 JP2009102349A6 (ja) | 2009-07-23 |
JP2009102349A5 JP2009102349A5 (ja) | 2010-03-04 |
JP5124431B2 true JP5124431B2 (ja) | 2013-01-23 |
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JP9532077A Withdrawn JP2000507226A (ja) | 1996-03-27 | 1997-03-26 | 血管疾病および異種移植におけるラパマイシン誘導体の使用 |
JP2008314494A Expired - Lifetime JP5124431B2 (ja) | 1996-03-27 | 2008-12-10 | 血管疾病および異種移植におけるラパマイシン誘導体の使用 |
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JP9532077A Withdrawn JP2000507226A (ja) | 1996-03-27 | 1997-03-26 | 血管疾病および異種移植におけるラパマイシン誘導体の使用 |
Country Status (30)
Country | Link |
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US (5) | US6384046B1 (ja) |
EP (3) | EP2008657B1 (ja) |
JP (2) | JP2000507226A (ja) |
KR (2) | KR100836971B1 (ja) |
CN (1) | CN1124135C (ja) |
AT (1) | ATE224194T1 (ja) |
AU (1) | AU716514B2 (ja) |
BR (1) | BR9708358A (ja) |
CA (1) | CA2247275C (ja) |
CY (1) | CY2404B1 (ja) |
CZ (1) | CZ292483B6 (ja) |
DE (1) | DE69715611T2 (ja) |
DK (2) | DK2008657T3 (ja) |
ES (2) | ES2184078T3 (ja) |
GB (1) | GB9606452D0 (ja) |
HK (1) | HK1018688A1 (ja) |
HU (1) | HU226422B1 (ja) |
ID (1) | ID17195A (ja) |
IL (1) | IL125812A (ja) |
MY (1) | MY117798A (ja) |
NO (1) | NO316667B1 (ja) |
NZ (1) | NZ331463A (ja) |
PL (1) | PL187732B1 (ja) |
PT (2) | PT893996E (ja) |
RU (1) | RU2214247C2 (ja) |
SI (1) | SI2008657T1 (ja) |
SK (1) | SK284343B6 (ja) |
TR (1) | TR199801919T2 (ja) |
WO (1) | WO1997035575A1 (ja) |
ZA (1) | ZA972719B (ja) |
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