JP2003119181A - Carboxylic acid derivative inhibiting binding of integrin to receptor - Google Patents

Carboxylic acid derivative inhibiting binding of integrin to receptor

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Publication number
JP2003119181A
JP2003119181A JP2002031953A JP2002031953A JP2003119181A JP 2003119181 A JP2003119181 A JP 2003119181A JP 2002031953 A JP2002031953 A JP 2002031953A JP 2002031953 A JP2002031953 A JP 2002031953A JP 2003119181 A JP2003119181 A JP 2003119181A
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Japan
Prior art keywords
amino
integrin
compound
acid
compounds
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Granted
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JP2002031953A
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Japanese (ja)
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JP4149172B2 (en
Inventor
Ronald J Biediger
ロナルド・ジエイ・ビーデイガー
Qi Chen
チー・チエン
Ian L Scott
イアン・エル・スコツト
Robert V Market
ロバート・ブイ・マーケツト
Wen Li
ウエン・リー
Jamal Kassir
ジヤマール・カシル
George W Holland
ジヨージ・ダブリユ・ホランド
Chengde Wu
チヨントー・ウー
Radford E Decker
イー・ラドフオード・デツカー
Jian Li
チエン・リー
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Encysive Pharmaceuticals Inc
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Texas Biotechnology Corp
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Priority claimed from US09/973,142 external-priority patent/US6972296B2/en
Application filed by Texas Biotechnology Corp filed Critical Texas Biotechnology Corp
Publication of JP2003119181A publication Critical patent/JP2003119181A/en
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Publication of JP4149172B2 publication Critical patent/JP4149172B2/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Abstract

PROBLEM TO BE SOLVED: To provide a method for inhibition of binding of α4 β1 integrin to its receptor, e.g. vascular cell adhesion molecule-1 (VCAM-1) and fibronectin, a compound inhibiting the binding and a pharmaceutically active composition comprising the compound. SOLUTION: (3S)-[( [1-(2-Chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2- dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)-propanoic acid derivative is used for control or prophylaxis of disease states in which the α4 β1 is involved.

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】（発明の分野）本発明は一般に、α４β１
インテグリンのその受容体、たとえばＶＣＡＭ−１（血
管細胞接着分子−１）およびフィブロネクチンへの結合
の阻害に関する。本発明は、この結合を阻害する化合
物；そのような化合物を含む製薬活性組成物；α４β１
が関与する疾病状態の制御または予防のために、上記の
ように、あるいは調合物内でのそのような化合物を使用
することにも関する。FIELD OF THE INVENTION The present invention generally relates to α 4 β 1
It relates to the inhibition of the binding of integrin to its receptors such as VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The present invention provides compounds that inhibit this binding; pharmaceutically active compositions containing such compounds; α 4 β 1.
It also relates to the use of such compounds as described above or in a formulation for the control or prophylaxis of a disease state involving S.

【０００２】（発明の背景）組織が微生物による侵入を
受けたり、損傷していると、ｌｅｕｋｏｃｙｔｅとも呼
ばれる白血球（Ｗｈｉｔｅ ｂｌｏｏｄ ｃｅｌｌ）
が、炎症反応で重要な役割を果たす。炎症反応の最も重
要な面の１つとして、細胞接着現象が挙げられる。一般
に白血球は血流中を循環していると考えられている。し
かし、組織が感染したり、損傷したりすると、白血球は
侵入または損傷された組織を認識し、毛細血管壁に結合
し、毛細血管を通じて影響を受けた組織内に移動する。
これらの現象は、細胞接着分子と呼ばれる一群のタンパ
ク質が仲介する。BACKGROUND OF THE INVENTION White blood cells, also called leukocyte, are used when tissue is invaded or damaged by microorganisms.
But play an important role in the inflammatory response. One of the most important aspects of the inflammatory response is the phenomenon of cell adhesion. It is generally considered that white blood cells circulate in the bloodstream. However, when a tissue is infected or damaged, leukocytes recognize the invaded or damaged tissue, bind to the capillary walls, and migrate through the capillaries into the affected tissue.
These phenomena are mediated by a group of proteins called cell adhesion molecules.

【０００３】顆粒球、単球およびリンパ球という主要な
３種類の白血球がある。α４β１インテグリン（非常に
遅い抗原−４という意味でＶＬＡ−４とも呼ばれる）
は、単球、リンパ球および２種類の下位クラスの顆粒
球：好酸球および好塩基球の表面で発現されるヘテロ二
量体タンパク質である。このタンパク質は、ＶＣＡＭ−
１およびフィブロネクチン、すなわち毛細血管の内壁上
に並ぶ内皮細胞に結合するタンパク質を認識および結合
する能力により、細胞接着において重要な役割を果た
す。There are three main types of white blood cells: granulocytes, monocytes and lymphocytes. α 4 β 1 integrin (also called VLA-4 in the sense of very slow antigen-4)
Is a heterodimeric protein expressed on the surface of monocytes, lymphocytes and two subclasses of granulocytes: eosinophils and basophils. This protein is VCAM-
Its ability to recognize and bind 1 and fibronectin, a protein that binds to endothelial cells that line the inner walls of capillaries, plays an important role in cell adhesion.

【０００４】毛細血管を取り巻く組織の感染および損傷
の後、内皮細胞は、感染と戦うために必要な白血球を結
合するのに不可欠な、ＶＣＡＭ−１を含む一連の接着細
胞を発現する。ＶＣＡＭ−１またはフィブロネクチンに
結合する前に、白血球は最初にある接着細胞に結合し、
その流れを遅くして、細胞が活性化された内皮細胞に沿
って「回転する」ようにする。単球、リンパ球、好塩基
球および好酸球は次に、α４β１インテグリンによっ
て、血管壁上のＶＣＡＭ−１およびフィブロネクチンに
堅く結合することができる。このような相互作用が、初
期の回転現象そのものだけではなく、これらの白血球が
損傷した組織内に移動することにも関与しているという
証拠がある。After infection and damage to the tissue surrounding the capillaries, endothelial cells express a series of adherent cells, including VCAM-1, which are essential for binding the leukocytes necessary to fight the infection. Before binding to VCAM-1 or fibronectin, leukocytes first bind to some adherent cells,
The flow is slowed so that the cells “roll” along with the activated endothelial cells. Monocytes, lymphocytes, basophils and eosinophils can then be tightly bound by the α 4 β 1 integrin to VCAM-1 and fibronectin on the vessel wall. There is evidence that such interactions are involved not only in the initial rotation phenomenon itself, but also in the migration of these leukocytes into damaged tissue.

【０００５】白血球の損傷部位への移動は、感染と戦
い、外来物質を破壊するのに役立つが、この移動が制御
できなくなる多くの例では、白血球がその部位に殺到
し、組織の損傷を広範囲に及ばせる。したがって、この
プロセスを阻害できる化合物が治療剤として有用であ
る。それゆえ、白血球のＶＣＡＭ−１およびフィブロネ
クチンへの結合を防止する阻害剤を開発することが有用
である。The migration of leukocytes to the site of injury helps fight infection and destroy foreign material, but in many instances where this migration is uncontrolled, leukocytes flood the site and cause extensive tissue damage. Reach. Therefore, compounds that can inhibit this process are useful as therapeutic agents. Therefore, it would be useful to develop inhibitors that prevent leukocyte binding to VCAM-1 and fibronectin.

【０００６】α４β１結合によって治療される疾病の一
部としては、これに限定されるわけではないが、アテロ
ーム性動脈硬化、リウマチ様関節炎、喘息、アレルギ
ー、多発性硬化症、狼瘡、炎症性腸疾患、移植片拒絶、
接触過敏症、タイプＩ糖尿病が挙げられる白血球におけ
る知見に加え、α４β１は、白血球、メラノーマ、リン
ホーマ、肉腫などの（種々の癌細胞）において見いださ
れている。α４β１を含む細胞接着がある種の癌の転移
に関与することも示唆されている。したがって、α４β
１の阻害剤は、一部の形態の癌にも有用である。Some of the diseases treated by α 4 β 1 binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergies, multiple sclerosis, lupus, inflammation. Enteritis, graft rejection,
In addition to findings in leukocytes, including contact hypersensitivity, type I diabetes, α 4 β 1 has been found in leukocytes, melanomas, lymphomas, sarcomas, etc. (various cancer cells). It has also been suggested that cell adhesion involving α 4 β 1 is involved in metastasis of certain cancers. Therefore, α 4 β
One inhibitor is also useful for some forms of cancer.

【０００７】α４β１のタンパク質への結合を阻害する
ペプチドの単離および生成は、米国特許第５，５１０，
３３２号に開示されている。結合を阻害するペプチドは
ＷＯ９５／１５９７３、ＥＰ ０ ３４１ ９１５、Ｅ
Ｐ ０ ４２２ ９３８Ａ１、米国特許第５，１９２，
７４６号およびＷＯ ９６／０６１０８に開示されてい
る。細胞接着と細胞接着仲介病理の阻害と予防に有用な
新規化合物は、ＷＯ ９６／２２９６６、ＷＯ ９８／
０４２４７、ＷＯ ９８／０４９１３に開示されてい
る。Isolation and production of peptides which inhibit the binding of α 4 β 1 to proteins is described in US Pat.
No. 332. Peptides that inhibit binding are WO 95/15973, EP 0 341 915, E
P 0 422 938A1, US Pat. No. 5,192,
746 and WO 96/06108. Novel compounds useful for inhibiting and preventing cell adhesion and cell adhesion-mediated pathologies are disclosed in WO 96/22966, WO 98 /
04247, WO 98/04913.

【０００８】したがって、α４β１結合の阻害剤である
新規化合物と、そのような新規化合物を含む製薬組成物
を提供することが目的である。Accordingly, it is an object to provide novel compounds which are inhibitors of α 4 β 1 binding, and pharmaceutical compositions containing such novel compounds.

【０００９】略語 以降のスキームおよび実施例で使用した略語は以下のと
おりである：ＢＯＣｔ−ブチルオキシカルボニル；ＤＭ
Ｆ ジメチルホルムアミド；ＴＨＦ テトラヒドロフラ
ン；ＤＭＥ ジメトキシエタン；ＤＭＳＯ ジメチスル
ホキシド；ＮＭＭ Ｎ−メチルモルフォリン；ＤＩＰＥ
Ａ ジイソプロピルエチルアミン；ＣＤＩ １，１’−
カルボニルジイミダゾール；ＴＢＳ ＴＲＩＳ緩衝生理
的食塩水；Ｍｓ メタンスルホニル、ＴＭＥＤＡ Ｎ，
Ｎ，Ｎ’Ｎ’−テトラメチルエチレンジアミン、ＤＣＥ
１，２−ジクロロエタン、ＮＣＳ Ｎ−クロロスクシ
ンイミド、ＮＢＳ Ｎ−ブロモスクシンイミド、ＤＰＰ
Ａ ジフェニルホスホリルアジド、ＤＥＡＤ ジエチル
アゾジカルボン酸、ＴＦＡＡ チリフルオロ酢酸無水
物、ＤＣＭ ジクロロメタン、ＬＨＭＤＳ リチウムビ
ス（チリメチルシリル）アミド、Ｃｂｚ ベンジロキシ
カルボニル。アミノ酸は以下のように省略する：Ｃ Ｌ
−システイン；Ｄ アスパラギン酸；Ｅ Ｌ−グルタミ
ン酸；Ｇ グリシン；Ｈ Ｌ−ヒスチジン；Ｉ Ｌ−イ
ソロイシン；Ｌ Ｌ−ロイシン；ＮＬ−アスパラギン；
Ｐ Ｌ−プロリン；Ｑ Ｌ−グルタミン；Ｓ Ｌ−セリ
ン；Ｔ Ｌ−トレオニン；Ｖ Ｌ−バリン；Ｗ Ｌ−ト
リプトファン。Abbreviations Abbreviations used in the schemes and examples that follow are as follows: BOCt-butyloxycarbonyl; DM
F dimethylformamide; THF tetrahydrofuran; DME dimethoxyethane; DMSO dimethysulfoxide; NMM N-methylmorpholine; DIPE
A diisopropylethylamine; CDI 1,1'-
Carbonyldiimidazole; TBS TRIS buffered saline; Ms methanesulfonyl, TMEDA N,
N, N'N'-tetramethylethylenediamine, DCE
1,2-dichloroethane, NCS N-chlorosuccinimide, NBS N-bromosuccinimide, DPP
A diphenylphosphoryl azide, DEAD diethyl azodicarboxylic acid, TFAA chilifluoroacetic anhydride, DCM dichloromethane, LHMDS lithium bis (chilymethylsilyl) amide, Cbz benzyloxycarbonyl. Amino acids are abbreviated as follows: C L
-Cysteine; D aspartic acid; EL-glutamic acid; G glycine; HL-histidine; IL-isoleucine; LL-leucine; NL-asparagine;
PL-proline; QL-glutamine; SL-serine; TL-threonine; VL-valine; WL-tryptophan.

【００１０】本発明の化合物を合成するのに使用する手
順の例は、以下のスキームに示す。本発明の代表的な化
合物の詳細な説明は、以下の実施例で述べる。An example of the procedure used to synthesize the compounds of the present invention is shown in the scheme below. A detailed description of representative compounds of this invention is provided in the Examples below.

【００１１】[0011]

【化１】 上のスキーム１は、実施例１で説明する手順を示す。[Chemical 1] Scheme 1 above illustrates the procedure described in Example 1.

【００１２】実施例２の手順を示すスキーム２を以下に
示す。Scheme 2 showing the procedure of Example 2 is shown below.

【００１３】[0013]

【化２】 [Chemical 2]

【００１４】本発明の化合物は、無機または有機酸から
誘導された製薬的に許容可能な塩の形で使用できる。
「製薬的に許容可能な塩」という表現は、正常な医学的
判定の範囲内で、ヒトやそれより下等な動物の組織に接
触させて使用するのに適し、過度の毒性、炎症反応、ア
レルギー反応などがなく、恩恵／リスク比が適正に釣り
合っている塩を意味する。製薬的に許容可能な塩は当業
者に既知である。たとえば、Ｓ． Ｍ． Ｂｅｒｇｅ
ｅｔ ａｌ．， は製薬的に許容可能な塩について、
Ｊ． Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｓｃｉｅｎｃｅ
ｓ、１９７７、６６：１以下参照で詳細に述べている。
塩は、本発明の化合物の最終的な単離および精製の間に
原位置で、あるいは遊離塩基性官能基を適切な有機酸と
独立に反応させることによって調製できる。代表的な酸
付加塩としては、これに限定されるわけではないが、酢
酸塩、アジピン酸塩、クエン酸塩、アスパラ酸塩、安息
香酸塩、ベンゼンスルホン酸塩、重硫酸塩、酪酸塩、シ
ョウノウ酸塩、ショウノウスルホン酸塩、ジグルコン酸
塩、グリセロリン酸塩、ヘミ硫酸塩、ヘプタン酸塩、ヘ
キサン酸塩、フマル酸塩、塩酸塩、臭化水素酸塩、ヨウ
化水素酸塩、２−ヒドロキシエタンスルホン酸（イソチ
オン酸塩）、乳酸塩、マレイン酸塩、メタンスルホン酸
塩、ニコチン酸塩、２−ナフタレンスルホン酸塩、シュ
ウ酸塩、パルミチン酸塩、ペクチン酸塩、過硫酸塩、３
−フェニルプロピオン酸塩、ピクリン酸塩、ピバル酸
塩、プロピオン酸塩、スクシン酸塩、酒石酸塩、チオシ
アン酸塩、リン酸塩、グルタミン酸塩、重炭酸塩、ｐ−
トルエンスルホン酸、ウンデカン酸が挙げられる。ま
た、塩基性窒素含有基は、メチル、エチル、プロピル、
および塩化、臭化ならびにヨウ化ブチルなどのハロゲン
化低級アルキル；硫酸ジメチル、ジエチル、ジブチルお
よびジアミルなどの硫酸ジアルキル；塩化、臭化および
ヨウ化デシル、ラウリル、ミリスチル、ステアリールな
どの長鎖ハロゲン化物；ハロゲン化アリールアルキルお
よびその他などの薬剤によって四級化できる。それによ
り、水溶性または油溶性または分散性生成物が得られ
る。製薬的に許容可能な酸付加塩を生成するのに使用で
きる酸の例としては、塩酸、臭化水素酸、硫酸、リン酸
などの無機酸と、シュウ酸、マレイン酸、スクシン酸お
よびクエン酸などの有機酸が挙げられる。The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
The expression "pharmaceutically acceptable salt" is suitable for use in contact with human or lower animal tissues, within normal medical judgment, for excessive toxicity, inflammatory reactions, It means a salt that has no allergic reaction and has a well-balanced benefit / risk ratio. Pharmaceutically acceptable salts are known to those skilled in the art. For example, S. M. Berge
et al. , For pharmaceutically acceptable salts,
J. Pharmaceutical Science
S., 1977, 66: 1 et seq.
The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or by reacting the free basic functionality independently with the appropriate organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, Camphor salt, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- Hydroxyethanesulfonic acid (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulfate, 3
-Phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-
Toluenesulfonic acid and undecanoic acid may be mentioned. Further, the basic nitrogen-containing group is methyl, ethyl, propyl,
And lower alkyl halides such as chloride, bromide and butyl iodide; dialkyl sulfates such as dimethyl sulfate, diethyl, dibutyl and diamyl; long chain halides such as chloride, bromide and decyl iodide, lauryl, myristyl, stearyl. It can be quaternized with agents such as arylalkyl halides and others. This gives a water-soluble or oil-soluble or dispersible product. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and oxalic acid, maleic acid, succinic acid and citric acid. Organic acids such as

【００１５】塩基付加塩は、本発明の化合物の最終的な
単離および精製の間に原位置で、カルボン酸含有部分
に、製薬的に許容可能な金属カチオンの水酸化物、炭酸
塩または重炭酸塩などの適切な塩基、あるいはアンモニ
アまたは有機一級、二級、または三級アミンを反応させ
ることによって調製できる。製薬的に許容可能な塩とし
ては、これに限定されるわけではないが、リチウム、ナ
トリウム、カリウム、カルシウム、マグネシウム、アル
ミニウム塩などのアルカリ金属またはアルカリ土類金属
に基づくカチオン、および特にアンモニウム、テトラメ
チルアンモニウム、テトラエチルアンモニウム、メチル
アンモニウム、ジメチルアンモニウム、トリメチルアン
モニウム、トリエチルアンモニウム、ジエチルアンモニ
ウム、エチルアンモニウムなどの非毒性四級アンモニア
およびアミンカチオンが挙げられる。塩基付加塩の生成
に有用な他の代表的な有機アミンとしては、エチレンジ
アミン、エタノールアミン、ジエタノールアミン、ピペ
リジン、ピペラジンなどが挙げられる。Base addition salts may be added in situ during the final isolation and purification of the compounds of the invention to the carboxylic acid-containing moiety by the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation. It can be prepared by reacting a suitable base such as a carbonate or ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal cations such as lithium, sodium, potassium, calcium, magnesium, aluminum salts, and especially ammonium, tetra Non-toxic quaternary ammonia and amine cations such as methyl ammonium, tetraethyl ammonium, methyl ammonium, dimethyl ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium, ethyl ammonium and the like. Other representative organic amines useful in the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.

【００１６】本発明の化合物の局所投与用剤形として
は、粉末、スプレー、軟膏および吸入剤が挙げられる。
活性化合物は滅菌条件下で、必要とされる製薬的に許容
可能な担体と必要なすべての防腐剤、緩衝液または推進
薬と混合する。眼用調合物、眼用軟膏、粉末および溶液
も、本発明の範囲内と考えられる。Dosage forms for topical administration of the compounds of this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a required pharmaceutically acceptable carrier and all required preservatives, buffers or propellants. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

【００１７】本発明の製薬組成物中の活性成分の実際の
用量レベルは、特定の患者に対する望ましい治療反応を
達成するために有効な活性化合物の量、組成および投与
方法を得るために変更できる。選択した用量レベルは、
特定の化合物の活性、投与経路、治療する症状の重症
度、治療を受ける患者の医療前歴によって変化する。し
かし、化合物の用量を望ましい治療効果を達成するため
に必要な用量より低いレベルで開始し、望ましい効果が
達成されるまで用量を徐々に増加することは、当業技術
の範囲である。The actual dosage level of active ingredient in the pharmaceutical compositions of the present invention may be varied to obtain the amount, composition and mode of administration of the active compound which is effective to achieve the desired therapeutic response in a particular patient. The selected dose level is
It will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, the medical history of the patient being treated. However, it is within the skill in the art to start a dose of the compound at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

【００１８】上の、または他の処置で使用する場合、本
発明の化合物の１つの治療上有効な量は純粋な形でも、
存在する場合には、製薬的に許容可能な塩、エステルま
たはプロドラッグの形でも使用できる。あるいは、化合
物は、１個以上の製薬的に許容可能な賦形剤と組合わせ
た、興味のある化合物を含む製薬組成物としても投与で
きる。本発明の化合物の「治療上有効な量」という表現
は、任意の医療処置に適用可能である適正な恩恵／リス
ク比で、障害を治療するのに十分な量を意味する。しか
し、本発明の化合物および組成物の全体的な日常の用法
は、健全な医療判断の範囲内で主治医が決定することが
理解される。特定の患者に対して治療上有効な具体的用
量レベルは、治療する障害および障害の重症度；使用す
る特定の化合物の活性；使用する特定の組成物；患者の
年齢、体重、身体全体の健康、性別、食餌；投与時間、
投与経路および使用する特定の化合物の排泄；治療期
間；使用する特定の化合物と組合わせて、または同時に
使用する薬剤；および医療技術において周知の要因を含
む、各種の要因によって変化する。たとえば、望ましい
治療効果を達成するのに必要な量よりも低いレベルで化
合物の用量を開始し、望ましい効果が達成されるまで用
量を徐々に増加することは、当業技術の十分範囲内であ
る。When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the invention may be in pure form,
When present, they can also be used in the form of pharmaceutically acceptable salts, esters or prodrugs. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of the compound of the invention means an amount sufficient to treat a disorder, with a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood, however, that the general daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for a particular patient will be the disorder and severity of the disorder being treated; the activity of the particular compound used; the particular composition used; the age, weight, general health of the patient. , Sex, diet; time of administration,
It will depend on a variety of factors, including the route of administration and excretion of the particular compound used; the duration of treatment; the drug used in combination with or concurrently with the particular compound used; and factors well known in the medical arts. For example, it is well within the skill of the art to start a dose of the compound at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. .

【００１９】ヒトまたはさらに下等な動物に投与され
る、本発明の化合物の１日分の総用量は、約０．０００
１〜約１０００ｍｇ／ｋｇ／日である。経口投与の場
合、さらに好ましい用量は、約０．００１〜約５ｍｇ／
ｋｇ／日の範囲となる。望ましい場合、有効な１日分の
用量を複数回の用量に分けて投与することもできる；結
果として、１回の用量の組成物は、１日の用量となる
量、またはそれを分けた量が含まれる。The total daily dose of the compounds of this invention administered to humans or lower animals is about 0.000.
1 to about 1000 mg / kg / day. For oral administration, a more preferred dose is about 0.001 to about 5 mg /
It will be in the range of kg / day. If desired, the effective daily dose can be divided into multiple doses; as a result, a single dose of the composition will result in a daily dose or in divided doses. Is included.

【００２０】本発明は、１個以上の非毒性の製薬的に許
容可能な担体とともに調合された本発明の化合物を含
む、製薬組成物も提供する。製薬組成物は、経口投与用
に固体または液体形で、非経口注射用または直腸投与用
に特別に調合できる。The present invention also provides a pharmaceutical composition comprising a compound of the present invention formulated with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be formulated in solid or liquid form for oral administration, specially for parenteral injection or rectal administration.

【００２１】本発明の製薬組成物は、ヒトまたは他の哺
乳類に経口的に、直腸により、非経口的に、くも膜下内
に、膣内に、腹腔内に、局所的に（粉末、軟膏または点
滴によって）投与できる。「非経口的に」という語は本
明細書で使用されるように、静脈内、筋肉内、腹膜内、
胸骨内、皮下、関節内を含む投与様式を指す。The pharmaceutical composition according to the invention is orally, rectally, parenterally, intrathecally, intravaginally, intraperitoneally, topically (powder, ointment or ointment in humans or other mammals). It can be administered by infusion. The term "parenterally" as used herein means intravenous, intramuscular, intraperitoneal,
Refers to administration modes including intrasternal, subcutaneous and intraarticular.

【００２２】別の態様において、本発明は、本発明の成
分と生理学的に耐用可能な希釈剤を含む製薬組成物を提
供する。本発明は特に、非経口注射用、鼻腔内送達用、
固体または液体形の経口投与用、直腸または局所投与用
の、本明細書では集合的に希釈剤と呼ばれる１個以上の
非毒性の生理学的に耐用可能または許容可能な希釈剤、
担体、アジュバントまたはビヒクルと組合わせた組成物
に上述したように調合された、１個以上の化合物を含
む。In another aspect, the present invention provides a pharmaceutical composition comprising a component of the invention and a physiologically tolerable diluent. The invention is particularly suitable for parenteral injection, intranasal delivery,
One or more non-toxic, physiologically tolerable or acceptable diluents, collectively referred to herein as diluents, for oral administration, in solid or liquid form, for rectal or topical administration,
It comprises one or more compounds formulated as described above in a composition in combination with a carrier, adjuvant or vehicle.

【００２３】組成物は、冠動脈内ステント（細かい金網
より成る管状の器具）または生分解性ポリマーを経由し
て標的部位に局所送達するためにカテーテルを通じて送
達することもできる。化合物は、標的送達のために抗体
などのリガンドに錯化させてもよい。The composition may also be delivered through a catheter for local delivery to a target site via an intracoronary stent (a tubular device consisting of fine wire mesh) or a biodegradable polymer. The compound may be complexed to a ligand such as an antibody for targeted delivery.

【００２４】非経口注射に適した組成物は、生理学的に
許容可能な滅菌水性または非水性溶液、分散液、懸濁液
またはエマルションおよび滅菌の注射可能溶液または分
散液中で復元可能な滅菌粉末を含む。適切な水性または
非水性担体、希釈剤、溶媒またはビヒクルとしては、
水、エタノール、ポリオール（プロピレングリコール、
ポリエチレングリコール、グリセロールなど）、植物油
（オリーブ油など）、オレイン酸エチルなどの注射可能
な有機エステル、およびその適切な混合物が挙げられ
る。Compositions suitable for parenteral injection include sterile physiologically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders reconstituted in sterile injectable solutions or dispersions. including. Suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include
Water, ethanol, polyol (propylene glycol,
Polyethylene glycol, glycerol etc.), vegetable oils (olive oil etc.), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.

【００２５】これらの組成物は、保存剤、濡れ剤、乳化
剤および分散剤などのアジュバントも含むことができ
る。微生物の作用は、たとえばパラベン、クロロブタノ
ール、フェノール、ソルビン酸などの抗生剤および抗菌
剤によって防止できる。注射可能な製薬形の長期吸収
は、たとえばモノステアリン酸アルミニウムおよびゼラ
チンなどの吸収を遅らせる薬剤の使用によって行える。These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The action of microorganisms can be prevented by antibiotics and antibacterial agents such as paraben, chlorobutanol, phenol and sorbic acid. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption such as aluminum monostearate and gelatin.

【００２６】懸濁液は活性化合物以外に、たとえばエト
キシ化イソステアリールアルコール、ポリオキシエチレ
ンソルビトールおよびソルビタンエーテル、微結晶セル
ロース、メタ水酸化アルミニウム、ベントナイト、寒天
およびトラガカント、またはこれらの物質の混合物など
の懸濁剤を含むことがある。In addition to the active compound, the suspension may be, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or mixtures of these substances. It may contain a suspending agent.

【００２７】ある場合において、薬剤の効果を長引かせ
るために、皮下または筋肉注射による薬剤の吸収を遅く
することが望ましい。これは、水溶性の乏しい結晶性ま
たはアモルファス材料の液体懸濁液を使用して行える。
ここで薬剤の吸収速度はその溶解速度に依存し、溶解速
度は次に結晶の大きさや結晶形によって変わることがあ
る。あるいは、非経口投与された薬剤形の遅延吸収は、
薬剤を油性ビヒクルに溶解または懸濁させることによっ
て行う。In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug by subcutaneous or intramuscular injection. This can be done using a liquid suspension of crystalline or amorphous material with poor water solubility.
The rate of absorption of the drug here depends on its rate of dissolution, which in turn may vary with the size and crystal form of the crystals. Alternatively, the delayed absorption of a parenterally administered drug form is
It is done by dissolving or suspending the drug in an oil vehicle.

【００２８】注射可能なデポー剤は、ポリアクチド−ポ
リグリコチドなどの生分解性ポリマー中で薬剤のマイク
ロカプセル化マトリクスを生成することによって作成す
る。薬剤のポリマーに対する割合、使用する特定のポリ
マーの性質によって、薬剤放出速度を制御できる。他の
生分解性ポリマーの例としては、ポリ（オルトエステ
ル）およびポリ（無水物）である。デポー剤用注射可能
調合物は、薬剤を、身体組織と適合性であるリポソーム
またはマイクロエマルション内に閉じ込めることによっ
ても調製できる。Injectable depots are made by forming a microencapsulated matrix of the drug in a biodegradable polymer such as polyactide-polyglycotide. The rate of drug release can be controlled by the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers are poly (orthoesters) and poly (anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

【００２９】注射可能な調合物は、たとえば細菌保持フ
ィルタを用いた濾過によって、または使用直前に滅菌水
または他の滅菌注射可能溶媒中に溶解または分散可能な
滅菌固体組成物の形で滅菌剤を含ませることによって、
滅菌できる。Injectable formulations may contain a sterilizing agent, eg, by filtration with a bacterial retention filter, or in the form of a sterile solid composition, which may be dissolved or dispersed in sterile water or other sterile injectable solvent immediately before use. By including
Can be sterilized.

【００３０】経口投与用の固体剤形としては、カプセ
ル、錠剤、丸薬、粉末または顆粒が挙げられる。このよ
うな固体剤形において活性化合物を、１個以上の不活性
で、製薬的に許容可能なクエン酸ナトリウムまたはリン
酸ジカルシウムなどの賦形剤または担体および／または
ａ）デンプン、ラクトース、スクロース、グルコース、
マンニトール、ケイ酸などの充填剤または増量剤；ｂ）
カルボキシメチルセルロース、アルギナート、ゼラチ
ン、ポリビニルピロリドン、スクロースおよびアラビア
ゴムなどの結合剤；ｃ）グリセロールなどの湿潤剤；
ｄ）寒天、炭酸カルシウム、ジャガイモまたはタピオカ
デンプンなどの崩壊剤；ｅ）パラフィンなどの溶解遅延
剤；ｆ）四級アンモニウム化合物などの吸収加速剤；
ｇ）セチルアルコールおよびモノステアリール酸グリセ
ロールなどの濡れ剤；ｈ）カオリンおよびベントナイト
粘土などの吸収剤；ｉ）タルク、ステアリール酸カルシ
ウム、ステアリール酸マグネシウム、固体ポリエチレン
グリコール、ラウリル硫酸ナトリウムおよびその混合物
などの潤滑剤と混合してもよい。Solid dosage forms for oral administration include capsules, tablets, pills, powders or granules. In such solid dosage forms the active compound is combined with one or more inert, pharmaceutically acceptable excipients or carriers such as sodium citrate or dicalcium phosphate and / or a) starch, lactose, sucrose. ,glucose,
Fillers or extenders such as mannitol, silicic acid; b)
Binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) wetting agents such as glycerol;
d) a disintegrating agent such as agar, calcium carbonate, potato or tapioca starch; e) a dissolution retardant such as paraffin; f) an absorption accelerator such as a quaternary ammonium compound;
g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; i) talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate and mixtures thereof. It may be mixed with a lubricant such as.

【００３１】同様のタイプの固体組成物も、ラクトース
または乳糖はもちろん、高分子量ポリエチレングリコー
ルなどのこのような賦形剤を用いて、軟質および硬質充
填ゼラチンカプセルの充填剤として使用できる。Similar types of solid compositions can be used as fillers in soft and hard filled gelatin capsules with such excipients as lactose or lactose as well as high molecular weight polyethylene glycols.

【００３２】錠剤、糖衣錠、カプセル、丸薬および顆粒
などの固体剤形は、腸溶コーティングおよび製薬調合技
術で周知の他のコーティングなどの、コーティングおよ
びシェルを用いて調製できる。これらは随意に乳白剤を
含み、これらは活性成分のみを、あるいは好ましくは腸
管のある部分において、随意に遅延させる方法で放出す
る。使用可能な埋め込み組成物は、ポリマー物質とワッ
クスを含む。Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They optionally contain opacifiers, which release the active ingredient only, or preferably in some part of the intestinal tract, in an optionally delayed manner. Embedding compositions that can be used include polymeric substances and waxes.

【００３３】活性化合物は、適切ならば、上述の１個以
上の賦形剤を用いて、マイクロカプセル化形でも使用で
きる。The active compounds can also be used in micro-encapsulated form, if appropriate, with one or more excipients as noted above.

【００３４】経口投与用の液体剤形としては、製薬的に
許容可能なエマルション、溶液、懸濁液、シロップおよ
びエリキシルが挙げられる。液体剤形は活性成分に加え
て、たとえばエチルアルコール，イソプロピルアルコー
ル、炭酸エチル、酢酸エチル、ベンジルアルコール、安
息香酸ベンジル、プロピレングリコール、１，３−ブチ
レングリコール、ジメチルホルムアミド、油（特に綿実
油、コーン油、胚芽油、オリーブ油、ヒマシ油およびゴ
マ油）、グリセロール、テトラヒドロフルフリル、ポリ
エチレングリコールおよびソルビタンの脂肪酸エステル
およびその混合物などの、水または溶媒、可溶化剤およ
び乳化剤、当業界で一般に使用される不活性希釈剤を含
むことがある。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms include, in addition to the active ingredient, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, corn oil). , Germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl, fatty acid esters of polyethylene glycol and sorbitan and mixtures thereof, water or solvents, solubilizers and emulsifiers, inerts commonly used in the art May contain diluent.

【００３５】不活性希釈剤のほかに、経口組成物は濡れ
剤、乳化剤および懸濁剤、甘味料、調味料、香料などの
アジュバントを含むこともある。In addition to the inert diluent, the oral composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and flavoring agents.

【００３６】直腸および膣投与用組成物は、本発明の化
合物を、室温では固体だが、体温では液体となるため、
直腸または膣孔で溶け、活性化合物を放出する、ココア
バター、ポリエチレングリコールまたは坐薬用ワックス
などの適切な非炎症性賦形剤または担体と混合すること
によって調製できる、坐薬であることが好ましい。Compositions for rectal and vaginal administration contain the compound of the invention as a solid at room temperature but a liquid at body temperature,
Preference is given to suppositories which can be prepared by mixing with suitable non-inflammatory excipients or carriers, such as cocoa butter, polyethylene glycols or suppository waxes, which dissolve in the rectal or vaginal pores and release the active compound.

【００３７】本発明の化合物はリポソームの形でも投与
できる。当業者に既知であるように、リポソームは一般
に、リン脂質または他の脂質物質から誘導される。リポ
ソームは、水性溶媒中に分散した単層または複数層の水
和液晶から生成される。非毒性の生理学的に許容可能お
よび代謝可能なであり、リポソームを生成できる脂質が
使用できる。リポソーム形の本発明の化合物は、本発明
の化合物に加えて、安定剤、保存剤、賦形剤などを含む
ことがかのうである。好ましい脂質は、独立にまたは一
緒に使用する、天然ならびに合成リン脂質およびホスフ
ァチジルコリン（レシチン）である。The compounds of the present invention can also be administered in the form of liposomes. As is known to those of skill in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are produced from unilamellar or multilamellar hydrated liquid crystals that are dispersed in an aqueous solvent. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compound of the present invention in liposome form may contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used independently or together.

【００３８】リポソームの生成方法は当業者に既知であ
る。たとえば、Ｐｒｅｓｃｏｔｔ編、Ｍｅｔｈｏｄｓ
ｉｎ Ｃｅｌｌ Ｂｉｏｌｏｇｙ， Ｖｏｌｕｍｅ Ｘ
ＩＶ、Ａｃａｄｅｍｉｃ Ｐｒｅｓｓ、Ｎｅｗ Ｙｏｒ
ｋ、Ｎ．Ｙ．（１９７６）、ｐ．３３以下を参照。Methods of forming liposomes are known to those of skill in the art. For example, Prescott edition, Methods
in Cell Biology, Volume X
IV, Academic Press, New Yor
k, N.N. Y. (1976), p. See 33 onwards.

【００３９】「製薬的に許容可能なプロドラッグ」とい
う語は本明細書で使用されるように、本発明の化合物
の、可能な場合は両性イオン形と同様に、健全な医療上
の判断の範囲内で、過度の毒性、炎症、アレルギー反応
などを与えずに、ヒトおよびそれより下等な動物の組織
で使用するのに適し、恩恵／リスク比のバランスが取れ
ており、所期の目的に効果的である、本発明の化合物の
プロドラッグを表す。本発明のプロドラッグは生体内
で、たとえば血液中での加水分解によって、上の式の親
化合物に変換される。完全な説明は、Ｔ． Ｈｉｇｕｃ
ｈｉ ａｎｄ Ｖ．Ｓｔｅｌｌａ、Ｐｒｏ−ｄｒｕｇｓ
ａｓ Ｎｏｖｅｌ ＤｅｌｉｖｅｒｙＳｙｓｔｅｍ
ｓ， Ｖ． １４ ｏｆ ｔｈｅ Ａ．Ｃ．Ｓ． Ｓｙ
ｍｐｏｓｉｕｍ Ｓｅｒｉｅｓ、およびＥｄｗａｒｄ
Ｂ． Ｒｏｃｈｅ編、Ｂｉｏｒｅｖｅｒｓｉｂｌｅ Ｃ
ａｒｒｉｅｒｓ ｉｎ Ｄｒｕｇ Ｄｅｓｉｇｎ、Ａｍ
ｅｒｉｃａｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ａｓｓ
ｏｃｉａｔｉｏｎ ａｎｄＰｅｒｇａｍｏｎ Ｐｒｅｓ
ｓ（１９８７）に与えられており、これらは引用するこ
とによって本明細書の一部となっている。The term "pharmaceutically acceptable prodrug," as used herein, refers to the sound medical judgment, as well as the zwitterionic form, if possible, of the compounds of the present invention. Suitable for use in human and lower animal tissues without undue toxicity, inflammation, allergic reactions, etc., within a range, with a well-balanced benefit / risk ratio and intended purpose. 2 represents a prodrug of a compound of the invention that is effective against The prodrugs of the present invention are converted in vivo to the parent compound of the above formula, for example by hydrolysis in blood. For a complete explanation, see T.W. Higuc
hi and V. Stella, Pro-drugs
as Novel Delivery System
s, V. 14 of the A. C. S. Sy
mposium Series, and Edward
B. Roche, Bioreversible C
arrests in Drug Design, Am
erican Pharmaceutical Ass
occurrence and Pergamon Pres
s (1987), which are incorporated herein by reference.

【００４０】哺乳類に投与された各種化合物の生体内変
換によって生成した本発明の化合物は、本発明の範囲内
に含まれるものとする。Compounds of the invention produced by biotransformation of various compounds administered to a mammal are intended to be included within the scope of this invention.

【００４１】本発明の化合物は、不斉中心またはキラル
中心が存在する場合に立体異性体として存在することが
ある。これらの立体異性体は、キラル炭素原子周囲の置
換基の立体構図によって、「Ｒ」または「Ｓ」である。
本発明は、各種の立体異性体とその混合物も検討する。
立体異性体は、鏡像異性体およびジアステレオマー、光
学異性体またはジアステレオマーの混合物を含む。本発
明の化合物の各立体異性体は、不斉中心またはキラル中
心を含む市販の開始物質から合成して調製するか、ラセ
ミ混合物を調製した後に、当業者に周知の分解を行って
調製できる。分解方法の例としては、（１）鏡像異性体
混合物のキラル助剤への付加、ジアステレオマーの生じ
た混合物の再結晶またはクロマトグラフィーによる分
離、および光学的純粋な生成物を助剤から遊離、あるい
は（２）キラルクロマトグラフィーカラム上の光学鏡像
異性体の混合物の直接分離がある。The compounds of the present invention may exist as stereoisomers when asymmetric or chiral centers are present. These stereoisomers are "R" or "S" depending on the stereochemistry of the substituents around the chiral carbon atom.
The present invention also contemplates various stereoisomers and mixtures thereof.
Stereoisomers include enantiomers and mixtures of diastereomers, optical isomers or diastereomers. Each stereoisomer of a compound of this invention may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparing a racemic mixture followed by decomposition well known to those skilled in the art. Examples of decomposition methods include (1) addition of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and release of the optically pure product from the auxiliary. Or (2) direct separation of a mixture of optical enantiomers on a chiral chromatography column.

【００４２】本発明の化合物は、半水和物などの水和形
を含めて、溶媒和形と同様に非溶媒和形でも存在可能で
ある。一般に、特に水やエタノールなどの製薬的に許容
可能な溶媒を用いた溶媒和形は、本発明の目的のために
は非溶媒形と同等である。The compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms such as hemihydrate. In general, the solvated forms, especially with pharmaceutically acceptable solvents such as water and ethanol, are equivalent to the unsolvated forms for the purposes of the present invention.

【００４３】別の態様において、本発明は、α４β１イ
ンテグリンのＶＣＡＭ−１への結合を阻害するプロセス
を検討する。本発明のプロセスは、生体外または生体内
のどちらでも使用できる。本発明のプロセスに従って、
α４β１インテグリンを発現する細胞は、有効阻害量の
本発明の化合物の存在下で、ＶＣＡＭ−１を発現する細
胞にさらされる。In another aspect, the present invention investigates a process of inhibiting the binding of α 4 β 1 integrin to VCAM-1. The process of the invention can be used either in vitro or in vivo. According to the process of the invention,
Cells expressing the α 4 β 1 integrin are exposed to cells expressing VCAM-1 in the presence of an effective inhibitory amount of a compound of the invention.

【００４４】α４β１インテグリンを発現する細胞は、
天然型の白血球、マスト細胞または、細胞表面でα４β
１を発現する他の細胞種、あるいはα４β１インテグリ
ンをコード化するポリヌクレオチド（たとえばゲノムＤ
ＮＡまたはｃＤＮＡ）を含む発現ベクターによって形質
移入された細胞が考えられる。特に好ましい実施形態に
おいて、α４β１インテグリンは、単球、リンパ球また
は顆粒球（たとえば好酸球または好塩基球）などの白血
球の表面に存在する。Cells expressing the α 4 β 1 integrin are
Native leukocytes, mast cells or α 4 β on the cell surface
Other cell types expressing 1 or a polynucleotide encoding an α 4 β 1 integrin (eg Genome D
Cells transfected with an expression vector containing NA or cDNA) are contemplated. In a particularly preferred embodiment, the α 4 β 1 integrin is present on the surface of leukocytes such as monocytes, lymphocytes or granulocytes (eg eosinophils or basophils).

【００４５】ＶＣＡＭ−１を発現する細胞は、天然型細
胞（たとえば内皮細胞）またはＶＣＡＭ−１をコード化
するポリヌクレオチドを含む発現ベクトルによって形質
移入された細胞が考えられる。ＶＣＡＭ−１を発現する
形質移入細胞を生成する方法は、当業者に既知である。The cell expressing VCAM-1 may be a natural cell (eg, endothelial cell) or a cell transfected with an expression vector containing a polynucleotide encoding VCAM-1. Methods of generating transfected cells expressing VCAM-1 are known to those of skill in the art.

【００４６】ＶＣＡＭ−１が細胞表面に存在する場合、
そのＶＣＡＭ−１の発現は、腫瘍壊死因子−α、インタ
ーロイキン−４およびインターロイキン−１βなどの炎
症性サイトカインによって誘起されることが好ましい。When VCAM-1 is present on the cell surface,
The expression of VCAM-1 is preferably induced by inflammatory cytokines such as tumor necrosis factor-α, interleukin-4 and interleukin-1β.

【００４７】α４β１インテグリンおよびＶＣＡＭ−１
を発現する細胞が生体内にある場合、本発明の化合物の
有効量を生物に投与する。化合物は本発明の製薬組成物
であることが好ましい。本発明のプロセスは、白血球細
胞の損傷組織への制御不能な移動に関係する疾病を治療
する場合に特に有用である。このような疾病としては、
これに限定されるわけではないが、喘息、アテローム性
動脈硬化、リウマチ様関節炎、アレルギー、多発性硬化
症、狼瘡、炎症性腸疾患、移植片拒絶、接触過敏症、タ
イプＩ糖尿病、白血病、脳腫瘍が挙げられる。投与は静
脈内、皮下、鼻腔内、経皮または経口送達によって実施
することが好ましい。Α 4 β 1 integrin and VCAM-1
When the cells that express the are in vivo, an effective amount of the compound of the present invention is administered to the organism. Preferably the compound is a pharmaceutical composition of the invention. The process of the present invention is particularly useful in treating diseases associated with uncontrolled migration of white blood cells into damaged tissue. Such diseases include:
Without limitation, asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, type I diabetes, leukemia, brain tumor Is mentioned. Administration is preferably by intravenous, subcutaneous, intranasal, transdermal or oral delivery.

【００４８】本発明は、α４β１インテグリンのタンパ
ク質への阻害を選択的に阻害するプロセスであって、イ
ンテグリンを有効阻害量の本発明の化合物の存在下で、
タンパク質に曝露することを含むプロセスも提供する。
好ましい実施形態において、α４β１インテグリンは、
天然型かα４β１インテグリンを発現するよう形質移入
された細胞のどちらでも、その細胞表面上で発現され
る。The present invention is a process for selectively inhibiting the inhibition of α 4 β 1 integrin on a protein, wherein integrin is present in the presence of an effective inhibitory amount of a compound of the present invention.
A process that includes exposing to the protein is also provided.
In a preferred embodiment, the α 4 β 1 integrin is
It is expressed on the cell surface of either native or cells transfected to express the α 4 β 1 integrin.

【００４９】α４β１インテグリンが結合するタンパク
質は、細胞表面上に発現させるか、または細胞外マトリ
クスの一部として発現させることができる。特に好まし
いタンパク質はフィブロネクチンまたはインバシンであ
る。The protein bound by the α 4 β 1 integrin can be expressed on the cell surface or as part of the extracellular matrix. A particularly preferred protein is fibronectin or invasin.

【００５０】本発明の化合物が結合を阻害する能力は、
以下の実施例で詳細に説明する。これらの実施例は本発
明の好ましい実施形態および効用について説明するため
に示すもので、これについて添付された請求項に別途明
記しない限り、本発明を制限するものではない。The ability of the compounds of the invention to inhibit binding is
The details will be described in the following examples. These examples are provided to illustrate preferred embodiments and utilities of the present invention and are not intended to limit the invention unless otherwise specified in the appended claims.

【００５１】本発明の化合物が結合を阻害する能力は、
以下の実施例で詳細に説明する。これらの実施例は本発
明の好ましい実施形態および効用について説明するため
に示すもので、これについて添付された請求項に別途明
記しない限り、本発明を制限するものではない。The ability of the compounds of the invention to inhibit binding is
The details will be described in the following examples. These examples are provided to illustrate preferred embodiments and utilities of the present invention and are not intended to limit the invention unless otherwise specified in the appended claims.

【００５２】実施例１ （３Ｓ）−３−〔（｛〔１−（２−クロロベンジル）−
４−ヒドロキシ−５−メチル−２−オキソ−１，２−ジ
ヒドロピジリン−３−イル〕アミノ｝カルボニル）アミ
ノ〕−３−（４−メチルフェニル）プロパン酸、１１９
の合成 ステップ１：乾燥窒素雰囲気下で水素化ナトリウム（鉱
油中６０％分散液３．６ｇ、９０ｍｍｏｌ）のＴＨＦ懸
濁液（３００ｍｌ）に、ＴＭＥＤＡ（１３．２ｍＬ、８
７．５ｍｍｏｌ）を加え、その混合物を−２０℃に冷却
した。メチルプロピオニルアセテート（９．６０ｍＬ、
７６．５ｍｍｏｌ）を一滴ずつ加え、その溶液をさらに
１５分間撹拌した。ｎ−ブチルリチウムの溶液（９０ｍ
Ｌ、ヘキサン中１．６Ｍ、１４４ｍｍｏｌ）を一滴ずつ
加え、結果として生じた混合物を−２０℃で１５分間撹
拌した。次いでギ酸メチル（６．０ｍＬ、９７ｍｍｏ
ｌ）を早急に加え、ＨＣｌ（２Ｎ、２５０ｍＬ）を用い
て急冷する前に混合物を１５分間撹拌した。反応物をジ
エチルエーテル（１５０ｍＬ）で希釈し、有機層を２回
より多く水で洗浄した。水性層を合わせ、飽和するまで
塩化ナトリウムを加えた。酢酸エチルを用いてこの混合
物を抽出した（３回）。元のエーテル層を飽和重炭酸ナ
トリウム溶液および水で洗浄した。合わせた水性洗浄物
を過剰のＨＣｌ（２Ｎ）を用いて酸性化し、塩化ナトリ
ウムを用いて飽和させ、酢酸エチルを用いて抽出した
（３回）。酢酸エチルの抽出物すべてを合わせ、ＭｇＳ
Ｏ４によって乾燥させた。結果として生じた混合物を粗
いシリカゲルによって真空濾過し、その濾過物を減圧下
で濃縮して、淡い黄色の油として１１４（８．２７ｇ、
６８％）を得た。さらなる精製をせずに、この物質を使
用した。Example 1 (3S) -3-[({[1- (2-chlorobenzyl)-
4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid, 119
Step 1: To a suspension of sodium hydride (60% dispersion in mineral oil, 3.6 g, 90 mmol) in THF (300 ml) under a dry nitrogen atmosphere, TMEDA (13.2 mL, 8
7.5 mmol) was added and the mixture was cooled to -20 ° C. Methyl propionyl acetate (9.60 mL,
(76.5 mmol) was added dropwise and the solution was stirred for a further 15 minutes. n-Butyllithium solution (90m
L, 1.6M in hexane, 144 mmol) was added dropwise and the resulting mixture was stirred at -20 ° C for 15 minutes. Then methyl formate (6.0 mL, 97 mmo
l) was added rapidly and the mixture was stirred for 15 minutes before being quenched with HCl (2N, 250 mL). The reaction was diluted with diethyl ether (150 mL) and the organic layer was washed twice more with water. The aqueous layers were combined and sodium chloride was added until saturated. The mixture was extracted with ethyl acetate (3 times). The original ether layer was washed with saturated sodium bicarbonate solution and water. The combined aqueous washes were acidified with excess HCl (2N), saturated with sodium chloride and extracted with ethyl acetate (3 times). Combine all the ethyl acetate extracts and add MgS
Dried with O 4 . The resulting mixture was vacuum filtered through crude silica gel and the filtrate was concentrated under reduced pressure to give 114 as a pale yellow oil (8.27 g,
68%). This material was used without further purification.

【００５３】ステップ２：室温で無水メタノール（２２
５ｍＬ）に溶かした１１４（３．９５ｇ、２５．０ｍｍ
ｏｌ）の溶液に、無水メタノール（２５ｍＬ）に溶かし
た２−クロロベンジルアミン（４．２ｇ、３０ｍｍｏ
ｌ）の溶液を添加用漏斗から一滴ずつ加えた。この溶液
を４５℃で一晩加熱し、次いで２時間かけて還流させ
た。反応混合物を室温に冷却し、乾燥状態に濃縮した。
残留物をジクロロメタン中に移し、濾過した。固体を回
収し、真空下で乾燥させて淡い黄色の固体として１１５
（２．２０ｇ、３５％）を得た。Step 2: At room temperature, anhydrous methanol (22
114 (3.95 g, 25.0 mm) dissolved in 5 mL
2-chlorobenzylamine (4.2 g, 30 mmo) dissolved in anhydrous methanol (25 mL).
The solution of l) was added drop-wise from the addition funnel. The solution was heated at 45 ° C. overnight and then refluxed for 2 hours. The reaction mixture was cooled to room temperature and concentrated to dryness.
The residue was taken up in dichloromethane and filtered. Collect the solid and dry under vacuum to give 115 as a pale yellow solid.
(2.20 g, 35%) was obtained.

【００５４】ステップ３：室温で氷酢酸（１１ｍＬ）に
溶かした１１５（８４０ｍｇ、３．４ｍｍｏｌ）の懸濁
液に、ＮａＮＯ２（４６ｍｇ、０．６７ｍｍｏｌ）、水
（０．９２ｍＬ）およびＨＮＯ３（７０％、０．８５ｍ
Ｌ、１３．４ｍｍｏｌ）を順に加えた。結果として生じ
た鮮明な黄色の溶液を室温で一晩撹拌し、次いでＣＨ ２
Ｃｌ２および水で希釈した。ＣＨ２Ｃｌ２を用いて水性
層を抽出し、有機層を合わせ、水（３回）およびブライ
ンで洗浄した。有機層をＭｇＳＯ４によって乾燥させ濾
過し、その濾過物を減圧下で濃縮して、鮮明な黄色の固
体として１１６（９１０ｍｇ、９２％）を得た。さらな
る精製をせずに、この物質を使用した。Step 3: Add glacial acetic acid (11 mL) at room temperature
Suspension of dissolved 115 (840 mg, 3.4 mmol)
Liquid, NaNOTwo(46 mg, 0.67 mmol), water
(0.92 mL) and HNOThree(70%, 0.85m
L, 13.4 mmol) in order. Resulting
The bright yellow solution was stirred at room temperature overnight, then CH. Two
ClTwoAnd diluted with water. CHTwoClTwoUsing water
Extract the layers, combine the organic layers, and water (3 times) and brine.
Washed with water. The organic layer is MgSOFourDried by filtration
And concentrate the filtrate under reduced pressure to give a bright yellow solid.
116 (910 mg, 92%) was obtained as a body. Sarana
This material was used without further purification.

【００５５】ステップ４：乾燥窒素雰囲気下の室温でＤ
ＭＦ（１０．３ｍＬ）に溶けている１１６（９１０ｍ
ｇ、３．１ｍｍｏｌ）の溶液に、亜鉛末（９０９ｍｇ、
１３．９ｍｍｏｌ）およびトリエチルアミン塩酸塩（２
３４０ｍｇ、１７．０ｍｍｏｌ）を加えた。結果として
生じた混合物を２時間かけて５５℃に加熱し、次いで室
温に冷却した。結果として生じた混合物に、固体として
のＣＤＩ（１００２ｍｇ、６．１８ｍｍｏｌ）を加え
た。添加によって、ガスの放出が起こった。次いでこの
混合物を１時間かけて８０℃に加熱し、室温に冷却し、
ＣＨ２Ｃｌ２およびＨＣｌ（２Ｎ）で希釈した。ＣＨ２
Ｃｌ２を用いて水性層を抽出し、有機層を合わせ、水
（４回）および塩水で洗浄した。有機層をＭｇＳＯ４に
よって乾燥させ濾過し、その濾過物を減圧下で濃縮し
て、黄色の固体として１１７（９２０ｍｇ）を得た。こ
の物質は少量のＤＭＦを含んでおり、精製せずに使用し
た。Step 4: D at room temperature under a dry nitrogen atmosphere
116 (910m) dissolved in MF (10.3mL)
g, 3.1 mmol) in a solution of zinc dust (909 mg,
13.9 mmol) and triethylamine hydrochloride (2
340 mg, 17.0 mmol) was added. The resulting mixture was heated to 55 ° C. for 2 hours then cooled to room temperature. To the resulting mixture was added CDI as a solid (1002 mg, 6.18 mmol). The addition caused gas evolution. The mixture is then heated to 80 ° C. for 1 hour, cooled to room temperature,
Diluted with CH 2 Cl 2 and HCl (2N). CH 2
The aqueous layer was extracted with Cl 2 and the organic layers were combined, washed with water (4 times) and brine. The organic layer was dried by MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give a yellow solid 117 (920 mg). This material contained a small amount of DMF and was used without purification.

【００５６】ステップ５：乾燥窒素雰囲気下で１１７
（原料９２０ｍｇ、理論値３．１ｍｍｏｌ）および８
（８００ｍｇ、３．８６ｍｍｏｌ）のＴＨＦ懸濁液（２
１ｍｌ）を一晩で５５℃に加熱し、室温に冷却し、次い
で酢酸エチルで希釈した。結果として生じた混合物をＨ
Ｃｌ（２Ｎ）およびブラインで洗浄し、有機層をＭｇＳ
Ｏ ４によって乾燥させ濾過した。その濾過物を減圧下で
濃縮し、結果として生じた残留物をシリカゲルクロマト
グラフィによって精製し、ヘキサン：酢酸エチル＝７：
３で溶離させ、青黄色の気泡として１１８（２ステップ
について１０９６ｍｇ、７１％）を得た。Step 5: 117 under dry nitrogen atmosphere
(Raw material 920 mg, theoretical value 3.1 mmol) and 8
(800 mg, 3.86 mmol) in THF (2
1 ml) overnight at 55 ° C., cooled to room temperature, then
Diluted with ethyl acetate. The resulting mixture is charged with H
Washed with Cl (2N) and brine, the organic layer was MgS
O FourDried by and filtered. The filtrate under reduced pressure
Concentrate and concentrate the resulting residue on silica gel.
Purified by chromatography, hexane: ethyl acetate = 7:
Elute with 3 to give 118 (2 steps
1096 mg, 71%) was obtained.

【００５７】ステップ６：室温でＴＨＦ（１８ｍＬ）に
溶けている１１８（１０９１ｍｇ、２．１９ｍｍｏｌ）
の溶液に、水酸化ナトリウム（２Ｎ、６ｍＬ）およびメ
タノール（１２ｍＬ）を加えた。その混合物を２０分間
撹拌し、次いで水で希釈し、エチルエーテルを用いて抽
出した。水性層をＨＣｌ（２Ｎ）を用いて酸性化し、酢
酸エチルを用いて抽出した。酢酸エチル層を水およびブ
ラインで洗浄し、ＭｇＳＯ４によって乾燥させ濾過し
た。その濾過物を減圧下で濃縮し、白色の泡として（３
Ｓ）−３−〔（｛〔１−（２−クロロベンジル）−４−
ヒドロキシ−５−メチル−２−オキソ−１，２−ジヒド
ロピジリン−３−イル〕アミノ｝カルボニル）アミノ〕
−３−（４−メチルフェニル）プロパン酸、１１９（定
量値１０４５ｍｇ）を得た。ＭＳ：計算値（Ｍ−Ｈ）−
＝４６８．１３ｍ／ｚ；実測値（Ｍ−Ｈ）−＝４６７．
９９ｍ／ｚ。Step 6: 118 (1091 mg, 2.19 mmol) dissolved in THF (18 mL) at room temperature
Sodium hydroxide (2N, 6 mL) and methanol (12 mL) were added to the solution of. The mixture was stirred for 20 minutes, then diluted with water and extracted with ethyl ether. The aqueous layer was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and filtered and dried by MgSO 4. The filtrate was concentrated under reduced pressure as a white foam (3
S) -3-[({[1- (2-chlorobenzyl) -4-
Hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) amino]
-3- (4-Methylphenyl) propanoic acid, 119 (quantitative value 1045 mg) was obtained. MS: Calculated value (M−H) −
= 468.13 m / z; measured value (MH) - = 467.
99 m / z.

【００５８】実施例２ （３Ｓ）−３−〔（｛〔１−（２−クロロベンジル）−
４−ヒドロキシ−２−オキソ−２，５，６，７−テトラ
ヒドロ−１Ｈ−シクロペンタ〔ｂ〕ピリジン−３−イ
ル〕アミノ｝カルボニル）アミノ〕−３−（４−メチル
フェニル）プロパン酸の合成 ステップ１：トルエン（４５ｍｌ）に溶けているエチル
２−オキソシクロペンタンカルボキシレート（３．３０
ｇ、２１．１ｍｍｏｌ）の溶液に、４−クロロベンジル
アミン（２．５６ｍＬ、２１．１ｍｍｏｌ）を加えた。
結果として生じた混合物をＤｅａｎ−Ｓｔａｒｋ ｔｒ
ａｐを介した水の共沸混合除去によって一晩還流した。
その反応混合物を減圧下で濃縮して、赤色の油として１
２７（５．９０ｇ、９９％）を得た。精製せずに、この
物質を使用した。Example 2 (3S) -3-[({[1- (2-chlorobenzyl)-
Synthesis step of 4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid 1: Ethyl 2-oxocyclopentanecarboxylate (3.30 dissolved in toluene (45 ml)
g, 21.1 mmol) was added 4-chlorobenzylamine (2.56 mL, 21.1 mmol).
The resulting mixture was Dean-Stark tr
Reflux overnight by azeotropic removal of water via ap.
The reaction mixture was concentrated under reduced pressure to 1 as a red oil.
27 (5.90 g, 99%) was obtained. This material was used without purification.

【００５９】ステップ２：乾燥窒素雰囲気下で０℃に冷
却した無水ＴＨＦ（７５ｍＬ）に溶かした１２７（１
１．０ｇ、３９．３ｍｍｏｌ）の溶液に、ＮａＨ（鉱油
中に分散している６０％分散液１．７３ｇ、４３．２ｍ
ｍｏｌ）を加えた。反応物を０℃で１０分間撹拌し、塩
化アセチル（３．９ｍＬ、５５ｍｍｏｌ）を加えた。反
応混合物を段階的に室温まで暖め、次いで一晩撹拌し
た。結果として生じた混合物を減圧下で濃縮し、氷水
（２００ｍＬ）とＨＣｌ（１Ｎ、２００ｍＬ）の混合物
を残留物に加えた。この混合物を酢酸エチル（３００ｍ
Ｌ）を用いて抽出して、酢酸エチル層をＭｇＳＯ４によ
って乾燥させ濾過した。その濾過物を減圧下で濃縮し、
茶色の油として１２８（１３．４ｇ）を得た。この物質
は鉱油を含んでいたが、精製せずに使用した。Step 2: 127 (1) dissolved in anhydrous THF (75 mL) cooled to 0 ° C. under a dry nitrogen atmosphere.
1.0 g, 39.3 mmol) solution, NaH (60% dispersion in mineral oil 1.73 g, 43.2 m)
mol) was added. The reaction was stirred at 0 ° C. for 10 minutes and acetyl chloride (3.9 mL, 55 mmol) was added. The reaction mixture was gradually warmed to room temperature and then stirred overnight. The resulting mixture was concentrated under reduced pressure and a mixture of ice water (200 mL) and HCl (1N, 200 mL) was added to the residue. This mixture was added to ethyl acetate (300m
And extracted with L), filtered and dried by MgSO 4 and the ethyl acetate layer. The filtrate was concentrated under reduced pressure,
128 (13.4 g) was obtained as a brown oil. This material contained mineral oil but was used without purification.

【００６０】ステップ３：乾燥窒素雰囲気下で０℃に冷
却した無水ＴＨＦ（５０ｍＬ）に溶かした未精製１２８
（１３．４ｇ、３９．３ｍｍｏｌ理論値）の溶液に、リ
チウムビス（トリメチルシリル）アミド（ＴＨＦ中１．
０Ｍ、１２５ｍＬ、１２５ｍｍｏｌ）をシリンジを介し
てゆっくりと加えた。反応混合物を室温まで暖め、次い
で一晩撹拌した。この混合物を減圧下で濃縮し、残留物
を酢酸エチル／ヘキサンによって粉砕し、濾過した。そ
の固体をＨＣｌ（１Ｎ、２５０ｍｌ）および水（５００
ｍｌ）で洗浄して、茶色の油として１２９（２ステップ
について５．４８ｇ、４８％）を得た。Step 3: Unpurified 128 dissolved in anhydrous THF (50 mL) cooled to 0 ° C. under a dry nitrogen atmosphere.
To a solution of (13.4 g, 39.3 mmol theoretical) lithium bis (trimethylsilyl) amide (1.
0M, 125 mL, 125 mmol) was added slowly via syringe. The reaction mixture was warmed to room temperature and then stirred overnight. The mixture was concentrated under reduced pressure and the residue was triturated with ethyl acetate / hexane and filtered. The solid was converted to HCl (1N, 250 ml) and water (500
ml) to give 129 as a brown oil (5.48 g, 48% for 2 steps).

【００６１】実施例２５に記載の手順に従って１２９か
ら、（３Ｓ）−３−〔（｛〔１−（２−クロロベンジ
ル）−４−ヒドロキシ−２−オキソ−２，５，６，７−
テトラヒドロ−１Ｈ−シクロペンタ〔ｂ〕ピリジン−３
−イル〕アミノ｝カルボニル）アミノ〕−３−（４−メ
チルフェニル）プロパン酸を合成した。ＭＳ：計算値
（Ｍ＋Ｈ）＋＝４９６．１６ｍ／ｚ；実測値（Ｍ＋Ｈ）
＋＝４９５．９９ｍ／ｚ。From 129 according to the procedure described in Example 25 from (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,6,7-
Tetrahydro-1H-cyclopenta [b] pyridine-3
-Yl] amino} carbonyl) amino] -3- (4-methylphenyl) propanoic acid was synthesized. MS: calculated (M + H) + = 496.16 m / z; found (M + H).
+ = 495.99 m / z.

【００６２】実施例３ ステップ５のエチル（３Ｓ）−３−（４−メチルフェニ
ル）プロパノエート、８の代わりにエチル（３Ｓ）−３
−〔３−（ジエチルアミノ）フェニル〕プロパノエート
を使用したこと以外は、実施例２５に記載の手順に従っ
て、（３Ｓ）−３−〔（｛〔１−（２−クロロベンジ
ル）−４−ヒドロキシ−５−メチル−２−オキソ−１，
２−ジヒドロピジリン−３−イル〕アミノ｝カルボニ
ル）アミノ〕−３−〔３−（ジエチルアミノ）フェニ
ル〕プロパン酸を合成した。ＭＳ：計算値（Ｍ−Ｈ）−
＝５２５．２９ｍ／ｚ；実測値（Ｍ−Ｈ）−＝５２５．
００ｍ／ｚ。Example 3 Ethyl (3S) -3- (4-methylphenyl) propanoate from step 5, ethyl (3S) -3 instead of 8.
(3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5] according to the procedure described in Example 25, except that-[3- (diethylamino) phenyl] propanoate was used. -Methyl-2-oxo-1,
2-Dihydropyridin-3-yl] amino} carbonyl) amino] -3- [3- (diethylamino) phenyl] propanoic acid was synthesized. MS: Calculated value (M−H) −
= 525.29 m / z; measured value (M-H) - = 525.
00 m / z.

【００６３】[0063]

【化３】 [Chemical 3]

【００６４】 （３Ｓ）−３−〔（｛〔１−（２−クロ ０．００５ 計算値（Ｍ−Ｈ）− ロベンジル）−４−ヒドロキシ−５−メ ＝４６８．１３ｍ／ チル−２−オキソ−１，２−ジヒドロピ ｚ；実測値（Ｍ−Ｈ ジリン−３−イル〕アミノ｝カルボニル ）−＝４６７．９９ ）アミノ〕−３−（４−メチルフェニル ｍ／ｚ ）プロパン酸 （３Ｓ）−３−〔（｛〔１−（２−クロ ０．００３ 計算値（Ｍ＋Ｈ）＋ ロベンジル）−４−ヒドロキシ−２−オ ＝４９６．１６ｍ／ キソ−２，５，６，７−テトラヒドロ− ｚ；実測値（Ｍ＋Ｈ １Ｈ−シクロペンタ〔ｂ〕ピリジン−３ ）＋＝４９５．９９ −イル〕アミノ｝カルボニル）アミノ〕 ｍ／ｚ −３−（４−メチルフェニル）プロパン 酸 （３Ｓ）−３−〔（｛〔１−（２−クロ ２ 計算値（Ｍ−Ｈ）− ロベンジル）−４−ヒドロキシ−５−メ ＝５２５．１９；実 チル−２−オキソ−１，２−ジヒドロピ 測値（Ｍ−Ｈ）−＝ ジリン−３−イル〕アミノ｝カルボニル ５２５．００ ）アミノ〕−３−〔３−（ジエチルアミ ノ）フェニル〕プロパン酸 ４７４６、４７８７および５１３６は、活性および／ま
たは薬物動態（ＰＫ）特性の点で、Ｃｙｃｌ ＣＩＰ２
に記載される化合物のグループに明らかな利点を提供す
る。４７４６、４７８７および５１３６において見られ
たわずかな構造的変化は、予期せぬ効能の増大を引き起
こした。主要なアッセイで４７４６は、Ｃｙｃｌ ＣＩ
Ｐ２に記載されるクラスの代表的化合物４４７３と比較
して、Ｒａｍｏｓ細胞へのＣＳ−１結合の阻害において
２倍の増大を示した（表１）。経口的に送達されたと
き、４７４６のＡＵＣ（ａｒｅａ−ｕｎｄｅｒ−ｃｕｒ
ｖｅ、薬剤への全体的な暴露の指標）は、４４７３に関
するＡＵＣと比較して大幅に増大した。化合物が経口的
に送達されたとき、４７８７はＣＳ−１結合の阻害にお
いて、ＡＵＣを保ちながら４４７３と比較すると大幅な
３倍の増大を示した。経口的に送達されたとき、５１３
６は４４７３に対して活性の５倍と大幅な増大、および
ＡＣＵの約２倍の増大を示した。[0064] (3S) -3-[({[1- (2-color 0.005 calculated value (MH)− Robenzyl) -4-hydroxy-5-me = 468.13 m / Cyl-2-oxo-1,2-dihydropyz; measured value (MH) Dilin-3-yl] amino} carbonyl)−= 467.99 ) Amino] -3- (4-methylphenyl m / z ) Propanoic acid (3S) -3-[({[1- (2-color 0.003 calculated value (M + H)+ Robenzyl) -4-hydroxy-2-o = 496.16 m / Exo-2,5,6,7-tetrahydro-z; Found value (M + H 1H-cyclopenta [b] pyridine-3)+= 495.99 -Yl] amino} carbonyl) amino] m / z -3- (4-methylphenyl) propane acid (3S) -3-[({[1- (2-Chlo 2 Calculated value (MH)− Robenzyl) -4-hydroxy-5-meth = 525.19; fruit Cyl-2-oxo-1,2-dihydropy value (MH)−= Dilin-3-yl] amino} carbonyl 525.00 ) Amino] -3- [3- (diethylamido) No) phenyl] propanoic acid 4746, 4787 and 5136 are active and / or
Or in terms of pharmacokinetic (PK) properties, Cycl CIP2
Provide a clear advantage to the group of compounds described in
It Seen at 4746, 4787 and 5136
Subtle structural changes lead to unexpected increases in efficacy
Rubbed The major assay, 4746, is Cycl CI
Compare with representative compound 4473 of the class described in P2
In the inhibition of CS-1 binding to Ramos cells
It showed a 2-fold increase (Table 1). Was delivered orally
4746 AUC (area-under-cur)
ve, an indicator of overall exposure to the drug)
Significantly increased compared to the AUC. Compound is oral
4787, when delivered to the liver, inhibits CS-1 binding.
And it's a lot better than 4473 while keeping AUC
It showed a 3-fold increase. 513 when delivered orally
6 is a 5-fold increase in activity over 4473, and
It showed an approximately 2-fold increase in ACU.

【００６５】４７４６、４７８７および５１３６のわず
かな構造的変化は、４４７３と比較して、全体的なプロ
フィールを抜本的に改善するとは考えられなかった。こ
れらの改善により経口的に送達されるとき、これら３つ
の化合物は、４４７３よりも病気を治療する際には効能
があるであろうと考えられる。The slight structural changes in 4746, 4787 and 5136 were not considered to drastically improve the overall profile compared to 4473. When delivered orally due to these improvements, it is believed that these three compounds would be more efficacious in treating disease than 4473.

【００６６】[0066]

【化４】 ａインテグリンを以下の病状で示した。[Chemical 4] a Integrin has the following pathologies:

【００６７】[0067]

【表１】 [Table 1]

【００６８】本発明は、以上の記述および実施例の方法
にて例示している。多くの変化がそれを考慮することで
当業者に理解されるようになる可能性があるので、以上
の記述は非限定的な例示として意図されている。付随さ
れる請求項の範囲および意図の範囲内でのすべてのその
ような変化は本明細書に含まれることが意図されてい
る。The invention is illustrated by the method described above and in the examples. The above description is intended as non-limiting illustrations, as many variations may become apparent to one of ordinary skill in the art in view of it. All such changes within the scope and spirit of the appended claims are intended to be included herein.

【００６９】以下の請求項で定義されたように、本発明
の概念および意図から逸脱することなしに、本明細書で
記述された本発明の方法の組成物、操作、および手配で
変更を行うことができる。Changes may be made in the composition, operation, and arrangement of the method of the invention described herein without departing from the concept and intent of the invention, as defined in the claims below. be able to.

【００７０】[0070]

【配列表】[Sequence list]

【００７１】[0071]

【化５】 [Chemical 5]

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｐ 3/10 Ａ６１Ｐ 3/10 9/10 9/10 11/06 11/06 19/02 19/02 25/00 25/00 29/00 29/00 １０１ １０１ 35/00 35/00 35/02 35/02 37/02 37/02 37/08 37/08 Ｃ０７Ｍ 7:00 Ｃ０７Ｍ 7:00 (72)発明者 チー・チエン アリカ合衆国、インデイアナ・46032、ノ ーマル、ビゲロウ・コート・14006 (72)発明者 イアン・エル・スコツト アリカ合衆国、ニユー・ヨーク・12053、 デランソン、リー・ドライブ・25 (72)発明者 ロバート・ブイ・マーケツト アリカ合衆国、テキサス・77584、ペアラ ンド、ビーコン・ヒル・ドライブ・3419 (72)発明者 ウエン・リー アリカ合衆国、テキサス・77584、ペアラ ンド、エツジウツド・ドライブ・3223 (72)発明者 ジヤマール・カシル アリカ合衆国、テキサス・77477、スタツ フオード、アンズ・ウエイ・310 (72)発明者 ジヨージ・ダブリユ・ホランド アリカ合衆国、テキサス・77007、ヒユー ストン、パーク・トレイル・レイン・402 (72)発明者 チヨントー・ウー アリカ合衆国、テキサス・77584、ペアラ ンド、ランシング・サークル・2511 (72)発明者 イー・ラドフオード・デツカー アリカ合衆国、テキサス・77018、ヒユー ストン、ウエスト・フオーテイセカンド・ ストリート・1078 (72)発明者 チエン・リー アリカ合衆国、テキサス・77382、ザ・ウ ツドランズ、ワイルドフラワー・トレイ ス・プレイス・22 Ｆターム(参考） 4C034 CB06 4C055 AA04 AA09 BA02 BA42 BA53 CA02 CA03 CA06 CA53 CB17 DA42 4C086 AA02 AA03 BC17 BC27 MA01 MA04 NA14 ZA01 ZA45 ZA59 ZA66 ZB07 ZB11 ZB13 ZB15 ZB26 ZB27 ZC35 ─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 7 Identification code FI theme code (reference) A61P 3/10 A61P 3/10 9/10 9/10 11/06 11/06 19/02 19/02 25 / 00 25/00 29/00 29/00 101 101 35/00 35/00 35/02 35/02 37/02 37/02 37/08 37/08 C07M 7:00 C07M 7:00 (72) Inventor Qi Chien Arica United States, Indiana 46032, Nomal, Bigelow Court 14006 (72) Inventor Ian El Scott Arica United States, New York 12053, Delanson, Lee Drive 25 (72) Inventor Robert -Buy Market Arica, Texas 77584, Pairland, Beacon Hill Drive-3419 (72) Inventor Wen Lee Arica, Texas 77584, Pairland, Ez Tudo Drive 3223 (72) Inventor Jiamal Kasir Arica United States, Texas 77477, Statford, Ahn's Way 310 (72) Inventor Gioji Dubriille Holland Arica United States, Texas 77007, Huystone, Park Park Trail Rain 402 (72) Inventor Chiyeon To Woo Arica United States, Texas 77584, Pairland, Lansing Circle 2511 (72) Inventor E Radoff Odd Decker Arica United States, Texas 77018, Huystone, West West Forty Second Street 1078 (72) Inventor Chien Lee Arica United States, Texas 77382, The Wutlands, Wildflower Trace Place 22 F Term (Reference) 4C034 CB06 4C055 AA04 AA09 BA02 BA42 BA53 CA02 CA03 CA06 CA53 CB17 DA42 4C086 AA02 AA03 BC17 BC27 MA01 MA04 NA14 ZA01 ZA45 ZA59 ZA66 ZB07 ZB11 ZB13 ZB15 ZB26 ZB27 ZC35

Claims (3)

【特許請求の範囲】[Claims] 【請求項１】 （３Ｓ）−３−〔（｛〔１−（２−クロ
ロベンジル）−４−ヒドロキシ−５−メチル−２−オキ
ソ−１，２−ジヒドロピジリン−３−イル〕アミノ｝カ
ルボニル）アミノ〕−３−（４−メチルフェニル）プロ
パン酸、または薬学的に許容されるその塩。1. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- (4-methylphenyl) propanoic acid, or a pharmaceutically acceptable salt thereof. 【請求項２】 （３Ｓ）−３−〔（｛〔１−（２−クロ
ロベンジル）−４−ヒドロキシ−２−オキソ−２，５，
６，７−テトラヒドロ−１Ｈ−シクロペンタ〔ｂ〕ピリ
ジン−３−イル〕アミノ｝カルボニル）アミノ〕−３−
（４−メチルフェニル）プロパン酸、または薬学的に許
容されるその塩。2. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-2-oxo-2,5,
6,7-Tetrahydro-1H-cyclopenta [b] pyridin-3-yl] amino} carbonyl) amino] -3-
(4-Methylphenyl) propanoic acid, or a pharmaceutically acceptable salt thereof. 【請求項３】 （３Ｓ）−３−〔（｛〔１−（２−クロ
ロベンジル）−４−ヒドロキシ−５−メチル−２−オキ
ソ−１，２−ジヒドロピジリン−３−イル〕アミノ｝カ
ルボニル）アミノ〕−３−〔３−（ジエチルアミノ）フ
ェニル〕プロパン酸、または薬学的に許容されるその
塩。3. (3S) -3-[({[1- (2-chlorobenzyl) -4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl] amino} carbonyl) Amino] -3- [3- (diethylamino) phenyl] propanoic acid, or a pharmaceutically acceptable salt thereof.
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US10875875B2 (en) * 2017-04-26 2020-12-29 Aviara Pharmaceuticals, Inc. Propionic acid derivatives and methods of use thereof
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