WO2012046772A1 - リンパ浮腫予防治療剤 - Google Patents
リンパ浮腫予防治療剤 Download PDFInfo
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- WO2012046772A1 WO2012046772A1 PCT/JP2011/072990 JP2011072990W WO2012046772A1 WO 2012046772 A1 WO2012046772 A1 WO 2012046772A1 JP 2011072990 W JP2011072990 W JP 2011072990W WO 2012046772 A1 WO2012046772 A1 WO 2012046772A1
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- lymphedema
- pitavastatin
- atorvastatin
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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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
- A61K31/47—Quinolines; Isoquinolines
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61P7/10—Antioedematous agents; Diuretics
Definitions
- the present invention relates to a prophylactic / therapeutic agent for lymphedema without a conventional effective treatment.
- Lymphedema is a serious disease that causes limb hypertrophy and dysfunction due to lymphatic dysfunction and lymph fluid accumulation, repetitive cellulitis, lymphatic leakage, and the like, and significantly lowers the patient's QOL.
- a serious disease Despite the fact that many patients have troubled their daily lives, there is no effective preventive / therapeutic method, and it can be dealt with by temporarily reducing edema through massage and compression treatment with elastic stockings. This is the current situation.
- this serious disease there is no clear diagnostic criteria, and there is no clear data on the number of patients because there is a low level of awareness among healthcare professionals that it is a disease that significantly impairs patient QOL. Is the current situation.
- Patent Document 1 As a therapeutic means for lymphedema, it has been proposed to increase NO (nitrogen monoxide) in lymphatic vessels (Patent Document 1). In this document, there is a statement that lymph flow is decreased by suppressing NO production, and conversely, if NO is enhanced, lymph flow is considered to be enhanced. Statins are described as examples. Patent document 2 describes that administration of VEGF-C improves lymphedema, and describes that lymphedema may be treated with an anti-inflammatory agent.
- an object of the present invention is to provide a new preventive / therapeutic agent effective for lymphedema without a conventional effective therapeutic means.
- the present inventor first made a lymphedema model by lymphatic vessel ligation in view of the frequent occurrence of lymphedema after lymph node dissection during surgery and gynecological surgery.
- ligation of several lymph vessels connecting the inguinal and axillary lymph nodes of mice causes edema similar to that of human lymph edema and leakage of lymph into the tissue with good reproducibility.
- statins which are HMG-CoA reductase inhibitors
- vascular endothelial NO synthase gene eNOS
- R 1 represents an organic group
- X represents —CH 2 CH 2 — or —CH ⁇ CH—
- R 2 represents a hydrogen atom or an alkyl group.
- a lactone derivative thereof or a salt thereof as an active ingredient [2] An indolyl group, an indenyl group, a pyridyl group, a pyrrolopyridyl group, a pyrazolopyridyl group, a thienopyridyl group, a pyrimidyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolidyl group, which R 1 may have a substituent
- the lymphedema preventive or therapeutic agent according to [1] which is a quinolyl group, a naphthyl group, a hexahydronaphthyl group, a cyclohexyl group, a phenylsilylphen
- lymphedema The agent for preventing and treating lymphedema according to [1], wherein the active ingredient is lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin, mevastatin, pitavastatin or a salt thereof.
- R 1 represents an organic group
- X represents —CH 2 CH 2 — or —CH ⁇ CH—
- R 2 represents a hydrogen atom or an alkyl group.
- a lactone derivative thereof or a salt thereof [6] An indolyl group, an indenyl group, a pyridyl group, a pyrrolopyridyl group, a pyrazolopyridyl group, a thienopyridyl group, a pyrimidyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, an indolidyl group, which R 1 may have a substituent,
- a lactone or a salt thereof which is a quinolyl group, a naphthyl group, a hexahydronaphthyl group, a cyclohexyl group, a phenylsilylphenyl
- R 1 represents an organic group
- X represents —CH 2 CH 2 — or —CH ⁇ CH—
- R 2 represents a hydrogen atom or an alkyl group.
- Use according to [9] which is a quinolyl group, a naphthyl group, a hexahydronaphthyl group, a cyclohexyl group, a phenylsilylphenyl group, a phenylthieny
- a method for preventing and treating lymphedema which comprises administering a compound represented by the formula: [14] Indolyl group, indenyl group, pyridyl group, pyrrolopyridyl group, pyrazolopyridyl group, thienopyridyl group, pyrimidyl group, pyrazolyl group, pyrrolyl group, imidazolyl group, indolidyl group, optionally substituted by R 1 [13]
- the method according to [13] which is a quinolyl group, a naphthyl group, a hexahydronaphthyl group, a cyclohexyl group, a phenylsilylphenyl group, a phenylthienyl group or a pheny
- lymphedema that has not been effective in the treatment can be remarkably suppressed, the QOL of patients after surgery and gynecological surgery can be remarkably improved.
- the organic group represented by R 1 of the compound represented by the formula (1) is preferably an organic group having a ring structure which may have a substituent.
- the organic group having a ring structure include indolyl group, indenyl group, pyridyl group, pyrrolopyridyl group, pyrazolopyridyl group, thienopyridyl group, pyrimidyl group, pyrazolyl group, pyrrolyl group, imidazolyl group, indolizyl group, quinolyl group, naphthyl group, A hexahydronaphthyl group, a cyclohexyl group, a phenylsilylphenyl group, a phenylthienyl group, and a phenylfuryl group are exemplified, and a hexahydronaphthyl group, an indolyl group, a pyridyl group,
- Substituents that may be substituted with organic groups having these ring structures include hydroxy groups, linear, branched or cyclic alkyl groups, alkyloxyalkyl groups, alkylcarbonyloxy groups, alkyl-substituted amino groups, and substituted groups. Examples include alkylsulfonylamino group, substituted phenylsulfonylamino group, carbamoyl group, halophenyl group, alkylphenyl group, alkoxyphenyl group, phenyl group and oxo group which may be substituted by one or two alkyl or phenyl groups. .
- substituents that may be substituted with an organic group having a ring structure, a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, or 1 to 4 acyloxy groups, alkyl substituted amino groups having 1 to 4 carbon atoms, alkyl substituted alkyl groups having 1 to 4 carbon atoms, alkylsulfonylamino groups having 1 to 4 carbon atoms, alkyl substituted phenylsulfonylamino groups having 1 to 4 carbon atoms, carbon numbers 1 to 4 alkyl-substituted carbamoyl groups, phenyl-substituted carbamoyl groups, fluorophenyl groups, bromophenyl groups, iodophenyl groups, methylphenyl groups, ethylphenyl groups, methoxyphenyl groups, ethoxyphenyl groups and
- Examples of the alkyl group represented by R 2 include linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms.
- the lactone derivative can be obtained by subjecting the corresponding compound represented by the formula (1) to a conventional lactonization method such as acidic conditions.
- the salt of the compound represented by the formula (1) and its lactone derivative is a physiologically acceptable salt, and is an alkali metal salt such as sodium salt or potassium salt, or an alkaline earth metal salt such as calcium salt or magnesium salt.
- Organic amine salts such as phenethylamine salts, ammonium salts, and the like, and sodium salts and calcium salts are more preferable.
- the active ingredient of the agent for preventing and treating lymphedema of the present invention includes lovastatin (US Pat. No. 4,231,938: (+)-(1S, 3R, 7S, 8S, 8aR) -1,2,3,7, 8,8a-Hexahydro-3,7-dimethyl-8- [2-[(2R, 4R) -tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl] ethyl] -1-naphthyl (S ) -2-methylbutyrate), simvastatin (US Pat. No.
- 2,569,746 (3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] -3,5-dihydroxy-6-heptenoic acid or Those salts are preferable, and pravastatin or a salt thereof, pitavastatin or a salt thereof, and atorvastatin or a salt thereof are particularly preferable.
- statins A compound represented by the formula (1), a lactone derivative thereof or a salt thereof (hereinafter also referred to as statins) remarkably suppresses lymphedema and suppresses leakage of lymph fluid into tissues. It is useful as a preventive and therapeutic agent.
- the lymphedema-inhibiting action of the statins of the present invention was obtained even in a model that does not express eNOS, and thus occurs independently of the NO producing action of statins.
- the lymphedema inhibitory action of statins becomes more prominent when administered before or after surgery, which is considered to be the cause of the development of lymphedema.
- statins are already widely used as therapeutic drugs for hypercholesterolemia, there is no problem in safety.
- statins in the present invention examples include oral administration such as tablets, capsules, granules, powders, syrups, etc. and intravenous injections, intramuscular injections, suppositories, inhalants, transdermal absorption agents, eye drops, and the like. Parenteral administration by an agent, a nasal drop, etc. is mentioned, but oral administration is preferable.
- this active ingredient alone or one or more other pharmaceutically acceptable excipients, binders, extenders, disintegrants, Surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, fragrances, coating agents, carriers, diluents and the like can be used in appropriate combinations.
- oral administration is preferred.
- it is preferable to adjust the pH in consideration of the stability of the active ingredient Japanese Patent Laid-Open No. 2-6406, Japanese Patent No. 2,774,037, WO 97/23200, etc.). .
- the dosage of these drugs varies depending on the weight, age, sex and symptoms of the patient, but in the case of a normal adult, 0.01 to 1000 mg per day as a compound represented by the formula (1), and further 0.1 to 100 mg, particularly 1 to 50 mg, is preferably orally administered in one or several divided doses.
- statin administration is that many lymphedema is onset several years after surgery
- a means of prophylactic administration before onset after surgery, to improve symptoms after onset Any means of administering to is desirable.
- the dosage is preferably as described above.
- Example (experimental method) (1) Creation of mouse abdominal wall lymphedema model Nembutal 60 mg / kg is intraperitoneally administered to male C57BL / 6J mice or e57S-deficient mice of C57BL / 6J genetic background at the time of surgery, and lymph nodes and lymph vessels are identified. 1% Evans Blue is injected subcutaneously into the back of the right foot, the back of the hand, and the buttocks. Remove the abdomen, identify the inguinal lymph nodes and axillary lymph nodes in the right abdominal wall by abdominal door-like skin incision, and connect the lymph vessels to two or three places near the axillary lymph nodes, After removing the axillary lymph node, the skin is sutured to finish. On the 7th day after the operation, an abdominal door-like skin incision is made again to collect abdominal wall tissue.
- statins 250 ⁇ l of statins dissolved in distilled water was orally administered once a day from 3 days before surgery to 7 days after surgery. Distilled water was administered to the control group of mice in the same manner.
- Fig. 1 shows the skin thickness of the upper inguinal slice 7 days after the normal group, the solvent (water) administration group, and the pitavastatin administration group (results of Experiment 1).
- gray squares are the results of wild-type mice.
- Black squares are the results for eNOS deficient mice.
- lymphedema was remarkably suppressed by pitavastatin administration.
- statins remarkably suppress lymphedema, and the action is independent of the presence or absence of eNOS expression. That is, it is clear that the inhibitory action of statins on lymphedema is not related to NO production.
- FIG. 2 the skin thickness (after 7 days) by administration of pitavastatin, atorvastatin and pravastatin is shown in FIG. 2 (experiment 2) and experiment 3) together). It can be seen that atorvastatin and pravastatin, as well as pitavastatin, significantly suppress lymphedema.
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Abstract
Description
従って、本発明の課題は、従来有効な治療手段のないリンパ浮腫に対して有効な新たな予防治療剤を提供することにある。
[1]次式(1)
で表わされる化合物、そのラクトン誘導体又はそれらの塩を有効成分として含有するリンパ浮腫予防治療剤。
[2]R1が置換基を有していてもよいインドリル基、インデニル基、ピリジル基、ピロロピリジル基、ピラゾロピリジル基、チエノピリジル基、ピリミジル基、ピラゾリル基、ピロリル基、イミダゾリル基、インドリジル基、キノリル基、ナフチル基、ヘキサヒドロナフチル基、シクロヘキシル基、フェニルシリルフェニル基、フェニルチエニル基又はフェニルフリル基である[1]記載のリンパ浮腫予防治療剤。
[3]有効成分が、ロバスタチン、シンバスタチン、プラバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ロスバスタチン、メバスタチン、ピタバスタチン又はそれらの塩である[1]記載のリンパ浮腫予防治療剤。
[4]有効成分が、プラバスタチン、アトルバスタチン、ピタバスタチン又はそれらの塩である[1]記載のリンパ浮腫予防治療剤。
[5]リンパ浮腫予防治療用の、次式(1)
で表わされる化合物、そのラクトン誘導体又はそれらの塩。
[6]R1が置換基を有していてもよいインドリル基、インデニル基、ピリジル基、ピロロピリジル基、ピラゾロピリジル基、チエノピリジル基、ピリミジル基、ピラゾリル基、ピロリル基、イミダゾリル基、インドリジル基、キノリル基、ナフチル基、ヘキサヒドロナフチル基、シクロヘキシル基、フェニルシリルフェニル基、フェニルチエニル基又はフェニルフリル基である[5]記載の化合物、そのラクトン体又はそれらの塩。
[7]ロバスタチン、シンバスタチン、プラバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ロスバスタチン、メバスタチン、ピタバスタチン又はそれらの塩である[5]記載の化合物又はそれらの塩。
[8]プラバスタチン、アトルバスタチン、ピタバスタチン又はそれらの塩である[5]記載の化合物又はそれらの塩。
[9]リンパ浮腫予防治療剤製造のための、次式(1)
で表わされる化合物、そのラクトン誘導体又はそれらの塩の使用。
[10]R1が置換基を有していてもよいインドリル基、インデニル基、ピリジル基、ピロロピリジル基、ピラゾロピリジル基、チエノピリジル基、ピリミジル基、ピラゾリル基、ピロリル基、イミダゾリル基、インドリジル基、キノリル基、ナフチル基、ヘキサヒドロナフチル基、シクロヘキシル基、フェニルシリルフェニル基、フェニルチエニル基又はフェニルフリル基である[9]記載の使用。
[11]有効成分が、ロバスタチン、シンバスタチン、プラバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ロスバスタチン、メバスタチン、ピタバスタチン又はそれらの塩である[9]記載の使用。
[12]有効成分が、プラバスタチン、アトルバスタチン、ピタバスタチン又はそれらの塩である[9]記載の使用。
[13]次式(1)
で表わされる化合物、そのラクトン誘導体又はそれらの塩を投与することを特徴とするリンパ浮腫の予防治療方法。
[14]R1が置換基を有していてもよいインドリル基、インデニル基、ピリジル基、ピロロピリジル基、ピラゾロピリジル基、チエノピリジル基、ピリミジル基、ピラゾリル基、ピロリル基、イミダゾリル基、インドリジル基、キノリル基、ナフチル基、ヘキサヒドロナフチル基、シクロヘキシル基、フェニルシリルフェニル基、フェニルチエニル基又はフェニルフリル基である[13]記載の方法。
[15]有効成分が、ロバスタチン、シンバスタチン、プラバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ロスバスタチン、メバスタチン、ピタバスタチン又はそれらの塩である[13]記載の方法。
[16]有効成分が、プラバスタチン、アトルバスタチン、ピタバスタチン又はそれらの塩である[13]記載の方法。
環構造を有する有機基としては、インドリル基、インデニル基、ピリジル基、ピロロピリジル基、ピラゾロピリジル基、チエノピリジル基、ピリミジル基、ピラゾリル基、ピロリル基、イミダゾリル基、インドリジル基、キノリル基、ナフチル基、ヘキサヒドロナフチル基、シクロヘキシル基、フェニルシリルフェニル基、フェニルチエニル基及びフェニルフリル基が挙げられ、特にヘキサヒドロナフチル基、インドリル基、ピリジル基、ピリミジル基、ピロリル基及びキノリル基が好ましい。
またこのような種々の剤型の医薬製剤を調製するには、この有効成分を単独で、又は他の1種以上の薬学的に許容される賦形剤、結合剤、増量剤、崩壊剤、界面活性剤、滑沢剤、分散剤、緩衝剤、保存剤、嬌味剤、香料、被膜剤、担体、希釈剤等を適宜組み合わせて用いることができる。
(実験方法)
(1)マウス腹壁リンパ浮腫モデル作成
手術時8週齢雄のC57BL/6Jマウス又はC57BL/6J遺伝的背景のeNOS欠損マウスにネンブタール60mg/kgを腹腔内投与し、リンパ節、リンパ管を同定するための1%エバンスブルーを右足背部、手背部、臀部に0.05mLずつ皮下注射する。腹部の除毛を行い、腹部扉状皮膚切開にて右の腹壁の鼡径リンパ節、腋窩リンパ節、それらを結ぶリンパ管を同定し、リンパ管を腋窩リンパ節近くで2~3箇所結紮し、腋窩リンパ節を切除した後、皮膚縫合して終了する。術後7日目に再び腹部扉状皮膚切開をして腹壁組織を採取する。
1日1回術前3日から術後7日に蒸留水で溶解したスタチン類を250μlずつ経口投与した。コントロール群のマウスには蒸留水を同様の方法で投与した。
実験1)ピタバスタチン10mg/kg/dayをC57BL/6Jマウス(n=4)とC57BL/6J遺伝的背景のeNOS欠損マウス(n=4)に投与した。
実験2)ピタバスタチン1mg/kg/day、アトルバスタチン2.5mg/kg/dayをC57BL/6Jマウス(各スタチンn=4)に投与した。
実験3)ピタバスタチン1mg/kg/day、アトルバスタチン1mg/kg/day、プラバスタチン1mg/kg/dayをC57BL/6Jマウス(各スタチンn=3,4,3)に投与した。
1)肉眼的検討
術後7日目、14日目に鼡径リンパ節に1%エバンスブルー0.05μlを局所注射してリンパ管造影を行い、リンパ液の漏出、走行を評価した。
2)皮下組織の厚さによる浮腫評価
組織はメタノール固定パラフィン切片をヘマトキシリン染色し、解剖学的に組織間液が貯留しやすいマウスの最下部位である鼡径上部切片の皮膚の厚さを計測した。
Claims (16)
- R1が置換基を有していてもよいインドリル基、インデニル基、ピリジル基、ピロロピリジル基、ピラゾロピリジル基、チエノピリジル基、ピリミジル基、ピラゾリル基、ピロリル基、イミダゾリル基、インドリジル基、キノリル基、ナフチル基、ヘキサヒドロナフチル基、シクロヘキシル基、フェニルシリルフェニル基、フェニルチエニル基又はフェニルフリル基である請求項1記載のリンパ浮腫予防治療剤。
- 有効成分が、ロバスタチン、シンバスタチン、プラバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ロスバスタチン、メバスタチン、ピタバスタチン又はそれらの塩である請求項1記載のリンパ浮腫予防治療剤。
- 有効成分が、プラバスタチン、アトルバスタチン、ピタバスタチン又はそれらの塩である請求項1記載のリンパ浮腫予防治療剤。
- R1が置換基を有していてもよいインドリル基、インデニル基、ピリジル基、ピロロピリジル基、ピラゾロピリジル基、チエノピリジル基、ピリミジル基、ピラゾリル基、ピロリル基、イミダゾリル基、インドリジル基、キノリル基、ナフチル基、ヘキサヒドロナフチル基、シクロヘキシル基、フェニルシリルフェニル基、フェニルチエニル基又はフェニルフリル基である請求項5記載の化合物、そのラクトン体又はそれらの塩。
- ロバスタチン、シンバスタチン、プラバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ロスバスタチン、メバスタチン、ピタバスタチン又はそれらの塩である請求項5記載の化合物又はそれらの塩。
- プラバスタチン、アトルバスタチン、ピタバスタチン又はそれらの塩である請求項5記載の化合物又はそれらの塩。
- R1が置換基を有していてもよいインドリル基、インデニル基、ピリジル基、ピロロピリジル基、ピラゾロピリジル基、チエノピリジル基、ピリミジル基、ピラゾリル基、ピロリル基、イミダゾリル基、インドリジル基、キノリル基、ナフチル基、ヘキサヒドロナフチル基、シクロヘキシル基、フェニルシリルフェニル基、フェニルチエニル基又はフェニルフリル基である請求項9記載の使用。
- 有効成分が、ロバスタチン、シンバスタチン、プラバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ロスバスタチン、メバスタチン、ピタバスタチン又はそれらの塩である請求項9記載の使用。
- 有効成分が、プラバスタチン、アトルバスタチン、ピタバスタチン又はそれらの塩である請求項9記載の使用。
- R1が置換基を有していてもよいインドリル基、インデニル基、ピリジル基、ピロロピリジル基、ピラゾロピリジル基、チエノピリジル基、ピリミジル基、ピラゾリル基、ピロリル基、イミダゾリル基、インドリジル基、キノリル基、ナフチル基、ヘキサヒドロナフチル基、シクロヘキシル基、フェニルシリルフェニル基、フェニルチエニル基又はフェニルフリル基である請求項13記載の方法。
- 有効成分が、ロバスタチン、シンバスタチン、プラバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ロスバスタチン、メバスタチン、ピタバスタチン又はそれらの塩である請求項13記載の方法。
- 有効成分が、プラバスタチン、アトルバスタチン、ピタバスタチン又はそれらの塩である請求項13記載の方法。
Priority Applications (5)
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CN2011800481646A CN103153299A (zh) | 2010-10-06 | 2011-10-05 | 淋巴水肿预防治疗剂 |
US13/878,136 US20130210860A1 (en) | 2010-10-06 | 2011-10-05 | Prophylactic and/or therapeutic agent against lymphedema |
KR1020137008414A KR20130137623A (ko) | 2010-10-06 | 2011-10-05 | 림프 부종 예방 치료제 |
EP11830704.0A EP2626069A4 (en) | 2010-10-06 | 2011-10-05 | A MEDICINAL PRODUCT FOR THE PREVENTION AND TREATMENT OF A DERY LYMPH |
JP2012537739A JPWO2012046772A1 (ja) | 2010-10-06 | 2011-10-05 | リンパ浮腫予防治療剤 |
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JP2010-226603 | 2010-10-06 | ||
JP2010226603 | 2010-10-06 |
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EP (1) | EP2626069A4 (ja) |
JP (1) | JPWO2012046772A1 (ja) |
KR (1) | KR20130137623A (ja) |
CN (1) | CN103153299A (ja) |
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2011
- 2011-10-05 CN CN2011800481646A patent/CN103153299A/zh active Pending
- 2011-10-05 US US13/878,136 patent/US20130210860A1/en not_active Abandoned
- 2011-10-05 KR KR1020137008414A patent/KR20130137623A/ko not_active Application Discontinuation
- 2011-10-05 JP JP2012537739A patent/JPWO2012046772A1/ja active Pending
- 2011-10-05 WO PCT/JP2011/072990 patent/WO2012046772A1/ja active Application Filing
- 2011-10-05 TW TW100136006A patent/TW201219037A/zh unknown
- 2011-10-05 EP EP11830704.0A patent/EP2626069A4/en not_active Withdrawn
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Also Published As
Publication number | Publication date |
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JPWO2012046772A1 (ja) | 2014-02-24 |
US20130210860A1 (en) | 2013-08-15 |
KR20130137623A (ko) | 2013-12-17 |
CN103153299A (zh) | 2013-06-12 |
EP2626069A4 (en) | 2014-03-19 |
EP2626069A1 (en) | 2013-08-14 |
TW201219037A (en) | 2012-05-16 |
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