TW200906381A

TW200906381A - Use of EDG receptor binding agents in cancer

Info

Publication number: TW200906381A
Application number: TW097139649A
Authority: TW
Inventors: Thomas Baumruker; Volker Brinkmann; Montagne Kenneth Richard La; Peter T Lassota; Diana Mechtcheriakova; Marjorie Wood Jeanette
Original assignee: Novartis Ag
Priority date: 2002-05-16
Filing date: 2003-05-15
Publication date: 2009-02-16
Also published as: KR101299873B1; KR20110094154A; PL396723A1; KR20050003460A; TW200307533A; KR20100133027A; DK1944026T3; TWI341197B; SI1944026T1; KR20130088904A; ES2428697T3; KR20120025018A; TWI340036B; PT1944026E

Abstract

Provided is a method for treating solid tumors, e. g tumor invasiveness, and particularly inhibiting or controlling deregulated angiogenesis, using a sphingosine-1-phosphate receptor agonist, optionally in combination with a chemotherapeutic agent. The invention also comprises a combination of a sphingosine-1-phosphate receptor agonist with a chemotherapeutic agent.

Description

200906381 九、發明說明：【發明所屬之技術領域】本發明係關於神經鞘胺醇磷酸（slp)受體激動劑之新穎用途’特別係用於治療癌症之用途。【先前技術】 S1P受體激動劑為加速淋巴細胞返回（LH)劑，該LH劑劑因淋巴細胞由企循環再分佈較佳可逆性再分佈之二次淋巴組織，提引出淋巴細胞減少，而未喚起全身性免疫抑制。自然細胞被隔離；來自血液的（:04及(::08 τ_細胞及B_細胞被刺激而遷移入淋巴結（LN)及貝葉氏集合淋巴結（pp)，如此例如抑制細胞滲濾至移植器官。 S1P受體激動劑典型係神經鞘胺醇類似物，例如2_經取代之2-胺基丙烷-u·二醇或2•胺基丙醇衍生物，例如包含式X基團化合物200906381 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to the novel use of sphingosine phosphate (slp) receptor agonists, particularly for the treatment of cancer. [Prior Art] The S1P receptor agonist is an accelerated lymphocyte return (LH) agent, which extracts lymphocytopenia due to a reversible redistribution of lymphocytes by a recirculating lymphocyte. Systemic immunosuppression was not evoked. Natural cells are isolated; blood (:04 and (::08 τ_ cells and B_ cells are stimulated to migrate into lymph nodes (LN) and Baye's collecting lymph nodes (pp), such as inhibiting cell percolation to transplantation An S1P receptor agonist is typically a sphingosine analog, such as a 2-substituted 2-aminopropane-u. diol or a 2-aminopropanol derivative, for example, a compound comprising a group X

Z Ο R3rR2zN-f-CH2R1z 其中 Z為Η、C丨-6院基、c2 6烯基、c2 6快基、苯基 '經以如取代之苯基·，經以丨至3個選自函原原子、CM環烷基、笨基及經以OH取代之苯基組成的組群之取代基取代之Ch烷基，或（:士-尺心基；其中Ro為〇H、醯氧基或式（a)殘基 133554.doc 200906381 其中A為直接鍵或〇’較佳為〇; R5z及各自分別為Η或選擇性地經以i、2或3個齒原子取代之。“烷基： ’Z Ο R3rR2zN-f-CH2R1z wherein Z is fluorene, C丨-6, cyclyl, c2 6 alkenyl, c2 6 fast group, phenyl 'substituted phenyl group, 经 to 3 selected from a Ch atom substituted with a substituent of a group consisting of a primary atom, a CM cycloalkyl group, a stupid group, and a group consisting of a phenyl group substituted with OH, or (: a stellate-nuclear group; wherein Ro is 〇H, a decyloxy group or Residue of formula (a) 133554.doc 200906381 wherein A is a direct bond or 〇' is preferably 〇; R5z and each are respectively oxime or optionally substituted with i, 2 or 3 tooth atoms. "Alkyl: '

Rlz為OH、醯氧基或式⑷殘基、以及&及u自分別為H、Cl.4院基或酿基β 式X基團為附著至一個部分作為端末基團之官能基，其可為親水性或親脂性，包含一或多個脂肪族、芳脂族及/ 或雜環族殘基，結果形成之分子其中乙及尺卜中之至少一者Rlz is OH, alkoxy or a residue of formula (4), and & and u are from H, Cl.4, or a group of the formula X, respectively, which is a functional group attached to a moiety as a terminal group. It may be hydrophilic or lipophilic, comprising one or more aliphatic, araliphatic and/or heterocyclic residues, resulting in a molecule of at least one of B and

為式⑷殘基或包含式⑷殘基，式\基團可於多個神經鞘胺醇-1-磷酸受體之一發訊作為激動劑。 S1P受體激動劑為化合物，該化合物於一或多個神經鞘胺醇-丨-構酸受體如sm至S1P8之一發訊作為激動劑。結合至S1P受體之激動劑例如可能導致分子内非同質三元體G 蛋白解離成為Ga-GTP及GPy-GTP，及/或增加激動劑占有之受體之磷酸化’以及下游發訊路徑/激酶之活化。sip受體激動劑之結合親和力可如後述第一段之說明測量。適當S1P受體激動劑例如為： -EP627406A1揭示之化合物，例如式I化合物 9H2〇R, r4rsn--ch2or2 1 k 其中R!為直鏈或分支（C12-22)碳鏈 -其可於鏈中有一鍵結或雜原子選自雙鍵、參鍵、〇、 S、NR6，其中R6為Η、烷基、芳烷基、醯基或烷氧羰基及羰基，及/或 133554.doc 200906381 -其可帶有烷氧基、烯氧基、炔氧基、芳烷氧基、醯基、烷基胺基、烷硫基、醯胺基、烷氧羰基、烷氧羰基胺基、醯氧基、烷基胺基甲醯基、硝基、齒原子、胺基、羥基亞胺基、羥基或羧基作為取代基；或 R1為 -苯基烧基其中烷基為直鏈或分支（C8·2^)碳鏈；或 -苯基烷基其中烷基為直鏈或分支（C1_30)碳鏈其中該苯基烷基係經以下列基團取代 -選擇性經以齒原子取代基之直鏈或分支（C62Q)碳鏈， -選擇性經以鹵原子取代基之直鏈或分支（C62Q)烷氧基鏈， -直鏈或分支（c6_2Q)烯氧基， -苯基烷氧基、鹵苯基烷氧基、苯基烷氧基烷基、苯氧基烷氧基或苯氧基烷基， -經以C6-2{)烷基取代之環烷基烷基， -經以C6-2〇烷基取代之雜芳基烷基， -雜環C6_2Q烷基或 -經以C2_2〇烷基取代之雜環烷基，以及其中該烷基部分具有 -於碳鏈，具有一個鍵結或一個雜原其係選自雙鍵、參鍵、0、S、亞磺醯基、磺醯基、或Nr6，其中r6定義如前，以及 -烷氧基、烯氧基、炔氧基、芳烷氧基、醯基、烷基胺基、烷硫基、酿胺基、烧氧羰基、烷氧羰基胺基、醯氧 133554.doc 200906381 基、烷基胺基甲醯基、硝基、鹵原子、胺基、經基亞胺基、羥基或羧基作為取代基，以及 R2、R3、R4及各自分別為Η、Ci.4;)^基或醢基 . 或其醫藥上可接受之鹽； -EP 1002792A1揭示之化合物’例如式II化合物The residue of formula (4) or the residue of formula (4) can be exemplified as an agonist at one of a plurality of sphingosine-1-phosphate receptors. The S1P receptor agonist is a compound which acts as an agonist in one or more sphingosine-丨-acid receptors such as sm to S1P8. An agonist that binds to the S1P receptor, for example, may result in dissociation of the intramolecular non-homogeneous ternary G protein into Ga-GTP and GMy-GTP, and/or increase phosphorylation of the receptor possessed by the agonist and downstream signaling pathways/ Activation of the kinase. The binding affinity of the sip acceptor agonist can be measured as described in the first paragraph below. Suitable S1P receptor agonists are, for example: - a compound disclosed by EP 627 406 A1, for example a compound of the formula I 9H2〇R, r4rsn--ch2or2 1 k wherein R! is a linear or branched (C12-22) carbon chain - which may be in the chain a bond or a hetero atom selected from the group consisting of a double bond, a hydrazone bond, a hydrazine, an S, a NR6 group, wherein R 6 is a fluorene, an alkyl group, an aralkyl group, a fluorenyl group or an alkoxycarbonyl group, and a carbonyl group, and/or 133554.doc 200906381 - May carry an alkoxy group, an alkenyloxy group, an alkynyloxy group, an aralkyloxy group, a decyl group, an alkylamino group, an alkylthio group, a decylamino group, an alkoxycarbonyl group, an alkoxycarbonylamino group, a decyloxy group, An alkylaminocarbyl group, a nitro group, a tooth atom, an amine group, a hydroxyimino group, a hydroxyl group or a carboxyl group as a substituent; or R1 is a -phenylalkyl group in which the alkyl group is a straight chain or a branch (C8·2^ a carbon chain; or a phenylalkyl group wherein the alkyl group is a linear or branched (C1_30) carbon chain wherein the phenylalkyl group is substituted with a group selected by a linear or branched substituent having a tooth atom (C62Q) carbon chain, - a linear or branched (C62Q) alkoxy chain optionally substituted with a halogen atom, - a straight or branched (c6_2Q) alkenyloxy group, a -phenylalkoxy group, a halogen Alkenyloxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, -cycloalkylalkyl substituted with C6-2{)alkyl, - via C6-2 a decyl-substituted heteroarylalkyl group, a heterocyclic C6_2Q alkyl group or a heterocycloalkyl group substituted with a C2_2 decyl group, and wherein the alkyl moiety has a - carbon chain, having a bond or a The pyrogen is selected from the group consisting of a double bond, a ginseng bond, a 0, S, a sulfinyl group, a sulfonyl group, or a Nr6 wherein r6 is as defined above, and an alkoxy group, an alkenyloxy group, an alkynyloxy group, an aralkyl group. Oxyl, fluorenyl, alkylamino, alkylthio, arylamino, alkoxycarbonyl, alkoxycarbonylamino, oxime 133,554.doc 200906381, alkylaminomethyl, nitro, halogen atom , an amine group, a transamilimino group, a hydroxyl group or a carboxyl group as a substituent, and R 2 , R 3 , R 4 and each of which are respectively an anthracene, a Ci. 4 or a sulfhydryl group; or a pharmaceutically acceptable salt thereof; Compounds disclosed by EP 1002792 A1, such as compounds of formula II

<jJH2OR'3 R-4R'5N-C-(CHz): CHjOR'j, 其中m為1至9，以及R'2、R，3、尺，4及汉，5各自分別為H、烷基或醯基，或其醫藥上可接受之鹽； -EP 0778263A1揭示之化合物，例如式化合物 (CH2)m.〇R»3<jJH2OR'3 R-4R'5N-C-(CHz): CHjOR'j, where m is 1 to 9, and R'2, R, 3, 尺, 4 and han, 5 are each H, alkane a base or a thiol group, or a pharmaceutically acceptable salt thereof; - a compound disclosed in EP 0778263 A1, for example a compound of the formula (CH2) m. 〇R»3

III 其中W為Η ’ C!.6烷基、C2 6烯基或c2 6炔基；未經取代或呈以OH取代之苯基；R"4〇(CH2)n ;或經以1至3個選自鹵原子C3·8%烷基、苯基及經以〇H取代之苯基組成的組群； X為Η或未經取代或經取代之直鏈烷基帶有碳原子數目 Ρ或帶有碳原子數為（ρ-1)之未經取代或經取代之直鏈烷氧基，例如經以1至3個選自下列基團組成的組群之取代基取代.Ck烧基、0H、Ci 6燒氧基、醯氧基、胺基、烧 133554.doc 200906381 基胺基、醯胺基、酮基、鹵c〗_6烷基、鹵原子、未經取代苯基以及經以1至3個選自C]_6烷基、OH、Cw烷氧基、醯基、醯氧基、胺基、C〗·6烧基胺基、醯胺基、_(^.6燒基及 _原子組成的組群之取代基取代之苯基；Y為Η、Cl_6烷基、OH、Ck烷氧基、醯基、醯氧基、胺基、c16烷基胺基、醯胺基、鹵C]·6烷基或鹵原子，及^單鍵或帶有碳原子數q之直鏈伸烷基， P及q各自分別為1至20之整數，但6Sp+qS23，m，為1、2 或3，η為2或3， «Λ、R"2、R"3及R”4各自分別為Η、Cw烷基或醯基，或其醫藥上可接受之鹽， -WO 02/18395揭示之化合物，例如式iVa或IVb化合物 — P =〇 I 1 f«1s (R2a)2N-|C-CH2-XjP =〇 yn2 R1b (j)H2 R,b 或 <pH2 r^il V 叫CH3丨va V Y,R4a |Vb xa為 O、S、NRls4-(CH2)na- .，該基為未經取代或經以1至4 個i原子取代；〜為1或2，Rls為Η或（Cl 4)烷基，該烷基為未經取代或經以鹵原子取代；Rla為Η、OH、（(^-4)烷基或 0(c〗-4)烷基，其中烷基為未經取代或經以1至3個鹵原子取代；Rlb為Η、OH或（(^-4)烷基，其中烷基為未經取代或經 133554.doc • 10· 200906381 以鹵原子取代；各個RSa分別係選自H或（Cl_4)烷基，該烷基為未經取代或經以鹵原子取代；R3a為Η、OH、函原子或〇(Ci_4)烷基，其中烷基為未經取代或經以鹵原子取代；以及Rn為Η、OH、鹵原子、（Cl·4)烷基，其中烷基為未經取代或經以羥基或0(Cl·4)烷基取代，其中烷基為未經取代或經以齒原子取代；Ya為-CH2-、_c(〇)_、_CH(〇H)… -C(=NOH)-、Ο或 S，以及 R4a 為（c4i4)烷基或（C4i4)烯基；或其醫藥上可接受之鹽； -WO 02/076995揭示之化合物，例如式V化合物III wherein W is Η 'C!.6 alkyl, C2 6 alkenyl or c2 6 alkynyl; unsubstituted or phenyl substituted with OH; R"4〇(CH2)n; or 1 to 3 a group selected from the group consisting of a halogen atom C3·8% alkyl group, a phenyl group and a phenyl group substituted with 〇H; X is a fluorene or unsubstituted or substituted linear alkyl group having a number of carbon atoms or a band An unsubstituted or substituted linear alkoxy group having a carbon number of (ρ-1), for example, substituted with a substituent of 1 to 3 groups selected from the group consisting of Ck alkyl, 0H , Ci 6 alkoxy group, decyloxy group, amine group, burned 133,554.doc 200906381 amide group, decylamino group, keto group, halogen group -6 alkyl group, halogen atom, unsubstituted phenyl group and 1 to 3 selected from C]-6 alkyl, OH, Cw alkoxy, decyl, decyloxy, amine, C -6 alkylamino, decyl, _(^.6 alkyl and _ atom Substituents substituted by a group of substituents; Y is hydrazine, Cl-6 alkyl, OH, Ck alkoxy, fluorenyl, decyloxy, amine, c16 alkylamino, decyl, halogen C] · 6 alkyl or halogen atom, and ^ single bond or linear alkyl group with a carbon number q, P and q are each It is not an integer from 1 to 20, but 6Sp+qS23,m, is 1, 2 or 3, η is 2 or 3. «Λ, R"2, R"3 and R"4 are each Η, Cw alkyl Or a thiol group, or a pharmaceutically acceptable salt thereof, a compound disclosed in WO 02/18395, for example a compound of the formula iVa or IVb - P = 〇I 1 f «1s (R2a) 2N-|C-CH2-XjP = 〇 Nyn2 R1b (j)H2 R,b or <pH2 r^il V is called CH3丨va VY, R4a |Vb xa is O, S, NRls4-(CH2)na-., the base is unsubstituted or 1 to 4 i atoms are substituted; ~ is 1 or 2, Rls is hydrazine or (Cl 4) alkyl, the alkyl group is unsubstituted or substituted with a halogen atom; Rla is hydrazine, OH, ((^-4) An alkyl group or a 0(c)-4)alkyl group wherein the alkyl group is unsubstituted or substituted with 1 to 3 halogen atoms; R1b is oxime, OH or ((^-4)alkyl, wherein alkyl Is unsubstituted or substituted with a halogen atom by 133554.doc • 10·200906381; each RSa is selected from H or (Cl_4) alkyl, respectively, which is unsubstituted or substituted with a halogen atom; R3a is ruthenium, An OH, a functional atom or a hydrazone (Ci_4) alkyl group, wherein the alkyl group is unsubstituted or substituted with a halogen atom; and Rn is fluorene, OH, a halogen atom, Cl. 4)alkyl, wherein the alkyl group is unsubstituted or substituted with a hydroxy group or a 0(Cl.4) alkyl group, wherein the alkyl group is unsubstituted or substituted with a tooth atom; Ya is -CH2-, _c (〇)_, _CH(〇H)... -C(=NOH)-, Ο or S, and R4a is (c4i4)alkyl or (C4i4)alkenyl; or a pharmaceutically acceptable salt thereof; -WO 02 /076995 discloses a compound, such as a compound of formula V

R 1cR 1c

R (cH2)mc-XcR?cR (cH2)mc-XcR?c

V 其中〇 «^為 1、2 或 3 ; Xc為〇或直接鍵； Rlc為Η ;選擇性地經以0H、醯基、鹵原子、丨〇環烷基、笨基或羥基-伸苯基取代之CM烷基；CM烯基；基；或選擇性經以OH取代之苯基； .P<0RSCII 〇其中Rsc為Η或選擇性經以1、2或3個鹵原子取代之Ci 4户基，以及尺^為Η或選擇性經以鹵原子取代之烧基； I33554.doc 11 200906381Wherein ^«^ is 1, 2 or 3; Xc is 〇 or a direct bond; Rlc is Η; selectively via 0H, fluorenyl, halogen, fluorenyl, phenyl or hydroxy-phenyl Substituted CM alkyl; CM alkenyl; phenyl; or phenyl substituted with OH; .P < 0RSCII 〇 where Rsc is hydrazine or selectively substituted with 1, 2 or 3 halogen atoms a base, and a crucible or a selective alkyl group substituted with a halogen atom; I33554.doc 11 200906381

Rk及Rt各自分別為Η、選擇性經以鹵原取代之c〗-4烷基、或醯基，以及Each of Rk and Rt is Η, optionally substituted with a halogen, c -7 alkyl, or fluorenyl, and

Rc為Cu-m烷基，其可於鏈中選擇性含有一個氧原子，及其選擇性經以硝基、_原子、胺基、羥基或羧基取代；或式（a)殘基Rc is a Cu-m alkyl group which may optionally contain an oxygen atom in the chain, and its selectivity is substituted with a nitro group, an atom, an amine group, a hydroxyl group or a carboxyl group; or a residue of the formula (a)

其中尺〜為Η、Cm烷基或Cm烷氧基，以及r8c為經取代之 C^-so烷醯基、苯基CN14烷基其中Ci i4烷基選擇性經以鹵原子或OH取代、環烷基c^4烷氧基或苯基Cii4烷氧基，其中該環烷基環或苯基環選擇性經以齒原子、Cw烷基及/或c〗_ 4烷氧基取代、苯基Q.h烷氧基_Cm4烷基、苯氧基匕^烷氧基或本乳基C】-】4烧基取代，Wherein the ruthenium is oxime, Cm alkyl or Cm alkoxy, and r8c is substituted C^-so alkyl fluorenyl, phenyl CN14 alkyl wherein the Ci i4 alkyl is selectively substituted with a halogen atom or OH, An alkyl c^4 alkoxy group or a phenyl Cii4 alkoxy group, wherein the cycloalkyl ring or the phenyl ring is optionally substituted with a tooth atom, a Cw alkyl group and/or a c alkoxy group, a phenyl group Qh alkoxy-Cm4 alkyl, phenoxy oxime alkoxy or the present milk group C]-] 4-alkyl group,

Rc為式（a)殘基，其中當Rlc^Ci4烷基、C26烯基或。^炔基時，R8c為烧氧基，或式VI化合物 ^4x^3x^Rc is a residue of formula (a) wherein Rlc^Ci4 alkyl, C26 alkenyl or. When alkynyl, R8c is an alkoxy group, or a compound of formula VI ^4x^3x^

R 其中〜為2、3或4R where ~ is 2, 3 or 4

Rlx為Η ;選擇性經以OH、醯基、齒原子、環烷基、苯基 133554.doc 12 200906381 或經基-伸苯基取代之Cm烷基；c2.6烯基；C2-6炔基；或選擇性經以OH取代之苯基；Rlx is Η; selective via OH, fluorenyl, dentate, cycloalkyl, phenyl 133554.doc 12 200906381 or Cm alkyl substituted by phenyl-phenyl; c2.6 alkenyl; C2-6 alkyne a base; or a phenyl group optionally substituted with OH;

Rh及Rh各自分別為Η、選擇性經以函原子或醯基取代之 C 1 -4烧基，Rh and Rh are each a C 1 -4 alkyl group which is selectively substituted with a functional atom or a thiol group,

Rsx為H、C!·4烧基或C!_4烧氧基，以及Rsx is H, C!·4 alkyl or C!_4 alkoxy, and

Rex為經以環烷基取代之Cl_2G烷醯基；環烷基（：114烷氧基，其中環烷基為選擇性經以鹵原子' Cl_4烷基及/或CN4烷氧基取代；苯基烷氧基其中該苯基環選擇性經以鹵原子、Cw烧基及/或(^_4烧氧基取代，於Rix為經以OH取代之C2·4烷基時，R0X亦為（^-"烷氧基；或當R〗x為C〗_4烷基時，r6x為戊氧基或己氧基，但當R5X為H或Rlx為曱基時，r6x非為苯基_伸丁氧基，或其醫藥上可接受之鹽； -W002/06268A1揭示之化合物，例如式νπ化合物Rex is a C 2 alkyl alkoxy group substituted by a cycloalkyl group; a cycloalkyl group (: 114 alkoxy group in which a cycloalkyl group is optionally substituted with a halogen atom 'Cl 4 alkyl group and/or a CN 4 alkoxy group; The alkoxy group wherein the phenyl ring is optionally substituted by a halogen atom, a Cw alkyl group and/or (^-4 alkoxy group, and when Rix is a C2·4 alkyl group substituted by OH, R0X is also (^-). "alkoxy; or when R x is C _4 alkyl, r6x is pentyloxy or hexyloxy, but when R5X is H or Rlx is fluorenyl, r6x is not phenyl-butoxy a compound, or a pharmaceutically acceptable salt thereof; a compound disclosed by -W002/06268A1, for example, a compound of the formula νπ

其中Rld及Rm各自分別為Η或胺基保護基； R3d為氫或羥基保護基； R4d為低碳烧基；〜為1至6之整數；Wherein Rld and Rm are each a hydrazine or an amine protecting group; R3d is a hydrogen or a hydroxy protecting group; R4d is a low carbon alkyl group; and ~ is an integer from 1 to 6;

Xd為伸乙基、伸乙烯基、伸乙炔基、具有式_d_CH2_之 133554.doc -13- 200906381 基團（其中D為羰基、-CH(OH)-、〇、s或N)、芳基或經以至多3個選自如後文定義之a組之取代基取代之芳基；Xd is an ethyl group, a vinyl group, an ethynyl group, a group of 133554.doc -13-200906381 having the formula _d_CH2_ (wherein D is a carbonyl group, -CH(OH)-, hydrazine, s or N), and aromatic Or an aryl group substituted with up to 3 substituents selected from the group a as defined hereinafter;

Yd為單鍵、Cm伸烷基、經以至多3個選自a組及b組之取代基取代之ci-ig伸炫基、於碳鏈中央或末端含有Ο或S之 C^o伸烧基、或於碳鏈中央或末端含有〇或s為經以至多3 個選自a組及b組之取代基取代之伸烷基；Yd is a single bond, a Cm alkyl group, a ci-ig extension group substituted with at most three substituents selected from the group a and the group b, and a C^o extension at the center or the end of the carbon chain. a base or a hydrazine or s at the center or the end of the carbon chain is an alkylene group substituted with up to 3 substituents selected from the group consisting of a and b;

Rsd為氫、環烷基、芳基、雜環基、經以至多3個選自a 組及b組取代基取代之環烷基、經以至多3個選自a組及b組取代基取代之芳基、或經以至多3個選自a組及b組取代基取代之雜環基；以及Rsd is hydrogen, cycloalkyl, aryl, heterocyclic, substituted with up to 3 cycloalkyl groups selected from group a and group b substituents, substituted with up to 3 substituents selected from group a and group b An aryl group, or a heterocyclic group substituted with up to three substituents selected from the group consisting of a and b;

Rm及R7d各自分別為Η或選自a組之取代基； <a組〉鹵原子、低碳炫基、鹵低碳烷基、低碳烷氧基、低碳烷硫基、羧基、低碳烷氧羰基、羥基、低碳脂肪族醯基、胺基、一-低碳烷基胺基、二-低碳烷基胺基、低碳脂肪族醯胺基、氰基或硝基； <b組 > 為環烧基、芳基、雜環基，其各自選擇性經以至多3個選自a組之取代基取代；但當Rw為氫時’ Yd為單鍵或直鏈Cm伸烷基，或其藥理上可接受之鹽或酯。 -JP-14316985(JP2002316985)揭示之化合物，例如式 νιπ 化合物：Rm and R7d are each a hydrazine or a substituent selected from the group a; <a group> a halogen atom, a lower carbonyl group, a halogen lower alkyl group, a lower alkoxy group, a lower alkyl group, a carboxyl group, and a lower group. Carboalkoxycarbonyl, hydroxy, lower carbon aliphatic fluorenyl, amine, mono-lower alkylamino, di-lower alkylamino, low carbon aliphatic decyl, cyano or nitro; <; group b> is a cycloalkyl group, an aryl group, a heterocyclic group, each of which is optionally substituted with up to three substituents selected from group a; but when Rw is hydrogen, 'Yd is a single bond or a straight chain Cm An alkyl group, or a pharmaceutically acceptable salt or ester thereof. -JP-14316985 (JP2002316985) discloses a compound, for example a compound of the formula: νιπ:

133554.doc • 14· 200906381 其中 Rle、R2e、R3e、R“、Rse、R6e、R7e、ne、父6及 γ。揭示於JP-14316985 ; 或其藥理上可接受之鹽或酯。 -WO 03/29184及WO 03/29205揭示之化合物，例如式以化合物133554.doc • 14· 200906381 wherein Rle, R2e, R3e, R“, Rse, R6e, R7e, ne, parent 6 and γ are disclosed in JP-14316985; or a pharmacologically acceptable salt or ester thereof. a compound disclosed in /29184 and WO 03/29205, for example, a compound of the formula

其中Χι為〇或S’以及Rlf、R2f、尺3{~及nf揭示於WO 03/ 29184及〇3/29205’例如2-胺基-2-[4-(3-芊氧基苯氧基）_2_ 氣苯基]丙基-1，3-丙烷-二醇或2-胺基-2-[4-(芊氧基苯硫基）_ 2 -乳笨基]丙基-1，3 -丙烧-二醇。當引述專利申請案時，化合物之相關主題併入本發明以供參照。醯基可為Ry-CO-殘基，其中心為Cl_0烷基、C3_6環烷基、本基或苯基-Cm烷基。除非另行陳述，否則烷基、烷氧基、烯基或炔基可為直鏈或分支。式I化合物中當作為R丨之碳鏈經取代時，較佳係經以卣原子、硝基、胺基、羥基或羧基取代。當碳鏈係由選擇性、左取代伸苯基岔斷時，碳鏈較佳為未經取代。當伸苯基部為呈取代時，較佳係、經齒原子、硝基、胺基、甲氧基、羥基或鲮基取代。較佳式I化合物為其中心為Cm烧基，選擇性地經以石肖 133554.doc -15- 200906381 基、鹵原子、胺基、羥基或叛基取代；更佳其中心為選擇 I·生經以鹵原子、取代之C6_M_烷基鏈取代之苯基烷基且烷基部分為選擇性經以羥基取代之CM烷基。更佳&為於苯基經以直鏈或分支且較佳為直鏈匕〜烷基鏈取代之笨基-Cw烷基。c^4烷基鏈可於鄰位、間位或對位且較佳於對位。較佳R2至R5各自為Η。較佳式I化合物為2-胺基-2-十四烷基-〗,％戊烷二醇。特佳sip受體激動劑為FTY720，亦即2_胺基_2_[2_(4_辛基笨基）乙基]丙烷-1，3-二醇呈自由態形式、或呈其醫藥上可接又之鹽形式（後文稱為化合物A) ’例如鹽酸鹽顯示如後：Wherein Χι is 〇 or S' and Rlf, R2f, 尺3{~ and nf are disclosed in WO 03/ 29184 and 〇 3/29205' such as 2-amino-2-[4-(3-decyloxyphenoxy) _2_ gas phenyl]propyl-1,3-propane-diol or 2-amino-2-[4-(decyloxyphenylthio)-2-phenyl-propyl]propyl-1,3- Propylene-diol. In connection with a patent application, the subject matter of the compounds is incorporated herein by reference. The thiol group may be a Ry-CO- residue centered on a C1-alkyl group, a C3-6 cycloalkyl group, a benzyl group or a phenyl-Cm-alkyl group. Unless otherwise stated, an alkyl, alkoxy, alkenyl or alkynyl group may be straight or branched. When the carbon chain as R is substituted in the compound of the formula I, it is preferably substituted with a ruthenium atom, a nitro group, an amine group, a hydroxyl group or a carboxyl group. When the carbon chain is cleaved by a selective, left-substituted phenyl group, the carbon chain is preferably unsubstituted. When the phenyl moiety is substituted, it is preferably substituted with a tooth atom, a nitro group, an amine group, a methoxy group, a hydroxyl group or a thiol group. Preferably, the compound of formula I has a Cm alkyl group at its center, and is optionally substituted with a diatom 133554.doc -15-200906381 group, a halogen atom, an amine group, a hydroxyl group or a thiol group; more preferably, the center is selected as the I. The phenylalkyl group substituted with a halogen atom, a substituted C6_M_alkyl chain, and the alkyl moiety is a CM alkyl group optionally substituted with a hydroxyl group. More preferably, the phenyl group is a benzyl-Cw alkyl group which is substituted by a linear or branched and preferably a linear hydrazine-alkyl chain. The c^4 alkyl chain may be in the ortho, meta or para position and preferably in the para position. Preferably, each of R2 to R5 is hydrazine. Preferred compounds of formula I are 2-amino-2-tetradecyl-, % pentanediol. The sip receptor agonist is FTY720, that is, 2-amino-2_[2_(4-octyl)ethyl]propane-1,3-diol is in a free form or is pharmaceutically acceptable The salt form (hereinafter referred to as Compound A) 'for example, the hydrochloride salt is shown as follows:

較佳式11化合物為其中R,2至R'5為Η以及m為4，亦即2-胺基-2-{2-[4-(卜_基-5_苯基戊基）苯基]乙基丨丙烷-13-二醇，呈自由態形式，或呈醫藥上可接受之鹽形式（後文稱之為化合物B)例如鹽酸鹽。較佳式III化合物為其中w為ch3，R”jR”3各自為Η，z2 為伸乙基’ X為庚氧基以及Y為Η ’亦即2-胺基-4-(4-庚氧基苯基）-2-甲基-丁醇，呈自由態形式，或呈醫藥可接受性鹽形式（後文稱之為化合物c)例如鹽酸鹽。以R_對映異構物為特佳。 133554.doc 16 200906381 較佳式IVa化合物為FTY720-磷酸鹽（4為Η , R3a為〇H，為〇 ’ Hla及Rlb為OH)。較佳式ivb化合物C-磷酸鹽（R2a為 Η，R3b為〇H，乂&為〇 ’ Ru及R lb為OH，\為〇及為庚基）。較佳式V化合物為化合物B-磷酸鹽。較佳式v化合物為磷酸一 _[(R)_2·胺基_2_甲基_4_(4_戊氧基-苯基）-丁基]酯。較佳式VIII化合物為（2R)_2-胺基-4-[3-(4-環己氧基丁基）苯并[b]嘧吩-6-基]-2-甲基丁-1-醇。 ^ ? 當式I至IX化合物分子内含有一或多個非對稱中心時，須了解本發明涵蓋多種光學異構物，以及其外消旋混合物、非對映異構物及其混合物。式ΙΠ或式IVb化合物於載有胺基之碳原子為非對稱時，較佳於此碳原子為R_組態。式I至式IX化合物之醫藥上可接受性鹽例如包括與無機酸生成之鹽如氫氣酸鹽、氫溴酸鹽及硫酸鹽；與有機酸生成之鹽如乙酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、苯甲酸鹽、檸檬酸鹽、蘋果酸鹽、曱烷磺酸鹽及笨磺酸鹽；或於適δ時，與金屬如鈉、鉀、鈣及鋁生成之鹽；與胺類如三乙基fe生成之鹽，以及與二驗基胺基酸如離胺酸生成之 ^本發明方法之化合物及鹽涵蓋水合物及溶劑合物形式。基於觀察得之活性，例如淋巴細胞之自動導向，如 EP627406A1或USP 6,〇〇4,565所述，於Slp受體激動劑利用作為免疫抑制劑’例如用於急性同質共體移植片排斥。今日發見S1P乂體激動劑具有令人感興趣之性質，因而讓其可用於癌症化學治療，特別實體腫瘤，特別惡化之實體腫 133554.doc -17- 200906381 特別用於抗癌瘤之治療。擴大實體腫瘤治療的全副武裝化合物無法造成疾病退行或穩定之病例。【發明内容】根據本發明之特殊發現，提供： .1 -種於有需要之個體治療實體腫瘤之方法，該方法包含對該個體投予治療有效量之—種包含一個式χ 基團之SIP受體激動劑或其醫藥上可接受之鹽。Preferred compounds of formula 11 are those wherein R, 2 to R'5 are oxime and m is 4, i.e., 2-amino-2-{2-[4-(bu_yl-5-phenylpentyl)phenyl The ethyl oxapropane-13-diol is in a free form or in the form of a pharmaceutically acceptable salt (hereinafter referred to as Compound B) such as a hydrochloride. Preferred compounds of formula III are those wherein w is ch3, R"jR"3 is each oxime, z2 is exoethyl 'X is heptyloxy and Y is Η', ie 2-amino-4-(4-heptyloxy) Phenylphenyl)-2-methyl-butanol, in free form, or in the form of a pharmaceutically acceptable salt (hereinafter referred to as compound c) such as the hydrochloride salt. It is particularly preferred to use the R_enantiomer. 133554.doc 16 200906381 The preferred compound of formula IVa is FTY720-phosphate (4 is ruthenium, R3a is 〇H, 〇'Hla and Rlb is OH). Preferred compound ivb is C-phosphate (R2a is ruthenium, R3b is 〇H, 乂& is ’' Ru and R lb is OH, \ is 〇 and is heptyl). The preferred compound of formula V is the compound B-phosphate. The compound of the preferred formula v is mono-[(R)_2.amino-2-methyl-4-(4-pentyloxy-phenyl)-butyl]phosphate. Preferably, the compound of formula VIII is (2R)_2-amino-4-[3-(4-cyclohexyloxybutyl)benzo[b]sulfon-6-yl]-2-methylbut-1- alcohol. When the compounds of formulae I to IX contain one or more asymmetric centers in the molecule, it is understood that the invention encompasses a wide variety of optical isomers, as well as racemic mixtures, diastereomers thereof and mixtures thereof. When the compound of formula ΙΠ or formula IVb is asymmetric with respect to the carbon atom carrying the amine group, it is preferred that the carbon atom be of the R_ configuration. The pharmaceutically acceptable salts of the compounds of the formulae I to IX include, for example, salts with inorganic acids such as hydrochlorides, hydrobromides and sulfates; and salts with organic acids such as acetates and fumarates. , maleic acid salt, benzoate salt, citrate salt, malate salt, decane sulfonate salt and sulfonate; or when formed at a suitable δ, with metals such as sodium, potassium, calcium and aluminum Salts; salts with amines such as triethyl fe, and compounds and salts of the methods of the invention formed with di-amino acids such as lysine include hydrates and solvate forms. Based on the observed activity, such as auto-directing of lymphocytes, as described in EP 627 406 A1 or USP 6, 〇〇 4, 565, the Slp receptor agonist is utilized as an immunosuppressant' for example for acute homogenous graft rejection. It is today found that S1P steroid agonists have interesting properties, which make them useful for cancer chemotherapy, especially solid tumors, especially exacerbated solid tumors. 133554.doc -17- 200906381 Especially for the treatment of anticancer tumors. A fully armed compound that expands the treatment of solid tumors does not cause cases of disease regression or stabilization. SUMMARY OF THE INVENTION In accordance with a particular finding of the present invention, there is provided: - a method of treating a solid tumor in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a SIP comprising a thiol group A receptor agonist or a pharmaceutically acceptable salt thereof.

1 一種於有需要之個體抑制實體腫瘤生長之；Γ法，該方法包含對該個體投予治療有效量之一種包含一個式X基團之S1P受體激動劑或其醫藥上可接受之鹽。 •3 一種於有需要之個體誘使腫瘤退行例如誘使腫瘤質塊縮小之方法，該方法包含對該個體投予治療有效量之種包含一個式X基團之sip受體激動劑或其醫藥上可接受之鹽。 4 一種於有需要之個體治療實體腫瘤入侵或此種腫瘤生長相關症狀之方法，該方法包含對該個體投予治療有政量之一種包含一個式X基團之Slp受體激動劑或其醫藥上可接受之鹽。 5 一種於有需要之個體預防腫瘤擴散或用於預防或抑制顯微轉之生長之方法，該方法包含對該個體投予 Μ療有效量之一種包含一個式X基團之S1P受體激動劑或其醫藥上可接受之鹽。 5 —種於有需要之個體抑制或控制失調血管新生，例如神經鞘胺醇-卜磷酸（S1P)媒介之血管新生之方 133554.doc -18 - 200906381 法，該方法包含對該個體投予治療有效量之一種包含一個式X基團之S1P受體激動劑或其醫藥上可接受之鹽。 1.7 一種於有需要之個體預防或治療新血管新生過程或血官新生失調相關疾病之方法，該方法包含對該個體投予治療有效量之一種包含一個式χ基團之sip受體激動劑或其醫藥上可接受之鹽。1 A method of inhibiting solid tumor growth in an individual in need thereof; the method comprising administering to the individual a therapeutically effective amount of an S1P receptor agonist comprising a group of formula X or a pharmaceutically acceptable salt thereof. • A method of inducing tumor regression, such as inducing tumor mass shrinkage, in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a sip receptor agonist comprising a group of formula X or a medicament thereof Acceptable salt. 4 A method for treating a solid tumor invasion or a symptom associated with such tumor growth in a subject in need thereof, the method comprising administering to the individual a therapeutic amount of a Slp receptor agonist comprising a group X group or a medicament thereof Acceptable salt. 5 A method for preventing tumor spread or for preventing or inhibiting the growth of microscopic turns in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of an S1P receptor agonist comprising a group of formula X Or a pharmaceutically acceptable salt thereof. 5 - an individual in need of inhibition or control of dysregulated angiogenesis, such as sphingosine-diphosphate (S1P) vector angiogenesis 133554.doc -18 - 200906381 method, the method comprising administering to the individual An effective amount of an S1P receptor agonist comprising a group of formula X or a pharmaceutically acceptable salt thereof. 1.7 A method for preventing or treating a neovascularization process or a disorder associated with a blood genital disorder in a subject in need thereof, the method comprising administering to the individual a therapeutically effective amount of a sip receptor agonist comprising a thiol group or Its pharmaceutically acceptable salt.

ϋ 「實體腫瘤」一詞表示淋巴癌以外之腫瘤及/或轉移（無論係位在何處），例如腦及其它中樞神經系統腫瘤（例如腦膜、腦、脊索、顱神經及中樞神經系統其它部分之腫瘤，例如神經膠母細胞瘤或髓質母細胞瘤）；頭頸癌；***腫瘤；循環系統腫瘤（例如心、縱膈及胸膜以及其它胸部器官、血管腫瘤及血管組織相關腫瘤）；#;世系統腫瘤（例如腎、腎盂、輸尿管、膀胱、其它以及非特定泌尿器官腫瘤）；胃腸道腫瘤（例如食道、胃、小腸、結腸、結W 腸、直腸乙狀結腸接合、直腸 '肛門及肛門孔道腫瘤）、涉及肝臟及肝内膽管、膽囊以其它非特定膽道部分、騰臟、其它及消化器官腫瘤）；口腔腫瘤（唇、舌、齒齦、口腔底、π顎及其它口腔部分、聪腺及其它唾腺部分^ m咽、_寶、下咽及唇、口腔及咽之其它部位）；生殖系統腫瘤（例如外陰、***、子宮頸、子宮體、宮、卵巢及其它女性生殖器官相關部位、胎盤、陰莖、: 護腺、睪丸以及其它***官相關部位腫瘤）；呼吸道腫瘤（例如鼻腔及中耳、附屬f、頭部、氣管、支氣管 133554.doc •19· 200906381一 The term “solid tumor” refers to tumors and/or metastases other than lymphoma (regardless of where the line is), such as the brain and other central nervous system tumors (eg meninges, brain, notochord, cranial nerves, and other parts of the central nervous system) Tumors, such as glioblastoma or medulloblastoma; head and neck cancer; breast tumors; circulatory tumors (eg, heart, mediastinum, and pleura, and other chest, vascular, and vascular tissue-related tumors); World system tumors (eg, kidney, renal pelvis, ureter, bladder, other, and non-specific urinary tumors); gastrointestinal tumors (eg, esophagus, stomach, small intestine, colon, knot intestine, rectosigmoid junction, rectal 'anal and anal cavity tumors) ), involving the liver and intrahepatic bile duct, gallbladder with other non-specific biliary parts, septic, other and digestive organ tumors; oral tumors (lips, tongue, gums, oral cavity, π 颚 and other oral parts, savage gland and Other salivary glands, pharyngeal, pharyngeal, hypopharyngeal and lip, oral and other parts of the pharynx; reproductive system tumors (eg vulva, Road, cervix, uterus, uterus, ovary and other female reproductive organs related parts, placenta, penis,: prostate, sputum and other male reproductive organs related tumors; respiratory tumors (such as nasal and middle ear, accessory f, Head, trachea, bronchus 133554.doc •19· 200906381

與肺臟腫瘤例如小細胞肺癌或非小細胞肺癌）；骨路系統腫瘤（例如四肢骨及關節軟骨、骨關節軟骨及其它部位腫瘤）；皮膚腫瘤（例如皮膚惡性黑素瘤、非黑素瘤皮膚癌、皮膚基底細胞癌、皮膚鱗狀細胞癌、中皮癌、卡波西氏肉瘤），以及涉及其它組織之腫瘤，包括周邊神經系統及自主神經系統、結締組織及軟組織、腹膜後及腹膜、眼部及附屬器官、曱狀腺、腎上腺及其它内分泌腺及相關結構腫瘤、繼發性非特化淋巴結惡性腫瘤、呼吸系統及消化系統及繼發性惡性腫瘤，以及其它部位之繼發性惡性腫瘤。於則文及後文述及腫瘤、腫瘤病癌瘤或癌症時另外或此外也暗示於原發器官或組織及/或於任何其它部位的轉移’而與腫瘤及/或轉移位置無關。田S1P梵體激動劑為式〗化合物如化合物A，或式I Va或 IVb化合物時，一具體實施例中該Slp受體激動劑係用於治療方法Μ、1.2、。或以供治療乳癌、攝護腺癌、膀胱癌、腎癌或肺癌以外之實體腫瘤。於系列進一步特定具體實施例或替代具體實施例中，本發明也提供 1.8 1.9 -種於有需要之個體增加化學治療劑活性或克服對化學治療劑之抗藥性之方法，包含對該個體投予治 '、有效里之S1P文體激動劑’例如包含式X基團之 ⑽受體激動劑或其醫藥上可接受之鹽，該Slp受體激動劑係與該化學治療劑同時投藥或循序投藥。才據1.8之方法，其中化學治療劑為針對宿主細胞之 133554.doc •20- 200906381 信號轉導路徑抑制劑、或涉及腫瘤形成及/或轉移形成之過程、或由腫瘤細胞利用於增生、存活、分化或發展出抗藥性之過程。 1.10前述方法，其中S1P受體激動劑係間歇投予。進步特疋具體實施例或替代例中，本發明也提供： 2.1 一種包含一個式X基團之S1P受體激動劑或其醫藥上可接受之鹽，其係用於如前文1丨至丨.4定義之任一種方法，較佳當S1P受體激動劑為式〗化合物如化合物A或式iVa或lvb化合物時，sip受體激動劑較佳係用於乳癌、攝護腺癌、膀胱癌、腎癌或肺癌以外之實體腫瘤。 2·2 一種SIP受體激動劑例如包含一個式χ基團之sip受體激動劑或其醫藥上可接受之鹽，其係用於前文1.5 至1.10或後文7定義之任一種方法。 3.1 一種包含一個式X基團之S1P受體激動劑或其醫藥上可接又之鹽，其係用製備一種醫藥組成物，該醫藥組成物供用於如前文L1至M定義之任一種方法，較佳菖S1P又體激動劑為式I化合物如化合物a或式^仏或IVb化合物時，s丨p受體激動劑較佳係用於乳癌、攝濩腺癌、膀胱癌、腎癌或肺癌以外之實體腫瘤。 3-2 一種S1P受體激動劑例如包含一個式X基團之S1P受體激動劑或其醫藥上可接受之鹽，其係用於製備供如上1.5至1.10或後文7定義之任一種方法用之醫藥組成物。 133554.doc 21 200906381 41、種用⑨如上M至!·4定義之種方法之醫藥組成=，包含包含一個式x基團之sip受體激動劑或其醫藥上可接受之鹽’連同一或多種醫藥上可接受之稀釋劑或載劑，較佳當S1P受體激動劑為式!化合物如化合物A或式IVa或IVb化合物時，sip受體激動劑較佳係用於乳癌、攝護腺癌、膀胱癌、腎癌或肺癌以外之實體腫瘤。And lung tumors such as small cell lung cancer or non-small cell lung cancer; osteopathic tumors (such as limb bone and articular cartilage, osteoarticular cartilage and other parts of the tumor); skin tumors (such as skin malignant melanoma, non-melanoma skin) Cancer, cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, mesothelioma, Kaposi's sarcoma, and tumors involving other tissues, including the peripheral nervous system and autonomic nervous system, connective tissue and soft tissue, retroperitoneum and peritoneum, Eyes and accessory organs, verrucous glands, adrenal glands and other endocrine glands and related structural tumors, secondary non-specific lymph node malignancies, respiratory and digestive system and secondary malignant tumors, and other secondary malignancies . Yu Zewen and the following description of tumors, oncological cancers or cancers also suggest that the transfer of the primary organ or tissue and/or any other site is independent of the tumor and/or metastatic location. When the S1P agonist is a compound such as Compound A, or a compound of Formula I Va or IVb, in a particular embodiment, the Slp receptor agonist is used in the treatment method Μ, 1.2. Or for the treatment of solid tumors other than breast cancer, prostate cancer, bladder cancer, kidney cancer or lung cancer. In a further specific embodiment or alternative embodiment of the series, the invention also provides a method for increasing the activity of a chemotherapeutic agent or overcoming resistance to a chemotherapeutic agent, comprising administering to the individual An effective S1P agonist', for example, a (10) receptor agonist comprising a group of formula X or a pharmaceutically acceptable salt thereof, which is administered simultaneously or sequentially with the chemotherapeutic agent. According to the method of 1.8, wherein the chemotherapeutic agent is a 133554.doc •20-200906381 signal transduction pathway inhibitor against a host cell, or a process involving tumor formation and/or metastasis formation, or is utilized by tumor cells for proliferation and survival. The process of differentiation or development of resistance. 1.10 The aforementioned method, wherein the S1P receptor agonist is administered intermittently. DETAILED DESCRIPTION OF THE INVENTION In particular embodiments or alternatives, the invention also provides: 2.1 An S1P receptor agonist comprising a group of formula X or a pharmaceutically acceptable salt thereof, as hereinbefore described. Or a sip receptor agonist is preferably used for breast cancer, prostate cancer, bladder cancer, preferably when the S1P receptor agonist is a compound such as compound A or a compound of formula iVa or lvb. A solid tumor other than kidney cancer or lung cancer. A SIP receptor agonist, for example, a sip receptor agonist comprising a hydrazine group or a pharmaceutically acceptable salt thereof, which is used in any of the methods defined in the above 1.5 to 1.10 or later. An S1P receptor agonist comprising a group of formula X or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for use in any of the methods defined in the foregoing L1 to M, Preferably, when the S1P agonist is a compound of formula I, such as compound a or a compound of formula IV or IVb, the s丨p receptor agonist is preferably used for breast cancer, salivary gland cancer, bladder cancer, kidney cancer or lung cancer. A solid tumor other than that. 3-2 An S1P receptor agonist, for example, an S1P receptor agonist comprising a group of formula X or a pharmaceutically acceptable salt thereof, for use in the preparation of any of the methods defined above in 1.5 to 1.10 or later Pharmaceutical composition used. 133554.doc 21 200906381 41, the pharmaceutical composition of the method defined by 9 above M to !·4, comprising a sip receptor agonist comprising a group of formula x or a pharmaceutically acceptable salt thereof A plurality of pharmaceutically acceptable diluents or carriers, preferably when the S1P receptor agonist is a compound of the formula: such as Compound A or a compound of Formula IVa or IVb, the sip receptor agonist is preferably used in breast cancer, prostate Solid tumors other than cancer, bladder cancer, kidney cancer or lung cancer.

4.2 一種供前述^至丨·…或後述7定義之任一種方法之醫：組成物，該組成物包含-種S1P受體激動劑，例如包含式X基團之S1P受體激動劑或其醫藥上可接受之 ^連同一或多種醫藥上可接受之稀釋劑或載劑》 5」-種醫藥組合物，包含a) 一第一劑，其為叩受體激動劑’例如包含-個式X基團之S1P受體激動劑或其醫樂上可接受之鹽，以及b)—種輔劑，其為化學治療劑例如定義如後。 5.2 一種醫藥組合物，包含定量a) -第-齊卜其為S1P受體激動劑，例如包含-個式χ基團之Slp受體激動劑或其醫藥上可接受之鹽，以及b) 一種輔劑，其為化學治療劑’其係選自如下xi)節定義之化合物俾產生協同治療效果。 6· -種如前文定義之方法，包含共同投予亦即同時或循序投予治療有效量之Slp受體激動劑，例如包含一個式X基團之S1p受體激動劑或其醫藥上可接受之鹽’以及-種第二藥物物質，該第二藥物物質為化 I33554.doc -22· 200906381 學治療劑，例如定義如後。 7. 一種於有需要之個體治療淋巴增生或骨髓增生病症之方法，例如用於治療腫瘤入侵或腫瘤生長相關症狀，該方法包含對該個體共同例如同時或循序投予 S1P受體激動劑，例如包含一個式χ基團之Sip受體激動劑或其醫藥上可接受之鹽，以及一種第二藥物物質，該第二藥物物質為化學治療劑，例如定義如後。「淋巴癌」表現血液及淋巴系統之腫瘤（例如何杰金氏病、非何杰金氏淋巴瘤、貝奇氏（Burkitt，s)淋巴瘤、愛滋病相關淋巴瘤、惡性免疫增生病、多發性骨髓瘤及惡性聚細胞瘤、肺紅自A病、急性或慢性骨髓性自血病、急性或慢性淋巴細胞性白血病、單核細胞白血病、其它特：細胞類型白血病、非特定細胞類型白血病、其它及非特定類淋巴、造血組織及相關組織之惡性腫瘤，例如彌漫性大細胞淋巴瘤、T-細胞淋巴瘤或表皮τ'細胞淋巴瘤）。骨髓癌包括急性或慢性骨髓性白血病。化學治療劑」-詞特別表示S1P受體激動劑以外的任何化學治療劑。包括（但非限制性）， i · 务香環轉化酶抑制劑， η.抗***劑、抗雄激素劑（特別用於攝護腺癌）或促性腺激素釋放因子激動劑，4.2 A medicinal composition comprising any one of the methods defined above or defined in the following 7, wherein the composition comprises an S1P receptor agonist, such as an S1P receptor agonist comprising a group of formula X or a pharmaceutical thereof An acceptable pharmaceutical or pharmaceutical composition comprising one or more pharmaceutically acceptable diluents, comprising a) a first agent which is a guanidine receptor agonist, for example comprising - a formula X A S1P receptor agonist of a group or a pharmaceutically acceptable salt thereof, and b) an adjuvant which is a chemotherapeutic agent, for example, as defined below. 5.2 A pharmaceutical composition comprising a quantitative amount of a) - sulphate as an S1P receptor agonist, for example, a Slp receptor agonist comprising a hydrazine group or a pharmaceutically acceptable salt thereof, and b) a An adjuvant, which is a chemotherapeutic agent that is selected from the group of compounds defined in section xi below, produces a synergistic therapeutic effect. 6. A method as defined above, comprising co-administering, ie simultaneously or sequentially, a therapeutically effective amount of a Slp receptor agonist, eg, a S1p receptor agonist comprising a group X group or a pharmaceutically acceptable amount thereof The salt 'and the second drug substance, the second drug substance is a therapeutic agent, for example, as defined below. 7. A method of treating a lymphoproliferative or myeloproliferative disorder in a subject in need thereof, for example for treating a tumor invasion or a tumor growth related symptom, the method comprising administering to the individual, for example, a simultaneous or sequential administration of an S1P receptor agonist, for example A Sip receptor agonist comprising a hydrazine group or a pharmaceutically acceptable salt thereof, and a second drug substance, which is a chemotherapeutic agent, for example as defined below. "Lymphoma" shows tumors of the blood and lymphatic system (eg how Jay's disease, non-Hodgkin's lymphoma, Burkitt's lymphoma, AIDS-associated lymphoma, malignant immune hyperplasia, multiple Myeloma and malignant polycytoma, lung red from A disease, acute or chronic myelogenous leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other special: cell type leukemia, non-specific cell type leukemia, other And malignant tumors of non-specific lymphoid, hematopoietic and related tissues, such as diffuse large cell lymphoma, T-cell lymphoma or epidermal tau cell lymphoma. Bone marrow cancer includes acute or chronic myelogenous leukemia. The term "chemotherapeutic agent" specifically means any chemotherapeutic agent other than the S1P receptor agonist. Including (but not limiting), i · aroma ring invertase inhibitors, η. antiestrogens, antiandrogens (especially for prostate cancer) or gonadotropin releasing factor agonists,

Hi·拓樸異構酶1抑制劑或拓樸異構酶II抑制劑， iv•微細管活化劑、燒化劑、抗腫瘤抗代謝化合物❹ 133554.doc -23 . 200906381 化合物， v.鎖定目標/降低蛋白質或脂質激肽酶活性或蛋白質或脂質鱗酸酶活性之化合物、其它抗血管新生化合物、或可誘生細胞分化過程之化合物， V1'緩激肽1受體或血管緊張肽II拮抗劑， νΠ·環氧合酶抑制劑、貳膦酸去乙醯化酶抑制劑、組織棘去乙酿化酶抑制劑、乙醯肝素酶抑制劑（防止乙酿肝素硫酸酯分解）例如PI_88，生物反應修飾劑，較佳為淋巴激素或干擾素，例如干擾素r、優必昆汀化抑制劑（ubiquitmation inhibitor)或可阻斷抗細胞凋亡路徑之抑制劑， vin. Ras腫瘤發生同質異形體抑制劑例如士尺以、κ_ Ras、或N-Ras，或法尼基轉移酶抑制劑例如l_ 744,832或 DK8G557， 1Χ·端粒酶抑制劑例如端粒酶靜止素， X.蛋白酶抑制劑、基質金屬蛋白酶抑制劑、蛋胺酸胺基肽酶抑制劑如本瓜麥（bengamide)或其衍生物，或蛋白粒（proteosome)抑制劑例如PS-341及/或 xi) mTOR抑制劑。「芳香環轉化酶抑制劑」一詞用於此處表示—種化合物其可抑制***的產生，亦即抑制酶基質雄烯二酮及睪丸固酮分別轉成雌酮及***。該詞包括（但非限制性）類固醇，特別亞特美斯坦（atamestane)、伊西美斯坦 (exemestane)及弗美斯坦（f〇rmestane)，及特別非類固醇尤 133554.doc -24- 200906381 其亞明諾路特他麥（aminoglutethimide)、羅格雷他麥 (roglethimide)、派利多路特他麥（pyridoglutethimide)、翠洛斯坦（trilostane)、特托拉同（testolactone)、奇托克諾左 (ketokonazole)、瓦羅左（vorozole)、法卓左（fadrozole)、阿納卓左（anastrozole)及雷卓左（letrozole)。伊西美斯坦例如可以出售形式亦即以商品名AROMASINtm投藥，伊西美斯坦例如可以出售形式例如以商品名LENTARONtm投藥。法卓左例如可以出售形式例如以商品名AFEMAtm投藥。阿納卓左例如可以出售形式例如以商品名ARIMIDEXtm投藥。雷卓左例如可以出售形式例如以商品名FEMARAtm或 FEMARtm投藥。亞明諾路特他麥例如可以出售形式例如以商品名ORIMETENtm投藥。包含化學治療劑其為芳香環轉化酶抑制劑之組合物特別適合用於治療激素受體陽性腫瘤例如乳癌。「抗***」一詞用於此處係有關一種可於***受體濃度拮抗***效果之化合物。該術語包括（但非限制性）塔莫西芬（tamoxifen)、富維斯創（fulvestrant)、拉洛西芬 (raloxifene)及拉洛西芬鹽酸鹽。塔莫西芬例如可以出售形式例如以商品名NOLVADEXTM投藥。拉洛西芬鹽酸鹽例如可以出售形式例如以商品名EVISTAtm投藥。富維斯創可如 US 4,659,516之揭示調配或可以出售形式例如以商品名 FASLODEXTM投藥。包含抗***劑化學治療劑之本發明組合物特別適合用於治療***受體陽性腫瘤例如乳癌。「抗雄激素劑」一詞用於此處表示任一種可抑制雄激素 133554.doc •25· 200906381 生物效應之物質，包括（但非限制性）拜卡路他麥 (bicalutamide)(CASODEXTM)，例如US 4,636,505 之揭示調配。「***釋放因子激動劑」一詞用於此處包括（但非限制性）阿布利斯（abarelix)、夠瑟林（goserelin)及夠瑟林乙酸鹽。夠瑟林揭示於US 4，100,274且例如可以出售形式例如以商品名ZOLADEXTM出售投藥。阿布利斯例如可如 US 5,843,901之揭示調配。「拓樸異構酶I抑制劑」一詞用於此處包括（但非限制性）托普堤坎（topotecan)、伊利諾堤坎（irinotecan)、9-硝基喜樹鹼及巨分子喜樹鹼軛合物PNU-166148(W099/17804之化合物A1)。伊利諾堤坎例如可以出售形式例如以商品名 CAMPTOSARtm出售投藥。托普堤坎例如可以出售形式例如以商品名HYCAMTINtm出售投藥。「拓樸異構酶II抑制劑」一詞用於此處包括（但非限制性）慈環素類（anthracyclines)例如阿黴素（doxorubicin)(包括微脂粒調配物例如CAELYXTM)、道諾汝必辛 (daunorubicin)、伊皮汝必辛（epirubicin)、依達汝必辛 (idarubicin)及尼莫汝必辛（nemorubicin)、慈S昆類米托桑村 (mitoxantrone)及艾索桑村（Iosoxantrone)，以及鬼臼毒類伊托波賽（etoposide)及添尼波赛（teniposide)。伊托波賽例如可以出售形式例如以商品名ETOPOPHOStm出售投藥。添尼波赛例如可以出售形式例如以商品名VM 26-BRISTOLtm 出售投藥。阿黴素例如可以出售形式例如以商品名 133554.doc -26- 200906381 ADRIBLASTINTMa售投藥。伊皮汝必辛例如可以出售形式例如以商品名FARMORUBICINtm出售投藥。依達汝必辛例如可以出售形式例如以商品名ZAVEDOSTM出售投藥。米托桑村例如可以出售形式例如以商品名NOVANTRON出售投藥。「微細管活化劑」表示微細管安定劑及微細管解除安定劑’包括（但非限制性）紫杉烧類例如太平洋紫杉紛 (paclitaxel)及朵西紫杉酚（docetaxel) ’長春花生物鹼類例如文布拉斯汀（vinblastine)特別文布拉斯汀硫酸鹽、文克利斯汀（vincristine)特別文克利斯汀硫酸鹽及文諾利賓 (vinorelbine)、迪可德莫來（discodermolides)及伊波西隆 (epothilones)及其衍生物例如伊波西隆B或其衍生物。太平洋紫杉酚例如可以出售形式例如以商品名TAXOLtm出售投藥。朵西紫杉酚例如可以出售形式例如以商品名 TAXOTEREtm出售投藥。文布拉斯汀例如可以出售形式例如以商品名VINBLASTIN R.P. TM出售投藥。文克利斯汀例如可以出售形式例如以商品名FARMISTIN出售投藥。迪可德莫來例如可如US 5,010,099之揭示獲得。「烷化劑」一詞用於此處包括（但非限制性）布沙芬 (busulfan)、克洛蘭布沙（chl〇rambucil)、賽洛弗法麥 (cyclophosphamide)、伊弗法麥（ifosfamide)、梅法蘭 (melphalan)或亞硝基尿素（BCNU或格利亞德（GliadelTM))。赛洛弗法麥例如可以出售形式例如以商品名cyclostintm 出售投藥。伊弗法麥例如可以出售形式例如以商品名 133554.doc -27- 200906381 HOLOXANTM出售投藥。「抗腫瘤抗代謝劑」一詞包括（但非限制性）5·氟尿嘧啶、卡佩西塔賓（capecitabine)、珍西塔賓（gemcitabine)、赛塔拉賓（cytarabine)、富路達拉賓（fludarabine)、硫鳥嘌呤、美索翠賽（methotrexate)及依達翠賽（edatrexate)。卡佩西塔賓例如可以出售形式例如以商品名XEL〇DATM出售投藥。珍西塔賓例如可以出售形式例如以商品名GEMZARtm 出售投藥。「鉑化合物」一詞用於此處包括（但非限制性）卡波普拉汀（carboplatin)、西斯普拉汀（cisplatin)、歐沙利普拉汀 (oxaliplatin)。卡波普拉汀例如可以出售形式例如以商品名 CARBOPLATtm出售投藥。歐沙利普拉汀例如可以出售形式例如以商品名ELOXATINtm出售投藥。「鎖定目標/蛋白質或脂質激酶活性之化合物或其它抗血管新生化合物」一詞用於此處包括（但非限制性）蛋白質酪胺酸激酶抑制劑及/或絲胺酸及/或蘇胺酸激酶抑制劑或脂質激酶抑制劑例如鎖定目標、降低或抑制下列各項因子之活性：受體酪胺酸激酶之表皮生長因子族群（EGFR、 ErbB2、ErbB3、ErbB2呈同質元極體或非同質二元體）、受體酪胺酸激酶之血管内皮生成因子族群（VEGFR)、血小板衍生生長因子受體（PDGFR)、纖維母細胞生長因子受體 (FGFR)、胰島素類生長因子受體1(IGF-1R)、TrK受體酪胺酸激酶族群、Axl受體酪胺酸激酶族群、Ret受體酪胺酸激酶族群、Kit/SCFR受體酪胺酸激酶、c-Abl族群成員及其基 133554.doc -28 - 200906381 因融合產物（例如BCR-Abl)、蛋白質激酶C (PKC)成員及絲胺酸/蘇胺酸激酶之Raf族群、MEK、SRC、JAK、FAK、 PDK或PI(3)激酶族群成員、或PI(3)-激酶-相關激酶族群成員、及/或環素（cyclin)-依賴型激酶族群（CDK)成員、以及具有其它活性機轉例如非關蛋白質或脂質激酶抑制活性機轉之抗血管新生化合物。鎖定目標、降低或抑制VEGFR活性化合物特別為可抑制 VEGF受體酪胺酸激酶、抑制VEGF受體或結合VEGF之化 Ο 合物、蛋白質或抗體，特別為WO 98/35958所概略及特別揭示之該等化合物、蛋白質或單株抗體，例如1-(4-氣苯胺基）-4-(4-吡啶基曱基）酞畊或其醫藥上可接受之鹽例如丁二酸鹽；揭示於WO 00/27820如N-芳基（硫基）蒽胺基酸醯胺衍生物例如2-[(4-吡啶基）曱基]胺基-N-[3-曱氧基-5-(三氟曱基）苯基]苄醯胺或2-[(1-氧化-4-吡啶基）曱基]胺基-N-[3-三氟甲基苯基]芊醯胺；或揭示於WO 00/09495、WO 00/59509、WO 98/11223、WO 00/27819及 EP 0 769 947 ;下 W 列參考文獻所述化合物：Μ· Prewett等人，癌症研究ϋ (1999) 5209-5218，F. Yuan等人，美國國家科學院議事錄93 期，14765-14770頁，1996年12月，Z. Zhu等人，癌症研究 58，1998，3209-3214，以及 J. Mordenti 等人於毒理病理學，第 27 卷，第 1期，第 14-21 頁，1999 年；WO 00/37502 及 WO 94/10202;血管靜止素（AngiostatinTM)，述於M. S· O’Reilly 等人，細胞 79，1994，315-328 ;内靜止素 (EndostatinTM)，述於 M. S. O'Reilly等人，細胞88 ’ 1997， 133554.doc -29- 200906381 277-285 ;蒽胺基酸醯胺類；ZD4190 ; ZD6474 ; SU5416 ; SU6668 ;或抗VEGF抗體或抗VEGF受體抗體例如 RuhMab 〇抗體一詞表示單株抗體、多株抗體、由至少2種完整抗體形成之多重特異性抗體、以及抗體片段，只要其具有所需生物活性即可。鎖定目標、降低或抑制表皮生長因子受體族群化合物特別為可抑制EGF受體酪胺酸激酶族群成員，例如EGF、 () ErbB2、ErbB3及ErbB4或結合至EGF或EGF相關酉己位子成員，或對ErbB及VEGF受體激酶有雙重抑制效果成員，特別為WO 97/02266概略揭示及特別揭示之該等化合物、蛋白質或單株抗體例如實施例39化合物；或揭示於EP 0 564 409、WO 99/03854、EP 0520722、EP 0 566 226、EP 0 787 722、EP 0 837 063、US 5,747,498 ' WO 98/10767、WO 97/30034、WO 97/49688、WO 97/38983 以及特別 WO 96/30347(例如稱作 CP 358774之化合物）、WO 96/33980(例〇如化合物ZD 1839)及WO 95/03283(例如化合物ZM 105180) 或 PCT/EP 02/08780 :例如蔡斯圖住梅（trastuzumab)、赫佩汀（HerpetinR)、賽圖西梅（cetuximab)、易瑞沙（Iressa)OSI-774、CI-1033、 EKB- 569、GW-2016、El.l、E2.4、E2.5、E6.2、E6.4、 E2.11、E6.3 或 E7.6.3。鎖定目標、降低或抑制PDGFR活性化合物特別為可抑制 PDGF受體化合物，例如N-苯基-2-嘧啶-胺衍生物如伊馬提 133554.doc -30- 200906381 尼（imatinib)。鎖定目標、降低或抑制c-Abl族群成員及其基因融合產物活性化合物例如N-苯基-2-嘧啶-胺衍生物例如伊馬提尼；PD180970 ; AG957 ;或 NSC 680410。鎖定目標、降低或抑制蛋白質激酶C、Raf、MEK、 SRC、JAK、FAK及PDK族群成員或PI(3)激酶或PI(3)激酶相關族群成員及/或環-依賴型激酶族群（CDK)成員活性化合物特別為EP 0 296 110揭示之該等史道羅波林〇 (staurosporine)衍生物例如米多史道林（midostaurin);其它化合物例如包括UCN-01、沙芬哥（safingol)、BAY 43-9006、布來歐坦汀（Bryostatin)l、佩利弗辛（Perifosine); U0126 ;艾莫弗辛（Ilmofosine) ; RO 3 1 8220及 RO 320432 ; G0 6976;艾西斯（Isis)3521;或 LY33353 1/LY379196。其它抗血管新生化合物為例如沙利竇邁（thalidomide) (THALOMID)及 TNP-470 ° 鎖定目標、降低或抑制蛋白質或脂質磷酸酶活性化合物〇例如為填酸酶1、填酸酶2A、PTEN或CDC25抑制劑，例如歐卡第克酸（okadaic acid)或其衍生物。可誘生細胞分化過程化合物例如為視黃酸、α T -或生育酚或a-、r-或占-生育三酚。環氧合酶抑制劑一詞用於此處包括（但非限制性）例如西樂克西（celecoxib)希樂葆（(CelebrexR))羅菲克西 (rofecoxib)(偉適（VioxxR))、伊托利克西（etoricoxib)、瓦德克西（valdecoxib)或5-炫•基-2-芳基胺基苯基乙酸例如5-曱 133554.doc -31 - 200906381 基-2-(21-氣-6，-氟苯胺基）苯基乙酸。「組織腺去乙醯化酶抑制劑」一詞用於此處包括（但非限制性）MS-27-275、SAHA、派羅沙麥（pyroxamide)、FR-901228 或瓦普洛酸（valproic acid)。「貳膦酸鹽」一詞用於此處包括（但非限制性）艾奇多尼克酸（etridonic acid)、克洛羅尼克酸（cl〇dronic acid)、提路羅尼克酸（tiludronic acid) '帕米羅尼克酸（pamidr〇nic acid)、亞蘭羅尼克酸（aien(jronic acid)、伊班羅尼克酸 (ibandronic acid)、萊斯羅尼克酸（risedr〇nic acid)及左羅尼克酸（zoledronic acid)。「艾奇多尼克酸」例如可以出售形式例如以商品名DIDRONEL出售投藥。「克洛羅尼克酸」例如可以出售形式例如以商品名B〇NEF〇S出售投藥。「提Hi·Topoisomerase 1 inhibitor or topoisomerase II inhibitor, iv•microtubule activator, burning agent, anti-tumor and anti-metabolite compound 133 133554.doc -23 . 200906381 compound, v. / compounds that reduce protein or lipid kininase activity or protein or lipid luciferase activity, other anti-angiogenic compounds, or compounds that induce cell differentiation, V1 'bradykinin 1 receptor or angiotensin II antagonism Agent, νΠ·cyclooxygenase inhibitor, phosphinic acid deacetylase inhibitor, tissue spine dehydrogenase inhibitor, heparinase inhibitor (preventing decomposition of beta-heparin sulfate) such as PI_88 , a biological response modifier, preferably a lymphokine or an interferon, such as interferon r, a ubiquitmation inhibitor or an inhibitor that blocks the anti-apoptotic pathway, vin. Ras tumor homogeneity Isoform inhibitors such as Shiji, κ_Ras, or N-Ras, or farnesyltransferase inhibitors such as l_744,832 or DK8G557, Χ telomerase inhibitors such as telomerase statin, X. protease inhibitors Matrix gold Protease inhibitors, Methionine peptidase inhibitors such as amine groups present melon wheat (, bengamide) or a derivative thereof, or protein particles (Proteosome) inhibitors such as PS-341 and / or xi) mTOR inhibitors. The term "aromatic ring-converting enzyme inhibitor" is used herein to mean a compound which inhibits the production of estrogen, i.e., inhibits the conversion of the enzymes, androstenedione and testosterone, to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, particularly atamestane, exemestane, and femstein (f〇rmestane), and particularly non-steroidal 133554.doc -24- 200906381 Aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole ), vorozole, fadrozole, anastrozole and letrozole. Isimestatin can be administered, e.g., under the trade name AROMASINtm, for example, and can be marketed, for example, under the trade name LENTARONtm. The method can be sold, for example, under the trade name AFEMAtm, for example. Anazoo can be administered, for example, under the trade name ARIMIDEXtm. Lei Zhuo Zuo can be administered, for example, under the trade name FEMARAtm or FEMARtm. The Yamano Lutta, for example, can be sold, for example, under the trade name ORIMETENtm. Compositions comprising a chemotherapeutic agent which is an aromatic cyclic converting enzyme inhibitor are particularly suitable for the treatment of hormone receptor positive tumors such as breast cancer. The term "antiestrogens" is used herein to refer to a compound that antagonizes the effects of estrogen at the estrogen receptor concentration. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen, for example, can be marketed, for example, under the trade name NOLVADEXTM. The raloxifene hydrochloride can be administered, for example, in the form as it is marketed under the trade name EVISTATM. Fuvis can be formulated, for example, as disclosed in US 4,659,516, for example, under the trade name FASLODEXTM. Compositions of the invention comprising an antiestrogen chemotherapeutic agent are particularly suitable for use in the treatment of estrogen receptor positive tumors such as breast cancer. The term "anti-androgen" is used herein to mean any substance that inhibits the biological effects of androgen 133554.doc •25· 200906381, including (but not limited to) bicalutamide (CASODEXTM), For example, the disclosure of US 4,636,505 is incorporated. The term "gonadotropin-releasing factor agonist" is used herein to include, but is not limited to, abarelix, goserelin, and sulindac acetate. Sellin is disclosed in U.S. Patent No. 4,100,274 and is, for example, available for sale, for example, under the trade name ZOLADEXTM. Ablis can be formulated, for example, as disclosed in U.S. Patent 5,843,901. The term "topoisomerase I inhibitor" is used here to include (but is not limited to) topotecan, irinotecan, 9-nitrocamptothecin, and macromolecules. The alkaloid conjugate PNU-166148 (compound A1 of WO99/17804). The Illinois can be sold, for example, under the trade name CAMPTOSARtm. Topecan, for example, can be sold, for example, under the trade name HYCAMTINtm. The term "topoisomerase II inhibitor" is used herein to include, but is not limited to, anthracyclines such as doxorubicin (including liposome formulations such as CAELYXTM), Daunol Daunorubicin, epirubicin, idarubicin and nemorubicin, mitoxantrone and Iosoxantrone ), as well as the podoviruses etoposide and teniposide. It is sold, for example, in the form sold, for example, under the trade name ETOPOPHOStm. Timibos is sold, for example, in the form sold, for example, under the trade name VM 26-BRISTOLtm. Doxorubicin, for example, can be sold, for example, under the trade name 133554.doc -26-200906381 ADRIBLASTINTMa. Epirubicin can be sold, for example, in the form of a product sold under the trade name FARMORUBICINtm. Indomethacin can be sold, for example, under the trade name ZAVEDOSTM. The Mitosan village can be sold, for example, under the trade name NOVANTRON. "Microtubule activator" means microtubule stabilizer and microtubule destabilizing agent 'including (but not limited to) taxanes such as paclitaxel and docetaxel 'vinca flower' Alkali such as vinblastine special von Brastin sulphate, vincristine special vincristine sulphate and vinorelbine, discodermolides And epothilones and derivatives thereof such as epoxil B or a derivative thereof. Pacific taxol can be sold, for example, in the form sold, for example, under the trade name TAXOLtm. Docetaxel can be sold, for example, in the form sold, for example, under the trade name TAXOTEREtm. The vebrastatin can be sold, for example, in the form as it is sold under the trade name VINBLASTIN R.P.TM. The vincentin can be sold, for example, in the form sold, for example, under the trade name FARMISTIN. Dico de Mo, for example, is available as disclosed in US 5,010,099. The term "alkylating agent" is used herein to include, but is not limited to, busulfan, chl〇rambucil, cyclophosphamide, ifosfamide. , melphalan or nitrosourea (BCNU or GliadelTM). Sylvester Fama can be sold, for example, in the form sold, for example, under the trade name cyclostintm. Ivorfam can be sold, for example, in the form sold, for example, under the trade name 133554.doc -27-200906381 HOLOXANTM. The term "anti-tumor antimetabolites" includes, but is not limited to, 5·fluorouracil, capecitabine, gemcitabine, cytarabine, fludarabine ), sulphur guanine, methotrexate and edatrexate. Capecitabine, for example, can be sold, for example, under the trade name XEL(R) DATM. Jansitabin can be sold, for example, in the form sold, for example under the trade name GEMZARtm. The term "platinum compound" is used herein to include, but is not limited to, carboplatin, cisplatin, oxaliplatin. Captopril is sold, for example, in the form sold, for example, under the trade name CARBOPLATtm. Oxaliplatin can be sold, for example, in the form as sold under the trade name ELOXATINtm. The term "locking target/protein or lipid kinase active compound or other anti-angiogenic compound" is used herein to include, but is not limited to, a protein tyrosine kinase inhibitor and/or a serine and/or a sulphonic acid. A kinase inhibitor or a lipid kinase inhibitor, for example, targets a target, reduces or inhibits the activity of the following factors: the epidermal growth factor population of the receptor tyrosine kinase (EGFR, ErbB2, ErbB3, ErbB2 is a homopolar or non-homogenous VEGF, vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), insulin-like growth factor receptor 1 (IGF) -1R), TrK receptor tyrosine kinase group, Axl receptor tyrosine kinase group, Ret receptor tyrosine kinase group, Kit/SCFR receptor tyrosine kinase, c-Abl group member and its group 133554 .doc -28 - 200906381 Due to fusion products (eg BCR-Abl), protein kinase C (PKC) members and the Raf group of serine/threonine kinase, MEK, SRC, JAK, FAK, PDK or PI(3) Kinase family members, or PI(3)-excited - related kinase group member, and / or prostacyclin (of cyclin) - dependent kinases groups (the CDK) member, and a transfer unit, for example, further active non-critical protein or lipid kinase inhibitory activity of the anti-angiogenic machine revolutions compound. Targeting, reducing or inhibiting VEGFR-active compounds are, in particular, compounds, proteins or antibodies which inhibit VEGF receptor tyrosine kinase, VEGF receptor or VEGF binding, in particular as outlined and specifically disclosed in WO 98/35958. Such compounds, proteins or monoclonal antibodies, such as 1-(4-anilino)-4-(4-pyridylfluorenyl) hydrazine or a pharmaceutically acceptable salt thereof, such as succinate; disclosed in WO 00/27820 such as N-aryl(thio)guanidinium amide derivatives such as 2-[(4-pyridyl)indenyl]amino-N-[3-decyloxy-5-(trifluoro) Mercapto)phenyl]benzamide or 2-[(1-oxo-4-pyridyl)indolyl]amino-N-[3-trifluoromethylphenyl]decylamine; or disclosed in WO 00 /09495, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; compounds described in the following W column references: Μ Prewett et al., Cancer Research ϋ (1999) 5209-5218, F. Yuan et al., Proceedings of the National Academy of Sciences, 93, 14765-14770, December 1996, Z. Zhu et al., Cancer Research 58, 1998, 3209-3214, and J. Mordenti et al. in Toxicology and Pathology, Volume 27, Issue 1, Issue 14 -21 pages, 1999; WO 00/37502 and WO 94/10202; AngiostatinTM, described in M. S. O'Reilly et al, Cell 79, 1994, 315-328; EndostatinTM ), described in MS O'Reilly et al, Cell 88 '1997, 133554.doc -29- 200906381 277-285; amidoxime; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF antibody or anti-VEGF The term "receptor antibody" such as the RuhMab(R) antibody means a monoclonal antibody, a plurality of antibodies, a multiplex specific antibody formed of at least two intact antibodies, and an antibody fragment as long as it has a desired biological activity. Targeting, reducing or inhibiting epidermal growth factor receptor population compounds, particularly members of the EGF receptor tyrosine kinase family, such as EGF, () ErbB2, ErbB3, and ErbB4, or binding to EGF or EGF-related 酉-self-members, or Members having dual inhibitory effects on ErbB and VEGF receptor kinases, particularly those compounds, proteins or monoclonal antibodies, such as the compound of Example 39, as disclosed and specifically disclosed in WO 97/02266; or as disclosed in EP 0 564 409, WO 99 /03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, US 5,747, 498 'WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and special WO 96/30347 ( For example, a compound called CP 358774), WO 96/33980 (for example, compound ZD 1839), and WO 95/03283 (for example, compound ZM 105180) or PCT/EP 02/08780: for example, trasuzumab, HerpetinR, cetuximab, Iressa OSI-774, CI-1033, EKB-569, GW-2016, El.l, E2.4, E2.5, E6 .2, E6.4, E2.11, E6.3 or E7.6.3. Targeting, reducing or inhibiting PDGFR-active compounds is particularly useful for inhibiting PDGF receptor compounds, such as N-phenyl-2-pyrimidine-amine derivatives such as Imati 133554.doc -30-200906381 imatinib. Targeting, reducing or inhibiting c-Abl population members and their gene fusion product active compounds such as N-phenyl-2-pyrimidine-amine derivatives such as imatinib; PD180970; AG957; or NSC 680410. Targeting, reducing or inhibiting protein kinase C, Raf, MEK, SRC, JAK, FAK, and PDK population members or PI(3) kinase or PI(3) kinase-associated population members and/or cyclo-dependent kinase population (CDK) The member active compounds are, in particular, the stourosporine derivatives such as midostaurin disclosed in EP 0 296 110; other compounds including, for example, UCN-01, safingol, BAY 43- 9006, Bryostatin l, Perifosine; U0126; Ilmofosine; RO 3 1 8220 and RO 320432; G0 6976; Isis 3521; LY33353 1/LY379196. Other anti-angiogenic compounds are, for example, thalidomide (THALOMID) and TNP-470 ° targeting targets, reducing or inhibiting protein or lipid phosphatase activity compounds such as ligase 1, antase 2A, PTEN or A CDC25 inhibitor, such as okadaic acid or a derivative thereof. Compounds which can induce cell differentiation processes are, for example, retinoic acid, α T - or tocopherol or a-, r- or octa-tocotrienol. The term cyclooxygenase inhibitor is used herein to include, but is not limited to, for example, celecoxib (CelebrexR) rofecoxib (VioxxR), Iraq. Etoricoxib, valdecoxib or 5-decyl-2-arylaminophenylacetic acid such as 5-indole 133554.doc -31 - 200906381 -2- (21-gas- 6,-fluoroanilino)phenylacetic acid. The term "tissue gland deacetylase inhibitor" is used herein to include, but is not limited to, MS-27-275, SAHA, pyroxamide, FR-901228 or valproic. Acid). The term "phosphonium phosphonate" is used herein to include, but is not limited to, etridonic acid, cl〇dronic acid, tiludronic acid. 'Pamidr〇nic acid, aaron (jronic acid), ibandronic acid, risedr〇nic acid and 左罗尼克"zoledronic acid", for example, can be sold, for example, under the trade name DIDRONEL. "Clononic acid" can be sold, for example, under the trade name B〇NEF〇S.

可以出售形式例如以商品名B〇NDRANAT出售Available for sale, for example under the trade name B〇NDRANAT

口服生物可利用 133554.doc ^抑制劑巴提馬斯塔類似物馬利馬斯塔 -32- 200906381 (marimastat)、普諾馬斯塔（prinomastat)、BMS-279251、 BAY 12-9566、TAA211 或 AAJ996。「mTOR抑制劑」一詞用於此處包括（但非限制性）拉帕黴素（rapamycin)(西羅利馬（sirolimus))或其衍生物。拉帕黴素為吸濕鏈絲菌（Streptomyces hygroscopicus)製造之已知巨環類抗生素。適當拉帕徽素衍生物包括式A化合物Oral bioavailable 133,554.doc ^Inhibitors Batimasta analogues Malimasta-32-200906381 (marimastat), prinomastat, BMS-279251, BAY 12-9566, TAA211 or AAJ996. The term "mTOR inhibitor" is used herein to include, but is not limited to, rapamycin (sirolimus) or a derivative thereof. Lappamycin is a known macrocyclic antibiotic produced by Streptomyces hygroscopicus. Appropriate Lappain derivatives include compounds of formula A

A 其中A of which

Rlaa為CH3或C3-6炔基，尺2以為H或-CH2-CH2-OH、3-經基-2-(經基甲基）-2-曱基丙酸基或四σ坐基，以及Rlaa is a CH3 or C3-6 alkynyl group, and the rule 2 is H or -CH2-CH2-OH, 3-yl-2-(ylmethyl)-2-mercaptopropanoate or a tetrasigma group, and

Xaa為=〇、（Η,Η)或（Η，ΟΗ) 但當乂3£1為=0以及Rlaa為CH3時’ R~2aa非為Η’ 或當R2aa為-CH2-CH2-OH時為其前驅藥，例如其生理上可水解鍵。式 A 化合物揭示於 WO 94/09010、WO 95/16691、WO 96/41807、USP 5，3 62,71 8 或 WO 99/15 530，各案以引用方式併入此處。可如該等參考文獻揭示製備或以類似方式製 133554.doc -33- 200906381 備較佳拉帕黴素衍生物為32-去酮基拉帕黴素、16-戊-2-炔基氧基-32-去酮基拉帕黴素、16-戊-2-炔基氧基-32(S)-二氫-拉帕黴素、16-戊-2·炔基氧基-32(S)-二氫-40-0-(2-羥基乙基）·拉帕黴素’及更佳40-0-(2-羥基乙基）-拉帕黴素。拉帕黴素衍生物之其它範例包括CCI779或40-[3-羥基-2-(經基甲基）-2-甲基丙酸]-拉帕黴素或其醫藥上可接受之鹽揭示於USP 5,362,718、ABT578或4〇-(四唑基）-拉帕黴素，特別 40-表-(四唑基拉帕黴素例如揭示於w〇 99/1553〇或拉帕徽素類似物（rapal〇gS)揭示’例如W〇 98/02441及WO 01/14387，例如 AP23573。各例中’引用專利範圍申請案或科學公開文獻時，該化合物之相關主題係以引用方式併入此處。同樣包含其醫藥上可接文之鹽、對應外消旋混合物、非對映異構物、對映異構物、互變異構物以及前文揭示化合物之對應晶體修改 (若存在）例如溶劑合物、水合物及多形性化合物，揭示於此處。可用於本發明組合物作為活性成分之化合物分別可以引述之參考文獻製備及投予。於本發明範圍内包含前述多於兩種分開活性成分的組合，亦即本發明範圍内之醫藥組合物包括三種或三種以上活性成分。此外，第一劑及輔劑並非完全相同成分。 S1P激動劑亦即包含式x基團之Slp激動劑用於治療前文斤述實體腫瘤之用’可於動物試驗方法以及於臨床試驗獲得驗證’例如試驗方法說明如後。 133554.doc -34- 200906381 【實施方式】 A.試官試驗 A.1抗腫瘤活性使用原先由乳癌分離之小鼠乳癌細胞系例如JygMC(A)。試驗程序之前，細胞數目調整為5x1 〇5供接種於新鮮培養基。細胞與含2.5 mM胸腺苷不含FCS之新鮮培養基共同培養12小時，然後以PBS洗兩次，接著加入帶有1 〇% FCS之新鮮培養基及又培養12小時。隨後細胞與含2.5 mM胸腺铝但不含F C S之新鮮培養基共同培養12小時。為了由塊狀物中釋放出細胞’細胞以PBS洗兩次，重新接種於含1〇% FCS之新鮮培養基。調整為同步之後，細胞含或未含不等浪度式I化合物共同培養3、6、9、12、18或24小時。使用 0.2。/。EDTA處理後收穫細胞，使用冰冷7〇%乙醇溶液固疋’於37 C使用250微克/毫升RNaseA(l-A型：Sigma化學公司）水解30分鐘，以及使用普皮定碘（pr〇pidium i〇dide)1〇毫克/毫升染色20分鐘。培養期之後，以庫特（c〇uher)計數器計算細胞以及藉SRB比色檢定分析測定細胞數目。此等情況下，生成S1P激動劑亦即鹽酸鹽形式化合物B，可於 10·12至1 ο·6μ之濃度抑制腫瘤細胞增生。 A.2 S1P媒介HUVEC管生成檢定分析用於管生成檢定分析，使用得自第2_8代繼代培養之 HUVEC，但收穫前之融合程度未大於7〇%。準備供檢定分析用之細胞係使用哈佩斯（Herpes)平衡食鹽水溶液出0^得自科隆内提（ci_tics)公司），然後使用月夷蛋白酶/edta 133554.doc •35· 200906381 (0.25毫克/毫升’得自科隆内提公司)進行胰蛋白酶消化分解。約90%細胞由孔板上剝離後，加入等量容積騰蛋白酶中和溶液（TNS得自科隆内提公司），細胞收集於錐形瓶，錐形瓶含有至少10毫升EBM_2(科隆内提公司）+〇1% BSA(西格瑪公司）培養基。細胞於1000 rpm離心5分鐘，去除上清液，以各5毫升ΕΒΜ·2 + 〇1% BSA替代。細胞使用 ▲球计數器sf算數目，細胞懸浮液容積調整而達到濃度 500,000細胞/毫升。錐形瓶係以1〇〇 nM試驗化合物以各⑺ 奈克/毫升百日咳毒素（PTx)準備，然後各試管内各加入复毫升細胞懸浮液。試管於37。(：，5%二氧化碳培養半小時。使用塗覆以纖維蛋白膠之富洛布拉克（Flu〇r〇_B1〇k)24_多孔插入孔板（8微米孔大小’菲肯（Faic〇n)#351 147)，替代孔孔板個別***進行遷移檢定分析。如前文說明準備前前培養細胞及試驗化合物’然後將1〇〇微升加至***孔板之適當孔内。300微升EBM-2 + 2%木炭汽提培養基不含Slp，添加至標示為無刺激㈠之孔底，300微升含S1P (500 nM)培養基添加至標示為刺激（+)孔底。孔板於37。(：，5%二氧化碳典養4小時。卡爾辛（Calcein)AM，50微克/小瓶（分子探針公司 #C3100)經由添加20微升DMSO至小瓶内準備。然後125毫升HBSS(每個孔板）溫熱至37°C，添加150微升至小瓶。然後小瓶内容物移回至剩餘HBSS，讓終濃度變成4微克/毫升卡爾辛AM。富洛布拉克孔板由孵育器中取出，分離頂***孔板， 133554.doc •36· 200906381 幸二輕拍打」去除黏在***件上的過量育培養。然後*** 板移至新鮮24孔孔板，孔板含有500微升/孔之4微克/毫升卡爾辛AM。然後孔板於37〇c，5%二氧化碳培育i 1/2小時。培養後’孔板於赛托弗洛（Cyt〇fluor)n以485奈米激光以及530奈米發光讀取。***件上的富洛布拉克塗層只允許細胞遷移至計數的底部。資料移至Excel計算，使用 SigmaPlot作出線圖，使用sigmaStat進行顯著性試驗^試驗 (圖 7)。管之形成係以4倍放大於3個分開野計算分支點數目（兩個個別索相連）定量。結果報告如後：處理組分支點 PBS 8±5 S1P 42±13 FTY720磷酸鹽 48±15 FTY720填酸鹽 +S1P 14±7 化合物C磷酸鹽 44±16 化合物C填酸鹽+S1P 18±6 結果證實FTY720-填酸鹽或化合物C麟酸鹽具有作為金管新生激動劑之獨特活性，但出乎意外地可作為S1P媒介血管新生拮抗劑。化合物C磷酸鹽較佳為外消旋混合物或R_ 對映異構物。PTx用作為抑制Gi a (EDG-1)媒介活性之對照組。 B.活體試驗 133554.doc -37- 200906381 B.1抗腫瘤活性抗腫瘤活性係以T/C%(處理組動物腫瘤容積除了對照組動物腫瘤容積乘以1 00之平均增加）表示。一份癌細胞（1X107)例如人類A375黑素瘤細胞移植至 BALB/c-mi/nu小鼠。腫瘤大小達到約1〇xl〇毫米時，動物任意分成四小組，開始接受式〗化合物處理。經2周處理後犧牲動物，此時收穫腫瘤及組織，且準備進行形態學分析及分子分析。腫瘤大小係以卡規測定。此種檢定分析中， S1P激動劑例如化合物B或c(磷酸鹽形式），當以〇5至5毫克/千克投藥時，相對於鹽水對照組可減慢腫瘤生長：例如化合物C-鹽酸鹽以2.5毫克/千克每周5次劑量投藥，結果獲得終T/C值30%。 B.2與VEGF-R蛋白質路胺酸激酶抑制劑組合移植人類MDA-MB-43 5***腫瘤之裸鼠使用VEGF_R蛋白質酪胺酸激酶抑制劑處理2周，例如丨^私氣苯胺基吡啶基甲基）酞畊丁二酸鹽使用劑量1〇〇毫克/千克每周口服 5次、S1P焚體激動劑例如化合物c(鹽酸鹽）使用劑量2 5毫克/千克靜脈注射每周5次或其組合。抗腫瘤功效係以前文指示之T/C%表示。化合物c鹽酸鹽與丨^‘氣苯胺基㈠_ 吡啶基曱基）酞畊丁二酸鹽比單獨個別藥劑之抗腫瘤效果較高（丁/(：〇/。27)(化合物C鹽酸鹽T/c 66% ;卜⑷氣苯胺基卜心 (4-吡啶基甲基）酞呼丁二酸鹽，T/c% 91)。當裸類A375黑素瘤細胞且以類似方式使用相同組合處理時，也獲付良好抗腫瘤反應：組合治療獲得T/c%丨5，個別藥劑 133554.doc -38- 200906381 單獨治療獲得T/C% 35及44。 B. 3抗腫瘤新生活性多孔腔室含有⑴神經鞘胺醇-1-磷酸鹽（5μΜ/室）或（Π)人 VEGF(1微克/室）於〇.5毫升0.8% w/v瓊脂（含有肝素，20單位/毫升），皮下移植入小鼠脅腹。S1P或VEGF誘使血管床組織環繞多孔室周圍生長。此項反應係與劑量有關，可經由組織稱重以及測定組織血液含量定量。小鼠每日一次接受⑴口服化合物Α(0·3、3、30或50毫克/千克）或（ii)靜脈注 D 射化合物C R對映異構物（2.5毫克/千克）或（iii)靜脈注射化合物C S對映異構物（2.5毫克/千克）或（iv) 口服或靜脈注射媒液（5 %葡萄糖，1〇毫克/千克）處理，處理係始於多孔腔室移植前4-6小時且持續4曰。最末劑量投藥後24小時，犧牲小鼠測定形成金管床化組織。環繞多孔腔室之血管床化組織重量及血液含量經測定。使用化合物A或化合物c R或 S對映異構物處理動物顯示血管床化組織重量及/或血液含量比單獨接受媒液處理動物少。 ^ C ·臨床試驗 C. l S1P受體激動劑如式I、Π4ΠΙ化合物如化合物A、B或 C之研究 2〇位患有進行中惡化階段實體腫瘤，且對標準治療有抗藥性或頌固病人接受劑量遞增研究測定之化合物劑量。每周以理學檢查及實驗室檢查調查病人之一般性臨床狀況。腫瘤及腫瘤轉變負擔之改變每2個月接受放射線檢查一次。最初病人接受處理2個月。隨後只要疾病不會進行且 133554.doc •39- 200906381 藥物之耐受性良好則繼續接受處理。主要評估變數：安全性（不良反應）、標準a清生化學及液子方面藉電腦斷層掃描（CT scan)或磁振造影（MRI) 算出腫瘤大小。 C-2組合治療適田臨床研九例如為患有惡化實體腫瘤之開放標蕺非隨機分組劑量遞增研究。此種研究特別證實本發明組合之各 #性成分之協同增效效果。詩增生性錢的有利效果可 (/ 4過研究結果直接決定，或經由如業界人士已知改變實驗設計決定。此等研究特別適合比較使用活性成分及使用本發月'且口之冶療效果。較佳藥劑⑷劑量遞增至達到最大耐受劑量，辅劑（b)劑量係以固定劑量投藥。另外，藥劑 ⑷以固疋劑！投藥，輔劑⑼劑量遞增。病人係每日或間歇接受藥劑⑷劑量。處理功效係於12、18或24周後以每6 周藉放射攝影評估腫瘤測定。 U 另外，安慰劑對照組雙盲研究可用來證實前述本發明組合物效果。 :獨使用S1P受體激動劑時，實施本發明方法所需每日 W夏例如係依據使用之化合物、宿主、投藥模式及接受治，之病潰嚴重程度決定。較佳每日劑量為G.1至1GG毫克以 “劑或平分多劑投藥。病人之適當每曰劑量約為口服例如、0毫克，S1P受體激動劑可藉任何習知途徑投藥，特別腸道例如口服投藥，例如呈錠劑、膠囊劑、飲用溶液劑，鼻内或肺臟（藉吸入）投藥或腸道外投藥，例如呈注 133554.doc -40· 200906381 射溶液劑或懸浮液劑劑型。口服投藥用適當單位劑型包入 _至30毫克，通常為0.25至3()毫克㈣受體激_ = -或多種醫藥上可接受之稀釋劑或载劑。為了抑制血管新生’重要地係選擇夠高劑量之Slp受體激動冑，原因在於低濃度slp受體激動劑或促進血管新生。sip激動劑投予病人時’提供抗血管新生效果之適當劑量可藉前文A、叹。所述遭度遞增及劑量遞增研究而選用。Xaa is =〇, (Η,Η) or (Η,ΟΗ) but when 乂3£1 is =0 and Rlaa is CH3, 'R~2aa is not Η' or when R2aa is -CH2-CH2-OH Its prodrug, such as its physiologically hydrolyzable bond. Compounds of formula A are disclosed in WO 94/09010, WO 95/16691, WO 96/41807, USP 5, 3 62, 71 8 or WO 99/15 530, each of which is incorporated herein by reference. It can be prepared as described in these references or in a similar manner. 133554.doc -33- 200906381 The preferred rapamycin derivative is 32-deketyl rapamycin, 16-pent-2-ynyloxy -32-deketyl rapamycin, 16-pent-2-ynyloxy-32(S)-dihydro-lapamycin, 16-pent-2-alkynyloxy-32(S) - Dihydro-40-0-(2-hydroxyethyl)-rapamycin' and more preferably 40-0-(2-hydroxyethyl)-rapamycin. Other examples of rapamycin derivatives include CCI779 or 40-[3-hydroxy-2-(transmethylmethyl)-2-methylpropionic acid]-rapamycin or a pharmaceutically acceptable salt thereof disclosed in USP 5, 362, 718, ABT 578 or 4 〇-(tetrazolyl)-rapamycin, in particular 40-epi-(tetrazolyl rapamycin, for example as disclosed in w〇99/1553〇 or rapain analog (rapal) 〇gS) discloses 'for example, W〇98/02441 and WO 01/14387, for example AP23573. In the case of 'citing patent application or scientific publication in each case, the relevant subject matter of the compound is incorporated herein by reference. Including pharmaceutically acceptable salts thereof, corresponding racemic mixtures, diastereomers, enantiomers, tautomers, and corresponding crystal modifications (if present) of the compounds disclosed herein, for example, solvates, Hydrates and polymorphic compounds are disclosed herein. Compounds useful as active ingredients in the compositions of the present invention can be prepared and administered separately from the cited references, and include more than two separate active ingredients as described above within the scope of the present invention. Combination, that is, a pharmaceutical composition package within the scope of the present invention Three or more active ingredients. In addition, the first agent and the adjuvant are not identical components. The S1P agonist, that is, the Slp agonist comprising the group of formula x, is used for the treatment of solid tumors before use. And obtained in clinical trials, for example, the test method is described later. 133554.doc -34- 200906381 [Embodiment] A. Tester test A.1 Antitumor activity A mouse breast cancer cell line originally isolated from breast cancer such as JygMC ( A). Before the test procedure, the number of cells was adjusted to 5x1 〇5 for inoculation in fresh medium. The cells were co-cultured with fresh medium containing 2.5 mM thymidine without FCS for 12 hours, then washed twice with PBS, followed by 1 with新鲜% FCS fresh medium and cultured for another 12 hours. The cells were then incubated with fresh medium containing 2.5 mM thymine aluminum but no FCS for 12 hours. In order to release the cells from the lumps, the cells were washed twice with PBS. The cells were inoculated with fresh medium containing 1% FCS. After adjustment to synchronization, the cells were co-cultured with or without unequal duration of the compound of formula I for 3, 6, 9, 12, 18 or 24 hours. After treatment with 0.2% EDTA, the cells were harvested, and lyophilized with ice-cold 7〇% ethanol solution at 37 C using 250 μg/ml RNaseA (type 1A: Sigma Chemical Co.) for 30 minutes, and using pupiidine iodine (pr 〇pidium i〇dide) stained for 1 min in milligrams/ml for 20 minutes. After the incubation period, the cells were counted in a c〇uher counter and the number of cells was determined by SRB colorimetric assay. In these cases, an S1P agonist was produced. That is, the compound B in the form of a hydrochloride can inhibit tumor cell proliferation at a concentration of 10.12 to 1 ο·6 μ. A.2 S1P medium HUVEC tube generation assay analysis For tube generation assay analysis, HUVEC was obtained from the 2nd to 8th generation subculture, but the degree of fusion before harvest was not more than 7〇%. Prepare the cell line for assay analysis using a Herpes balanced aqueous solution of salt to obtain 0^ from Cologne (ci_tics), then use Heliconase/edta 133554.doc •35· 200906381 (0.25 mg/ml 'From Cologne's company) for trypsin digestion. After about 90% of the cells were stripped from the well plate, an equal volume of transcriptase neutralization solution (TNS from Cologne) was added and the cells were collected in conical flasks containing at least 10 ml of EBM_2 (Cologne) ) + 〇 1% BSA (Sigma) medium. The cells were centrifuged at 1000 rpm for 5 minutes, and the supernatant was removed and replaced with 5 ml of each of ΕΒΜ·2 + 〇1% BSA. The cells were counted using the ▲ ball counter sf, and the cell suspension volume was adjusted to reach a concentration of 500,000 cells/ml. The Erlenmeyer flask was prepared with 1 〇〇 nM test compound in each (7) Ng/ml pertussis toxin (PTx), and then each milliliter of cell suspension was added to each tube. The test tube is at 37. (:, 5% carbon dioxide was incubated for half an hour. Use a fibrin glue-coated Frobrak (Flu〇r〇_B1〇k) 24_ porous insert plate (8 micron pore size 'Facon (Faic〇n ) #351 147), replace the wells with individual inserts for migration assay analysis. As described above, pre-pre-pre-culture cells and test compounds' then add 1 μL of microliters to the appropriate wells of the insert well. 300 μl EBM -2 + 2% charcoal stripping medium does not contain Slp, added to the bottom of the well labeled as non-irritating (a), and 300 microliters of medium containing S1P (500 nM) is added to the bottom of the well indicated stimulus (+). (:, 5% carbon dioxide for 4 hours. Calcein AM, 50 μg/vial (Molecular Probes Inc. #C3100) was prepared by adding 20 μl of DMSO to the vial. Then 125 ml of HBSS (each well plate) Warm to 37 ° C and add 150 μl to the vial. The contents of the vial are then transferred back to the remaining HBSS and the final concentration is changed to 4 μg/ml Carlsin AM. The Frobrak well plate is removed from the incubator and separated. Top inserting orifice plate, 133554.doc •36· 200906381 Fortunately, two tapping to remove the sticky insert Excessive culture on the plate. The insert was then transferred to a fresh 24-well plate containing 500 μl/well of 4 μg/ml Carlsin AM. The plate was then incubated at 37 ° C, 5% CO 2 i 1/2 Hours. After incubation, the well plates were read on a Cyt〇fluor n with a 485 nm laser and 530 nm luminescence. The Flobrak coating on the insert allowed only cells to migrate to the bottom of the count. The data was transferred to Excel calculation, the line graph was made using SigmaPlot, and the significance test was performed using sigmaStat (Fig. 7). The tube formation was calculated by 4 times magnification in 3 separate fields to calculate the number of branch points (two individual cables connected) The results are reported as follows: Treatment group branch point PBS 8±5 S1P 42±13 FTY720 phosphate 48±15 FTY720 sate + S1P 14±7 Compound C phosphate 44±16 Compound C sate + S1P 18±6 The results confirmed that FTY720-Late or Compound C-Caltate has unique activity as a neonatal agonist of gold tube, but unexpectedly acts as an S1P vector angiogenesis antagonist. Compound C phosphate is preferably a racemic mixture or R_ Enantiomers. PTx is used as a suppression Gi a (EDG-1) vector activity control group B. In vivo test 133554.doc -37- 200906381 B.1 Antitumor activity Antitumor activity is T/C% (treatment group animal tumor volume except control animal tumor The volume is multiplied by an average increase of 100.) A cancer cell (1X107) such as human A375 melanoma cells is transplanted into BALB/c-mi/nu mice. When the tumor size reached about 1〇xl〇mm, the animals were arbitrarily divided into four groups and began to receive compound treatment. The animals were sacrificed after 2 weeks of treatment, at which time tumors and tissues were harvested and prepared for morphological analysis and molecular analysis. Tumor size was determined by a caliper. In this assay, an S1P agonist such as Compound B or c (phosphate form), when administered at 5 to 5 mg/kg, slows tumor growth relative to the saline control: eg, Compound C-hydrochloride Administration at 2.5 mg/kg 5 doses per week resulted in a final T/C value of 30%. B.2 transplantation of human MDA-MB-43 5 breast tumor in combination with VEGF-R protein glutaminase inhibitor in nude mice treated with VEGF_R protein tyrosine kinase inhibitor for 2 weeks, such as 私私私私苯苯苯Methyl) succinic acid succinate salt is administered at a dose of 1 mg/kg 5 times a week orally, S1P incinerator agonist such as compound c (hydrochloride) is administered intravenously at a dose of 25 mg/kg 5 times a week or Its combination. The anti-tumor efficacy is indicated by the T/C% indicated in the previous section. The anti-tumor effect of compound c hydrochloride and 丨^'-anilino(1)-pyridyl sulfhydryl) succinic acid succinate is higher than that of individual agents alone (butyl/(: 〇/.27) (compound C hydrochloride) T/c 66%; Bu (4) aero-aniline-based (4-pyridylmethyl) succinate, T/c% 91). When naked A375 melanoma cells and use the same combination in a similar manner At the time of treatment, a good anti-tumor response was also obtained: T/c% 丨5 was obtained by combination therapy, and T/C% 35 and 44 were obtained by individual treatment 133554.doc -38-200906381. B. 3 Anti-tumor nascent active porous The chamber contains (1) sphingosine-1-phosphate (5 μΜ/room) or (Π) human VEGF (1 μg/chamber) in 5. 5 ml 0.8% w/v agar (containing heparin, 20 units/ml) Subcutaneously transplanted into the flank of mice. S1P or VEGF induces the growth of vascular bed tissue around the porous chamber. This reaction is dose-dependent and can be quantified by tissue weighing and determination of tissue blood content. Mouse once daily (1) Oral compound hydrazine (0.3, 3, 30 or 50 mg/kg) or (ii) intravenous D compound CR enantiomer (2.5 mg/kg) or (iii) intravenous administration of the compound CS enantiomer (2.5 mg/kg) or (iv) oral or intravenous vehicle (5 % glucose, 1 mg/kg), starting with a porous chamber prior to transplantation 4-6 hours and continued for 4 曰. At 24 hours after the last dose administration, the sacrificial mouse was assayed to form a gold tube bed tissue. The vascularized tissue weight and blood content around the porous chamber were determined. Compound A or compound c R was used. Or S-enantiomer-treated animals showed less vascularized tissue weight and/or blood content than animals treated with vehicle alone. ^ C · Clinical trial C. l S1P receptor agonist such as formula I, Π4ΠΙ compound such as compound Study of A, B, or C 2 patients with a solid tumor in the ongoing stage of deterioration, and who were resistant to standard treatment or who received a dose escalation study from a tamping patient. Weekly physiology and laboratory tests were performed to investigate patients. General clinical status. Changes in tumor and tumor transformation burden are radiologically checked every 2 months. Initially the patient is treated for 2 months. As long as the disease does not occur and 133,554. c •39- 200906381 If the drug is well tolerated, continue to be treated. Main evaluation variables: safety (adverse reactions), standard a clear chemistry and liquids by CT scan or magnetic resonance imaging (MRI) The tumor size is calculated. C-2 combination therapy, for example, is an open-label non-randomized dose escalation study of patients with exacerbated solid tumors. This study specifically confirms the synergistic effect of each of the ingredients of the combination of the present invention. The beneficial effects of poetic proliferative money can be determined directly by the research results or by changing the experimental design as known to the industry. These studies are particularly suitable for comparing the use of active ingredients and the use of this month's treatment. The preferred agent (4) is dosed up to the maximum tolerated dose and the adjuvant (b) dose is administered in a fixed dose. In addition, the drug (4) is a solidifying agent! Dosing, adjuvant (9) dose increase. The patient receives a dose of the agent (4) daily or intermittently. Treatment efficacy was assessed by radiographic imaging every 6 weeks after 12, 18 or 24 weeks. U In addition, a double-blind study of the placebo control group was used to confirm the effects of the aforementioned composition of the present invention. When the S1P receptor agonist is used alone, the daily daily dose required for carrying out the method of the present invention is determined, for example, depending on the compound to be used, the host, the mode of administration, and the severity of the disease. Preferably, the daily dose is from G.1 to 1 GG mg in a dose or in multiple doses. The appropriate dose per patient is about orally administered, for example, 0 mg, and the S1P receptor agonist can be administered by any conventional route, particularly intestines. The route is, for example, administered orally, for example, in the form of a troche, a capsule, a drinking solution, intranasal or pulmonary (by inhalation) or parenteral administration, for example, in the form of a 133554.doc -40.200906381 injection solution or suspension. The appropriate unit dosage form for oral administration is _ to 30 mg, usually 0.25 to 3 (mg) (four) Receptor _ = - or a variety of pharmaceutically acceptable diluents or carriers. In order to inhibit angiogenesis, important selection A high dose of Slp receptor is irritated because of a low concentration of the slp receptor agonist or promotes angiogenesis. When a sip agonist is administered to a patient, the appropriate dose to provide an anti-angiogenic effect can be sighed by the foregoing A. Selected for degree-increasing and dose-increasing studies.

，發明組合物也可組合手術介人、輕微長時間全體體溫升尚及/或光照射療法施用。投予本發明之醫藥組合物可獲得有益效果例如協同增效療效’例如有關減慢、中止或逆轉腫瘤的生成，腫瘤轉移的散播或生長，或延長腫瘤反應或金管新生抑制持續時間’也可獲得其它有利效果例如副作用較低，生活品質改良或死亡率卩罹病率減低，&等效果係肖施用切明組合之單-醫藥活性成分之單一治療作比較，特別係用於治：對已知抗癌劑之其它化學治療頑固之腫瘤的治療。另一項效果為可使用較低劑量至本發明組合活性成分，。亥知丨里不僅較小，同時施用次數也減少；或可用於減低副作用發生率’同時控制腫瘤的生長。此點係根據病人期望及需求決定。根據本發明之一具體實施例，較佳醫藥組合物包含 a)式 I、II、in、IVa、lvb、V 或 VI例如化合物 A、B 或 C，以及 )乍為輔劑’ 一或多種如上⑴）、（iii)、（iv)、（v)、（vii)或 I33554.doc 41 200906381 ⑻段指示之化合物例如卡波普拉江、西斯普拉;丁、太平 ’平紫杉酚、杂西紫杉酚、珍西塔賓、阿黴素、鎖定目標、降低或抑制蛋白質酪胺酸激酶4 ^ β s 文戲酶之血官内皮生長因子族群 FR)或血小板衍生生長 U于又體（PDGFR)、貳膦酸鹽或mTOR抑制劑活性之化合物。The inventive compositions may also be administered in combination with surgery, mildly long-term whole body temperature rise and/or light irradiation therapy. Administration of the pharmaceutical compositions of the present invention may yield beneficial effects such as synergistic effects such as, for example, slowing down, halting or reversing tumor formation, spreading or growing tumor metastases, or prolonging tumor response or duration of neonatal inhibition. Other advantageous effects such as lower side effects, improved quality of life or reduced mortality rate, & efficacies are compared with single treatments of single-medical active ingredients in combination with singly, especially for treatment: Other chemotherapy for anticancer agents for the treatment of stubborn tumors. Another effect is that a lower dose can be used to combine the active ingredients of the present invention. It is not only small, but also the number of applications is reduced; or it can be used to reduce the incidence of side effects while controlling the growth of tumors. This is determined by the patient's expectations and needs. According to a particular embodiment of the invention, the preferred pharmaceutical composition comprises a) a formula I, II, in, IVa, lvb, V or VI such as compound A, B or C, and 乍 as an adjuvant' one or more (1)), (iii), (iv), (v), (vii) or I33554.doc 41 200906381 Compounds indicated in paragraph 8 (8), such as Capopra River, Sispra; Ding, Taiping's Taxol, Miscellaneous paclitaxel, quetiapine, doxorubicin, targeting, reducing or inhibiting protein tyrosine kinase 4^β s venom of the blood-stained endothelial growth factor population FR) or platelet-derived growth U to the body (PDGFR) a compound that is active in the phosphinate or mTOR inhibitor.

:發明之又—具體實施例係有關sip受體激動劑⑷組合予π療d (b)用於治療淋巴癌或骨髓癌例如前文揭示之用組合，可包含例如布沙芬、賽塔拉賓、6_硫鳥嗓吟、 :路達拉員、經基尿素、普卡巴蔡、布利歐黴素或美索翠赛作為額外輔劑b)。拓樸異構酶Π抑制劑例如道諾汝必辛或特別敎目標、降低或抑制pdgfr活性或“Η族群成員活性及其基因融合產物如伊馬提尼之化合物較佳用作為輔劑b)例如用於治療淋巴癌。同投予」或「組合投予」等詞用於此處表示涵蓋投 ‘定化療劑的單一病人，意圖包括無需藉相同途徑或同時投予藥劑之治療計畫。、發月之目的係提供一種醫藥組成物包含定量且為對抗增生惡性病治療有效量之本發明組合物。此種组成物中’第一藥劑a)及辅劑b)可共同投藥，接續投藥、或以組合单位劑型或兩個分開單位劑型投藥。單位劑型也可為固定組合。本發明醫藥組成物可以已知方式或適合供腸道例如口服或直腸以及腸道外投予哺乳類（溫血動物）包括人類之方式製備，組成物包含、;A、底士 & a 取初匕3 ~療有效量之至少一種藥理活性組合成 133554.doc -42- 200906381 分（例如前文指示），或組合一或多種或稀釋劑，特別適合供腸道或腸道外投藥。可接受之載劑適當醫藥組成物例含有約〇1%至約999 :“°%活性成分。經口或腸道外投藥用之^ :圭約1%至製劑例如為單位劑型例如糖衣鍵、錠劑、职=療之醫藥安瓿。除非另行指示，否則係以已知製:劑或检劑或習知之混合、造粒、包糖衣、溶解及;束==例如利用解個別劑量之各單位劑型所含組合成分之單位八？。須了非有效量，經由单位含1E本身並特別”：劑量單位來達成所需有效量。特別冶療有效量之本發明組合之個別循序或以任一種順序投予，各成分可分開或呈：1同：：二:：如根據本發明延遲增生惡性病之進行或治：=: §. \ 3 :):又予呈自由態或醫藥可接受性鹽形式之荜 =:Γ態或醫藥可接受性鹽形式之輔：該量=:以任何順序循序進行使用劑量為治療有效 ^ =為協同增效有效量’例如以對應此處揭示用量之母曰劑里或間歇劑量。本發明組合物之個別組合成分可於治療過程中於不同時間分開投藥，或以分開劑型或單一组合劑型同時投藥。此外，投藥一詞也涵蓋使用組合成分前驅樂，該前驅藥於活體内將轉成組合成分。因此須了解本發明涵蓋同時或交替治療，「投藥」一詞也可據此解譯說明0 本發明級合物採用之各種組合成分之有效劑量可依據採用之特定化合物或醫藥組成物、投藥模式、治療病情、治 I33554.doc -43 - 200906381 療病情嚴重程；δ： .撒，據多項變。如此，本發明組合之用法用量係根、素L括投藥途徑以及病人肝腎功能藝之醫師、臨床治療師或獸醫師可決定且處方預防熟^ ^ 亭止疾病進行所需有效量之單—活性成分。達成活= 刀於有效但又無毒範圍内之較佳化處方需要基於活性成分對目標位置之生物利用率動力學資料。Further in the invention - a specific embodiment relates to a sip receptor agonist (4) combined with π therapy d (b) for the treatment of lymphoid or myeloid cancer, such as the combinations disclosed above, which may include, for example, brassafen, sitabin, 6_thioguanine, : Ludala, transurea urea, puqabacai, briomycin or mesotrix as an additional adjuvant b). Topoisomerase inhibitors such as daunson or specific targets, reducing or inhibiting pdgfr activity or "a member of the steroid group and its gene fusion products such as imatinib are preferably used as an adjuvant b) For example, for the treatment of lymphoma. The terms "administered" or "combined administration" are used herein to mean a single patient that encompasses a chemotherapeutic agent, and is intended to include a treatment plan that does not require the same route or concurrent administration of the agent. The purpose of the present invention is to provide a pharmaceutical composition comprising a composition of the invention in a quantitative amount and in a therapeutically effective amount against a proliferative malignant disease. The "first agent a" and the adjuvant b) in such a composition may be administered together, or may be administered in combination or in a combined unit dosage form or in two separate unit dosage forms. The unit dosage form can also be a fixed combination. The pharmaceutical composition of the present invention can be prepared in a known manner or suitable for administration to the intestines, for example, orally or rectally, and parenterally, to mammals (warm-blooded animals) including humans, the composition comprising, A, shi & a 3 ~ The therapeutically effective amount of at least one pharmacologically active combination is 133,554.doc -42 - 200906381 (for example as indicated above), or a combination of one or more or diluents, particularly suitable for enteral or parenteral administration. Acceptable Carriers Suitable pharmaceutical compositions contain from about 1% to about 999: "% active ingredient. Orally or parenterally administered ^: about 1% to the preparation, for example, a unit dosage form such as a sugar-coated label, ingot Agents, occupations, and therapeutic ampoules, unless otherwise indicated, by known agents: agents or test agents or conventionally mixed, granulated, sugar coated, dissolved, and bundled == for example, the use of individual dosage forms for individual dosages The unit of the contained component is eight Å. An ineffective amount is required, and the desired effective amount is achieved by the unit containing 1E itself and in particular: the dosage unit. In particular, a therapeutically effective amount of the combination of the invention may be administered individually or in any order, and the ingredients may be separated or present as: 1 with:: 2:: as in accordance with the invention, delaying the progression or treatment of a proliferative malignant disease: =: § . \ 3 :): Also in the free form or in the form of a pharmaceutically acceptable salt 荜 =: Γ 或 or pharmaceutically acceptable salt form supplement: the amount =: in any order, the dosage is therapeutically effective ^ = A synergistically effective amount is, for example, in a parenteral or intermittent dose corresponding to the amounts disclosed herein. The individual components of the compositions of the present invention may be administered separately at different times during the course of treatment, or may be administered simultaneously in separate dosage forms or in a single combination dosage form. In addition, the term medication also covers the use of a combination of pre-drivers that will be converted into a combination in vivo. Therefore, it should be understood that the present invention encompasses simultaneous or alternating treatment, and the term "administration" can also be interpreted accordingly. The effective dosage of the various components of the composition of the present invention can be based on the particular compound or pharmaceutical composition employed, and the mode of administration. , treatment of the disease, treatment I33554.doc -43 - 200906381 treatment of serious illness; δ: . Sa, according to a number of changes. Thus, the dosage of the combination of the present invention, the dosage of the compound, the route of administration of the drug, and the physician, clinical therapist or veterinarian of the patient's liver and kidney function can determine and prescribe the effective amount of the active ingredient in the prevention of the disease. ingredient. A better prescription for achieving a live = knife in an effective but non-toxic range requires a bioavailability kinetic data based on the active ingredient versus the target site.

U 第一藥劑或成分⑷之每日劑量當'然係依據多項因素改變’例如選用之化合物、治療之特定病情及期望效果。但通常以每日劑量約0.H00毫克以單劑或平分多劑投予— SM體激動劑例如化合物A、8或。時可達成滿意效果。 S1P受體激動劑可藉任-種習知途徑投藥，特別為腸道例、”里例如以錠劑、膠囊劑、飲用溶液劑劑型投藥，或腸道外投藥例如以注射溶液劑或懸浮液劑劑型投藥。口服投藥用之適當單位劑型包含約〇毫克成分⑷例如〇」至 25毫克成分（a)連同一或多種醫藥上可接受之稀釋劑或載劑0 法卓左可以約0.5至約10毫克/日，且較佳約！至約2·5毫克/日之劑量範圍口服投予人體。伊西美斯坦可以約5至約 200毫克/日，且較佳約10至約25毫克/日之劑量範圍口服投予人體，或以約50至約500毫克/日，且較佳約1〇〇至約25〇毫克/日之劑量範圍投予。若藥物係以分開醫藥組成物投予，則可呈GB 2，177,700揭示之形式投予。弗美斯坦可以約100至約500毫克/曰，且較佳約250至約3〇〇毫克/日之劑量範圍投予人體。阿納卓左可以約0.25至約2〇毫克/日，且 133554.doc •44· 200906381 較佳約〇.5至約2.5毫克/日之劑量範圍口服投予人體。亞明諾路特他麥可以約200至約500毫克/日之劑量範圍投予人體。塔莫西芬檸檬酸鹽可以約10至約40毫克/日之劑量範圍投予人體。文布拉斯汀可以約1.5至10毫克/平方米日之劑量範圍投予人體。文克利斯汀硫酸鹽可以約〇〇25至〇〇5毫克/千克體重•周之劑量範圍投予人體。文諾利賓可以約10至50毫克/平方米日之劑量範圍投予人體。伊托波賽磷酸鹽可以約25至115毫克/平方米日例如56.8 或η3·6毫克/平方米日之劑量範圍投予人體。添尼波賽可以約75至150毫克之劑量範圍約略每2周一次投予人體。阿黴素可以約1〇至1〇〇毫克/平方米日例如25或 5〇毫克/平方米曰之劑量範圍投予人體。伊皮汝必辛可以約10至200毫克/平方米日之劑量範圍投予人體。依達汝必辛可以約0.5至50毫克/平方米曰之劑量範圍投予人體。米托桑村可以約2.5至25毫克/平方米日之劑量範圍投予人體。太平洋紫杉酚可以約50至300毫克/平方米日之劑量範圍投予人體。朵西紫杉酚可以約25至！〇〇毫克/平方米曰之劑量範圍投予人體。賽洛弗法麥可以約50至15〇〇毫克/平方米日之劑量範圍投予人體。梅法蘭可以約〇.5至1〇毫克/平方米日之劑量範圍投予人體。 I33554.doc -45· 200906381 5,_尿料可以約50至1_毫克/平方米日例如_毫克/平古只、，之齊j量範圍投予人體。卡佩西塔賓可以約至⑽〇宅克/平方米曰之劑量範圍投予人體。珍西塔賓鹽酸鹽可乂、.勺1000毫克/平方米/周之劑量範圍投予人體。美索翠賽可以約5至500毫克/平方米日之劑量範圍投予人體。托普堤坎可以約1至5毫克/平方米日之劑量範圍投予人體伊利諾k坎可以約5〇至35〇毫克/平方米日之劑量範圍投予人體。卡波普拉汀可以約2〇〇至4〇〇毫克/平方米約每4周一次之劑I範圍投予人體。西斯普拉汀可以約25至75毫克/平方米約每3周一次之劑量範圍投予人體。歐沙利普拉汀可以約50至85毫克/平方米約每2周一次之劑量範圍投予人體。伊馬提尼可以約2.5至850毫克/日，更佳5至600毫克/ 日’及最佳20至300毫克/日之劑量範圍投予人體。亞蘭羅尼克酸可以約5至1 0毫克/曰之劑量範圍投予人體。克洛羅尼克酸可以約750至1500毫克/日之劑量範圍投予人體。艾奇多尼克酸可以約200至400毫克/曰之劑量範圍投予人體。伊班羅尼克酸可以約1至4毫克每3至4周一次之劑量範圍投予人體。萊斯羅尼克酸可以約20至30毫克/日之劑量範圍投予人體。帕米羅尼克酸可以約1 5至90毫克每 3至4周一次之劑量範圍投予人體。提路羅尼克酸可以約 200至400毫克/日之劑量範圍投予人體。蔡斯圖住梅可以約1至4毫克/平方米/周之劑量範圍投予人體。 133554.doc -46 - 200906381 拜卡路他麥可以約25至5〇毫克/平方米/日之劑量範圍投予人體。 1-(4-氯苯胺基）_4·(4_吡啶基曱基）酞畊或其鹽例如丁二酉夂鹽可以約50至15〇〇毫克/日，更佳約1〇〇至75〇毫克/日，及最佳約250至500毫克/日之劑量範圍投予人體。拉帕黴素或其衍生物例如為4〇_〇·(2_羥基乙基）_拉帕黴素可以約0.1至25毫克之劑量範圍投予人體。調配例：軟膠囊劑U The daily dose of the first agent or ingredient (4) is 'depending on a number of factors' such as the compound selected, the particular condition being treated, and the desired effect. However, it is usually administered in a single dose or in divided doses at a daily dose of about 0. H00 mg - a SM agonist such as Compound A, 8 or. Satisfactory results can be achieved. The S1P receptor agonist can be administered by any conventional means, particularly for intestinal administration, for example, in the form of tablets, capsules, drinking solutions, or parenteral administration, for example, injectable solutions or suspensions. Dosage form dosage. Suitable unit dosage forms for oral administration include about 〇 milligrams of ingredients (4) such as 〇 to 25 milligrams of ingredients (a) with one or more pharmaceutically acceptable diluents or carriers. 0 卓卓 left can be from about 0.5 to about 10 MG/day, and better! The dosage form is administered orally to the human body in a dose range of about 2.5 mg/day. Isterestim can be administered orally to the human body in a dosage range of from about 5 to about 200 mg/day, and preferably from about 10 to about 25 mg/day, or from about 50 to about 500 mg/day, and preferably about 1 Torr. A dose range of about 25 mg/day is administered. If the drug is administered as a separate pharmaceutical composition, it can be administered in the form disclosed in GB 2,177,700. Vermeertan can be administered to the human body in a dosage range of from about 100 to about 500 mg/Torr, and preferably from about 250 to about 3 mg/day. Anadrox can be administered orally to the human body in a dosage range of from about 0.25 to about 2 mg/day, and 133,554.doc •44.200906381, preferably from about .5 to about 2.5 mg/day. Yaminolutta can be administered to humans in a dosage range of from about 200 to about 500 mg/day. Tamoxifene citrate can be administered to the human body in a dosage range of from about 10 to about 40 mg/day. The von Brastin can be administered to the human body in a dosage range of about 1.5 to 10 mg/m 2 . Winkstein sulphate can be administered to the human body at a dose ranging from about 〇25 to 〇〇5 mg/kg body weight per week. Venoxolbin can be administered to the human body in a dose range of about 10 to 50 mg/m2. The itopose phosphate can be administered to the human body in a dosage range of about 25 to 115 mg/m 2 day, for example 56.8 or η 3 · 6 mg/m 2 . Teniper can be administered to the human body approximately every 2 weeks in a dose range of approximately 75 to 150 mg. Doxorubicin can be administered to the human body in a dosage range of from about 1 to about 1 mg/m2, for example, 25 or 5 mg/m2. Epirubicin can be administered to the human body in a dose range of about 10 to 200 mg/m 2 . Idazin can be administered to the human body in a dose range of about 0.5 to 50 mg/m 2 . The village of Mitosan can be administered to the human body in a dose range of about 2.5 to 25 mg/m2. Pacific taxol can be administered to the human body in a dosage range of about 50 to 300 mg/m 2 . Docetaxel can be about 25 to! The dosage range of 〇〇mg/m2 is administered to the human body. The Safir Fama can be administered to the human body in a dose range of about 50 to 15 mg/m2. Mellon can be administered to the human body at a dose ranging from about 5 to 1 mg/m2. I33554.doc -45· 200906381 5, _ Urine can be administered to the human body in a range of about 50 to 1 mg/m2, for example, _mg/Pinggu. Capistabin can be administered to the human body in a dose range of approximately (10) 宅克/m2. Jessitabin hydrochloride can be administered to the human body in a dose range of 1000 mg/m 2 /week. Mesotrix can be administered to the human body in a dose range of about 5 to 500 mg/m2. Topotecan can be administered to the human body in a dose range of about 1 to 5 mg/m 2 for a human dose of about 5 to 35 mg per square meter. Captopril can be administered to the human body in a range of about 2 to 4 mg/m 2 about once every 4 weeks. Sisplatin can be administered to the human body in a dosage range of about 25 to 75 mg/m 2 about once every 3 weeks. Oxaliplatin can be administered to the human body in a dosage range of about 50 to 85 mg/m 2 about once every 2 weeks. Imatinib can be administered to the human body in a dosage range of about 2.5 to 850 mg/day, preferably 5 to 600 mg/day and preferably 20 to 300 mg/day. The ryanonic acid can be administered to the human in a dosage range of about 5 to 10 mg/m. Clotrockic acid can be administered to the human body in a dosage range of about 750 to 1500 mg/day. Acidoconic acid can be administered to the human body in a dosage range of about 200 to 400 mg/曰. Iban roric acid can be administered to the human body in a dosage range of about 1 to 4 mg every 3 to 4 weeks. Leszonic acid can be administered to the human body in a dosage range of about 20 to 30 mg/day. Pamidonic acid can be administered to the human body in a dosage range of about 15 to 90 mg every 3 to 4 weeks. Tiluroic acid can be administered to the human body in a dosage range of about 200 to 400 mg/day. Zeiss Tumei can be administered to the human body in a dose range of about 1 to 4 mg/m 2 /week. 133554.doc -46 - 200906381 拜卡路他麦 can be administered to the human body in a dose range of about 25 to 5 mg/m 2 /day. 1-(4-chloroanilino)-4·(4-pyridylfluorenyl) hydrazine or a salt thereof such as butyl hydrazine salt may be about 50 to 15 mg/day, more preferably about 1 to 75 mg/ A dose range of about 250 to 500 mg/day is administered to the human body. The rapamycin or a derivative thereof, for example, 4〇_〇·(2-hydroxyethyl)-rapamycin can be administered to the human body in a dose ranging from about 0.1 to 25 mg. Formulation example: soft capsule

30毫克 300毫克 20毫克 350毫克式I化合物如化合物Α鹽酸鹽聚乙二醇3〇〇玻利索貝（Polysorbate)80 總量 sip受體激動劑例如包含式χ基團之S1P受體激動劑於根據本發明使用要求劑量範圍之耐受性良好。例如化合物A 之急性LDw於大鼠及猴大於10毫克/千克口服劑量。又另一方面，本發明係關於使用S1P激動劑作為前血管新生藥物。後來發現誘生新-血管新生為多種疾病（例如心肌血官新生、創傷癒合或糖尿病性血管功能異常/血管病變）之絕佳治療目標。如前文說明，高濃度S1P受體激動劑（2 μΜ或以上如2_5 μΜ或0.5-1 μΜ)具有抗血管新生功效，Slp受體激動劑可抑制VEGF誘生血管新生。相反地，低濃度（〇」_丨μΜ例如〇.卜 0.5 μΜ或0.5-1 pM)SlP激動劑對血管新生有提升效果，石可增強VEGF媒介血管新生。如此，Slp激動劑用於血管新 133554.doc -47- 200906381 生有雙相效果。如此，本發明進一步提供： 8. 一種S1P激動劑例如包含式X基團之Slp激動劑例如化合物A或化合物A_磷酸鹽用於誘生新_血管新生過程之用途’例如用作為前血管新生劑例如用於適合促進血管新生之適應症。琢樂物係用於治療或預防經由種製備藥物30 mg 300 mg 20 mg 350 mg of a compound of formula I such as the compound hydrazine hydrochloride polyethylene glycol 3 〇〇 Polysorbate 80 total sip receptor agonist such as S1P receptor agonist comprising a hydrazine group The tolerance to use of the required dosage range in accordance with the present invention is good. For example, the acute LDw of Compound A is greater than 10 mg/kg oral dose in rats and monkeys. In still another aspect, the invention relates to the use of an S1P agonist as a pro-angiogenic drug. It was later discovered that inducing neo-angiogenesis is an excellent therapeutic target for a variety of diseases, such as cardiac muscle regeneration, wound healing, or diabetic vascular dysfunction/vascular disease. As indicated above, high concentrations of S1P receptor agonists (2 μΜ or more, such as 2_5 μΜ or 0.5-1 μΜ) have anti-angiogenic effects, and Slp receptor agonists inhibit VEGF-induced angiogenesis. Conversely, a low concentration of 〇丨丨 Μ Μ 卜卜卜 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Thus, Slp agonists are used in vascular new 133554.doc -47- 200906381 to produce a biphasic effect. Thus, the present invention further provides: 8. An S1P agonist such as a Slp agonist comprising a group of formula X, such as Compound A or Compound A-phosphate, for use in inducing a neo-angiogenic process, eg, for use as a pro-angiogenesis The agent is used, for example, for indications suitable for promoting angiogenesis.琢乐物系 is used to treat or prevent the preparation of drugs

抑制新-血管新生過程而媒介例如藉抗血管新生因子媒介之疾病，例如用於適合促進血管新生之疾病，例如用於創傷癒合或治療心肌梗塞或糖尿病性血管功能異f/A管病變’該方法包含使用S1P受體激動劑例如包含式χ基團川激動劑例如化合物A或化合物冬磷酸鹽作為活性成分。 1〇· -種治療或預防疾病之方法’該疾病係經由抑制新_ ▲管新生過程而媒介例如藉抗血管新生因子媒介之疾病，例如用於適合促進血管新生之疾病’例如用於創傷癒合或治療心肌梗塞或糖尿功能異管病變，該方法包含對需要此種治療之個體投予有效量之sip受體激動劑例如包含式χ基團S1P激動劑例如化合物八或化合物冬鱗酸鹽。適合促進血管新生之S1P激動劑包括如前文就癌症治療定義之化合物’例如包含式x基團之Slp激動劑或根據心至IX之化合物或其醫藥上可接受之性心旨。較佳⑽激動劑為化合物A-磷酸鹽。S1P激動劑可單獨使用，或组合一或多種其它可促進血管新生之藥劑wVegf使用。〇 I33554.doc -48- 200906381 為了促進血管新生，重要地係選用夠低劑量之S1P受體激動劑，原因在於高濃度S1P受體激動劑會抑制血管新生。當S1P激動劑投予病人時，提供前驅血管新生效果之適當劑量可經由前文於A、；8及C所述之濃度遞增研究及劑量遞增研究選定。使用下列縮寫： BSA:牛血清白蛋白 ECGS :内皮細胞生長因子組合Ecl :增強化學發光 S :神經鞘胺醇-丨_磷酸 PBS :磷酸鹽緩衝食鹽水 JNK 1/2 : c-接合·Ν_端基激酶RT :室溫 1/2 TF當量：組織因子當量 EGR-1 /NFAT :早期生長反應蛋白質丨/活化τ細胞核因子 F1P:化合物A-磷酸鹽（FTY720-磷酸鹽） S1P受體激動劑例如包含式X基團之S1P激動劑用於促進血管新生之用途例如可根據後述方法驗證。 D.細胞培養及材料人類臍靜脈内皮細胞（HUVEC)於37°C及5%二氧化碳於培養基M199培養’培養基M199補充2〇% scs(海克隆 (HyClone) ’猶他州，羅格），；[單位/毫升肝素，5〇微克/毫升ECGS，2 mM麩胺，1〇〇單位/毫升青黴素及〇丨毫克/毫升鏈黴素。用於實驗之細胞高達繼代培養第5代。短時間缺乏營養之HUVEC係將含1% SCS之M199剝除營養經歷5小時時間獲得。重組人VEGF!65係得自普莫西爾（PromoCeu)(德 133554.doc -49· 200906381 國，海德堡）。磷酸特異性ERK1/2、p38激酶多株抗體、單磷酸ERK1/2抗體及LumiGLO化學發光劑係得自新英格蘭生物實驗室（麻省，貝佛利）、多株ΙκΒ抗體係得自聖塔克魯茲生技公司（加州，聖塔克魯茲）。過氧化酶軛合驢抗兔免疫球蛋白G(IgG)及羊抗小鼠igG係購自艾莫山（Amersham)生命科學公司（英國，艾莫山）。伊莫比隆（Imm〇bil〇n)_p轉移膜為米利玻（Millipore)(麻省，貝多弗）產品。神經鞘胺醇係得自西格瑪化學公司；S1P係得自拜歐莫（Bi〇m〇l)公司。化合物A-磷酸鹽備用溶液係藉下述方案製備。化合物A•磷酸鹽溶解於使用濃縮鹽酸追蹤的甲醇（〇.5毫克化合物八_磷酸鹽於500微升甲醇加2微升鹽酸）。所得溶液溶劑於真空蒸發去除，所彳于殘餘物再度溶解（變化法1)於〇. 1 %脫脂B $ a 於無菌去離子水溶液（500微升）或（變化法2)溶解於〇 5%崔頓（Trit〇n)X-100於去離子水。所得備用溶液（2 5 mM)經過超音波振盪處理且儲存於4°C。凝血檢定分析細胞播種於6孔平板，80-90%融合及生長隔夜。由孔板上到下細胞’根據Clauss，M.，生物化學期刊271，17629- 17634 (1996) ’ Mechtcheriakova，D.，血液93，3811-3823 (1999)所述方法分析組織因子活性。簡言之，與vegf (1.5 福）、丁仰-<2(10〇單位/毫升）、8(〇.5_2 41^)，81?(0.5-2 μΜ)，化合物Α(0.5-2 μΜ)及化合物A-磷酸鹽（0.5-2 μΜ)誘A disease that inhibits the neo-angiogenesis process, such as a disease that is mediated by an anti-angiogenic factor, such as a disease suitable for promoting angiogenesis, such as for wound healing or treatment of myocardial infarction or diabetic vascular dysfunction f/A tube lesions. The method comprises using an S1P receptor agonist, for example, comprising a guanidine group agonist such as Compound A or a compound winter phosphate as an active ingredient. 1. A method for treating or preventing a disease by mediated by a new _ _ tube neonatal process, for example, by an anti-angiogenic factor vector, for example, for a disease suitable for promoting angiogenesis, for example, for wound healing Or treating myocardial infarction or urinary dysfunction, the method comprising administering to an individual in need of such treatment an effective amount of a sip receptor agonist, for example comprising a sulfhydryl group S1P agonist, such as Compound VIII or a compound winter sulphate. S1P agonists suitable for promoting angiogenesis include, for example, a compound as defined above for cancer treatment, e.g., a Slp agonist comprising a group of formula x or a compound according to the heart to IX or a pharmaceutically acceptable sexual purpose thereof. Preferably, the (10) agonist is the compound A-phosphate. The S1P agonist can be used alone or in combination with one or more other agents that promote angiogenesis, wVegf. 〇 I33554.doc -48- 200906381 In order to promote angiogenesis, it is important to use a low dose of S1P receptor agonist because high concentrations of S1P receptor agonists inhibit angiogenesis. When a S1P agonist is administered to a patient, an appropriate dose to provide a precursor angiogenic effect can be selected by the concentration escalation studies and dose escalation studies described above in A, 8 and C. The following abbreviations are used: BSA: Bovine serum albumin ECGS: Endothelial cell growth factor combination Ecl: Enhanced chemiluminescence S: Sphingosine-丨-phosphate PBS: Phosphate buffered saline JNK 1/2 : c-join·Ν_ End group kinase RT: room temperature 1/2 TF equivalent: tissue factor equivalent EGR-1 / NFAT: early growth response protein 丨 / activation tau cell nuclear factor F1P: compound A-phosphate (FTY720-phosphate) S1P receptor agonist For example, the use of an S1P agonist comprising a group of formula X for promoting angiogenesis can be verified, for example, according to the method described later. D. Cell culture and material Human umbilical vein endothelial cells (HUVEC) were cultured at 37 ° C and 5% carbon dioxide in medium M199 'medium M199 supplement 2% scs (HyClone 'Utah, Rogge),; Unit / ml heparin, 5 〇 microgram / ml ECGS, 2 mM glutamine, 1 〇〇 unit / ml penicillin and 〇丨 mg / ml streptomycin. The cells used in the experiments were up to the fifth generation of subculture. The HUVEC strain, which lacked nutrients for a short period of time, was obtained by stripping the nutrient of M199 containing 1% SCS for 5 hours. Recombinant human VEGF!65 was obtained from PromoCeu (German 133554.doc -49.200906381, Heidelberg). Phospho-specific ERK1/2, p38 kinase polyclonal antibody, ERK1/2 antibody and LumiGLO chemiluminescence were obtained from New England Biolab (Beverly, MA), and multiple ΙκΒ anti-systems were obtained from Santa Cruz Biotech (Santa Cruz, CA). The peroxidase conjugate anti-rabbit immunoglobulin G (IgG) and the goat anti-mouse igG were purchased from Amersham Life Sciences (Emo Mountain, UK). The Imm〇bil〇n_p transfer membrane is a product of Millipore (Med., Bedford). Sphingosine was obtained from Sigma Chemical Company; S1P was obtained from Bi〇m〇l. The compound A-phosphate stock solution was prepared by the following protocol. Compound A•phosphate was dissolved in methanol traced with concentrated hydrochloric acid (〇5 mg of compound octaphosphate in 500 μl of methanol plus 2 μl of hydrochloric acid). The solvent of the obtained solution is removed by evaporation in vacuo, and the residue is dissolved again (variation 1) in 〇. 1% defatted B$ a in sterile deionized water (500 μl) or (variation 2) dissolved in 〇 5% Trit〇n X-100 is in deionized water. The resulting stock solution (25 mM) was subjected to ultrasonic vibration treatment and stored at 4 °C. Coagulation assay analysis Cells were seeded in 6-well plates at 80-90% confluence and grown overnight. Tissue factor activity was analyzed by the method described by Clauss, M., J. Biol. Chem. 271, 17629-17634 (1996) ' Mechtcheriakova, D., Blood 93, 3811-3823 (1999). In short, with vegf (1.5 blessings), Ding Yang-<2 (10〇 units/ml), 8 (〇.5_2 41^), 81? (0.5-2 μΜ), compound Α (0.5-2 μΜ) ) and compound A-phosphate (0.5-2 μΜ)

導4小時後’細胞洗兩次，且刮下於1毫升凝血緩衝液（12 mM乙酸納’ 7 mM巴比妥酸二乙酯及13〇氯化鈉；pH 133554.doc -50- 200906381 7·4)。50微升再懸浮細胞混合50微升檸檬酸化血聚，使用 5〇微升氯化鈣溶液於37°C再鈣化後測定凝血時間。使用得自兔腦血栓形成質之標準曲線測定TF當量。 E.西方墨點分析經各項處理後，細胞以冷PBS洗兩次，於ι〇〇微升 Laemmli緩衝液内溶解’刮下且於95艺加熱5分鐘。藉SDs_ PAGE分離總細胞溶解產物及移至伊莫比隆-p膜。該膜使用含0.1。/〇吞恩（Tween)-20及3%脫脂乳之pbS封阻3 〇分鐘，於室溫與一次抗體於封阻緩衝液稀釋共同培養丨小時。所得膜使用含0.1%吞恩_2〇 PBS洗三次各5分鐘，且於室溫與過氧化酶軛合二次抗體共同培育〗小時。於洗滌步驟後，臈與ECL反應劑共同培養丨分鐘，視需要曝露於該膜。用於使用另一種抗體重新探測，膜於PBs洗兩次，於55〇c使用汽提緩衝液（62.5 mM Tris-HCL，pH 6.8，2% SDS，100 mM 2-巯基乙醇）汽提3〇分鐘，於室溫使用pBs洗三次$分鐘。各次免疫偵測之後，膜濕包裹於沙朗瑞（SaranWrap)於 4°C儲存。於馬奇傑（Matrigei)之試管試驗血管新生檢定分析内皮細胞於生長因子減少馬奇傑基體（BD生科公司）形狀 I成毛細管狀結構係根據製造程序進行。簡言之，經過胰蛋白酶消化，再懸浮於不含血清之M199培養基，仁3有大丑胰蛋白酶抑制劑（1毫克/毫升，西格瑪公司）。離“後’細胞以〇·5χ1〇5細胞/毫升密度再懸浮於不含血清之培養基’細胞懸浮液係於無及有下列各種刺激物存在 133554.doc •51 - 200906381 下’播種於預先塗覆有50微升馬奇傑之96孔細胞培養孔板 (克斯塔（(：(^&〇，康寧公司）：乂£〇?於1.511]^，81?於0.1-2 μΜ ’ s於0.5-2 μΜ，化合物Α於0.5-2 μΜ，及化合物Α-磷酸鹽於0.1-2 μΜ。8小時後’馬奇傑於細胞使用3%甲路於pbsAfter 4 hours, the cells were washed twice and scraped off in 1 ml of clotting buffer (12 mM sodium acetate '7 mM diethyl barbiturate and 13 〇 sodium chloride; pH 133554.doc -50- 200906381 7 · 4). Fifty microliters of resuspended cells were mixed with 50 microliters of citrated blood aggregate, and the clotting time was measured after recalcification at 37 ° C using 5 Torr of microliter of calcium chloride solution. The TF equivalent was determined using a standard curve derived from rabbit cerebral thrombosis. E. Western blot analysis After each treatment, the cells were washed twice with cold PBS, dissolved in ι〇〇μL Laemmli buffer, and scraped and heated at 95° for 5 minutes. Total cell lysates were separated by SDs_PAGE and transferred to the imomolon-p membrane. The film used contained 0.1. / Tween-20 (Tween)-20 and 3% skim milk pbS blocked for 3 minutes, co-cultured with primary antibody in blocking buffer for a few hours at room temperature. The resulting membrane was washed three times for 5 minutes with 0.1% ton 2 PBS and co-incubated with peroxidase conjugated secondary antibody at room temperature for one hour. After the washing step, the hydrazine is co-cultured with the ECL reagent for a minute, and is exposed to the film as needed. For re-detection with another antibody, the membrane was washed twice in PBs and stripped at 55 °c using stripping buffer (62.5 mM Tris-HCL, pH 6.8, 2% SDS, 100 mM 2-mercaptoethanol). In minutes, wash with pBs for three minutes at room temperature. After each immunodetection, the membrane was wet wrapped in Saran Wrap and stored at 4 °C. In vitro test analysis of angiogenesis in Matrigei's test tube Endothelial cells in growth factor reduced Machij matrix (BD Biotech) shape I into a capillary structure according to the manufacturing procedure. Briefly, after trypsinization, resuspended in serum-free M199 medium, Ren 3 had a large ugly trypsin inhibitor (1 mg/ml, Sigma). The "post-cell" was resuspended in serum-free medium at a density of 〇·5χ1〇5 cells/ml. The cell suspension was present in the absence of the following various irritants. 133554.doc •51 - 200906381 A 96-well cell culture well plate covered with 50 μl of Ma Qijie (Ksta ((:(^&〇, Corning): 〇£〇? at 1.511]^, 81? at 0.1-2 μΜ ' s at 0.5 -2 μΜ, compound Α 0.5-2 μΜ, and compound Α-phosphate at 0.1-2 μΜ. After 8 hours, 'Machijie uses 3% road in pbs

固定且維持於4。(：。結果係以裝配有冷CCD相機（卡 (Kappa) GmbH ,德國，格萊坎）之尼康化亞弗（Nik〇n Diaphot)顯微鏡拍攝之影像，由重複進行試驗之各孔所得兩個顯微鏡試驗，直接計算分支點數目而定量獲得結果。 F·於馬奇傑之管生成檢定分析試管試驗中，化合物_a磷酸鹽誘生内皮細胞形態發生，且可能涉及仏媒介發訊路徑化合物A及化合物A_磷酸鹽對内皮細胞形態分化的影響係於馬奇傑使用試管試驗血管新生檢定分析測定。内皮細胞形態發生是-項複雜過程’要求細胞·胞外基質交互作用，接著為基質的重新模式化，刺激遷移，細胞·細胞交互作用，以及血管周圍蛋白質分解。如圖丨所示，化合物 A-磷酸鹽可以鐘形劑量相依性方式促進毛細管狀網路生成，顯示最大活性於約〇.5 μΜβ每個顯微鏡視野之分支數，反映出誘導刺激強度，分支數可媳美化合物八_鱗酸越及，顯著超越VEGF觸發的效果。化合物Α本身於〇.W μΜ具有比較化合物冬磷酸鹽微弱但一致的增強效果。化合物Α-麟酸鹽及化合物八祀.⑽不會衰減ν咖媒介再度模式化，反而係與多肽生長因子合作（例如參考圖2)。此外’化合物Α·磷酸鹽以及Slp刺激管生成完毒素（PTX，50奈克/毫升）抑制 «叹鲁素疋一種（^。―型 133554.doc •52- 200906381 非同質三兀體G蛋白抑制劑。可解譯為於化合物A_磷酸鹽刺激生物反應（參考圖3)可能涉& EDG_1(slPi)受體媒介的發訊事件。神經鞘胺醇的本身強度似乎比sip更低，神經鞘胺醇於1 μΜ可衰減S 1P及化合物A-磷酸鹽誘生毛細管狀結構的反應，但對VEGF誘生管生成物抑制作用（例如參考圓4)。就此方面而言，神經鞘胺醇之表現與化合物a不同。i料指出S與S1P間平衡對内皮細胞之活化/也管新生有關鍵重要性，最可能係透過EDG受體族群。重要地，高 t /農度神經稍胺醇及化合物Α(2-5 μΜ)抑制VEGF觸發管生成。該資料提示於試管試驗化合物Α及化合物八_磷酸鹽對血管新生顯示雙相劑量相依性效果。 G.藉化合物A-磷酸鹽活化ERK1/2 MAP激酶透過Μ AP激酶之信號轉導於多種内皮細胞功能扮演關鍵角色。使用0.5 μΜ化合物Α-磷酸鹽處理HUVEC，結果導致 ERK1/2之一過性活化，磷酸化/活化尖峰出現於1〇分鐘， 20分鐘時返回基準線（例如參考圖5)。於HUVEC並未偵測得藉化合物A-磷酸鹽活化p3 8激酶之JNK1 /2。此外，化合物A-磷酸鹽以劑量相依性方式觸發erkI/2活化，於2 μΜ 顯示較強活性’此點係與管生成檢定分析的結果成對比，管生成檢定分析中化合物Α-磷酸鹽於2 μΜ之強度比0.5 μΜ 低。化合物Α或S於處理5分鐘至60分鐘範圍皆未於内皮細胞之動力學誘生MAP激酶活化。為了估計發炎/NFkB相依性方案於内皮細胞之化合物A_磷酸鹽刺激生物反應上可能扮演的角色，膜再度使用抗ΙκΒ抗體探測。ΙκΒ濃度不受化 133554.doc -53- 200906381 合物A-磷酸鹽處理影響。此外，内皮細胞使用化合物A-磷酸鹽處理無法誘生E選擇素（E-Selectin)表現成為NFkB依賴型二次反應基因。如此，資料強力指出化合物A-磷酸鹽發訊未涉及NFkB活化，NFkB活化為内皮細胞急性發炎反應的主要串級反應。 H. 化合物A及化合物A-磷酸鹽未誘生内皮細胞組織因子反應典型發炎刺激TNF-cx及主要血管新生生長因子VEGF對内皮細胞之重要特性為其向上調節組織因子的強度。測試化合物A、化合物A-磷酸鹽、S或S1P是否也可於HUVEC誘生組織因子。資料驗證此等化合物單獨或組合時皆未升高組織因子活性（例如參考圖6)。化合物A及化合物A-磷酸鹽略為提升VEGF誘生組織因子，但未能提升TNF-α誘生組織因子。所得資料集合指出化合物A、化合物A-磷酸鹽、S及 S1P對血管新生VEGF之發炎TNF-α產生機械方面獨特的作用。 I. S1P受體激動劑對個別人類S1P受體之結合親和力可以下述檢定分析測定：人S1P受體一過性轉移感染入HEK293細胞 EDG受體及Gi蛋白質經過轉殖，對EDG受體、Gi-a、Gi-β及Gi-γ的4種cNDAs混合，使用磷酸鈣沉澱法，用來轉移感染HEK293細胞單層（M. Wigler等人，細胞。1977 ; 11 ; 223以及DS. Im等人，分子藥理學。2000 ; 57 ; 753)。簡言之，含25微克DNA及0.25 Μ氯化鈣之DNA混合物添加至 133554.doc •54- 200906381 HEPES緩衝2 mM磷酸氫二鈉。次融合HEK293細胞單層使用25 mM氣酿毒化，然後DNA沉澱施用至細胞。4小時後，單層以磷酸鹽緩衝鹽水洗滌，再度饋入培養基（90% 1:1杜別克改性必須培養基（DMEM) : F-12 +10%胎牛血清）。加入DNA後48-72小時，細胞刮入於冰上含有10%蔗糖 HME 緩衝液（以 mM 表示：20 HEPES，5 MgCl2，1 EDTA，pH 7.4)，且使用當斯（Dounce)均化器破壞而收穫細胞。於80〇xg離心後，上清液以HME不含蔗糖稀釋，及於 Π 100,000xg離心1小時。所得丸粒再度均化且於100,000xg離心第2小時。粗產物膜丸粒再懸浮於含蔗糖之HME，取出一份，浸泡在液態氮中簡短冷凍。膜儲存於70°C。藉布瑞福（Bradford)蛋白檢定分析以分光方式測定蛋白質濃度。使用S1P受體/HEK293膜製劑之GTPyS結合檢定分析 GTPyS結合實驗係如DS· Im等人，分子藥理學，2000 ; 57 ; 753所述進行。配位子媒介GTPyS結合至G蛋白質係於 GTP結合緩衝液（以 mM表示：50 HEPES，100 NaCl，10 I MgCl2，pH 7.5)，使用25微克得自一過性感染HEK293細胞之膜製劑測定。配位子係於10 μΜ GDP及0.1 nM [35S]GTPyS(1200 Ci/毫莫耳）存在下添加至膜，且於30°C培育30分鐘。使用布蘭代（Brandel)收穫機（麻里蘭州，蓋瑟堡）將結合的GTPyS與未結合的GTPYS分離，且使用液體閃爍計數器計數。【圖式簡單說明】囷1 133554.doc -55- 200906381 顯示化合物A-磷酸鹽可以鐘形劑量相依性方式強力促進毛細管狀網路生成，顯示最大活性於約0 · 5 μΜ。圓2 顯示化合物Α-磷酸鹽及化合物Α於0.5-1 μΜ時，不會衰減VEGF媒介之重新模式化’反而係與多肽生長因子合作。圓3 顯示化合物Α-磷酸鹽及S1P媒介管生成實際上可由百日咳毒素（ΡΤΧ，50奈克/毫升）完全抑制，ρτχ是一種ai/。型非同質三元體G蛋白抑制劑。可解譯為EDG-1(S1P!)受體媒介發訊事件可能涉及化合物A-磷酸鹽刺激生物反應。圓4 顯示神經鞘胺醇於i μΜ時，本身似乎比S1P之強度弱，衰減S1P及化合物冬磷酸鹽誘生毛細管狀結構之能力，而對VEGF-誘生管生成不具有抑制效果。就此方面而言，神經鞘胺醇之表現係與化合物A不同。資料指出神經鞘胺醇與S1P間之平衡似乎對内皮細胞活化/血管新生相當重要，最可能透過EDG受體族群發揮作用。|緊地，高濃度神經鞘胺醇及化合物人（2_5 μΜ)可抑制Vegf觸發管生成。圖5 .4 丁HUVEC使用化合物八_攝酸鹽於〇·5 _處理可能導致ERK1/2的—過性活&，磷酸化/活化尖峰出現於10分鐘，及於2〇分鐘時返回基準線。圓6 133554.doc -56- 200906381 試驗化合物A、化合物A-磷酸鹽、神經鞘胺醇或SIP是否確實對HUVEC誘生組織因子。資料證實單獨此等化合物或組合使用皆未升高組織因子活性，如圖6所示。化合物A 及化合物A-磷酸鹽略為增強VEGF，但未增強TNF- -誘生組織因子。圖7 化合物C於S1P媒介HUVEC管生成檢定分析之影響。Fixed and maintained at 4. (: The result is an image taken with a Nik〇n Diaphot microscope equipped with a cold CCD camera (Kappa GmbH, Glekan, Germany), two of which were obtained from repeated experiments. Microscopic test, directly calculate the number of branch points and quantitatively obtain the results. F· in the tube assay of Ma Qijie assay test, compound _a phosphate induces endothelial cell morphogenesis, and may involve 仏 media signaling pathway compound A and compounds The effect of A_phosphate on endothelial cell morphological differentiation was determined by Ma Qijie using a test tube angiogenesis assay. Endothelial cell morphogenesis is a complex process that requires cell-extracellular matrix interaction, followed by remodeling of the matrix, Stimulation of migration, cell-cell interaction, and perivascular protein breakdown. As shown in Figure 化合物, compound A-phosphate promotes capillary network formation in a bell-shaped dose-dependent manner, showing maximum activity at approximately 〇5 μΜβ per The number of branches in the field of view of the microscope reflects the intensity of the induced stimulus, and the number of branches is comparable to that of the compound. Significantly surpasses the effect of VEGF triggering. The compound Α itself has a weak but consistent enhancement effect of the compound compound phosphatase in the 〇.W μ 。. The compound Α- 麟酸盐 and the compound gossip. (10) does not attenuate the ν coffee medium re-patterning Instead, it cooperates with the polypeptide growth factor (for example, refer to Figure 2). In addition, the 'compound Α·phosphate and the Slp-stimulated tube toxin (PTX, 50 Ng/ml) inhibits the stagnation of 叹疋疋 ( 133554.doc •52- 200906381 Non-homogeneous triterpenoid G protein inhibitor. Can be interpreted as a compound A_phosphate-stimulated biological response (refer to Figure 3) may involve & EDG_1 (slPi) receptor media signaling events The sphingosine itself appears to be less intense than sip, and sphingosine at 1 μΜ attenuates the reaction of S 1P and compound A-phosphate to induce capillary structures, but inhibits VEGF-induced tube formation ( For example, reference circle 4). In this respect, sphingosine ishave differently than compound a. i indicates that the balance between S and S1P is critical for endothelial cell activation/regeneration, most likely through EDG. Family Importantly, high t/agronomic neuroglycolamine and compound guanidine (2-5 μΜ) inhibit VEGF-triggered tube formation. This data suggests that the test compound Α and the compound octaphosphate show a biphasic dose to angiogenesis. Dependence effect. G. Activation of ERK1/2 MAP kinase by compound A-phosphate plays a key role in signal transduction of 激酶 AP kinase to various endothelial cell functions. Treatment of HUVEC with 0.5 μΜ compound Α-phosphate results in ERK1/ 2 One-pass activation, phosphorylation/activation spikes appear at 1 minute, returning to the baseline at 20 minutes (see, for example, Figure 5). JNK1 /2, which activates p3 8 kinase by compound A-phosphate, was not detected by HUVEC. In addition, the compound A-phosphate triggers erkI/2 activation in a dose-dependent manner and shows a stronger activity at 2 μΜ. This point is in contrast to the results of the tube generation assay, which is the compound bismuth-phosphate in the tube generation assay. The intensity of 2 μΜ is lower than 0.5 μΜ. Compounds Α or S were not subjected to kinetic induction of MAP kinase activation by endothelial cells in the range of 5 minutes to 60 minutes of treatment. To estimate the role that the inflammatory/NFkB-dependent regimen may play in endothelial cell compound A-phosphate-stimulated biological responses, membranes were again probed with anti-ΙκΒ antibodies. ΙκΒ concentration is not affected 133554.doc -53- 200906381 Compound A-phosphate treatment effect. In addition, endothelial cells treated with compound A-phosphate did not induce E-Selectin to be expressed as an NFkB-dependent secondary response gene. Thus, the data strongly suggest that the compound A-phosphate signaling is not involved in NFkB activation, and that NFkB activation is a major cascade reaction in the acute inflammatory response of endothelial cells. H. Compound A and Compound A-phosphate are not induced by endothelial cell tissue factor response. Typical inflammatory stimulating TNF-cx and the major angiogenic growth factor VEGF are important properties of endothelium for its upward regulation of tissue factor strength. Test compound A, compound A-phosphate, S or S1P can also induce tissue factor in HUVEC. The data verified that these compounds did not increase tissue factor activity either alone or in combination (see, for example, Figure 6). Compound A and Compound A-phosphate slightly increased VEGF-induced tissue factor but failed to enhance TNF-α-induced tissue factor. The resulting data set indicates that Compound A, Compounds A-phosphate, S and S1P have a mechanically unique effect on the inflammatory TNF-α of angiogenic VEGF. I. The binding affinity of S1P receptor agonists to individual human S1P receptors can be determined by the following assay: Human S1P receptor transient transfer into HEK293 cells EDG receptor and Gi protein are transfected, to EDG receptors, Four cNDAs of Gi-a, Gi-β and Gi-γ were mixed and used to transfer HEK293 cell monolayers using calcium phosphate precipitation (M. Wigler et al., Cells. 1977; 11; 223 and DS. Im et al. Human, Molecular Pharmacology. 2000; 57; 753). Briefly, a DNA mixture containing 25 micrograms of DNA and 0.25 milliliters of calcium chloride was added to 133554.doc • 54-200906381 HEPES buffered 2 mM disodium hydrogen phosphate. The sub-fused HEK293 cell monolayer was poisoned with 25 mM gas and then applied to the cells by DNA precipitation. After 4 hours, the monolayer was washed with phosphate buffered saline and fed again to the medium (90% 1:1 Dubuque Modified Essential Medium (DMEM): F-12 + 10% fetal bovine serum). 48-72 hours after DNA addition, cells were scraped onto ice containing 10% sucrose HME buffer (expressed in mM: 20 HEPES, 5 MgCl2, 1 EDTA, pH 7.4) and disrupted using a Dounce homogenizer Harvest the cells. After centrifugation at 80 〇 xg, the supernatant was diluted with HME without sucrose and centrifuged at 100,000 x g for 1 hour. The pellet obtained was again homogenized and centrifuged at 100,000 x g for the second hour. The crude product pellet was resuspended in HME containing sucrose, and one portion was taken out and immersed in liquid nitrogen for brief freezing. The membrane was stored at 70 °C. Protein concentration was determined spectroscopically by Bradford protein assay. GTPyS binding assay using S1P receptor/HEK293 membrane preparation GTPyS binding assay line was performed as described by DS· Im et al., Molecular Pharmacology, 2000; 57; 753. The ligand vector GTPyS was bound to the G protein line in GTP binding buffer (expressed in mM: 50 HEPES, 100 NaCl, 10 I MgCl2, pH 7.5) using 25 micrograms of membrane preparation obtained from transiently infected HEK293 cells. The ligand was added to the membrane in the presence of 10 μΜ GDP and 0.1 nM [35S]GTPyS (1200 Ci/mole) and incubated at 30 °C for 30 minutes. The bound GTPyS was separated from unbound GTPYS using a Brandel harvester (German, Gull.) and counted using a liquid scintillation counter. [Simple description of the diagram] 囷1 133554.doc -55- 200906381 shows that the compound A-phosphate can strongly promote capillary network formation in a bell-shaped dose-dependent manner, showing a maximum activity of about 0.5 μm. Circle 2 shows that the compound bismuth-phosphate and the compound Α at 0.5-1 μΜ do not attenuate the remodeling of the VEGF vector and instead work with the polypeptide growth factor. Circle 3 shows that the compound bismuth-phosphate and S1P media tube formation can be completely inhibited by the pertussis toxin (ΡΤΧ, 50 Ng/ml), which is an ai/. Type of non-homogeneous ternary G protein inhibitor. Interpretable as EDG-1 (S1P!) Receptor Media A signaling event may involve a compound A-phosphate stimulating biological response. Circle 4 shows that sphingosine itself appears to be weaker than S1P when it is i μΜ, attenuating the ability of S1P and compound winter phosphate to induce capillary structures, but has no inhibitory effect on VEGF-induced tube formation. In this respect, sphingosine is expressed differently than compound A. The data suggest that the balance between sphingosine and S1P appears to be important for endothelial cell activation/angiogenesis, most likely through the EDG receptor population. Tightly, high concentrations of sphingosine and compounds (2_5 μΜ) inhibit Vegf trigger tube formation. Figure 5.4.4 Ding HUVEC using the compound octadecanoate in 〇·5 _ treatment may lead to ERK1/2-passive activity & phosphorylation/activation spikes appear in 10 minutes and return to baseline at 2 〇 minutes line. Round 6 133554.doc -56- 200906381 Test compound A, compound A-phosphate, sphingosine or SIP is indeed a factor inducing tissue factor to HUVEC. The data demonstrates that these compounds alone or in combination did not increase tissue factor activity, as shown in Figure 6. Compound A and Compound A-phosphate slightly enhanced VEGF but did not enhance TNF--induced tissue factor. Figure 7. Effect of Compound C on the assay of S1P media HUVEC tube generation assay.

133554.doc 57-133554.doc 57-

Claims

200906381 十、申請專利範圍： 1. 一種sip受體激動劑之用途，其係用於製備預防或治療由新血管新生過程媒介或與血管新生失調關聯的疾病之醫藥品，該S1P受體激動劑為包含式χ基團之化合物或其醫藥上可接受之鹽： Z ^ΛζΝ——ch2ru x200906381 X. Patent Application Range: 1. The use of a sip receptor agonist for the preparation of a medicament for preventing or treating a disease associated with a neovascularization process vector or an angiogenesis disorder, the S1P receptor agonist A compound containing a hydrazine group or a pharmaceutically acceptable salt thereof: Z ^ΛζΝ——ch2ru x

其中 Z為H、Ci-6烧基、C2-6烯基、c2_6炔基、苯基、經〇^取代之苯基；經1至3個選自鹵素、c3 8環烷基、苯基及經或 OH取代之苯基組成的組群之取代基取代之Ci6烷基 CH2-R4j ’其中R4z為〇H、醯氧基或式⑷殘基 ⑻ .7一 1 g、〇〜其中Z!為直接鍵或0,較佳為〇; r5z及r6z各自分別為Η 或視情況經1、2或3個鹵素原子取代之Cl_4烷基； Rij OH、醯氧基或式⑷殘基、以及r2z及r3z各自分別為 H、Ci_4烧基或醯基，或式IX化合物：Wherein Z is H, Ci-6 alkyl, C2-6 alkenyl, c2-6 alkynyl, phenyl, phenyl substituted by hydrazine; 1 to 3 selected from halogen, c3 8 cycloalkyl, phenyl and Ci6 alkyl CH2-R4j ' substituted by a substituent of a group consisting of OH substituted phenyl wherein R4z is 〇H, decyloxy or the residue of formula (4). 7-1 g, Z~ wherein Z! a direct bond or 0, preferably 〇; each of r5z and r6z is Η or a Cl_4 alkyl group substituted by 1, 2 or 3 halogen atoms, respectively; Rij OH, a decyloxy group or a residue of formula (4), and r2z and Each of r3z is H, Ci_4 alkyl or sulfhydryl, or a compound of formula IX:

NH.NH.

ch2oh CH,OH 133554.doc IX 200906381 其中 Rlf為鹵素、三鹵代甲基、羥基、具有1至7個碳原子之低碳烷基、苯基、芳烷基、具有1至4個碳原子之低碳烷氧基、三氟曱基氧基、經取代或未經取代之苯氧基、ϊ衣己基甲基氧基、經取代或未經取代之芳烧基氧基、吡啶基甲基氧基、肉桂基氧基、萘基甲基氧基、苯氧基曱基、髮基甲基、經基乙基、具有1至4個碳原子之低碳烷硫基、具有1至4個碳原子之低碳烷基亞磺醯基、具有1至4個碳原子之低碳烷基磺醯基、苄硫基、乙醯基、硝基或氰基； Rk為氫、鹵素、三_代甲基、具有1至4個碳原子之低碳烷氧基、具有1至7個碳原子之低碳烷基、苯乙基或苄氧基； R3f為氫、齒素、三_代甲基、具有1至4個碳原子之低碳炫氧基、經基1氧基、具有1至7個碳原子之低碳烷基、苯基或具有1至4個碳原子之低碳烷氧基曱基； Xf為 S、so或 so2 ; π f為1至4之整數，或式IVa化合物或其醫藥上可接受之鹽： I33554.doc 200906381Ch2oh CH, OH 133554.doc IX 200906381 wherein Rlf is halogen, trihalomethyl, hydroxy, lower alkyl having 1 to 7 carbon atoms, phenyl, aralkyl, having 1 to 4 carbon atoms Lower alkoxy, trifluorodecyloxy, substituted or unsubstituted phenoxy, decylhexylmethyloxy, substituted or unsubstituted aryloxy, pyridylmethyloxy , cinnamoyloxy, naphthylmethyloxy, phenoxyindenyl, propylmethyl, phenylethyl, lower alkylthio having 1 to 4 carbon atoms, having 1 to 4 carbons a lower alkyl sulfinyl group of an atom, a lower alkylsulfonyl group having 1 to 4 carbon atoms, a benzylthio group, an ethyl sulfonium group, a nitro group or a cyano group; Rk is hydrogen, halogen, tri-generation a methyl group, a lower alkoxy group having 1 to 4 carbon atoms, a lower alkyl group having 1 to 7 carbon atoms, a phenethyl group or a benzyloxy group; R3f is hydrogen, dentate, tri-methyl group a lower carbon oxyoxy group having 1 to 4 carbon atoms, a methoxy group having 1 to 7 carbon atoms, a phenyl group having 1 to 7 carbon atoms, or a lower alkoxy group having 1 to 4 carbon atoms曱基; Xf is S, So or so2 ; π f is an integer from 1 to 4, or a compound of the formula IVa or a pharmaceutically acceptable salt thereof: I33554.doc 200906381

R IVa 其中Xa為O、S、NRls4 -(CH2)na-基團，該基團為未經取代或經1至4個鹵素取代；113為1或2，Rls為Η或（(^_4)院〇基，該烷基為未經取代或經鹵素取代；Rla為Η、ΟΗ、 (C!·4)烷基或〇(CU4)烷基，其中該烷基為未經取代或經1 至3個鹵素取代；Rlb為Η、OH或（Cw)烷基，其中該烧基為未經取代或經齒素取代；各個分別係選自Η或 (Cl.4)烧基，該烧基為未經取代或經鹵素取代；Rh為 Η、OH、鹵素或0((:,-4)烷基，其中該烷基為未經取代或經鹵素取代。 2. 3. 如請求項1之用途，其中該醫藥品係用於預防或治療腫瘤’尤其是實體腫瘤。如請求項2之用途，其中該S1P受體激動劑為2_胺基_2_[2_ (4_辛基苯基）乙基]丙烷_1，3-二醇或式IVa化合物，其中 2a為Η ’ R3々〇H ’又3為〇且Rla及Rib各自為〇H (此化合物稱為FTY720_磷酸鹽），或其醫藥上可接受之鹽。 —種S1P受體激動劑之用途，其係用於製備預防或治療 =防或治療淋巴增生或骨髓增生病症之醫藥品，尤其是月髓癌，該S1P受體激動劑為如請求項i所定義之式以化 133554.doc 200906381 合物。 5. 如凊求項1至4中任—項之用途’其中該醫藥品係間歇投 -^· 〇 6. 如凊求項1至4中任—項之用途，其中該醫藥品係與化學治療劑同時或先後投予。 7. 如申请專利範圍第6項之用途，其中該化學治療劑係選白 !· 芳香環轉化酶抑制劑，、’ 丨丨’抗雕激素劑、抗雄激素劑或***釋放因子激動劑， 111·拓樸異構酶Ϊ抑制劑或拓樸異構酶1]：抑制劑， 1ν·微細管活化劑、烷化劑、抗腫瘤抗代謝化合物或始化合物， ν.鎖定目標/降低蛋白質或脂質激肽酶活性或蛋白質或脂質磷酸酶活性之化合物、其它抗血管新生化 / 合物、或可誘生細胞分化過程之化合物， vi, 緩激肽1受體或血管緊張肽II拮抗劑， vii. 環氧合酶抑制劑、貳膦酸去乙醯化酶抑制劑、組織腺去乙醯化酶抑制劑、乙醯肝素酶抑制劑，生物反應修飾劑’優必昆汀化抑制劑（ubiquitinati()n inhibitor)或可阻斷抗細胞凋亡路徑之抑制劑， viii· Ras腫瘤發生同質異形體抑制劑， ix. 端粒酶抑制劑， X.蛋白酶抑制劑、基質金屬蛋白酶抑制劑、蛋胺酸 133554.doc 200906381 胺基肽酶抑制劑，或蛋白粒抑制劑，及/或 xi. mTOR抑制劑。R IVa wherein Xa is an O, S, NR ls 4 -(CH 2 ) na- group, which group is unsubstituted or substituted with 1 to 4 halogens; 113 is 1 or 2, and Rls is Η or ((^_4) Alkyl, the alkyl group is unsubstituted or substituted by halogen; Rla is hydrazine, hydrazine, (C!.4) alkyl or fluorenyl (CU4) alkyl, wherein the alkyl group is unsubstituted or via 1 to 3 halogen substituted; R 1b is hydrazine, OH or (Cw) alkyl, wherein the alkyl group is unsubstituted or substituted by dentate; each is selected from the group consisting of hydrazine or (Cl. 4) alkyl, the alkyl group being Unsubstituted or substituted by halogen; Rh is hydrazine, OH, halogen or 0((:,-4)alkyl, wherein the alkyl group is unsubstituted or substituted by halogen. 2. 3. Use as claimed in claim 1 Wherein the pharmaceutical system is for preventing or treating a tumor, in particular a solid tumor. The use of the item 2, wherein the S1P receptor agonist is 2-amino-2_[2_(4-octylphenyl)B a propane-1,3-diol or a compound of the formula IVa, wherein 2a is Η 'R3々〇H' and 3 is ruthenium and each of Rla and Rib is 〇H (this compound is referred to as FTY720_phosphate), or A pharmaceutically acceptable salt. Use of an S1P receptor agonist It is used for the preparation of a medicament for preventing or treating = preventing or treating lymphoproliferative or myeloproliferative disorders, especially lunar marrow cancer, and the S1P receptor agonist is as defined in the claim i to 133554.doc 200906381 5. For the use of any of the items 1 to 4, wherein the pharmaceutical product is intermittently administered - ^· 〇 6. For the use of any of items 1 to 4, wherein the pharmaceutical system is Simultaneously or sequentially with a chemotherapeutic agent. 7. For the use of the scope of the patent application, the chemotherapeutic agent is white! · Aromatic ring-converting enzyme inhibitor, ''' anti-carving hormone agent, anti- Androgen or gonadotropin-releasing factor agonist, 111·topoisomerase inhibitor or topoisomerase 1]: inhibitor, 1ν·microtubule activator, alkylating agent, anti-tumor and anti-metabolite compound Or a compound, ν. a compound that locks a target/lowering protein or lipopeptidase activity or protein or lipid phosphatase activity, another anti-angiogenic biochemical, or a compound that induces cell differentiation, vi, irritant Peptide 1 receptor or angiotensin II antagonist, vii. Cyclooxygenase inhibitor, phosphinic acid deacetylase inhibitor, tissue gland deacetylase inhibitor, acetoinase inhibitor, bioreactor modifier Inhibitors of ubiquitinati()n inhibitors or blocking anti-apoptotic pathways, viii· Ras tumorigenic isoform inhibitors, ix. telomerase inhibitors, X. protease inhibitors, matrix Metalloproteinase inhibitor, methionine 133554.doc 200906381 Aminopeptidase inhibitor, or protein granule inhibitor, and/or xi. mTOR inhibitor.

133554.doc133554.doc