JP2003516351A - Collagen-induced platelet aggregation inhibitor - Google Patents
Collagen-induced platelet aggregation inhibitorInfo
- Publication number
- JP2003516351A JP2003516351A JP2001543099A JP2001543099A JP2003516351A JP 2003516351 A JP2003516351 A JP 2003516351A JP 2001543099 A JP2001543099 A JP 2001543099A JP 2001543099 A JP2001543099 A JP 2001543099A JP 2003516351 A JP2003516351 A JP 2003516351A
- Authority
- JP
- Japan
- Prior art keywords
- platelet aggregation
- collagen
- compound
- induced
- induced platelet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
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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
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- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
(57)【要約】 本発明は、BTKおよびコラーゲン誘導血小板凝集を阻害する化合物または組成物の薬学的有効量を患者に投与することを含む、血小板凝集状態の治療または予防に有用な療法について述べる。前記血小板凝集状態は、心血管、造血および脳血管の疾患を含む。 (57) [Summary] The present invention describes a therapy useful for treating or preventing a platelet aggregation condition, comprising administering to a patient a pharmaceutically effective amount of a compound or composition that inhibits BTK and collagen-induced platelet aggregation. The platelet aggregation status includes cardiovascular, hematopoietic and cerebrovascular diseases.
Description
【０００１】
本出願は、ＰＣＴによる国際特許出願として、米国法人(U.S. national corpo
ration)であるParker Hughes Institute（米国を除く全ての国における出願人）
、米国市民(U.S. citizen)であるFatih M. Uckun（米国のみにおける出願人）の
名で、全ての国を指定して２０００年１１月２９日に提出する。This application is an international patent application filed by PCT as a US corporation (US national corpo
ration) Parker Hughes Institute (Applicant in all countries except USA)
, US citizen, Fatih M. Uckun (Applicant in the United States only), filed on November 29, 2000, designating all countries.
【０００２】
（発明の分野）
本発明は、患者(subject)の疾患または血小板凝集状態を治療または予防する
療法に関する。この方法は、血小板凝集、そして特にコラーゲン誘導血小板凝集
を阻害する化合物の薬学的有効量を投与することを含む。FIELD OF THE INVENTION The present invention relates to therapies for treating or preventing disease or platelet aggregation in a subject. The method comprises administering a pharmaceutically effective amount of a compound that inhibits platelet aggregation, and in particular collagen-induced platelet aggregation.
【０００３】
（発明の背景）
心臓疾患は今日の社会における普遍的な死因であり、しばしば虚血性症候群(i
schemic syndromes)の結果として起こる。この虚血性症候群は、血管形成術(ang
ioplasty)、頚動脈血管内膜切除術(carotid endarterectomy)、血管片吻合術(an
astomosis of vascular grafts)、およびその他の心血管術(cardiovascular dev
ices)後の心筋梗塞(myocardial infarction)、慢性不安定狭心症(chronic unsta
ble angina)、一過性虚血性発作と卒中(transient ischemic attacks and strok
es)、末梢血管疾患(peripheral vascular disease)、動脈血栓症(arterial thro
mbosis)、子癇前症(preeclampsia)、塞栓症(embolism)、再狭窄(restenosis)お
よび／または血栓症(thrombosis)を含むアテローム性動脈硬化症(atheroscleros
is)および動脈硬化症(arteriosclerosis)によって引き起こされる。これら症候
群は、血管壁上または管腔内(on vessel walls or within the lumen)での血液
由来メディエータ(blood-born mediators)による血小板凝集から始まり、その結
果血流を制限するコラーゲンを生成すると考えられる多様な狭窄的および閉塞的
血管障害(stenotic and occlusive vascular disorders)を代表する。BACKGROUND OF THE INVENTION Heart disease is a common cause of death in today's society, often with ischemic syndrome (i.
Schematic syndromes). This ischemic syndrome is an angioplasty procedure.
ioplasty), carotid endarterectomy, vascular anastomosis (an
astomosis of vascular grafts) and other cardiovascular dev
myocardial infarction after ices, chronic unstable angina
ble angina), transient ischemic attacks and strok
es), peripheral vascular disease, arterial thro
mbosis), preeclampsia, embolism, restenosis and / or atherosclerosis, including thrombosis.
is) and arteriosclerosis. These syndromes are thought to begin with platelet aggregation by blood-born mediators on the vessel walls or within the lumen, resulting in the production of collagen that limits blood flow. It represents a variety of stenotic and occlusive vascular disorders.
【０００４】
血小板凝集の基礎的なメカニズムはよく研究されている。そのメカニズムは、
管腔内狭窄(narrowing of the lumen)、プラーク形成(plaque formation) 、お
よび異物(foreign bodies)／医療具(medical instruments)の存在等の血管損傷(
blood vessel injury)から始まる。この損傷は、血小板活性化と、フィブリノー
ゲンおよびリガンドの結合とにつながる。The basic mechanism of platelet aggregation has been well studied. The mechanism is
Vascular damage such as narrowing of the lumen, plaque formation, and the presence of foreign bodies / medical instruments
blood vessel injury). This damage leads to platelet activation and binding of fibrinogen and ligand.
【０００５】
Bruton'sチロシンキナーゼ(BTK)は、タンパク質チロシンキナーゼ(PTKs)のBTK
/Tecファミリーの一員であり、B系統リンパ細胞(B-lineage lymphoid cells)の
増殖(growth)および分化(differentiation)を調節するシグナル伝達経路(signal
transduction pathways)に関連する細胞質PTK(cytoplasmic PTK)である(Rawlin
gs, D. J., and Witte, O. N. (1994) Immunol. Rev. 138, 105-119; Kurosaki
, T. (1997) Curr Opin. Immunol. 9, 309-318; and Uckun, F. M. (1998) Bioc
hemical Pharmacology, et al., 56, 683-691)。BTKは、多様な細胞外リガンド
とそれらの細胞表面レセプターとの結合から始まるシグナル伝達経路に参加する
。ホスホリパーゼC-γ2媒介によるカルシウム動員(calcium mobilization)の誘
導(induction)には、B細胞抗原レセプター(BCR)のリガンド結合に続いて、PTKs
Lyn および Sykの共同した活動(Kurosaki, T. (1997) Curr Opin. Immunol. 9,
309-318)によるBTK活性化が必要である(Kurosaki, T. (1997) Curr Opin. Immun
ol. 9, 309-318)。BTKは、コラーゲンレセプターグリコプロテインVI(GP VI)‐F
cレセプターガンマ(FcRγ)鎖結合シグナリングに参加する。FcRγ鎖における免
疫レセプターチロシンベース活性化モチーフ(immune-receptor tyrosine based
activation motif(ITAM))のチロシンリン酸化は、ホスホリパーゼCガンマ2(PLC
γ 2)のリン酸化および活性化につながる。活性化PLCγ 2は、PI-4,5-二リン酸(
PIP2)をイノシトール三リン酸(IP3)に変換し、細胞内カルシウム動員につなげる
。Bruton's tyrosine kinase (BTK) is a protein tyrosine kinase (PTKs) BTK
/ Tec family member, a signal transduction pathway that regulates the growth and differentiation of B-lineage lymphoid cells.
It is a cytoplasmic PTK (Rawlin) associated with transduction pathways.
gs, DJ, and Witte, ON (1994) Immunol. Rev. 138, 105-119; Kurosaki
, T. (1997) Curr Opin. Immunol. 9, 309-318; and Uckun, FM (1998) Bioc
hemical Pharmacology, et al., 56, 683-691). BTK participates in a signaling pathway that begins with the binding of various extracellular ligands to their cell surface receptors. Induction of phospholipase C-γ2-mediated calcium mobilization involves ligand binding of the B cell antigen receptor (BCR) followed by PTKs
Joint activities of Lyn and Syk (Kurosaki, T. (1997) Curr Opin. Immunol. 9,
309-318) is required for BTK activation (Kurosaki, T. (1997) Curr Opin. Immun
ol. 9, 309-318). BTK is a collagen receptor glycoprotein VI (GP VI) -F
Participates in c-receptor gamma (FcRγ) chain binding signaling. Immunoreceptor tyrosine based activation motif in FcRγ chain
Tyrosine phosphorylation of activation motif (ITAM) is caused by phospholipase C gamma 2 (PLC
It leads to phosphorylation and activation of γ 2). Activated PLCγ 2 is a PI-4,5-diphosphate (
PIP2) is converted to inositol triphosphate (IP3), which leads to intracellular calcium mobilization.
【０００６】
トロンビン誘導血小板凝集とは、血液中でプロトロンビンから形成されるトロ
ンビンという酵素に応答した血小板凝集のことである。コラーゲン誘導血小板凝
集とは、コラーゲンというタンパク質に応答した血小板凝集のことである。Thrombin-induced platelet aggregation is platelet aggregation in response to an enzyme called thrombin formed from prothrombin in blood. Collagen-induced platelet aggregation is platelet aggregation in response to a protein called collagen.
【０００７】
Gelotteの米国特許第5,972,967号およびScarboroughらの米国特許第5,968,902
号は、フィブリノーゲンの結合を制限することにより血小板への結合を阻害する
一定の化合物および組成物について記述している。それにも関わらず、血小板凝
集状態を治療または予防するための化合物および改良された方法の発見が依然と
して必要とされている。Gelotte US Pat. No. 5,972,967 and Scarborough et al. US Pat. No. 5,968,902
The publication describes certain compounds and compositions that inhibit binding to platelets by limiting the binding of fibrinogen. Nevertheless, there remains a need for discovery of compounds and improved methods for treating or preventing platelet aggregation conditions.
【０００８】
（発明の要約）
この場で具体的に表現し、かつ大まかに記述する本発明の目的に従えば、本発
明の一つの側面は、下記式の化合物または薬学的に許容可能なその酸付加塩の有
効量を投与することによる血小板凝集阻害方法に関する。SUMMARY OF THE INVENTION According to the objectives of the present invention, which are specifically expressed herein and generally described, one aspect of the present invention is a compound of the formula: It relates to a method for inhibiting platelet aggregation by administering an effective amount of an acid addition salt.
【化３】 [Chemical 3]
【０００９】
本発明の第二の側面は、下記式の化合物または薬学的に許容可能なその酸付加
塩の有効量を患者(subject)に投与することを含む、患者の疾患または血小板凝
集状態を予防または治療する方法に関する。A second aspect of the present invention comprises the administration of an effective amount of a compound of the formula below or a pharmaceutically acceptable acid addition salt thereof to a subject to determine the disease or platelet aggregation state of the patient. It relates to a method of prevention or treatment.
【化４】 [Chemical 4]
【００１０】
本発明のさらなる利点は、一部は下記の記述の中に述べられており、そして一
部は、その記述から明白であるかまたは本発明の実施により習得できるであろう
。本発明の利点は、特に、添付した特許請求の範囲に示す要素およびその組み合
わせにより、実現し、そして達成できるであろう。上記の一般的記述および下記
の詳細な記述の両方は、単に例示的および説明的なものであり、そして、特許請
求する本発明を制限するものではないと理解すべきである。Additional advantages of the invention are set forth, in part, in the description below, and in part will be apparent from, or may be learned by, practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that both the foregoing general description and the following detailed description are merely exemplary and explanatory and are not intended to limit the claimed invention.
【００１１】
添付の図面は、本明細書に組み込まれ、その一部を構成し、いくつかの実施例
を図解し、そして、前記記述とともに、本発明の原理を説明する役割を果たす。The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments, and together with the above description serve to explain the principles of the invention.
【００１２】
（図面の簡単な説明）
図１ａ〜１ｆは、実施例１の実験結果を示すグラフであり、５マイクログラム
毎ミリリットルのコラーゲンによる２０分間（図１ａ）および２４時間（図１ｄ
）と、２マイクログラム毎ミリリットルのコラーゲンによる２０分間（図１ｂ）
および２４時間（図１ｅ）と、トロンビンによる２０分間（図１ｃ）および２４
時間（図１ｆ）の血小板凝集効果を含む。BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1a-1f are graphs showing the experimental results of Example 1, 20 μm (FIG. 1a) and 24 h (FIG. 1d) with 5 micrograms per milliliter of collagen.
) And 2 micrograms per milliliter of collagen for 20 minutes (FIG. 1b).
And 24 hours (FIG. 1e) and 20 minutes with thrombin (FIG. 1c) and 24
Includes platelet aggregation effect over time (FIG. 1f).
【００１３】
図２は、実施例２の実験結果を示すグラフであり、LFM-A13による選択的で用
量依存性のコラーゲン誘導血小板凝集を含む。FIG. 2 is a graph showing the experimental results of Example 2, which includes selective and dose-dependent collagen-induced platelet aggregation by LFM-A13.
【００１４】
（好ましい実施形態の説明）
本発明は、以下における本発明の好ましい実施形態の詳細な説明およびそこに
含まれる実施例と、図面ならびにその前述および後述する説明とを参照すること
により、さらに容易に理解することができる。DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention refers to the following detailed description of preferred embodiments of the invention and the examples contained therein, and the drawings and the foregoing and subsequent description thereof, It is easier to understand.
【００１５】
本明細書およびそれに伴う特許請求の範囲では、いくつかの用語については、
下記の意味を有すると定義すべきであり、そのように基準を作成する。In this specification and the claims that follow, some terms are
It should be defined as having the following meaning, and the criteria should be developed accordingly.
【００１６】
本明細書および末尾の特許請求の範囲で、ある組成物中における特定成分の重
量部(parts by weight)に言及するときは、その成分と、その組成物中における
他の任意の成分との間の重量関係を示し、重量部(part by weight)で表す。In this specification and the claims that follow, when referring to the parts by weight of a particular ingredient in a composition, that ingredient and any other ingredients in the composition And the weight relationship between and is expressed in parts by weight.
【００１７】
「血小板凝集」とは、血小板または赤血球が一箇所に群がる(clumping togeth
er)ことを意味する。この場で使用する「血小板凝集阻害」とは、血小板凝集の
速度を遅くすることと、血小板凝集を完全に消去すること(eliminating)および
／または防止すること(preventing)とを含む。さらに、「血小板機能阻害」とは
、血小板機能を低下させることと、血小板機能を完全に消去すること(eliminati
ng)および／または防止すること(preventing)とを含む。血小板凝集状態は、塞
栓形成(embolus formation)、血栓溶解合併症(thrombolytic complications)、
播種性血管内コンゲロパシー(disseminated intravascular comgelopathy)、血
栓症(thrombosis)、冠状動脈性心疾患(coronary heart disease)、血栓塞栓症合
併症(thromboembolic complications)、心筋梗塞(myocardial infarction)、再
狭窄(restenosis)、および心房細動内における心房血栓形成(atrial thrombosis
formation in atrial fibrillation)、血管形成術(angioplasty)、頚動脈血管
内膜切除術(carotid endarterectomy)、血管片吻合術(anastomosis of vascular
grafts)、および心血管術への慢性被爆後(chronic exposure to cardiovascula
r devices)の慢性不安定狭心症(chronic unstable angina)、一過性虚血性発作
と卒中(transient ischemic attacks and strokes)、末梢血管疾患(peripheral
vascular disease)、動脈血栓症(arterial thrombosis)、子癇前症(preeclampsi
a)、塞栓症(embolism)、再狭窄(restenosis)および／または血栓症(thrombosis)
を含むが、これらに限定されない。そのような状態は、血栓治療(thermbolytid
therapy)の最中または術後、血管形成術の後、および冠状動脈バイパス術(coron
ary artery bypass)の後の血栓塞栓症(thromboembolism)および再閉塞(reocclsi
on)によっても引き起こされ得る。“Platelet aggregation” refers to clumping togeth of platelets or red blood cells.
er) means that. As used herein, “inhibition of platelet aggregation” includes slowing the rate of platelet aggregation and completely eliminating and / or preventing platelet aggregation. Furthermore, "inhibition of platelet function" means to reduce platelet function and to completely eliminate platelet function (eliminati
ng) and / or preventing. Platelet aggregation status, embolus formation, thrombolytic complications,
Disseminated intravascular comgelopathy, thrombosis, coronary heart disease, thromboembolic complications, myocardial infarction, restenosis And atrial thrombosis in atrial fibrillation
formation in atrial fibrillation), angioplasty, carotid endarterectomy, anastomosis of vascular
grafts) and chronic exposure to cardiovascula
r devices) chronic unstable angina, transient ischemic attacks and strokes, peripheral vascular disease (peripheral)
vascular disease, arterial thrombosis, preeclampsi
a), embolism, restenosis and / or thrombosis
But is not limited to. Such a condition is associated with thrombosis treatment (thermbolytid
therapy or postoperatively, after angioplasty, and coronary artery bypass grafting
thromboembolism and reocclusion after ary artery bypass
on).
【００１８】
「トロンビン誘導血小板凝集」とは、血中でプロトロンビンから形成されるト
ロンビンという酵素に応答しての血小板凝集を含む。“Thrombin-induced platelet aggregation” includes platelet aggregation in response to the enzyme thrombin formed in blood from prothrombin.
【００１９】
「コラーゲン誘導血小板凝集」とは、コラーゲンというタンパク質に応答して
の血小板凝集を含む。“Collagen-induced platelet aggregation” includes platelet aggregation in response to a protein called collagen.
【００２０】
一貫して使用する「接触(contacting)」とは、少なくとも一種類の細胞（例え
ば、神経細胞(neural cell)、幹細胞(stem cell)、心臓細胞(cardiac cell)）を
ある種の薬剤（例えば、血小板凝集および特にコラーゲン誘導血小板凝集を阻害
する化合物）に暴露する事例を意味する。“Contacting”, as used consistently, refers to at least one type of cell (eg, neural cell, stem cell, cardiac cell) as a certain drug. It refers to the case of exposure to (eg compounds that inhibit platelet aggregation and especially collagen-induced platelet aggregation).
【００２１】
「患者(subject)」という用語は、一個体を意味する。好ましくは、前記患者
は、霊長類等の哺乳類であり、そして、より好ましくはヒトである。したがって
、前記「患者」は、飼養化された動物(domesticated animals)（例えば、ネコ、
イヌ等）、家畜(livestock)（例えば、ウシ、ウマ、ブタ、ヒツジ、ヤギ等）、
および実験動物(laboratory animals)（例えば、マウス、ウサギ、ラット、モル
モット(guinea pig)等）を含むことが可能である。The term “subject” means an individual. Preferably, the patient is a mammal such as a primate, and more preferably a human. Thus, the "patient" is a domesticated animal (eg, a cat,
Dogs, etc.), livestock (eg cows, horses, pigs, sheep, goats, etc.),
And laboratory animals (eg, mouse, rabbit, rat, guinea pig, etc.).
【００２２】
一般的に、「治療上有効量(therapeutically effective amount)」、「治療上
有効用量(therapeutically effective dose)」および「有効量(effective amoun
t)」とは、希望の結果（血小板凝集の治療または予防）を達成するために必要な
量を意味する。この技術分野における通常の技能を有する個人は、本発明で使用
される、血小板凝集および特にコラーゲン誘導血小板凝集を阻害する種々の化合
物について、力価(potency)およびしたがって「有効量」が変化し得ることを認
識できるであろう。この技術分野の技能者は、化合物の力価を容易に評価するこ
とができる。Generally, a “therapeutically effective amount”, a “therapeutically effective dose” and an “effective amoun”
"t)" means the amount required to achieve the desired result (treatment or prevention of platelet aggregation). Individuals having ordinary skill in the art may vary in potency and thus "effective amount" for the various compounds used in the present invention that inhibit platelet aggregation and particularly collagen-induced platelet aggregation. You can recognize that. Those skilled in the art can easily assess the potency of a compound.
【００２３】
「薬学的に許容可能」とは、その材料が生物学的(biologically)でないか、ま
たは好ましくなくないことを意味する。すなわち、前記材料が、一個体に対し、
望ましくない生物学的効果を何ら引き起こすことなく、または、それが含まれて
いる薬学的組成物における他のどの成分(components)とも有害な方法で相互作用
することなく、選択した二環式化合物(bicyclic compound)と共に投与できるこ
とである。“Pharmaceutically acceptable” means that the material is not biologically or less preferred. That is, the material, for one individual,
The selected bicyclic compound without causing any undesired biological effect or interacting in a deleterious manner with any other components in the pharmaceutical composition in which it is contained. It can be administered with a bicyclic compound).
【００２４】
本発明での使用に好ましい化合物は、下記（式Ｉ）にその構造を示すα−シア
ノ−β−ヒドロキシ−β−メチル−Ｎ−（２，５−ジブロモフェニル）−プロペ
ンアミド(LFM-A13)または薬学的に許容可能なその塩である。A preferred compound for use in the present invention is α-cyano-β-hydroxy-β-methyl-N- (2,5-dibromophenyl) -propenamide (LFM) whose structure is shown below (formula I). -A13) or a pharmaceutically acceptable salt thereof.
【化５】 [Chemical 5]
【００２５】
α−シアノ−β−ヒドロキシ−β−メチル−Ｎ−（２，５−ジブロモフェニル
）−プロペンアミド(LFM-A13)のキャラクタリゼーションデータを以下に示す。The characterization data for α-cyano-β-hydroxy-β-methyl-N- (2,5-dibromophenyl) -propenamide (LFM-A13) is shown below.
【００２６】
融点: 148 〜 150°C; IR (KBr): 3353, 2211, 1648 および 1590 cm-1; 1H NM
R (DMSO-d6): δ 11.41 (s, 1H, NH), 8.57 (d, J = 2.4 Hz, 1H, ArH), 7.55 (
d, J = 8.7 Hz, 1H, ArH), 7.14 (dd, J = 8.7, 2.4 Hz, 1H, ArH), 7.10 (s br
, 1H, OH), 2.17 (s, 3H, CH3); MS (EI) m/z 362 (M+ + 4), 360 (M+ + 2), 35
8 (M+), 253, 251, 249, 150.Melting point: 148-150 ° C; IR (KBr): 3353, 2211, 1648 and 1590 cm -1 ; 1 H NM
R (DMSO-d 6 ): δ 11.41 (s, 1H, NH), 8.57 (d, J = 2.4 Hz, 1H, ArH), 7.55 (
d, J = 8.7 Hz, 1H, ArH), 7.14 (dd, J = 8.7, 2.4 Hz, 1H, ArH), 7.10 (s br
, 1H, OH), 2.17 (s, 3H, CH 3 ); MS (EI) m / z 362 (M + + 4), 360 (M + + 2), 35
8 (M + ), 253, 251, 249, 150.
【００２７】
本発明には、α−シアノ−β−ヒドロキシ−β−メチル−Ｎ−（２，５−ジブ
ロモフェニル）−プロペンアミド(LFM-A13)またはその他本発明に有用な任意の
化合物の薬学的に許容可能な塩を使用することができる。許容可能な塩の例とし
ては、生理学的に許容可能なアニオンを形成する酸と共に形成された有機酸付加
塩がある。この塩は、トルエンスルホン酸塩、メタンスルホン酸塩、酢酸塩、ク
エン酸塩、マロン酸塩、酒石酸塩(tartarate)、コハク酸塩、安息香酸塩、アス
コルビン酸塩、α−ケトグルタル酸塩、およびα−グリセロリン酸塩を含むが、
これらに限定されない。そして、好適な無機塩を形成しても良い。この塩は、塩
酸塩、硝酸塩、重炭酸塩および炭酸塩を含むが、これらに限定されない。The present invention provides a pharmaceutical preparation of α-cyano-β-hydroxy-β-methyl-N- (2,5-dibromophenyl) -propenamide (LFM-A13) or any other compound useful in the present invention. Pharmaceutically acceptable salts can be used. Examples of acceptable salts are organic acid addition salts formed with acids which form physiologically acceptable anions. This salt includes toluene sulfonate, methane sulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, and It contains α-glycerophosphate,
It is not limited to these. Then, a suitable inorganic salt may be formed. This salt includes, but is not limited to, hydrochloride, nitrate, bicarbonate and carbonate.
【００２８】
許容可能な塩は、この技術分野で周知の標準的な方法を用いて得ることができ
る。例えば、アミン等の十分な塩基性化合物を、好適な酸と反応させることによ
り、生理学的に許容可能なアニオンを与える。Acceptable salts can be obtained using standard methods well known in the art. For example, a sufficiently basic compound such as an amine is reacted with a suitable acid to provide a physiologically acceptable anion.
【００２９】
［合成法］
本発明の化合物は、合成有機化学者に一般的に知られている技術を用いて容易
に合成することができる。前記化合物を製造しおよび修飾するための好適な実験
方法は、UckunらのPCT公開出願WO99/54286号に記載されており、その開示は、参
照によりこの場に組み込まれる。[Synthesis Method] The compound of the present invention can be easily synthesized by using a technique generally known to a synthetic organic chemist. Suitable experimental methods for making and modifying said compounds are described in Uckun et al. PCT published application WO 99/54286, the disclosure of which is hereby incorporated by reference.
【００３０】
［効用および投与(Utility and Administration)］
これと共に含まれる療法は、血小板凝集状態の治療または予防に有用であり、
BTKを阻害しおよび血小板凝集特にコラーゲン誘導血小板凝集を阻害する化合物
または組成物の薬学的有効量を患者に投与することを含む。Utility and Administration The therapies included therewith are useful for treating or preventing a platelet aggregation condition,
Administering to the patient a pharmaceutically effective amount of a compound or composition that inhibits BTK and inhibits platelet aggregation, particularly collagen-induced platelet aggregation.
【００３１】
前記血小板凝集状態は、心血管、造血(hematopoietic)および脳血管の疾患を
含む。これには、塞栓形成(embolus formation)、血栓溶解合併症(thrombolytic
complications)、播種性血管内コンゲロパシー(disseminated intravascular c
omgelopathy)、血栓症(thrombosis)、冠状動脈性心疾患(coronary heart diseas
e)、血栓塞栓症合併症(thromboembolic complications)、心筋梗塞(myocardial
infarction)、再狭窄(restenosis)、または心房細動内における心房血栓形成(at
rial thrombosis formation in atrial fibrillation)等があるが、これらに限
定されない。そのような血小板凝集阻害は、コラーゲン経路を、トロンビン誘導
血小板凝集を含む他の経路に対し選択的にターゲットとすることができる。The platelet aggregation state includes cardiovascular, hematopoietic and cerebrovascular diseases. This includes embolus formation and thrombolytic complications.
complications), disseminated intravascular c
omgelopathy), thrombosis, coronary heart diseas
e), thromboembolic complications, myocardial infarction
infarction), restenosis, or atrial thrombosis within atrial fibrillation (at
rial thrombosis formation in atrial fibrillation) and the like, but are not limited thereto. Such inhibition of platelet aggregation can target the collagen pathway selectively to other pathways including thrombin-induced platelet aggregation.
【００３２】
前記方法は、そのような化合物もしくは組成物に細胞を接触させるか、または
それら化合物もしくは組成物の治療上有効量を患者に投与することを含む。一実
施形態では、前記細胞は、血液および免疫系の一部である。すなわち、赤血球、
巨核球(megakaryocytes)、マクロファージ（例えば、単球(monocytes)、結合組
織マクロファージ(connective tissue macrophages)、ランゲルハンス細胞、破
骨細胞(osteoclasts)、樹状細胞(dendritic cells)、ミクログリア細胞(microgl
ial cells)）、好中球、好酸球、好塩基球、マスト細胞、Ｔリンパ細胞（例えば
、ヘルパーＴ細胞、サプレッサーＴ細胞、キラーＴ細胞）、Ｂリンパ細胞（例え
ば、IgM, IgG, IgA, IgE）、キラー細胞、および幹細胞ならびに血液および免疫
系の少し分化した前駆体(committed progenitors)を含む。他の実施形態では、
前記細胞は、骨格筋細胞(skeletal muscle cells)（例えば、赤色(red)、白色(w
hite)、中間(intermediate)、筋紡錘(muscle spindle)、衛星(satellite)細胞）
、心筋細胞（例えば、普通、結節点、プルキンエ繊維(ordinary, nodal, Purkin
je fiber)）、平滑筋細胞、および筋上皮細胞(myoepithelial cells)等の収縮性
細胞(contractile cells)である。The method comprises contacting cells with such compounds or compositions, or administering to a patient a therapeutically effective amount of such compounds or compositions. In one embodiment, the cells are part of the blood and immune system. Ie red blood cells,
Megakaryocytes, macrophages (for example, monocytes, connective tissue macrophages, Langerhans cells, osteoclasts, dendritic cells, microglial cells (microgl)
ial cells), neutrophils, eosinophils, basophils, mast cells, T lymphocytes (eg helper T cells, suppressor T cells, killer T cells), B lymphocytes (eg IgM, IgG, IgA). , IgE), killer cells, and stem cells as well as slightly committed precursors of the blood and immune system. In other embodiments,
The cells are skeletal muscle cells (e.g., red, white (w
hite), intermediate, muscle spindle, satellite cell)
, Cardiomyocytes (eg, normal, nodal points, Purkinje fibers (ordinary, nodal, Purkin
je fiber), smooth muscle cells, and contractile cells such as myoepithelial cells.
【００３３】
この技術分野では、この場に記述する標準テスト(standard tests)を用いて、
またはその他同様なテストを用いて血小板凝集阻害を定量(determine)する方法
は周知である。前記方法は、少なくとも10%のコラーゲン誘導血小板凝集減少を
起こすことが好ましく、それは、例えば、15%, 20%, 25%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, 100%,またはその間の任意の量を含み、より好ましくは90%であ
る。同様に、前記方法は、例えば15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80
%, 90%, 100%を含む少なくとも10%のコラーゲン誘導細胞内カルシウム動員(calc
ium mobilization)を起こすのが望ましい。In this technical field, using standard tests described here,
Or other methods for determining platelet aggregation inhibition using similar tests are well known. The method preferably results in at least 10% collagen-induced reduction in platelet aggregation, which is, for example, 15%, 20%, 25%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, 100%, or any amount in between, more preferably 90%. Similarly, the method is, for example, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80
%, 90%, 100%, including at least 10% collagen-induced intracellular calcium mobilization (calc
It is desirable to cause (ium mobilization).
【００３４】
前記減少は、例えば、クロノロジー血小板凝集計(chronology platelet aggre
gometer)のオプティカルインピーダンス(optical impedence)を比較することに
より測定できる。そして、その他任意の公知の測定方法も使用できる。例えば、
（１）コラーゲン刺激のもとでは、コラーゲン誘導細胞内カルシウム動員のレベ
ルは時間と共に増加し、そして、そのため、前記測定は、コラーゲン誘導細胞内
カルシウムレベルの測定を含むことが可能である。または、（２）コラーゲン刺
激のもとでは、リン酸化PLCg 2レベルは時間と共に増加し、そして、そのため、
前記測定は、リン酸化PLCg 2レベルの測定を含むことが可能である。[0034] The decrease can be measured, for example, by a chronology platelet aggreometer.
It can be measured by comparing the optical impedance of the gometer. Further, any other known measuring method can be used. For example,
(1) Under collagen stimulation, the level of collagen-induced intracellular calcium mobilization increases with time, and so the measurement can include measurement of collagen-induced intracellular calcium level. Or (2) under collagen stimulation, phosphorylated PLCg 2 levels increase over time, and thus,
The measurement can include measurement of phosphorylated PLCg 2 levels.
【００３５】
細胞は、例えば、前記化合物を培養基(culture medium)に加える（持緒点滴(c
ontinuous infusion)により、ボーラス配送(bolus delivery)により、または、
前記培養基を前記薬剤を含む培養基と交換することにより）ことにより、in vit
roで接触させることができる。または、前記薬剤を細胞外液に加える（局所配送
(local delivery)、全身配送(systemic delivery)、吸入(inhalation)、静脈注
射(intravenous injection)、ボーラス配送、または持緒点滴により）ことによ
り、in vivoで接触させることができる。細胞または細胞のポピュレーション(po
pulation)に対する「接触」の期間は、前記化合物が、細胞を浸漬している前記
培養基または細胞外液の中で、生理学的有効レベルまたは推定(presumed)生理学
的有効レベルで存在する時間により決定される。好ましくは、前記接触期間は１
〜９６時間であり、より好ましくは２４時間である。しかし、そのような時間は
、前記化合物の半減期に基づいて変化するし、さらに、この技術分野の技能者が
普遍的な実験(routine experimentation)を行うことにより最適化できる。The cells are prepared by adding the compound to a culture medium (for example, carrying drip (catch
ontinuous infusion), by bolus delivery, or
By replacing the culture medium with a culture medium containing the drug).
It can be contacted with ro. Alternatively, the drug is added to extracellular fluid (local delivery
Contact can be made in vivo by (local delivery), systemic delivery, inhalation, intravenous injection, bolus delivery, or by instillation. Cell or population of cells (po
The period of "contact" to the pulation) is determined by the time that the compound is present at the physiologically effective level or the presumed physiologically effective level in the culture medium in which the cells are immersed or the extracellular fluid. It Preferably, the contact period is 1
~ 96 hours, more preferably 24 hours. However, such times will vary based on the half-life of the compound and can be further optimized by one of skill in the art by routine experimentation.
【００３６】
［薬学的製剤(Pharmaceutical Formulations)］
本発明で有用な化合物は、薬学的組成物として製剤し、そして、選択した投与
経路に適合させた種々の形態でヒト患者または飼養化された動物(domestic anim
al)等の哺乳動物ホスト(mammalian host)に投与することが可能である。前記投
与経路とは、すなわち、経口的または非経口的、吸入による経鼻内(intranassal
yy)、経静脈、経筋肉、局所的または皮下経路である。Pharmaceutical Formulations The compounds useful in the present invention are formulated as pharmaceutical compositions and human patients or domesticated animals in various forms adapted to the chosen route of administration. (domestic anim
It is possible to administer to a mammalian host such as al). The routes of administration are: oral or parenteral, intranasal by inhalation.
yy), intravenous, transmuscular, topical or subcutaneous routes.
【００３７】
本発明の化合物は、配送遺伝子療法(gene therapy methods of delivery)を用
いて投与することもできる。例えば、米国特許第5,399,346号を見ると、参照す
ることによりその全体が組み込まれる。配送遺伝子療法の使用により、本発明の
化合物に対応する遺伝子に感染した(transfected)一次細胞(primary cells)は、
特定の器官、組織、移植片、腫瘍、または細胞を標的とする組織特異性プロモー
タ(tissue specific promoters)にさらに感染させることができる。The compounds of the present invention can also be administered using gene therapy methods of delivery. For example, see US Pat. No. 5,399,346, which is incorporated by reference in its entirety. By the use of delivery gene therapy, the primary cells that have been transfected with the gene corresponding to the compound of the present invention are:
Tissue specific promoters that target specific organs, tissues, grafts, tumors, or cells can be further infected.
【００３８】
したがって、前記化合物は、例えば、不活性希釈剤(inert diluent)または同
化性可食担体(assimilable edible carrier)等の薬学的に許容可能なビヒクルと
組み合せて経口的に全身投与することができる。それらは、ハードまたはソフト
シェルのゼラチンカプセルに封入しても良く、圧縮してタブレットとしても良く
、または患者の食事(patient's diet)のための食物に直接組み込んでも良い。経
口治療投与(oral therapeutic administration)のために、前記活性化合物は、
一種類またはそれ以上の賦形剤(excipients)と組み合わせ、そして、摂取可能錠
剤(ingestible tablets)、バッカル錠剤(buccal tablets)、トローチ、カプセル
、エリキシル剤(elixirs)、懸濁剤(suspensions)、シロップ、オブラート(wafer
s)等の形態で使用することができる。そのような組成物(compositions)および調
製物(preparations)は、少なくとも０．１％の活性化合物を含むことが好ましい
。前記組成物および調製物のパーセンテージは、当然、可変的であり、そして、
好ましくは、与えられた単位用量形態(unit dosage form)の重量に対して約２か
ら約６０％の間が良い。そのような薬学的有用組成物中における活性化合物の量
は、有効用量レベルが得られるような量である。Thus, the compound may be administered systemically orally, for example in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. it can. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into food for the patient's diet. For oral therapeutic administration, the active compound is
In combination with one or more excipients, and ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups , Oblate (wafer
s) and the like. Such compositions and preparations preferably contain at least 0.1% of active compound. The percentages of the compositions and preparations are, of course, variable, and
Preferably, it is between about 2 and about 60% by weight of the given unit dosage form. The amount of active compound in such pharmaceutically useful compositions is such that an effective dosage level will be obtained.
【００３９】
錠剤、トローチ、ピル、カプセル等は、下記のものを含んでいても良い。すな
わち、トラガカントゴム(gum tragacanth)、アラビアゴム(acacia)、コーンスタ
ーチまたはゼラチン等の結合剤(binders)、リン酸ジカルシウム(dicalcium phos
phate)等の賦形剤(excipients)、コーンスターチ、ポテトスターチ、アルギン酸
等の崩壊剤(disintegrating agent)、ステアリン酸マグネシウム等の滑剤(lubri
cant)、およびスクロース、フルクトース、ラクトースもしくはアスパルテーム
等の甘味料、またはペパーミント、サリチル酸メチル(oil of wintergreen)、も
しくはチェリーフレーバー(cherry flavoring)等の香料(flavoring agent)を加
えて良い。前記単位用量形態がカプセルである場合は、上記タイプの材料に加え
、植物油またはポリエチレングリコール等の液状担体を含んでいても良い。その
他種々の材料が、コーティングとして、または固形単位用量形態の物理的形態を
整える(modify)ために存在しても良い。例えば、錠剤、ピルまたはカプセルは、
ゼラチン、ワックス、シェラックまたは糖衣等でコートして良い。シロップまた
はエリキシル剤は、前記活性化合物、甘味料としてのスクロースまたはフルクト
ース、保存料としてのメチルおよびプロピルパラベン、色素、およびチェリーま
たはオレンジフレーバー等の香料を含んでいても良い。無論、あらゆる単位用量
形態を調製するためのあらゆる材料は、使用する量において、薬学的に許容可能
かつ本質的に無毒であるべきである。さらに、前記活性化合物は、徐放性調製物
およびデバイス(sustained-release preparations and devices)に組み込んでも
良い。Tablets, troches, pills, capsules and the like may include: That is, gum tragacanth, acacia, binders such as cornstarch or gelatin, dicalcium phos
Excipients such as phate), corn starch, potato starch, disintegrating agents such as alginic acid, lubricants such as magnesium stearate (lubri)
cant) and sweeteners such as sucrose, fructose, lactose or aspartame, or flavoring agents such as peppermint, methyl salicylate (oil of wintergreen), or cherry flavoring. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present as coatings or to modify the physical form of a solid unit dosage form. For example, tablets, pills or capsules
It may be coated with gelatin, wax, shellac or sugar coating. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, all materials for preparing any unit dosage form should be pharmaceutically acceptable and essentially non-toxic in the amounts used. In addition, the active compound may be incorporated into sustained-release preparations and devices.
【００４０】
前記活性化合物は、静脈内に(intravenously)または腹腔内に(intraperitonea
lly)、点滴(infusion)または注射(injection)により投与して良い。前記活性化
合物またはその塩の溶液は、水を用いて、任意に無毒な界面活性剤(surfactant)
と混合して調製することができる。分散剤(dispersions)は、グリセロール、液
状ポリエチレングリコール、トリアセチン、もしくはそれらの混合物を用いて、
またはオイル(oils)を用いて調製することもできる。保存および使用における通
常の条件下では、それら調製物は、微生物の増殖を防ぐために保存料を含む。The active compound may be administered intravenously or intraperitoneally (intraperitonea
It may be administered by lly), infusion or injection. The solution of the active compound or its salt is treated with water, optionally with a non-toxic surfactant.
It can be prepared by mixing with. Dispersions are glycerol, liquid polyethylene glycol, triacetin, or a mixture thereof,
Alternatively, it can be prepared using oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
【００４１】
注射または点滴に好適な薬学的用量形態は、活性成分を含む無菌水溶液もしく
は分散液(dispersions)または無菌粉末を含むことが可能である。前記活性成分
は、無菌の注射可能または点滴可能な溶液または分散液の即時調製に適合させる
ため、任意にリポソーム中に封入して良い。全てのケースでは、最終の剤型(dos
age form)は、製造および保存条件下において、無菌、流動性(fluid)かつ安定で
なければならない。液状担体またはビヒクルは、溶媒または液状分散媒であって
良い。それらの例としては、水、エタノール、ポリオール（例えば、グリセロー
ル、プロピレングリコール、液状ポリエチレングリコール等）、植物油、無毒性
グリセリルエステル、およびそれらの好適な混合物が含まれる。適切な流動性の
維持は、例えば、リポソームの形成により、分散液の場合は要求される粒子サイ
ズを維持することにより、または界面活性剤の使用により可能である。微生物の
活動防止は、種々の抗バクテリアおよび抗菌剤により、例えば、パラベン、クロ
ロブタノール、フェノール、ソルビン酸、チメロサール等により達成することが
できる。多くのケースにおいて、等張剤(isotonic agents)、例えば、糖、緩衝
剤(buffers)または塩化ナトリウム等を含むことが好ましい。注射可能組成物(in
jectable compositions)における長時間の吸収(prolonged absorption)は、前記
組成物中に吸収遅延剤を使用することにより、例えば、モノステアリン酸アルミ
ニウムおよびゼラチンにより達成することができる。Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient. The active ingredient may optionally be encapsulated in liposomes for suitability for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the final dosage form (dos
The age form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle may be a solvent or liquid dispersion medium. Examples thereof include water, ethanol, polyols (eg glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. Maintaining the proper fluidity is possible, for example, by forming liposomes, in the case of dispersions by maintaining the required particle size or by the use of surfactants. Prevention of microbial activity can be achieved by various antibacterial and antibacterial agents, for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents such as sugars, buffers or sodium chloride. Injectable composition (in
Prolonged absorption in jectable compositions can be achieved by using absorption delaying agents in the composition, for example with aluminum monostearate and gelatin.
【００４２】
無菌注射可能溶液は、適切な溶媒中における必要量の前記活性化合物を、上に
列挙した種々のその他の成分とともに組み込み、次に、必要であれば滅菌濾過(f
ilter sterilization)して調製する。無菌注射可能溶液調製用無菌粉末の場合は
、好ましい調製方法は、吸引乾燥(vacuum drying)および凍結乾燥(freeze dryin
g)技術であり、それにより、前記活性成分に加えて滅菌濾過済み溶液中に存在す
る任意の追加の望ましい成分を含む粉末を得る。Sterile injectable solutions incorporate the required amount of the active compound in a suitable solvent with various of the other ingredients enumerated above, and then sterile filtered (f
ilter sterilization). For sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze dry in
g) technology, whereby a powder is obtained which comprises, in addition to the active ingredient, any additional desired ingredients present in the sterile filtered solution.
【００４３】
局所投与のために、前記の化合物は、すなわちそれが液体の場合には、純物質
の形態(pure form)で適用しても良い。しかしながら、一般的には、それらを皮
膚に投与するには、組成物または製剤として、皮膚科学的に許容可能な担体と組
み合せてすることが望ましい。その担体は固体でも液体でも良い。For topical administration, the compound may be applied in pure form, ie when it is a liquid. However, it is generally desirable to administer them to the skin as a composition or formulation in combination with a dermatologically acceptable carrier. The carrier may be solid or liquid.
【００４４】
有用な固形担体(solid carriers)としては、タルク、粘土(clay)、微結晶セル
ロース、シリカ、アルミナ等のような微細固体が含まれる。有用な液状担体(liq
uid carriers)としては、任意に無毒性界面活性剤の助けにより前記化合物を効
果的なレベルで溶解または分散させることができる水、ヒドロキシアルキル(hyd
roxyalkyls)もしくはグリセロールまたは水−アルコール／グリセロールブレン
ドが含まれる。特性を使用目的(given use)に対し最適化させるために、芳香剤(
fragrances)および追加の抗微生物剤(antimicrobial agents)等の助剤を加えて
も良い。出来上がった液状組成物は、吸収性パッド(absorbent pads)を通じて適
用しても良いし、含浸包帯(impregnate bandages)およびその他の包帯剤(dressi
ngs)に使用しても、または、ポンプタイプもしくはエアロゾル噴霧器を使用して
患部(affected area)に噴霧しても良い。Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carrier (liq
The uid carriers include water, hydroxyalkyl (hydalkyl), which can dissolve or disperse the compound at an effective level, optionally with the aid of non-toxic surfactants.
roxyalkyls) or glycerol or water-alcohol / glycerol blends. In order to optimize the properties for given use, fragrances (
Auxiliaries such as fragrances and additional antimicrobial agents may be added. The resulting liquid composition may be applied through absorbent pads, impregnate bandages and other dressings.
ngs) or may be sprayed onto the affected area using a pump type or aerosol nebulizer.
【００４５】
塗布可能な(spreadable)ペースト、ゲル、軟膏、ソープ等を形成して使用者の
皮膚に直接適用するために、合成ポリマー、脂肪酸、脂肪酸塩およびエステル、
脂肪族アルコール、修飾型セルロース(modified celluloses)または修飾型無機
材料(modified mineral materials)等の増粘剤(thickeners)も液状担体とともに
用いることができる。Synthetic polymers, fatty acids, fatty acid salts and esters, to form spreadable pastes, gels, ointments, soaps, etc. for direct application to the user's skin.
Thickeners such as aliphatic alcohols, modified celluloses or modified mineral materials can also be used with the liquid carrier.
【００４６】
式Ｉの化合物を皮膚に配送するために使用できる有用な皮膚科学的組成物の例
は、当業者公知である。例えば、Jacquetら(米国特許第4,608,392号)、Geria (
米国特許第4,992,478号)、Smithら(米国特許第4,559,157号)およびWortzman (米
国特許第4,820,508号)を参照のこと。Examples of useful dermatological compositions that can be used to deliver the compounds of formula I to the skin are known to those skilled in the art. For example, Jacquet et al. (U.S. Pat.No. 4,608,392), Geria (
See US Pat. No. 4,992,478), Smith et al. (US Pat. No. 4,559,157) and Wortzman (US Pat. No. 4,820,508).
【００４７】
前記化合物の実用的用量(useful dosages)は、それらのin vitro活性と動物モ
デルにおけるin vivo活性とを比較して決定することができる。マウスおよびそ
の他の動物における有効用量のヒトに対する外挿法は、当業者公知である。例え
ば、米国特許第4,938,949号を参照のこと。Useful dosages of the compounds can be determined by comparing their in vitro activity with their in vivo activity in animal models. Extrapolation of effective doses for humans in mice and other animals is known to those of skill in the art. See, eg, US Pat. No. 4,938,949.
【００４８】
一般に、ローション等の液状組成物中における式Ｉの化合物の濃度は、約０．
１〜２５重量％であり、好ましくは、約０．５〜１０重量％である。ゲルまたは
パウダー等の半固体または固体状組成物における濃度は、約０．１〜５重量％、
好ましくは約０．５〜２．５重量％である。Generally, the concentration of the compound of formula I in a liquid composition such as a lotion will be about 0.
1 to 25% by weight, preferably about 0.5 to 10% by weight. The concentration in a semi-solid or solid composition such as a gel or a powder is about 0.1-5% by weight,
It is preferably about 0.5 to 2.5% by weight.
【００４９】
治療における使用に必要な前記化合物、またはその活性な塩もしくは誘導体の
量は、選択した特定の塩によってのみならず、投与経路、患者における治療すべ
き症状(condition)の性質および年齢および体調(condition)によっても、そして
、最終的には、主治医または臨床医(attendant physician or clinician)の裁量
によって変化する。さらに、前記化合物の用量は、標的とする細胞、腫瘍、組織
、移植片または器官に依存して変化する。The amount of the compound, or active salt or derivative thereof, required for use in therapy depends not only on the particular salt selected, but on the route of administration, the nature and age of the condition to be treated in the patient and It also depends on the condition, and ultimately on the discretion of the attending physician or clinician. Further, the dose of the compound will vary depending on the targeted cell, tumor, tissue, graft or organ.
【００５０】
しかしながら、一般には、適切な用量は、約0.5から約100 mg/kgの範囲であり
、例えば、一日に約10から約75 mg/kg体重、例としては一日に患者(recipient)
のキログラム体重当たり3から約50 mg、好ましくは6から90 mg/kg/日の範囲、最
も好ましくは15から60 mg/kg/日の範囲である。Generally, however, suitable doses will be in the range of about 0.5 to about 100 mg / kg, for example about 10 to about 75 mg / kg body weight daily, eg, daily patient. )
Per kilogram body weight of 3 to about 50 mg, preferably 6 to 90 mg / kg / day, most preferably 15 to 60 mg / kg / day.
【００５１】
前記化合物は、単位用量形態(unit dosage form)として好適に投与することが
できる。一単位用量形態当たり、活性成分を、例えば5から1000 mg、好適には10
から750 mg、最も好適には50から500 mg含む。The compounds may suitably be administered as a unit dosage form. The active ingredient is, for example, from 5 to 1000 mg, preferably 10 per unit dosage form.
To 750 mg, most preferably 50 to 500 mg.
【００５２】
理想的には、前記活性成分は、前記活性化合物の最大血漿中濃度(peak plasma
concentrations)が、約0.0005から約300 μM、好ましくは約.001から100 μM、
より好ましくは、約1から約100 μMを達成するように投与するのが良い。このこ
とは、例えば、前記活性成分の一定濃度を任意に生理食塩水に溶かして静脈内注
射することにより、または巨丸(bolus)として経口投与することにより達成でき
る。望ましい血中レベルは、前記活性成分の約0.0005〜50.0 mg/kg/時を与える
持緒点滴により、または約0.004〜150 mg/kgを含む間欠式点滴(intermittent in
fusions)により維持することができる。Ideally, the active ingredient is the peak plasma concentration of the active compound.
concentrations) is about 0.0005 to about 300 μM, preferably about .001 to 100 μM,
More preferably, it may be administered to achieve about 1 to about 100 μM. This can be achieved, for example, by optionally dissolving a fixed concentration of the active ingredient in saline and injecting it intravenously or orally as a bolus. Desirable blood levels are achieved by a tail drip infusion that provides about 0.0005-50.0 mg / kg / hour of the active ingredient, or an intermittent infusion containing about 0.004-150 mg / kg.
fusions).
【００５３】
望ましい用量は、単一用量として、または適切な間隔で投与される分割用量と
して、例えば一日当たり２回、３回、４回もしくはそれ以上の副次的用量(sub-d
oses)として好適に提供することができる。前記副次的用量は、それ自体をさら
に分割することができる。例えば、注入器(insufflator)による複数回吸入(mult
iple inhalations)、または眼中への複数滴の適用等により、多数の不連続で緩
い間隔の投与に分割できる。The desired dose may be as a single dose or as divided doses administered at appropriate intervals, for example two, three, four or more sub-dose per day.
oses). The sub-dose may itself be subdivided. For example, multiple inhalations by an insufflator
iple inhalations), or application of multiple drops into the eye, etc., to divide into a number of discrete, loosely spaced administrations.
【００５４】
投与管理(administration regimen)は、長期間(long-term)における毎日の処
置を含むことが可能である。「長期間」とは、少なくとも二週間および好ましく
は数週間、数ヵ月間または数年間の持続期間を意味する。この用量範囲において
必要な調節(necessary modifications)は、この技術分野における通常の技能者
がこの場で教示を与える普遍的実験を用いるのみで決定することができる。Remi
ngton's Pharmaceutical Sciences (Martin, E.W., ed. 4), Mack Publishing C
o., Easton, PA.を参照のこと。前記用量は、万一何か複雑な自体(complication
)が起きた場合には、個々の医師(physician)が調節することも可能である。An administration regimen can include daily treatment on a long-term. By "long-term" is meant a duration of at least two weeks and preferably weeks, months or years. The necessary modifications in this dose range can be determined using only routine experimentation, given the in-situ teaching by one of ordinary skill in the art. Remi
ngton's Pharmaceutical Sciences (Martin, EW, ed. 4), Mack Publishing C
o., Easton, PA. The above-mentioned dose should be
If it occurs, it can be adjusted by the individual physician.
【００５５】 本発明を、以下の非限定的な実施例により詳細に説明する。[0055] The invention is illustrated in detail by the following non-limiting examples.
【００５６】
［実施例］
以下の実施例は、この場に特許請求した化合物、組成物、物品(articles)、デ
バイス(devices)および／または方法をいかにして作製し評価するか、この技術
分野の通常の技能者に対し完全な開示および記述を提供するために発表する。そ
して、本発明を例示することのみを意図し、発明者らが彼らの発明として認識す
るものの範囲を限定することを意図しない。数値（例えば、量、温度等）に関し
ては、精度を確保するよう努力したが、幾分かの誤差および偏差を考慮すべきで
ある。特に示さない限り、部(parts)とは重量部(parts by weight)であり、温度
は℃または絶対温度であり、そして、圧力は、大気圧またはその近辺である。EXAMPLES The following examples are examples of how to make and evaluate the compounds, compositions, articles, devices and / or methods claimed herein, in this technical field. Present to provide full disclosure and description to the ordinary technician of the. And, it is intended only to exemplify the invention and not to limit the scope of what the inventors recognize as their invention. Efforts have been made to ensure accuracy with respect to numbers (eg, amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperatures are in degrees Celsius or absolute temperatures, and pressure is at or near atmospheric pressure.
【００５７】
（実施例１）
100μMのLFM-A13で20分間または24時間処理した血小板を、0.1 U/mlのトロン
ビンまたは10μg/mlのコラーゲンで刺激した。対照(control)についての血小板
凝集は、Chronolog Model 560デュアルチャンバ血小板凝集計(Dual Chamber Pla
telet Aggregometer)で追跡した(monitored)。LFM-A13は、高いおよび低い用量
のコラーゲンに応答する血小板(platelet)を顕著に減少させた（図１ａ、１ｄお
よび図１ｂ、１ｅに示す通りである）。Example 1 Platelets treated with 100 μM LFM-A13 for 20 minutes or 24 hours were stimulated with 0.1 U / ml thrombin or 10 μg / ml collagen. The platelet aggregation for the control is a Chronolog Model 560 Dual Chamber Plasimeter.
telet aggregometer). LFM-A13 significantly reduced platelets in response to high and low doses of collagen (as shown in Figures 1a, 1d and 1b, 1e).
【００５８】
トロンビン誘導血小板凝集については、LFM-A13による顕著な効果は何も記録
されなかった（図１ｃ、１ｆに示す）。LFM-A13で24時間処理した血小板は、前
記化合物で20分間処理したものと同様に応答した。図１に、その結果を示す。No significant effect of LFM-A13 was recorded on thrombin-induced platelet aggregation (shown in Figures 1c, 1f). Platelets treated with LFM-A13 for 24 hours responded similarly to those treated with the compound for 20 minutes. The result is shown in FIG.
【００５９】
（実施例２）
種々濃度のLFM-A13で処理した血小板を、2μg/mlのコラーゲンおよび0.1 U/ml
のトロンビンで刺激した。対照についての血小板凝集は、Chronolog Model 560
デュアルチャンバ血小板凝集計で追跡した。LFM-A13は、2μg/mlのコラーゲンに
応答する血小板を2.78μMのIC50値へ、そして、5μg/mlのコラーゲンに応答する
血小板を66.1μMのIC50値へと顕著に減少させた。トロンビン誘導血小板凝集反
応に対しては、顕著な効果は何ら記録されなかった。図２に、その結果を記す。Example 2 Platelets treated with various concentrations of LFM-A13 were treated with 2 μg / ml collagen and 0.1 U / ml.
Stimulated with thrombin. Platelet aggregation for controls is based on Chronolog Model 560
Followed with a dual chamber aggregometer. LFM-A13 significantly reduced platelets responsive to 2 μg / ml collagen to an IC 50 value of 2.78 μM and platelets responsive to 5 μg / ml collagen to an IC 50 value of 66.1 μM. No significant effect was recorded on thrombin-induced platelet aggregation. The results are shown in FIG.
【００６０】
（実施例３）
血小板を、37℃において30分間、100μMのLFM-A13またはDMSOでインキュベー
トし、そして次に、2μg/mlのコラーゲンで刺激した。前記試料は、BTKに対して
増感させた(raised against BTK)抗体を用いて免疫沈降反応にかけた。そのBTK
免疫複合体を、免疫キナーゼアッセイにかけた。追加のBTK免疫複合体を採集し
、2倍SDS還元サンプルバッファ(2x SDS reducing sample buffer)で煮沸し、8％
ポリアクリルアミドゲルで分別し(fractionated)、PVDF膜に移し(transferred)
、そして、ウェスタンブロッティング解析(western blotting analysis)によりB
TKの存在を試験した。BTKの酵素活性（活性度指数(activity index)）は、自動
リン酸化(autophosphorylation)(PIU)を、比重走査ユニット(densitometric sca
nning units)(DSU)におけるプロテインバンド(protein bands)の比重(relative
density)と比較して評価した。表１にその結果を示す。これは、LFM-A13がBTKキ
ナーゼ活性を顕著に阻害したことを表す。Example 3 Platelets were incubated with 100 μM LFM-A13 or DMSO for 30 minutes at 37 ° C. and then stimulated with 2 μg / ml collagen. The sample was subjected to immunoprecipitation with an antibody against raised BTK. That BTK
The immune complex was subjected to an immunokinase assay. Additional BTK immune complex is collected and boiled in 2x SDS reducing sample buffer, 8%
Fractionated by polyacrylamide gel and transferred to PVDF membrane
, And B by Western blotting analysis
The presence of TK was tested. The enzyme activity (activity index) of BTK can be measured by autophosphorylation (PIU) using a specific scanning unit (densitometric sca).
nning units) (DSU)
density) and evaluated. The results are shown in Table 1. This indicates that LFM-A13 markedly inhibited BTK kinase activity.
【００６１】[0061]
【表１】 [Table 1]
【００６２】
（実施例４）
血小板を、37℃において30分間、100μMのLFM-A13またはDMSOでインキュベー
トし、そして次に、2μg/mlのコラーゲンで刺激した。前記試料は、PLCg2に対し
て増感させた(raised against PLCg2)抗体を用いて免疫沈降反応にかけ、そして
、抗ホスホチロシン抗体(antibodies against phosphotyrosine)に対して免疫ブ
ロットした(immunoblotted)。膜は、PLCg2に対して増感させた抗体でストリップ
し、リプローブした(stripped and reprobed)。コラーゲン刺激後30から45秒の
間に、リン酸化PLCg2レベルの増加が見られた。LFM-A13処理した場合はPLCg2リ
ン酸化は何ら記録されなかった。したがって、LFM-A13は、コラーゲン誘導PLCg2
チロシンリン酸化を阻害した。Example 4 Platelets were incubated with 100 μM LFM-A13 or DMSO for 30 minutes at 37 ° C. and then stimulated with 2 μg / ml collagen. The samples were immunoprecipitated with antibodies raised against PLCg2 and immunoblotted against antibodies against phosphotyrosine. Membranes were stripped and reprobed with an antibody sensitized to PLCg2. An increase in phosphorylated PLCg2 levels was seen between 30 and 45 seconds after collagen stimulation. No PLCg2 phosphorylation was recorded when treated with LFM-A13. Therefore, LFM-A13 is a collagen-induced PLCg2
Inhibited tyrosine phosphorylation.
【００６３】
（実施例５）
血小板を、37℃で15分間、3 mMのfura-3 (Molecular Probes、オレゴン州ユー
ジーン)と共にロードした(loaded)。短時間の洗浄(10分間, 3000 rpm)に続き、
前記血小板をHepes緩衝液に再懸濁させ(1×108個細胞/ml)、そして、100μM LFM
-A13の存在下または非存在下、コラーゲン(20μg/ml)で刺激した。蛍光の変化は
、分光蛍光計(spectrofluorimeter)で追跡した。LFM-A13は、コラーゲン誘導カ
ルシウム動員を、顕著に減少させた（阻害した）。Example 5 Platelets were loaded with 3 mM fura-3 (Molecular Probes, Eugene, Oreg.) At 37 ° C. for 15 minutes. Following a brief wash (10 minutes, 3000 rpm),
The platelets were resuspended in Hepes buffer (1 × 10 8 cells / ml) and 100 μM LFM.
-Stimulated with collagen (20 μg / ml) in the presence or absence of A13. Changes in fluorescence were followed with a spectrofluorimeter. LFM-A13 markedly reduced (inhibited) collagen-induced calcium mobilization.
【００６４】
（実施例６）
血小板（1×109個）を、37℃で30分間、100μM LFM-A13の存在下または非存在
下でインキュベートした。血小板を、37℃で種々の時間、2μg/mlのコラーゲン
により刺激した。活性化は、氷冷した20%過塩素酸の添加により停止させた。イ
ノシトール1,4,5-三リン酸生産物の量は、Amershamの検出キット(detection kit
)を用いて測定した。その結果は、コラーゲン刺激によるPI-PLC活性をLFM-A13が
阻害したことを表す。下記表２に、前記結果を示す。Example 6 Platelets (1 × 10 9 cells) were incubated at 37 ° C. for 30 minutes in the presence or absence of 100 μM LFM-A13. Platelets were stimulated with 2 μg / ml collagen for various times at 37 ° C. Activation was stopped by the addition of ice-cold 20% perchloric acid. The amount of inositol 1,4,5-trisphosphate product is determined by Amersham's detection kit.
) Was used for the measurement. The result shows that LFM-A13 inhibited the PI-PLC activity stimulated by collagen. The results are shown in Table 2 below.
【００６５】[0065]
【表２】 [Table 2]
【００６６】
（実施例７）
LFM-A13で長期に(25mg/kg/36日)および短時間に(40 mg/kg/1時間)処理した両
方のC57BL/6マウスにおける凝血時間(clotting times)を、XIDおよび対照(contr
ol)マウスにおける凝血時間と比較した。XIDマウスの血液は、CBA対照マウスよ
りも約２分後に凝血した。このパターンに続き、長期処理マウス由来の血液も、
対照よりも２分後に凝血した。この結果は、LFM-A13が血液凝血時間を減少させ
ることを表す。下記表３に結果を示す。Example 7 Clotting times in both C57BL / 6 mice treated with LFM-A13 for a long time (25 mg / kg / 36 days) and a short time (40 mg / kg / 1 hour). , XID and control (contr
ol) compared to the clotting time in mice. Blood from XID mice clotted approximately 2 minutes later than CBA control mice. Following this pattern, blood from long-term treated mice
Blood was clotted 2 minutes later than the control. This result indicates that LFM-A13 reduces blood coagulation time. The results are shown in Table 3 below.
【００６７】[0067]
【表３】 [Table 3]
【００６８】
本出願を通じて、多様な出版物を参照している。これら出版物における開示内
容の全体は、この場において、参照により本出願に組み込まれ、本発明が属する
技術の状態をさらに全体的に記述する。Throughout this application, various publications are referenced. The entire disclosures in these publications are hereby incorporated by reference into the present application to more generally describe the state of the art to which this invention pertains.
【００６９】
本発明においては、この発明の範囲または理念から離れない限り多様な修飾お
よびバリエーションが可能であることは、この技術分野の技能者にとっては明白
である。本発明における他の実施形態は、本明細書およびこの場に開示した発明
の実施を考慮すれば、この技術分野の技能者にとっては明白である。本明細書お
よび実施例は、単なる例示であると考慮されることを意図しており、本発明の真
の範囲および理念は、続く特許請求の範囲に示す。It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those of skill in the art in view of this specification and practice of the invention disclosed herein. The specification and examples are intended to be considered exemplary only and the true scope and spirit of the invention is set forth in the following claims.
【図１】 実施例１の実験結果を示すグラフである。[Figure 1] 3 is a graph showing the experimental results of Example 1.
【図２】 実施例２の実験結果を示すグラフである。[Fig. 2] 7 is a graph showing the experimental results of Example 2.
【手続補正書】
【提出日】平成１４年６月７日（２００２．６．７）
【手続補正１】
【補正対象書類名】明細書
【補正対象項目名】特許請求の範囲
【補正方法】変更
【補正の内容】
【特許請求の範囲】
【請求項１】 下記式の化合物または薬学的に許容可能なその酸付加塩の有効
量を投与することを含む、患者(subject)の血小板凝集阻害方法。
【化１】
【請求項２】 前記化合物がコラーゲン誘導血小板凝集を選択的に阻害する請
求項１記載の方法。
【請求項３】 前記方法が、トロンビン誘導血小板凝集を顕著に阻害せず、コ
ラーゲン誘導血小板凝集を阻害するために特異的に働く請求項１記載の方法。
【請求項４】 下記式の化合物または薬学的に許容可能なその酸付加塩の有効
量を患者(subject)に投与することを含む、患者の疾患または血小板凝集状態を
予防または治療する方法。
【化２】
【請求項５】 前記疾患または状態が、血栓塞栓症合併症(thromboembolic co
mplications)の危険性を伴う心血管(cardiovascular)、脳血管(cerbrovascular)
、または血液(hematologic)の疾患を含む請求項４記載の方法。
【請求項６】 前記血小板凝集状態が、塞栓形成(embolus formation)、血栓
溶解合併症(thrombolytic complications)、播種性血管内コンゲロパシー(disse
minated intravascular comgelopathy)、血栓症(thrombosis)、冠状動脈性心疾
患(coronary heart disease)、血栓塞栓症合併症(thromboembolic complication
s)、心筋梗塞(myocardial infarction)、再狭窄(restenosis)、または心房細動
内における心房血栓形成(atrial thrombosis formation in atrial fibrillatio
n)を含む請求項５記載の方法。 【請求項７】 下記式の化合物または薬学的に許容可能なその酸付加塩の有効 量を投与することを含む、患者の塞栓症(embolism)を阻害する方法。 【化３】
【請求項８】 前記塞栓症が、塞栓形成(embolus formation)、血栓溶解合併
症(thrombolytic complications)、血栓症(thrombosis)、血栓塞栓症合併症(thr omboembolic complications)、または心房血栓(atrial thrombosis)を含む請求
項７記載の方法。 【請求項９】 前記塞栓症が血栓塞栓症(thromboembolism)である請求項７記
載の方法。 【請求項１０】 下記式の化合物または薬学的に許容可能なその酸付加塩の有 効量を投与することを含む、患者のコラーゲン誘導細胞内カルシウム動員、コラ ーゲン誘導PLCγ2生産、またはコラーゲン誘導イノシトール1,4,5-三リン酸生産 を阻害する方法。 【化４】
【請求項１１】 下記式の化合物または薬学的に許容可能なその酸付加塩の有 効量を投与することを含む、患者の血液凝血時間(blood-clotting time)を増加
させる方法。 【化５】
【手続補正２】
【補正対象書類名】明細書
【補正対象項目名】００６６
【補正方法】変更
【補正の内容】
【００６６】
（実施例７）
LFM-A13で長期に(25mg/kg/36日)および短時間に(40 mg/kg/1時間)処理した両
方のC57BL/6マウスにおける凝血時間(clotting times)を、XIDおよび対照(contr
ol)マウスにおける凝血時間と比較した。XIDマウスの血液は、CBA対照マウスよ
りも約２分後に凝血した。このパターンに続き、長期処理マウス由来の血液も、
対照よりも２分後に凝血した。この結果は、LFM-A13が血液凝血時間を増加させ
ることを表す。下記表３に結果を示す。[Procedure amendment] [Submission date] June 7, 2002 (2002.6.7) [Procedure amendment 1] [Document name to be amended] Description [Item name to be amended] Claims [Amendment method] Modifications Amendments Claims 1. Inhibiting platelet aggregation in a subject, comprising administering an effective amount of a compound of the formula: or a pharmaceutically acceptable acid addition salt thereof. Method. [Chemical 1] 2. The method of claim 1, wherein said compound selectively inhibits collagen-induced platelet aggregation. 3. The method of claim 1, wherein the method does not significantly inhibit thrombin-induced platelet aggregation, but acts specifically to inhibit collagen-induced platelet aggregation. 4. A method for preventing or treating a disease or a platelet aggregation condition in a patient, comprising administering to the subject an effective amount of a compound of the formula: or a pharmaceutically acceptable acid addition salt thereof. [Chemical 2] 5. The disease or condition is a thromboembolic co-occurrence.
cardiovascular, cerbrovascular with the risk of mplications)
Or a hematologic disorder. 6. The platelet aggregation state is embolus formation, thrombolytic complications, disseminated intravascular congeropathy.
minated intravascular comgelopathy), thrombosis, coronary heart disease, thromboembolic complication
s), myocardial infarction, restenosis, or atrial thrombosis formation in atrial fibrillatio
The method of claim 5 including n). 7. A method of inhibiting embolism in a patient comprising administering an effective amount of a compound of the formula: or a pharmaceutically acceptable acid addition salt thereof . [Chemical 3] 8. The embolism is a combination of embolus formation and thrombolysis.
Claims that include thrombolytic complications , thrombosis, thromboembolic complications, or atrial thrombosis
Item 7. The method according to Item 7. 9. The method according to claim 7, wherein the embolism is thromboembolism.
How to list. 10. An antibody against the compound or effective amount of a pharmaceutically acceptable acid addition salt thereof of the formula, collagen-induced intracellular calcium mobilization of the patient, collagen induced PLCγ2 production, or collagen-induced inositol A method of inhibiting 1,4,5-trisphosphate production . [Chemical 4] Containing 11. formula of the compound or the administration of effective amount of a pharmaceutically acceptable acid addition salt thereof, increases the patient's blood clotting times (blood-clotting time)
How to make. [Chemical 5] [Procedure Amendment 2] [Name of Documents to Amend] Specification [Name of Items to Amend] 0066 [Correction Method] Change [Details of Amendment] [0066] (Example 7) With LFM-A13 for a long time (25 mg / kg / 36 The Clotting times in both C57BL / 6 mice treated with (day) and short time (40 mg / kg / 1 hour) were determined using XID and control (contr).
ol) compared to the clotting time in mice. Blood from XID mice clotted approximately 2 minutes later than CBA control mice. Following this pattern, blood from long-term treated mice
Blood was clotted 2 minutes later than the control. This result indicates that LFM-A13 increases blood coagulation time. The results are shown in Table 3 below.
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Claims (6)
量を投与することを含む、患者(subject)の血小板凝集阻害方法。 【化１】 1. A method for inhibiting platelet aggregation in a subject, which comprises administering an effective amount of a compound of the following formula or a pharmaceutically acceptable acid addition salt thereof. [Chemical 1]
求項１記載の方法。2. The method of claim 1, wherein said compound selectively inhibits collagen-induced platelet aggregation.
ラーゲン誘導血小板凝集を阻害するために特異的に働く請求項１記載の方法。3. The method of claim 1, wherein the method does not significantly inhibit thrombin-induced platelet aggregation, but acts specifically to inhibit collagen-induced platelet aggregation.
量を患者(subject)に投与することを含む、患者の疾患または血小板凝集状態を
予防または治療する方法。 【化２】 4. A method for preventing or treating a disease or a platelet aggregation condition in a patient, comprising administering to the subject an effective amount of a compound of the formula: or a pharmaceutically acceptable acid addition salt thereof. [Chemical 2]
mplications)の危険性を伴う心血管(cardiovascular)、脳血管(cerbrovascular)
、または血液(hematologic)の疾患を含む請求項４記載の方法。5. The disease or condition is a thromboembolic co-occurrence.
cardiovascular, cerbrovascular with the risk of mplications)
Or a hematologic disorder.
溶解合併症(thrombolytic complications)、播種性血管内コンゲロパシー(disse
minated intravascular comgelopathy)、血栓症(thrombosis)、冠状動脈性心疾
患(coronary heart disease)、血栓塞栓症合併症(thromboembolic complication
s)、心筋梗塞(myocardial infarction)、再狭窄(restenosis)、または心房細動
内における心房血栓形成(atrial thrombosis formation in atrial fibrillatio
n)を含む請求項５記載の方法。6. The platelet aggregation state is embolus formation, thrombolytic complications, disseminated intravascular congeropathy.
minated intravascular comgelopathy), thrombosis, coronary heart disease, thromboembolic complication
s), myocardial infarction, restenosis, or atrial thrombosis formation in atrial fibrillatio
The method of claim 5 including n).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16810399P | 1999-11-30 | 1999-11-30 | |
| US60/168,103 | 1999-11-30 | ||
| PCT/US2000/042370 WO2001041754A2 (en) | 1999-11-30 | 2000-11-29 | Inhibitors of collagen-induced platelet aggregation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2003516351A true JP2003516351A (en) | 2003-05-13 |
Family
ID=22610139
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2001543099A Withdrawn JP2003516351A (en) | 1999-11-30 | 2000-11-29 | Collagen-induced platelet aggregation inhibitor |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1235567A2 (en) |
| JP (1) | JP2003516351A (en) |
| AU (1) | AU4508601A (en) |
| CA (1) | CA2390857A1 (en) |
| WO (1) | WO2001041754A2 (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7691839B2 (en) | 2005-09-28 | 2010-04-06 | Biovascular, Inc. | Methods and compositions for blocking platelet and cell adhesion, cell migration and inflammation |
| RU2008133161A (en) | 2006-01-13 | 2010-02-20 | Фармасайкликс, Инк. (Us) | Tyrosine kinase inhibitors and their use |
| EP2201840B1 (en) | 2006-09-22 | 2011-11-02 | Pharmacyclics, Inc. | Inhibitors of Bruton's Tyrosine Kinase |
| US20120101114A1 (en) | 2007-03-28 | 2012-04-26 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
| EP2307025B1 (en) | 2008-07-16 | 2017-09-20 | Pharmacyclics LLC | Inhibitors of bruton's tyrosine kinase for the treatment of solid tumors |
| CA3113343A1 (en) | 2010-06-03 | 2011-12-08 | Pharmacyclics Llc | Use of inhibitors of bruton's tyrosine kinase (btk) in the treatment of follicular lymphoma |
| AU2012283775A1 (en) | 2011-07-13 | 2014-01-23 | Pharmacyclics Llc | Inhibitors of Bruton's tyrosine kinase |
| US8377946B1 (en) | 2011-12-30 | 2013-02-19 | Pharmacyclics, Inc. | Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors |
| KR20190040370A (en) | 2012-06-04 | 2019-04-17 | 파마싸이클릭스 엘엘씨 | Crystalline forms of a bruton's tyrosine kinase inhibitor |
| EP3550031A1 (en) | 2012-07-24 | 2019-10-09 | Pharmacyclics, LLC | Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (btk) |
| MX2015006168A (en) | 2012-11-15 | 2015-08-10 | Pharmacyclics Inc | Pyrrolopyrimidine compounds as kinase inhibitors. |
| JP6800750B2 (en) | 2013-08-02 | 2020-12-16 | ファーマサイクリックス エルエルシー | Treatment method for solid tumors |
| ES2709509T3 (en) | 2013-08-12 | 2019-04-16 | Pharmacyclics Llc | Procedures for the treatment of cancer amplified by HER2 |
| EA201690618A1 (en) | 2013-09-30 | 2016-09-30 | Фармасайкликс Элэлси | BLUTON TYROSINKINASE INHIBITORS |
| EP3060218A4 (en) | 2013-10-25 | 2017-07-19 | Pharmacyclics LLC | Methods of treating and preventing graft versus host disease |
| WO2015143400A1 (en) | 2014-03-20 | 2015-09-24 | Pharmacyclics, Inc. | Phospholipase c gamma 2 and resistance associated mutations |
| US9533991B2 (en) | 2014-08-01 | 2017-01-03 | Pharmacyclics Llc | Inhibitors of Bruton's tyrosine kinase |
| JP2017523206A (en) | 2014-08-07 | 2017-08-17 | ファーマサイクリックス エルエルシー | New formulation of breton-type tyrosine kinase inhibitor |
| IL315294A (en) | 2015-03-03 | 2024-10-01 | Pharmacyclics Llc | Pharmaceutical formulations of bruton's tyrosine kinase inhibitor |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE59407413D1 (en) * | 1993-01-08 | 1999-01-21 | Hoechst Ag | Use of leflunomide to inhibit interleukin 1 beta |
| GB9322781D0 (en) * | 1993-11-04 | 1993-12-22 | Roussel Lab Ltd | Aromatic amides |
| US6011051A (en) * | 1996-07-31 | 2000-01-04 | Hoechst Aktiengesellschaft | Use of isoxazole and crotonamide derivatives for the modulation of apoptosis |
| JP2002512216A (en) * | 1998-04-17 | 2002-04-23 | パーカー ヒューズ インスティテュート | BTK inhibitors and methods for identification and use thereof |
| US6306897B1 (en) * | 1999-03-19 | 2001-10-23 | Parker Hughes Institute | Calanolides for inhibiting BTK |
-
2000
- 2000-11-29 EP EP00992536A patent/EP1235567A2/en not_active Withdrawn
- 2000-11-29 AU AU45086/01A patent/AU4508601A/en not_active Abandoned
- 2000-11-29 WO PCT/US2000/042370 patent/WO2001041754A2/en not_active Application Discontinuation
- 2000-11-29 JP JP2001543099A patent/JP2003516351A/en not_active Withdrawn
- 2000-11-29 CA CA002390857A patent/CA2390857A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| CA2390857A1 (en) | 2001-06-14 |
| WO2001041754A3 (en) | 2002-03-21 |
| WO2001041754A2 (en) | 2001-06-14 |
| WO2001041754A8 (en) | 2003-10-23 |
| AU4508601A (en) | 2001-06-18 |
| WO2001041754A9 (en) | 2002-08-01 |
| EP1235567A2 (en) | 2002-09-04 |
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