JP2005508300A5

JP2005508300A5 -

Info

Publication number: JP2005508300A5
Application number: JP2003507098A
Authority: JP
Filing date: 2002-06-21
Publication date: 2006-01-05
Anticipated expiration: 2022-06-21

Description

フォーカルアドヒージョンキナーゼ（ＦＡＫ）はインテグリン媒介シグナル伝達経路に関与する非受容体チロシンキナーゼである。ＦＡＫはフォーカルコンタクト部位においてインテグリンと同時局在化しており、ＦＡＫの活性化およびそのチロシンホスホリル化は多くの細胞型においてその細胞外リガンドに結合しているインテグリンに依存していることがわかっている。幾つかの試験結果によれば、ＦＡＫ阻害剤が癌の治療に有用であるという仮説が裏付けられている。例えば、ＦＡＫ欠損細胞は化学走性シグナルに応答した遊走が乏しくＦＡＫのＣ末端ドメインの過剰発現により細胞の増殖と化学走性遊走がブロックされ（Ｓｉｅｇｅｔａｌ.，Ｊ．ＣｅｌｌＳｃｉｅｎｃｅ，１９９９，１１２，
２６７７−２６９１；ＲｉｃｈａｒｄｓｏｎＡ．ａｎｄＰａｒｓｏｎｓＴ.，Ｃ
ｅｌｌ，１９９７，９７，２２１−２３１）；更に、ＦＡＫアンチセンスオリゴヌクレオチドを投与された腫瘍細胞はその付着性を消失し、アポトーシスを起こした（Ｘｕｅｔ
ａｌ.，ＣｅｌｌＧｒｏｗｔｈＤｉｆｆｅｒ．１９９６，４，４１２−４１８）。
ＦＡＫは前立腺、乳房、甲状腺、結腸および肺の癌において過剰発現されることが報告されている。ＦＡＫの発現濃度は最も旺盛な表現型を示す腫瘍と直接相関している。 Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in integrin-mediated signal transduction pathways. FAK is co-localized with integrin at the focal contact site, and activation of FAK and its tyrosine phosphorylation are known to depend on integrin binding to its extracellular ligand in many cell types. . Several test results support the hypothesis that FAK inhibitors are useful in the treatment of cancer. For example, FAK-deficient cells have poor migration in response to chemotaxis signals and overexpression of the FAK C-terminal domain blocks cell growth and chemotaxis migration (Sieg et al., J. Cell Science, 1999, 112). ,
2677-2691; Richardson A. et al. and Parsons T., C
further, tumor cells administered with FAK antisense oligonucleotides lost their adherence and caused apoptosis (Xu et al., 1997, 97, 221-231).
al., Cell Growth Differ. 1996, 4, 412-418).
FAK has been reported to be overexpressed in prostate, breast, thyroid, colon and lung cancers. The expression level of FAK correlates directly with the tumor that shows the most vigorous phenotype.

本発明の組成物は製薬上許容しうるアジュバントまたは賦形剤１種以上を用いて慣用的な方法に従って調製してよい。アジュバントは特に希釈剤、滅菌水性媒体、および、種々の非毒性の有機溶媒を包含する。組成物は錠剤、丸薬、顆粒、粉末、水性の溶液または懸濁液、注者用溶液、エリキシルまたはシロップの形態で提供してよく、そして、甘味料、フレーバー剤、着色料または安定化剤よりなる群から選択される物質１種以上を含有することにより製薬上許容しうる製剤を得てよい。溶媒および溶媒中の活性物質の含有量の選択は一般的に活性化合物の溶解度および化学的特性、特定の投与方法および薬学的慣行において参照すべき条件に従って決定される。例えば錠剤を調製するためには、乳糖、クエン酸ナトリウム、炭酸カルシウム、リン酸２カルシウムのような賦形剤および澱粉、アルギン酸および特定の珪酸塩複合体のような錠剤崩壊剤を、ステアリン酸マグネシウム、ラウリル硫酸ナトリウムおよびタルクのような潤滑剤と組み合わせて使用してよい。カプセルを調製するためには、乳糖および高分子量のポリエチレングリコールを使用するのが好都合である。水性懸濁液を用いる場合は、それらは懸濁を促進する乳化剤を含有することができる。スクロース、エタノール、ポリエチレングリコール、プロピレングリコール、グリセロールおよびクロロホルムまたはそれらの混合物のような希釈剤も使用してよい。 The compositions of the present invention may be prepared according to conventional methods using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include in particular diluents, sterile aqueous media, and various non-toxic organic solvents. The composition may be provided in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, pouring solutions, elixirs or syrups, and over sweeteners, flavors, colorants or stabilizers A pharmaceutically acceptable formulation may be obtained by containing one or more substances selected from the group consisting of: The choice of the solvent and the content of the active substance in the solvent is generally determined according to the solubility and chemical properties of the active compound, the particular mode of administration and the conditions to be referenced in pharmaceutical practice. For example, to prepare tablets, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and tablet disintegrants such as starch, alginic acid and certain silicate complexes can be used with magnesium stearate. May be used in combination with lubricants such as sodium lauryl sulfate and talc. To prepare the capsules, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used, they can contain emulsifiers that facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

Claims

Formula I below:

[Where:
R ¹ is hydrogen, —C (═O) —NY ¹ Y ² , —C (═O) —OR ⁵ , —SO ₂ —NY ¹ Y ² , —SO ₂ —R ⁷ , —C (═O) R ⁷ or
R ¹ represents alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or cycloalkylalkyl, each optionally aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, —CHO or a 5-, 6- or 7-membered cyclic acetal derivative of —CHO, —C (═O) —NY ¹ Y ² , —C (═O) —OR ⁵ , —NY ¹ Y ² , —N ^{(R 6) -C (= O} ) -R 7, -N (R 6) -C (= O) -NY 3 Y 4, -N (R 6) -SO 2 -R 7, -N (R 6 ) -SO ₂ -N
Substituted with one or more groups selected from Y ³ Y ⁴ , —OR ⁷ , —C (═O) —R ⁷ , hydroxy, alkoxy and carboxy;
R ² is hydrogen, acyl, alkylenedioxy, alkenyl, alkenyloxy, alkynyl, aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, R ⁴ , —C (═O) —NY ¹ Y ² , ^{-C (= O) -OR 5,} -NY 1 Y 2, -N (R 6) -C (= O) -R 7, -N (R 6) -C (= O) -NY 3 Y 4, ^{-N (R 6) -C (=} O) -OR 7, -N (R 6) -SO 2 -R 7, -N (R 6) -SO 2 -NY 3 Y 4, -SO 2 -NY 1 One or more groups selected from Y ² and —ZR ⁴ are shown;
R ³ is H, cyano, halo, hydroxy, nitro, R ⁴ , NY ¹ Y ² , —ZR ⁴ , —C (═O)
^{-OR 5, -C (= O)} -R 7, -C (= O) -NY 1 Y 2, -N (R 8) -C (= O) -R 4, -N (
^{R 8) -C (= O)} -NY 1 Y 2, -N (R 8) -C (= O) -OR 5, -SO 2 -NY 3 Y 4 or -
N (R ⁸ ) —SO ₂ —R ⁷ , or
R ³ represents aryl, heteroaryl, alkenyl or alkynyl, each optionally aryl, cyano, halo, hydroxy, heteroaryl, heterocycloalkyl, nitro, —C (═O) —NY ¹ Y ² , —C ( ^{^{= O) -OR 5, -NY 1}} Y 2, -N (R 6) -C (= O) -R 7, -N (R 6) -C (= O) -NY 3 Y 4, -N ( ^{R 6) -C (= O)} -OR 7, -N (R 6) -SO 2 -R 7, -N (R 6) -SO 2 -NY 3 Y 4, -SO 2 -NY 1 Y 2, and it is substituted one group selected from -ZR ⁴ or more;
R ⁴ is alkyl, cycloalkyl or cycloalkylalkyl, each optionally aryl, cycloalkyl, cyano, halo, heteroaryl, heterocycloalkyl, hydroxy, —CHO or 5, 6 or 7 of such —CHO. cyclic acetal derivatives of the ^{members, -C (= O) -NY 1} Y 2, -C (= O) -OR 5, -NY 1 Y 2, -N (R 6) -C (= O) -R 7, ^{-N (R 6) -C (=} O) -NY 3 Y 4, -N (R 6) -SO 2 -R 7, -N (R 6) -SO 2 -
Substituted with one or more groups selected from NY ³ Y ⁴ , —OR ⁷ and —C (═O) —R ⁷ , wherein R ⁴ is optionally O, S (O) _n and NR Interrupted by a group selected from ⁶ ;
R ⁵ represents hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
R ⁶ represents hydrogen or lower alkyl;
R ⁷ represents alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
R ⁸ represents hydrogen or lower alkyl;
Y ¹ and Y ² are independently of each other hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl, optionally aryl, halo, heteroaryl, hydroxy, —C (═O) —NY ³ Y ⁴ , —C (═O) —OR ⁵ , —NY ³ Y ⁴ , —N (R ⁶ ) —C (═O) —R ⁷
^{, -N (R 6) -C (} = O) -NY 3 Y 4, -N (R 6) -SO 2 -R 7, -N (R 6) -SO 2 -NY 3
Are substituted with one or more groups selected from Y ⁴ or —OR ⁷ ; or the group —NY ¹ Y ² may form a cyclic amine;
Y ³ or Y ⁴ independently of one another are hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group —NY ³ Y ⁴ may form a cyclic amine ;
Z represents O or S (O) n;
n is an integer of 0 or 1 or 2, or an N-oxide, prodrug, acid biological equivalent, pharmaceutically acceptable salt or solvate of such a compound; such a salt Or N-oxide, prodrug or acid biological equivalent of a solvate.

R ¹ is substituted hydrogen, C _1-4 alkyl, C _1-4 alkyl substituted with halo, C _1-4 alkyl substituted with hydroxy, in ^{-N (R 6) C (=} O) -R 7 C _1-4 ^{alkyl, -C (= O) -NY 1} Y 2 compound of claim 1, wherein a cycloalkylalkyl substituted with been C _1-4 alkyl or hydroxy substituted in the.

R ¹ is hydrogen, —CH ₃ , —CH ₂ CH ₃ , —CH ₂ CF ₃ or

The compound according to claim 1, wherein

The compound according to claim ¹ , wherein R ¹ is hydrogen.

R ² is carboxy or an acid biological equivalent, hydroxy, alkyl substituted with carboxy, heteroaryl, or R ² is R ⁴ is alkyl —OR ⁴ , R ⁴ is one hydroxy group or -OR ^4, R ⁴ is alkyl or cycloalkylalkyl substituted -OR ^4, R ⁴ is alkyl substituted by an alkoxy group one or more is replaced by a carboxy group one or more above and either an alkyl or -OR ^4, R ⁴ is cycloalkyl is -OR ⁴ is -C (= O) cycloalkyl substituted with -NY ¹ Y ^2, or, R ² is R is an alkyl -C (= O) or is -R or R ² ^{-C (= O) -NY 1 Y} 2 or ^{-N (R 6) -C (=} O) according to claim 1 to 4 is -R ^7, The compound of any one of these.

The compound according to any one of claims 1 to 4, wherein R ² is -OCH ₃ or -CONHC (CH ₃ ) ₂ CH ₂ OH.

R ² is A compound according to claim 1 is -OCH _3.

R ³ is hydrogen, cyano, optionally substituted aryl, optionally substituted heteroaryl, alkyl, alkyl substituted with one or more halogen atoms, substituted with —C (═O) —NY ¹ Y ² Alkyl, substituted with —OR ⁷ , or R ³ is —ZR ⁴ , —C (═O) —OR ⁵ , —C (═O) —NY ¹ Y ² or —NY ^1. a compound according to any one of claims 1 to 7 is Y ^2.

R ³ is hydrogen, cyano, pyridyl, trifluoromethyl, —CH ₂ —CH ₂ —C (═O) NH
_{_{CH 3, -OCF 2 H, -C}} (O) -NH-C (CH 3) 2 -CH 2 OH or

The compound according to any one of claims 1 to 7.

A compound according to any one of claims 1 to 7 R ³ is -OCH _3.

The compound according to any one of claims 1 to 10, wherein R ² is bonded to the 5-position of the indole ring.

The following groups:

The compound of any one of Claims 1-11 couple | bonded with 3rd-position of an indole ring.

The following compounds:

2. A compound according to claim 1, an N-oxide, prodrug, pharmaceutically acceptable salt or solvate of such a compound; an N-oxide or prodrug of such a salt or solvate.

The following compounds:

2. A compound according to claim 1, an N-oxide, prodrug, pharmaceutically acceptable salt or solvate of such a compound; or an N-oxide or prodrug of such a salt or solvate.

15. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of any one of claims 1-14 together with one or more pharmaceutically acceptable carriers or excipients.

An inhibitor of the catalytic activity of Syk, comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 14 or a pharmaceutically effective amount of the composition according to claim 15.

A therapeutic agent for an inflammatory disease comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 14 or a pharmaceutically effective amount of the composition according to claim 15.

16. An inhibitor of FAK catalytic activity comprising a pharmaceutically effective amount of the compound of any one of claims 1-14 or a pharmaceutically effective amount of the composition of claim 15.

An inhibitor of KDR catalytic activity comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 14 or a pharmaceutically effective amount of the composition according to claim 15.

An inhibitor of the catalytic activity of Aurora 2 comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 14 or a pharmaceutically effective amount of the composition according to claim 15.

A therapeutic agent for cancer comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 14 or a pharmaceutically effective amount of the composition according to claim 15.

The therapeutic agent according to claim 17, wherein the inflammatory disease is asthma, inflammatory dermatosis, allergic rhinitis, allergic conjunctivitis or arthritis.

If the inflammatory disease is asthma, psoriasis, herpes dermatitis, eczema, necrotizing vasculitis, dermatovasculitis, bullous disease, allergic rhinitis, allergic conjunctivitis, arthritis, rheumatoid arthritis, rubella arthritis, psoriatic arthritis or The therapeutic agent according to claim 17, which is osteoarthritis.

A therapeutic agent for chronic obstructive pulmonary disease comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 14 or a pharmaceutically effective amount of the composition according to claim 15.

The therapeutic agent according to claim 21, wherein the cancer to be treated is colorectal, prostate, breast, thyroid, skin, colon or lung cancer.