JP2007503468A - 免疫抑制化合物および組成物 - Google Patents
免疫抑制化合物および組成物 Download PDFInfo
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- JP2007503468A JP2007503468A JP2006533199A JP2006533199A JP2007503468A JP 2007503468 A JP2007503468 A JP 2007503468A JP 2006533199 A JP2006533199 A JP 2006533199A JP 2006533199 A JP2006533199 A JP 2006533199A JP 2007503468 A JP2007503468 A JP 2007503468A
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- JP
- Japan
- Prior art keywords
- ethyl
- propionic acid
- benzylamino
- trifluoromethyl
- benzyloxyimino
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 156
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- 238000000034 method Methods 0.000 claims abstract description 35
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- 102000036530 EDG receptors Human genes 0.000 claims abstract description 23
- 108091007263 EDG receptors Proteins 0.000 claims abstract description 23
- 201000010099 disease Diseases 0.000 claims abstract description 22
- 230000001404 mediated effect Effects 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 20
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- 208000035475 disorder Diseases 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
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- 125000000217 alkyl group Chemical group 0.000 claims description 91
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- 150000003839 salts Chemical class 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 28
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- WKUPACYIFYSYLA-UHFFFAOYSA-N 3-[[4-[n-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-c-methylcarbonimidoyl]-2-ethylphenyl]methylamino]propanoic acid Chemical compound C1=C(CNCCC(O)=O)C(CC)=CC(C(C)=NOCC=2C=C(C(C3CCCCC3)=CC=2)C(F)(F)F)=C1 WKUPACYIFYSYLA-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- KIHYPELVXPAIDH-UHFFFAOYSA-N 1-[[4-[n-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-c-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid Chemical compound CCC1=CC(C(C)=NOCC=2C=C(C(C3CCCCC3)=CC=2)C(F)(F)F)=CC=C1CN1CC(C(O)=O)C1 KIHYPELVXPAIDH-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 229940002612 prodrug Drugs 0.000 claims description 11
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- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 claims description 10
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- 125000001544 thienyl group Chemical group 0.000 claims description 10
- 241001465754 Metazoa Species 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
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- 125000002541 furyl group Chemical group 0.000 claims description 6
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
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- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 230000004075 alteration Effects 0.000 claims description 5
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
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- 230000001154 acute effect Effects 0.000 claims description 4
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 4
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- SDGIPQJVFIMNII-UHFFFAOYSA-N 3-[[2-chloro-6-[n-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-c-methylcarbonimidoyl]pyridin-3-yl]methylamino]propanoic acid Chemical compound C=1C=C(CNCCC(O)=O)C(Cl)=NC=1C(C)=NOCC(C=C1C(F)(F)F)=CC=C1C1CCCCC1 SDGIPQJVFIMNII-UHFFFAOYSA-N 0.000 claims description 3
- 206010052779 Transplant rejections Diseases 0.000 claims description 3
- 125000004450 alkenylene group Chemical group 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
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Abstract
Description
本出願は、米国仮特許出願番号60/471,931(2003年5月19日出願)および米国仮特許出願番号60/561,968(2004年4月14日出願)の優先権の利益を主張する。これらの出願の全部の記載は、引用により、その全体として、かつすべての目的に関して、本出願に包含される。
技術分野
本発明は、リンパ球相互作用が介在する疾患または障害、特にEDG受容体介在シグナル伝達が関連する疾患の処置または予防に有用な免疫抑制化合物の新規クラスを提供する。
EDG受容体は、密接に関係した、脂質活性化G−タンパク質結合受容体のファミリーに属する。EDG−1、EDG−3、EDG−5、EDG−6、およびEDG−8(各々S1P1、S1P3、S1P2、S1P4、およびS1P5とも呼ばれる)は、スフィンゴシン−1−ホスフェート(S1P)に特異的な受容体である。EDG2、EDG4、およびEDG7(各々LPA1、LPA2、およびLPA3とも呼ばれる)は、リゾホスファチジン酸(lysophosphatidic)(LPA)に特異的な受容体である。S1P受容体アイソタイプの中で、EDG−1、EDG−3およびEDG−5は種々の組織で広範囲に発現されるが、一方EDG−6の発現は主としてリンパ組織および血小板で、そしてEDG−8は中枢神経系で確認される。EDG受容体はシグナル伝達を担い、細胞発育、増殖、維持、移動、分化、可塑性およびアポトーシスを含む細胞過程において重要な役割を演ずると考えられている。あるEDG受容体は、リンパ球相互作用が介在する疾患、例えば、移植拒絶反応、自己免疫性疾患、炎症性疾患、感染症および癌と関連する。EDG受容体活性の変更が、これらの疾患の病態および/または総体症状に関与する。したがって、それ自体EDG受容体の活性を変える分子が、このような疾患の処置における治療剤として有用である。
本出願は、式IaおよびIb:
Aは−C(O)OR5、−OP(O)(OR5)2、−P(O)(OR5)2、−S(O)2OR5、−P(O)(R5)OR5および1H−テトラゾール−5−イルから選択され;ここで、各R5は独立して水素およびC1−6アルキルから選択され;
Wは結合、C1−3アルキレン、C2−3アルケニレンから選択され;
YはC6−10アリールおよびC2−9ヘテロアリールから選択され;ここで、Yの任意のアリールまたはヘテロアリールは、所望によりハロ、ヒドロキシ、ニトロ、C1−6アルキル、C1−6アルコキシ、ハロ−置換C1−6アルキルおよびハロ−置換C1−6アルコキシから選択される1個から3個のラジカルで置換されていてよく;
から選択され;
R1はC6−10アリールおよびC2−9ヘテロアリールから選択され;ここで、R1の任意のアリールまたはヘテロアリールは所望によりC6−10アリールC0−4アルキル、C2−9ヘテロアリールC0−4アルキル、C3−8シクロアルキルC0−4アルキル、C3−8ヘテロシクロアルキルC0−4アルキルまたはC1−6アルキルから選択されるラジカルで置換されており;ここで、R1の任意のアリール基、ヘテロアリール基、シクロアルキル基またはヘテロシクロアルキル基は、所望によりハロ、C1−6アルキル、C1−6アルコキシ、ハロ−置換−C1−6アルキルおよびハロ−置換−C1−6アルコキシから選択される1個から5個のラジカルで置換されていてよく;そしてR1の任意のアルキル基は、所望により、−S−、−S(O)−、−S(O)2−、−NR5−および−O−から選択される原子または基で置換されたメチレンを有してよく;ここで、R5は水素またはC1−6アルキルから選択され;
R2は水素、C1−6アルキル、C2−6アルケニル、C2−6アルキニルおよびハロ置換C1−6アルキルから選択され;
R3およびR4は、独立して、水素、C1−6アルキル、ハロ、ヒドロキシ、C1−6アルコキシ、ハロ−置換C1−6アルキルおよびハロ−置換C1−6アルコキシから選択される。〕
から選択される化合物ならびにそのN−オキシド誘導体、プロドラッグ誘導体、保護された誘導体、個々の異性体および異性体の混合物;およびこのような化合物の薬学的に許容される塩および溶媒和物(例えば水和物)に関する。
本発明は、リンパ球相互作用が介在する疾患または障害の処置および/または予防に有用な化合物を提供する。また提供されるのは、このような疾患または障害を処置する方法である。
本明細書中、特記しない限り:
基または他の基、例えばハロ−置換−アルキル、アルコキシ、アシル、アルキルチオ、アルキルスルホニルおよびアルキルスルフィニルの構造要素としての“アルキル”は、直鎖または分枝鎖のいずれでもあり得る。基または他の基の構造要素としての“アルケニル”は、1個またはそれ以上の炭素−炭素二重結合を含み、かつ直鎖または分枝鎖のいずれでもあり得る。すべての二重結合は、cis−またはtrans−立体配置であり得る。基または他の基の構造要素としての“アルキニル”は、少なくとも1個のC≡C三重結合を含み、かつまた1個またはそれ以上のC=C二重結合を含んでよく、かつ、可能である限り、直鎖または分枝鎖のいずれでもあり得る。単独または他の基の構造要素としてのシクロアルキル基は、3から8炭素原子、好ましくは3から6炭素原子を含んでよい。“アルキレン”および“アルケニレン”は、各々“アルキル”基および“アルケニル”基に由来する2価基である。本明細書中、R1の任意のアルキル基は、所望により、−S−、−S(O)−、−S(O)2−、−NR20−および−O−(式中、R20は水素またはC1−6アルキルである)から選択される群のメンバーで中断されていてよい。このような基は、−CH2−O−CH2−、−CH2−S(O)2−CH2−、−(CH2)2−NR20−CH2−、−CH2−O−(CH2)2−などを含む。
本発明は、リンパ球相互作用が介在する疾患または障害の処置または予防に有用な化合物を提供する。一つの態様において、式IaまたはIbの化合物に関して、R1が、所望によりC6−10アリールC0−4アルキル、C2−9ヘテロアリールC0−4アルキル、C3−8シクロアルキルC0−4アルキル、C3−8ヘテロシクロアルキルC0−4アルキルまたはC1−6アルキルで置換されているフェニル、ナフチルまたはチエニルであり;ここで、R1の任意のアリール基、ヘテロアリール基、シクロアルキル基またはヘテロシクロアルキル基は、所望によりハロ、C1−6アルキル、C1−6アルコキシ、ハロ−置換−C1−6アルキルおよびハロ−置換−C1−6アルコキシから選択される1個から5個のラジカルで置換されていてよく;そしてR1の任意のアルキル基は、所望により、−S−、−S(O)−、−S(O)2−、−NR5−および−O−から選択される原子または基で置換されたメチレンを有してよく;ここで、R5は水素またはC1−6アルキルである。
から選択される。
から選択される。
から選択される。
から選択される。
遊離形または薬学的に許容される塩形の式IaまたはIbの化合物は、例えば、実施例6のインビトロおよびインビボ試験で示されるような、価値のある薬理学的特性、例えばリンパ球再循環調節特性を示し、したがって、治療に適用される。式IaまたはIbの化合物は、好ましくは1×10−11から1×10−5Mの範囲の、好ましくは50nMより小さいEC50を示す。本化合物は、1個またはそれ以上のEDG/S1P受容体、好ましくはEDG−1/S1P−1に選択性を示す。本発明のEDG−1/S1P−1選択的モジュレーターは、EDG−1/S1P−1への、および1個またはそれ以上のEDG/S1P受容体(例えば、EDG−3/S1P−3、EDG−5/S1P−2、EDG−6/S1P−4、およびEDG−8/S1P−5)への化合物の結合をアッセイすることにより同定できる。EDG−1/S1P−1選択的モジュレーターは、通常、EDG−1/S1P−1受容体に1×10−11から1×10−5Mの範囲の、好ましくは50nMより小さい、より好ましくは5nMより小さいEC50を示す。それはまた1個またはそれ以上の他のEDG/S1P受容体についてEDG−1/S1P−1のEC50よりも少なくとも5、10、25、50、100、500、または1000倍高いEC50を示す。故に、EDG−1/S1P−1調節化合物のいくつかは、EDG−1/S1P−1について5nMより小さいEC50を示し、その1個またはそれ以上の他のEDG/S1P受容体についてのEC50は、少なくとも100nMまたはそれより高い。EDG/S1P受容体に対する結合活性を測定する以外に、EDG−1/S1P−1選択的薬剤はまたEDG/S1P受容体が介在する細胞過程または活性を調節する薬剤の能力を試験することにより同定できる。
1.1 処置を必要とする対象における、例えば、上記の通りの、リンパ球が介在する障害または疾患を予防または処置する方法であり、該対象に、有効量の式IaもしくはIbの化合物またはその薬学的に許容される塩を投与することを含む、方法。
i. アロマターゼ阻害剤、
ii. 抗エストロゲン、抗アンドロゲン(とりわけ前立腺癌の場合)またはゴナドレリンアゴニスト、
iii. トポイソメラーゼI阻害剤またはトポイソメラーゼII阻害剤、
iv. 微小管活性化剤、アルキル化薬剤、抗新生物代謝拮抗剤またはプラチン化合物、
v. タンパク質または脂質キナーゼ活性またはタンパク質または脂質ホスファターゼ活性をターゲッティング/減少させる化合物、さらなる抗血管形成化合物または細胞分化過程を誘発する化合物、
vi. ブラジキニン1受容体またはアンギオテンシンIIアンタゴニスト、
vii. シクロオキシゲナーゼ阻害剤、ビスホスホネート、ヒストンデアセチラーゼ阻害剤、ヘパラナーゼ阻害剤(ヘパランスルフェート分解を防止)、例えばPI−88、生物学的応答修飾剤、好ましくはリンフォカインまたはインターフェロン、例えばインターフェロン□、ユビキチン化阻害剤、または抗アポトーシス経路を遮断する阻害剤、
viii.Ras発癌性アイソフォーム、例えばH−Ras、K−RasまたはN−Rasの阻害剤、またはファルネシルトランスフェラーゼ阻害剤、例えばL−744,832またはDK8G557、
ix. テロメラーゼ阻害剤、例えばテロメスタチン、
x. プロテアーゼ阻害剤、マトリックスメタロプロテイナーゼ阻害剤、メチオニンアミノペプチダーゼ阻害剤、例えばベンガミドまたはその誘導体、またはプロテオソーム阻害剤、例えばPS−341、および/または
xi. mTOR阻害剤
を含むが、これらに限定されない。
5. 治療的有効非毒性量の式IaもしくはIbの化合物と、少なくとも一個の第2医薬物質、例えば上記の通りの、例えば免疫抑制剤、免疫調節剤、抗炎症剤または化学療法剤を、例えば同時にまたは連続して併用投与することを含む、上記で定義の方法。
本発明はまた本発明の免疫調節化合物の製造法も含む。記載の反応において、反応性官能基、例えばヒドロキシ基、アミノ基、イミノ基、チオ基またはカルボキシ基を、これらが最終産物で望まれるとき、それらの望ましくない反応への参加を避けるために、保護する必要があり得る。慣用の保護基を標準的慣習にしたがって使用でき、例えば、T.W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry”, John Wiley and Sons, 1991を参照のこと。
本発明の化合物は、薬学的に許容される酸付加塩として、遊離塩基の形の化合物と薬学的に許容される無機または有機酸を反応させることにより製造できる。あるいは、本発明の化合物の薬学的に許容される塩基付加塩は、遊離塩基の形の化合物と薬学的に許容される無機または有機塩基を反応させることにより製造できる。あるいは、本発明の化合物の塩形は、塩の出発物質または中間体の使用により製造できる。
(a)式2の化合物と式3の化合物を反応させる;そして
(b)所望により本発明の化合物を薬学的に許容される塩に変換する;
(c)所望により塩の形の本発明の化合物を、非塩形に変換する;
(d)所望により非酸化形の本発明の化合物を薬学的に許容されるN−オキシドに変換する;
(e)所望によりN−オキシド形の本発明の化合物をその非酸化形に変換する;
(f)所望により本発明の化合物の個々の異性体を異性体の混合物から分離する;
(g)所望により非誘導体である本発明の化合物を薬学的に許容されるプロドラッグ誘導体に変換する;そして
(h)所望により本発明の化合物のプロドラッグ誘導体をその非誘導体形に変換する。
下記実施例は代表的化合物の製造の詳細な記載を提供し、本発明を説明するために提供するが、限定するものではない。
3−{4−[1−(2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸
3−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−エチル−ベンジルアミノ}−プロピオン酸
1−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−エチル−ベンジル}−アゼチジン−3−カルボン酸
3−({2−クロロ−6−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ピリジン−3−イルメチル}−アミノ)−プロピオン酸
3−({6−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−エチル−ピリジン−3−イルメチル}−アミノ)−プロピオン酸
式IaまたはIbの化合物は生物学的活性を示す
A. インビトロ:ヒトEDG受容体を発現するCHO細胞から調製した膜へのGTP[γ− 35 S]の結合を測定するGPCR活性化アッセイ
EDG−1(S1P1)GTP[γ−35S]結合アッセイ:均質化膜を、ヒトEDG−1 N−末端c−mycタグを安定に発現するCHO細胞クローンから調製する。細胞を2個の850cm2ローラーボトル中の懸濁液で、3日または4日増殖させ、その後収集する。細胞を遠沈させ、冷PBSで洗浄し、<20mlの緩衝液A(20mM HEPES、pH7.4、10mM EDTA、無EDTAの完全プロテアーゼ阻害剤カクテル[1錠/25ml])に再懸濁する。細胞懸濁液を氷上で、Polytronホモジナイザーを使用して、30000rpmで各15秒の3インターバルで均質化する。ホモジネートを最初に2000rpmで卓上式低速遠心器で10分遠心する。上清を、細胞ストレーナーを通した後、次いで、50,000×gで25分、4℃で遠心する。ペレットを緩衝液B(15%グリセロール、20mM HEPES、pH7.4、0.1mM EDTA、無EDTAの完全プロテアーゼ阻害剤カクテル[1錠/10ml])に再懸濁する。調製物のタンパク質濃度をBCAタンパク質アッセイキット(Pierce)を使用して、BSAを標準として用いて決定する。膜をアリコートに分け、−80℃で凍結保存する。
本発明の化合物を、EDG−1、EDG−3、EDG−5、およびEDG−6に対するアゴニスト活性について、FLIPRカルシウム流動アッセイで試験する。簡単に言うと、EDG受容体を発現するCHO細胞を、5%FBSと500μg/mlのG418を含むF−12K培地(ATCC)に維持する。アッセイ前に、細胞を384黒色透明底プレートに、10,000細胞/ウェル/25μlの密度で、1%FBS含有F−12Kの培地に播く。二日目に、細胞を3回(各25μl)洗浄緩衝液で洗浄する。約25μlの色素を各ウェルに添加し、1時間、37℃および5%CO2でインキュベートする。細胞を次いで4回洗浄緩衝液(各25μl)で洗浄する。カルシウム流動を、25μlのSEQ2871溶液を各細胞のウェルに添加後に測定する。同じアッセイを、異なるEDG受容体を発現する細胞で行う。FLIPRカルシウム流動アッセイにおける力価を、3分インターバルにわたり測定し、EDG−1活性化に相対的な、最大ピーク高パーセンテージ応答として定量する。
循環しているリンパ球の測定:化合物をDMSOに溶解し、4%DMSO(v/v、最終濃度)の最終濃度を得るために希釈し、次いで、一定用量のTween80 25%/H2O、v/vで希釈する。Tween80 25%/H2O(200μl)、4%DMSO、およびFTY720(10μg)を各々ネガティブおよびポジティブコントロールとして包含させる。マウス(C57bl/6雄、6−10週齢)に250−300μLの化合物溶液を経口で、短いイソフルラン麻酔下に胃管栄養法により投与する。
(i)スフィンゴシン−1−ホスフェート(5μM/チャンバー)または(ii)ヒトVEGF(1μg/チャンバー)の0.5mlの0.8%w/v寒天(ヘパリン、20U/ml含有)溶液を含む、多孔性チャンバーをマウスの横腹に皮下にインプラントする。S1PまたはVEGFは、チャンバー周囲の血管組織の増殖を誘導する。この応答は用量依存性であり、組織の重量および血液含量の測定により定量できる。マウスに、チャンバーのインプラントの前4−6時間に開始して、1日1回、式IaもしくはIbの化合物を経口または静脈内投与し、4日間続ける。動物を最後の投与24時間後に血管組織の測定のために殺す。チャンバー周囲の血管組織の重量および血液含量を測定する。式IaもしくはIbの化合物で処置した動物は、媒体単独で処置した動物と比較して、血管組織の重量および/または血液含量の減少を示した。式IaまたはIbの化合物は、約0.3から約3mg/kgの投与量で投与したとき、抗血管形成である。
乳癌から元々単離したマウス乳癌細胞系、例えばJygMC(A)を使用する。工程前に、新鮮培地に播くために、細胞数を5×105に調節する。細胞を、2.5mMのチミジン含有、FCS非含有新鮮培地で、12時間インキュベートし、PBSで2回洗浄し、続いて10%FCS含有新鮮培地を添加し、さらに12時間インキュベートする。その後、細胞を2.5mMのチミジン含有、FCS非含有新鮮培地で12時間インキュベートする。細胞をブロックから解放するために、細胞を2回PBS洗浄し、10%FCS含有新鮮培に再び播く。同調後、細胞を種々の濃度の式IaもしくはIbの化合物の存在下または非存在下、3、6、9、12、18または24時間インキュベートする。細胞を0.2%EDTAで処理後収集し、氷冷70%エタノール溶液で固定し、250μg/mlのRNaseA(タイプ1−A:Sigma Chem. Co.)で、37℃で30分加水分解し、10mg/mlのヨウ化プロピジウムで20分染色する。インキュベーション期間の後、細胞数を、CoulterカウンターおよびSRB比色アッセイの両方で測定する。これらの条件下、式IaまたはIbの化合物は、腫瘍細胞の増殖を、10−12から10−6Mの範囲の濃度で阻害する。
Claims (12)
- 式IaおよびIb:
Aは−C(O)OR5、−OP(O)(OR5)2、−P(O)(OR5)2、−S(O)2OR5、−P(O)(R5)OR5および1H−テトラゾール−5−イルから選択され;ここで、各R5は独立してから水素およびC1−6アルキル選択され;
Wは結合、C1−3アルキレン、C2−3アルケニレンから選択され;
YはC6−10アリールおよびC2−9ヘテロアリールから選択され;ここで、Yの任意のアリールまたはヘテロアリールは、所望によりハロ、ヒドロキシ、ニトロ、C1−6アルキル、C1−6アルコキシ、ハロ−置換C1−6アルキルおよびハロ−置換C1−6アルコキシから選択される1個から3個のラジカルで置換されていてよく;
Zは:
から選択され;
R1はC6−10アリールおよびC2−9ヘテロアリールから選択され;ここで、R1の任意のアリールまたはヘテロアリールは所望によりC6−10アリールC0−4アルキル、C2−9ヘテロアリールC0−4アルキル、C3−8シクロアルキルC0−4アルキル、C3−8ヘテロシクロアルキルC0−4アルキルまたはC1−6アルキルから選択されるラジカルで置換されており;ここで、R1の任意のアリール基、ヘテロアリール基、シクロアルキル基またはヘテロシクロアルキル基は、所望によりハロ、C1−6アルキル、C1−6アルコキシ、ハロ−置換−C1−6アルキルおよびハロ−置換−C1−6アルコキシから選択される1個から5個のラジカルで置換されていてよく;そしてR1の任意のアルキル基は、所望により、−S−、−S(O)−、−S(O)2−、−NR5−および−O−から選択される原子または基で置換されたメチレンを有してよく;ここで、R5は水素またはC1−6アルキルから選択され;
R2は水素、C1−6アルキル、C2−6アルケニル、C2−6アルキニルおよびハロ置換C1−6アルキルから選択され;
R3およびR4は、独立して、水素、C1−6アルキル、ハロ、ヒドロキシ、C1−6アルコキシ、ハロ−置換C1−6アルキルおよびハロ−置換C1−6アルコキシから選択される。〕
の化合物ならびにその薬学的に許容される塩、水和物、溶媒和物、異性体およびプロドラッグ。 - R1が、所望によりC6−10アリールC0−4アルキル、C2−9ヘテロアリールC0−4アルキル、C3−8シクロアルキルC0−4アルキル、C3−8ヘテロシクロアルキルC0−4アルキルまたはC1−6アルキルで置換されているフェニル、ナフチルまたはチエニルであり;ここで、R1の任意のアリール基、ヘテロアリール基、シクロアルキル基またはヘテロシクロアルキル基は、所望によりハロ、C1−6アルキル、C1−6アルコキシ、ハロ−置換−C1−6アルキルおよびハロ−置換−C1−6アルコキシから選択される1個から5個のラジカルで置換されていてよく;そしてR1の任意のアルキル基は、所望により、−S−、−S(O)−、−S(O)2−、−NR5−および−O−から選択される原子または基で置換されたメチレンを有してよく;ここで、R5は水素またはC1−6アルキルである、請求項1記載の化合物。
- R1が:
から選択される、請求項1記載の化合物。 - Yがフェニル、ピリジニル、チエニルおよびフラニルから選択され;ここで、Yの任意のフェニル、ピリジニル、チエニルまたはフラニルは、所望により、メチル、エチル、シクロプロピル、クロロ、ブロモ、フルオロおよびメトキシから選択される1個から3個のラジカルで置換されている;またはYがフェニルであるとき、R6がYの炭素原子に結合し、3,4−ジヒドロ−1H−イソキノリン−2−イルを形成できる、請求項5記載の化合物。
- 3−{4−[1−(2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−エチル−ベンジルアミノ}−プロピオン酸、1−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−エチル−ベンジル}−アゼチジン−3−カルボン酸、3−({2−クロロ−6−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ピリジン−3−イルメチル}−アミノ)−プロピオン酸、3−({6−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−エチル−ピリジン−3−イルメチル}−アミノ)−プロピオン酸、3−{4−[1−(ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、4−{4−[1−(ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−酪酸、1−{4−[1−(ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジル}−アゼチジン−3−カルボン酸、1−{4−[1−(ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジル}−ピペリジン−3−カルボン酸、{4−[1−(ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−酢酸、3−{4−[1−(ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−シクロペンタンカルボン酸、3−{4−[1−(4'−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(5−フェニル−フラン−2−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(3'−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(3−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4'−メトキシ−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(ビフェニル−3−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−チオフェン−2−イル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−チオフェン−2−イル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4'−フルオロ−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4'−トリフルオロメトキシ−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(3'−トリフルオロメトキシ−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、1−{4−[1−(2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジル}−アゼチジン−3−カルボン酸、1−{4−[1−(2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジル}−ピロリジン−3−カルボン酸、1−{4−[1−(2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジル}−ピペリジン−3−カルボン酸、3−{4−[1−(3'−メトキシ−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、2−ヒドロキシ−3−{4−[1−(2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4'−メチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−フェニル−チオフェン−2−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、1−{4−[1−(ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジル}−ピロリジン−3−カルボン酸、3−{4−[1−(4−フラン−3−イル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−チオフェン−3−イル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−チオフェン−3−イル−2−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、2−フルオロ−3−{4−[1−(2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−酪酸、3−{4−[1−(5−フェニル−チオフェン−2−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−シクロヘキシル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(3−フルオロ−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4'−フルオロ−2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4'−メチル−2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−フラン−2−イル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(2'−フルオロ−2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−(4−{1−[4−(3,3−ジメチル−ブチル)−3−トリフルオロメチル−ベンジルオキシイミノ]−エチル}−ベンジルアミノ)−プロピオン酸、3−{4−[1−(4−フラン−3−イル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−ピリジン−3−イル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−ピリジン−4−イル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(2−フルオロ−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−({2−メトキシ−6−[1−(2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ピリジン−3−イルメチル}−アミノ)−プロピオン酸、3−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−エチル−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{2−ブロモ−4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−シクロペンチル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{2−クロロ−4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−({6−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ピリジン−3−イルメチル}−アミノ)−プロピオン酸、3−({5−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−チオフェン−2−イルメチル}−アミノ)−プロピオン酸、3−({5−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ピリジン−2−イルメチル}−アミノ)−プロピオン酸、3−({5−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−フラン−2−イルメチル}−アミノ)−プロピオン酸、3−({2−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ピリジン−4−イルメチル}−アミノ)−プロピオン酸、3−{4−[1−(4−シクロヘキシル−3−フルオロ−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{2−クロロ−4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、1−{6−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−エチル−ピリジン−3−イルメチル}−アゼチジン−3−カルボン酸、3−{2−エチル−4−[1−(4−ピペリジン−1−イル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−シクロヘキシル−3−メチル−ベンジルオキシイミノ)−エチル]−2−エチル−ベンジルアミノ}−プロピオン酸、3−{4−[1−(3−クロロ−4−シクロヘキシル−ベンジルオキシイミノ)−エチル]−2−エチル−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−シクロヘキシル−3−メトキシ−ベンジルオキシイミノ)−エチル]−2−エチル−ベンジルアミノ}−プロピオン酸、1−{4−[1−(4−シクロヘキシル−3−メトキシ−ベンジルオキシイミノ)−エチル]−2−エチル−ベンジル}−アゼチジン−3−カルボン酸、3−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−メチル−ベンジルアミノ}−プロピオン酸、1−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−メチル−ベンジル}−アゼチジン−3−カルボン酸、3−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−シクロプロピル−ベンジルアミノ}−プロピオン酸、1−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−シクロプロピル−ベンジル}−アゼチジン−3−カルボン酸、3−{2−エチル−4−[1−(2−トリフルオロメチル−ビフェニル−4−イルメトキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、1−{4−[1−(4−シクロヘキシル−3−エチル−ベンジルオキシイミノ)−エチル]−2−エチル−ベンジル}−アゼチジン−3−カルボン酸、1−{4−[1−(4−シクロヘキシル−3−メチル−ベンジルオキシイミノ)−エチル]−2−エチル−ベンジル}−アゼチジン−3−カルボン酸、1−{2−クロロ−4−[1−(4−シクロヘキシル−3−エチル−ベンジルオキシイミノ)−エチル]−ベンジル}−アゼチジン−3−カルボン酸、3−{2−クロロ−4−[1−(4−シクロヘキシル−3−エチル−ベンジルオキシイミノ)−エチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−フルオロ−ベンジルアミノ}−プロピオン酸、1−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−2−フルオロ−ベンジル}−アゼチジン−3−カルボン酸、3−{6−[1−(4−シクロヘキシル−3−トリフルオロメチル−ベンジルオキシイミノ)−エチル]−3,4−ジヒドロ−1H−イソキノリン−2−イル}−プロピオン酸、3−{6−[1−(4−シクロヘキシル−3−エチル−ベンジルオキシイミノ)−エチル]−3,4−ジヒドロ−1H−イソキノリン−2−イル}−プロピオン酸、3−{4−[1−(2−トリフルオロメチル−ビフェニル−4−イル)−エチリデンアミノオキシメチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−フェニル)−エチリデンアミノオキシメチル]−ベンジルアミノ}−プロピオン酸、3−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−フェニル)−エチリデンアミノオキシ
メチル]−2−エチル−ベンジルアミノ}−プロピオン酸、1−{4−[1−(4−シクロヘキシル−3−トリフルオロメチル−フェニル)−エチリデンアミノオキシメチル]−2−エチル−ベンジル}−アゼチジン−3−カルボン酸および1−{4−[1−(4−シクロヘキシル−3−エチル−フェニル)−エチリデンアミノオキシメチル]−2−エチル−ベンジル}−アゼチジン−3−カルボン酸から選択される、請求項6記載の化合物。 - 治療的有効量の請求項1記載の化合物を、薬学的に許容される賦形剤と共に含む、医薬組成物。
- 動物における、EDG/S1P受容体介在シグナル伝達の変更が、その疾患の病態および/または総体症状を予防、阻害または軽減できるものである疾患を処置する方法であり、動物に治療的有効量の請求項1記載の化合物を投与することを含む、方法。
- 対象における、リンパ球が介在する障害または疾患を予防または処置する、急性もしくは慢性移植拒絶反応またはT細胞介在炎症性または自己免疫性疾患を予防または処置する、無秩序な血管形成を阻害または制御する、または新規血管形成過程が介在するまたは無秩序な血管形成が関連する疾患を予防または処置する方法であり、有効量の請求項1の化合物またはその薬学的に許容される塩を投与することを含む、方法。
- 動物における、EDG/S1P受容体介在シグナル伝達の変更が、その疾患の病態および/または総体症状に関与するものである疾患の処置用医薬の製造における、請求項1記載の化合物の使用。
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Cited By (10)
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JPWO2005020882A1 (ja) * | 2003-08-29 | 2006-10-26 | 小野薬品工業株式会社 | S1p受容体結合能を有する化合物およびその医薬用途 |
JP2007523909A (ja) * | 2004-02-24 | 2007-08-23 | アイアールエム・リミテッド・ライアビリティ・カンパニー | 免疫抑制性化合物および組成物 |
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