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    公开号:AU2004240637A1
    申请号:U2004240637
    申请日:2004-05-19
    公开日:2004-12-02
    发明作者:Yi Fan；Wenqi Gao；Nathanael S. Gray；Yuan Mi；Shifeng Pan
    申请人:IRM LLC；
    IPC主号:A61K
    专利说明:
    WO 2004/103306 PCT/US2004/015603 IMMUNOSUPPRESSANT COMPOUNDS AND COMPOSITIONS CROSS-REFERENCE TO RELATED APPLICATIONS 5 This application claims the benefit of priority to U.S. Provisional Patent Application Number 60/471,931 (filed 19 May 2003) and U.S. Provisional Patent Application Number 60/561,968 (filed 14 April 2004). The full disclosures of these applications are incorporated herein by reference in their entirety and for all purposes. BACKGROUND OF THE INVENTION 10 Field of the Invention The invention provides a novel class of immunosuppressant compounds useful in the treatment or prevention of diseases or disorders mediated by lymphocyte interactions, particularly diseases associated with EDG receptor mediated signal transduction. Background 15 EDG receptors belong to a family of closely related, lipid activated G protein coupled receptors. EDG-1, EDG-3, EDG-5, EDG-6, and EDG-8 (also respectively termed SIP1, SlP3, S1P2, SlP4, and S1P5) are identified as receptors specific for sphingosine-1-phosphate (SlP). EDG2, EDG4, and EDG7 (also termed LPA1, LPA2, and LPA3, respectively) are receptors specific for lysophosphatidic (LPA). Among the SlP 20 receptor isotypes, EDG-1, EDG-3 and EDG-5 are widely expressed in various tissues, whereas the expression of EDG-6 is confined largely to lymphoid tissues and platelets, and that of EDG-8 to the central nervous system. EDG receptors are responsible for signal transduction and are thought to play an important role in cell processes involving cell development, proliferation, maintenance, migration, differentiation, plasticity and apoptosis. 25 Certain EDG receptors are associated with diseases mediated by lymphocyte interactions, for example, in transplantation rejection, autoimmune diseases, inflammatory diseases, infectious diseases and cancer. An alteration in EDG receptor activity contributes to the 1 WO 2004/103306 PCT/US2004/015603 pathology and/or symptomology of these diseases. Accordingly, molecules that themselves alter the activity of EDG receptors are useful as therapeutic agents in the treatment of such diseases. 5 SUMMARY OF THE INVENTION This application relates to compounds selected from Formula Ia and Ib:
    R
    4
    R
    3
    R
    4
    R
    3 A A R2 z Y R Z Ys.W .0, N 2 W N R 1 Ia NR Ib in which: 10 A is chosen from -C(O)ORs, -OP(O)(OR) 2 , -P(O)(OR) 2 , -S(O) 2 0R 5 , P(O)(RS)OR 5 and IH-tetrazol-5-yl; wherein each R 5 is independently chosen from hydrogen and CI.
    6 alkyl; W is chosen from a bond, C 1
    .
    3 alkylene, C 2
    .
    3 alkenylene; Y is chosen from C 6
    -
    1 oaryl and C2- 9 heteroaryl; wherein any aryl or heteroaryl 15 of Y can be optionally substituted with 1 to 3 radicals chosen from halo, hydroxy, nitro, C 1 . 6 alkyl, C 1
    -
    6 alkoxy, halo-substituted C 1 6 alkyl and halo-substituted CI 6 alkoxy; Z is chosen from: 2 WO 2004/103306 PCT/US2004/015603 *N N N* Rk k R 6 "Y** N N Xk * N N RNF F
    R
    6 * N* R,* R, F 0 Ne and2 wherein the left and right asterisks of Z indicate the point of attachment between C(R 3 )(R4)- and A of Formula la or Ib, respectively; R 6 is chosen from hydrogen and C 1 . 5 6 alkyl; and J, and J2 are independently methylene or a heteroatom chosen from S, 0 and
    NR
    5 ; wherein R 5 is chosen from hydrogen and CI- 6 alkyl; and any alkylene of Z can be further substituted by one to three radicals chosen from halo, hydroxy, CI- 6 alkyl; or R 6 can be attached to a carbon atom of Y to form a 5-7 member ring; Ri is chosen from C 6
    -
    1 oaryl and C 2
    .
    9 heteroaryl; wherein any aryl or heteroaryl 10 of R 1 is optionally substituted by a radical chosen from C 6
    .
    1 oarylCo.
    4 alkyl, C 2
    .
    9 heteroarylCo. 4 alkyl, C 3
    .
    8 cycloalkylCo.
    4 alkyl, C 3
    -
    8 heterocycloalkylCo.
    4 alkyl or C 1
    .
    6 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R, can be optionally substituted by one to five radicals chosen from halo, C 1
    .
    6 alkyl, CI- 6 alkoxy, halo-substituted-CI- 6 alkyl and halo substituted-C 1 6 alkoxy; and any alkyl group of R, can optionally have a methylene replaced 15 by an atom or group chosen from -S-, -S(O)-, -S(O) 2 -, -NRs- and -0-; wherein R 5 is chosen from hydrogen or C1.
    6 alkyl; R2 is chosen from hydrogen, CI- 6 alkyl, C 2
    -
    6 alkenyl, C 2
    -
    6 alkynyl and halo substituted C I 6 alkyl; 3 WO 2004/103306 PCT/US2004/015603
    R
    3 and R 4 are independently chosen from hydrogen, CI- 6 alkyl, halo, hydroxy, C 1 . 6alkoxy, halo-substituted C 1
    .
    6 alkyl and halo-substituted C1.
    6 alkoxy; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of 5 such compounds. A second aspect of the invention is a pharmaceutical composition which contains a compound of Formula Ia or lb or an N-oxide derivative, individual isomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients. 10 A third aspect of the invention is a method for treating a disease in an animal in which alteration of EDG receptor mediated signal transduction can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula Ia or lb or a N-oxide derivative, individual isomer or mixture of isomers thereof; or a 15 pharmaceutically acceptable salt thereof A fourth aspect of the invention is the use of a compound of Formula Ia or Ib in the manufacture of a medicament for treating a disease in an animal in which alteration of EDG receptor mediated signal transduction contributes to the pathology and/or symptomology of the disease. 20 A fifth aspect of the invention is a process for preparing compounds of Formula Ia or Lb and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts thereof. DESCRIPTION OF THE PREFERRED EMBODIMENTS The invention provides compounds that are useful in the treatment and/or 25 prevention of diseases or disorders mediated by lymphocyte interactions. Also provided are methods for treating such diseases or disorders. Definitions In this specification, unless otherwise defined: "Alkyl" as a group and as a structural element of other groups, for example halo 30 substituted-alkyl, alkoxy, acyl, alkylthio, alkylsulfonyl and alkylsulfinyl, can be either 4 WO 2004/103306 PCT/US2004/015603 straight-chained or branched. "Alkenyl" as a group and as a structural element of other groups contains one or more carbon-carbon double bonds, and can be either straight-chain, or branched. Any double bonds can be in the cis- or trans- configuration. "Alkynyl" as a group and as structural element of other groups and compounds contains at least one C =C 5 triple bond and can also contain one or more C=C double bonds, and can, so far as possible, be either straight-chain or branched. Any cycloalkyl group, alone or as a structural element of other groups can contain from 3 to 8 carbon atoms, preferably from 3 to 6 carbon atoms. "Alkylene" and "alkenylene" are divalent radicals derived from "alkyl" and "alkenyl" groups, respectively. In this application, any alkyl group of R 1 can be optionally interrupted 10 by a member of the group selected from -S-, -S(O)-, -S(O) 2 -, -NR 20 - and -0- (wherein
    R
    20 is hydrogen or Ci- 6 alkyl). These groups include -CH 2
    -O-CH
    2 -, -CH 2 -S(0) 2
    -CH
    2 -, (CH 2
    )
    2
    -NR
    20
    -CH
    2 -, -CH 2 -0-(CH 2
    )
    2 -, and the like. "Aryl" means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms. For example, C 6
    -
    12 aryl can be phenyl, biphenyl or naphthyl, 15 preferably phenyl. A fused bicyclic ring can be partially saturated, for example, 1,2,3,4 tetrahydro-naphthalene, and the like. "Arylene" means a divalent radical derived from an aryl group. For example, arylene as used in this application can be-phenylene, biphenylene, naphthylene and the like. "Halo" or "halogen" means F, Cl, Br or I, preferably F or Cl. Halo-substituted 20 alkyl groups and compounds can be partially halogenated or perhalogenated, whereby in the case of multiple halogenation, the halogen substituents can be identical or different. A preferred perhalogenated alkyl group is for example trifluoromethyl or trifluoromethoxy. "Heteroaryl" means aryl, as defined in this application, with the addition of at least one heteroatom moiety selected from N, 0 or S, and each ring is comprised of 5 to 6 ring 25 atoms, unless otherwise stated. For example, C 2 heteroaryl includes oxadiazole, triazole, and the like. C 9 heteroaryl includes quinoline, 1,2,3,4-tetrahydro-quinoline, and the like. C 2 9 heteroaryl as used in this application includes thienyl, pyridinyl, furanyl, isoxazolyl, benzoxazolyl or benzo[1,3]dioxolyl, preferably thienyl, furanyl or pyridinyl. "Heteroarylene" means heteroaryl, as defined in this application, provided that the ring 30 assembly comprises a divalent radical. A fused bicyclic heteroaryl ring system can be 5 WO 2004/103306 PCT/US2004/015603 partially saturated, for example, 2,3-dihydro-1H-isoindole, 1,2,3,4-tetrahydro-quinoline, and the like. As used in the present invention, an EDG-1 selective compound (agent or modulator) has a specificity that is selective for EDG-l over EDG-3 and over one or more of 5 EDG-5, EDG-6, and EDG-8. As used herein, selectivity for one EDG receptor (a "selective receptor") over another EDG receptor (a "non-selective receptor") means that the compound has a much higher potency in inducing activities mediated by the selective EDG receptor (e.g., EDG-1) than that for the non-selective SlP-specific EDG receptor. If measured in a GTP-yS binding assay (as described in the Example below), an EDG-I selective compound 10 typically has an EC50 (effective concentration that causes 50% of the maximum response) for a selective receptor (EDG-1) that is at least 5, 10, 25, 50, 100, 500, or 1000 fold lower than its EC50 for a non-selective receptor (e.g., one or more of EDG-3, EDG-5, EDG-6, and EDG-8). Detailed Description of the Invention 15 The invention provides compounds that are useful for treating or preventing diseases or disorders that are mediated by lymphocyte interactions. In one embodiment, for compounds of Formula Ia or Ib, R 1 is phenyl, naphthyl or thienyl optionally substituted by C6loarylCo.4alkyl, C 2
    -
    9 heteroarylCo4alkyl, C3.scycloalkylCo.
    4 alkyl, C 3
    -
    8 heterocycloalkylCo. 4 alkyl or C1.
    6 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R 1 20 can be optionally substituted by one to five radicals chosen from halo, C 1
    .
    6 alkyl, C 1
    .
    6 alkoxy, halo-substituted-C 1
    .
    6 alkyl and halo-substituted-C 1
    .
    6 alkoxy; and any alkyl group of R 1 can optionally have a methylene replaced by an atom or group chosen from -S-, -S(O)-, S(0) 2 -, -NR 5 - and -0-; wherein R 5 is hydrogen or C I- 6 alkyl. In another embodiment, Y is chosen from: 25 6 WO 2004/103306 PCT/US2004/015603 N I- TI - * N N S' zzI 0 R7
    R
    7 * * ;. - * - * ; K 1 ;and * - wherein R 7 is hydrogen or C 1
    _
    6 alkyl; and the left and right asterisks of Y indicate the point of attachment a) either between -C(R 2 )=NOWR and the -CR 3 R4-, or between -CR 3
    R
    4 - and 5 C(R 2 )=NOWRi of Formula Ia, respectively, or b) either between -CR 3
    R
    4 - and W or between W and -CR 3
    R
    4 - of Formula Ib, respectively; wherein any aryl or heteroaryl of Y can be optionally substituted with 1 to 3 radicals chosen from halo, hydroxy, nitro, C I.
    6 alkyl,
    C
    1 .alkoxy, halo-substituted CI- 6 alkyl and halo-substituted C1.
    6 alkoxy. In a further embodiment, R 1 is chosen from: 10 R<, S <0O
    R
    9 ; R 9 r and R8 RS wherein the asterisk is the point of attachment of R, with W; Rg is C 6 -ioarylCo. 4 alkyl, C 2 -gheteroarylCo.
    4 alkyl, C 3 .scycloalkylCo.
    4 alkyl, C 3 .sheterocycloalkylCo.4alkyl or C 1 . 15 6 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R 8 can be optionally substituted by one to three radicals chosen from halo, C 1
    .
    6 alkyl, CI- 6 alkoxy, halo substituted-C 1 .-alkyl and halo-substituted-C 1
    .
    6 alkoxy; and any alkyl group of R 8 can optionally have a methylene replaced by an atom or group chosen from -S-, -S(O)-, S(O) 2 -, -NR 5 - and -0-; wherein R 5 is hydrogen or C 1
    .
    6 alkyl; and R 9 is chosen from halo, 20 C 1 6 alkyl, C 1 6 alkoxy, halo-substituted-C 1
    -
    6 alkyl and halo-substituted-C- 6 alkoxy. In another embodiment, A is -C(O)OH; Z is chosen from: 7 WO 2004/103306 PCT/US2004/015603 * 'N *** ; * * *-N * *; N N N * *.N
    R
    6 OH R F wherein the left and right asterisks of Z indicate the point of attachment between C(R 3 )(R4)- and A of Formula Ia or lb, respectively; R 6 is chosen from hydrogen and C 1 . 5 6 alkyl; and R 3 and R 4 are both hydrogen. In a further embodiment, Y is chosen from phenyl, pyridinyl, thienyl and furanyl; wherein any phenyl, pyridinyl, thienyl or furanyl of Y is optionally substituted with 1 to 3 radicals chosen from methyl, ethyl, cyclopropyl, chloro, bromo, fluoro and methoxy; or where Y is phenyl, R 6 can be attached to a carbon atom of Y to form 3,4-dihydro-1H 10 isoquinolin-2-yl. In another embodiment, W is a bond or methylene; Ri is chosen from:
    R
    8 n '- S <0O R9- and R 9
    R
    8
    R
    8 15 wherein R 8 is chosen from phenyl, cyclohexyl, thienyl, 3,3-dimethyl-butyl, pyridinyl, cyclopentyl and piperidinyl; wherein R 8 can be optionally substituted by 1 to 3 radicals chosen from trifluoromethyl, methoxy, fluoro, triflouromethoxy and methyl; and R 9 is chosen from trifluoromethyl, fluoro, methyl, chloro, methoxy and ethyl. Preferred compounds of the invention include: 3-{4-[I-(2-Trifluoromethyl-biphenyl 20 4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[l-(4-Cyclohexyl-3 trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionic acid, 1-{4-[1-(4 Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3 carboxylic acid, 3-({2-Chloro-6-[I-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl] pyridin-3-ylmethyl}-amino)-propionic acid, 3-({6-[1-(4-Cyclohexyl-3-trifluoromethyl 25 benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl}-amino)-propionic acid, 3-{4-[1 (Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 4-{4-[1-(Biphenyl-4 8 WO 2004/103306 PCT/US2004/015603 ylmethoxyimino)-ethyl]-benzylamino}-butyric acid, 1-{4-[1-(Biphenyl-4-ylmethoxyimino) ethyl]-benzyl} -azetidine-3-carboxylic acid, 1-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl] benzyl}-piperidine-3-carboxylic acid, {4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl] benzylamino} -acetic acid, 3-{4-[I-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino} 5 cyclopentanecarboxylic acid, 3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-ylmethoxyimino) ethyl]-benzylamino} -propionic acid, 3-{4-[I-(5-Phenyl-furan-2-ylmethoxyimino)-ethyl] benzylamino}-propionic acid, 3-{4-[1-(3'-Trifluoromethyl-biphenyl-4-ylmethoxyimino) ethyl]-benzylamino} -propionic acid, 3-{4-[1-(3-Trifluoromethyl-biphenyl-4 ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4'-Methoxy-biphenyl-4 10 ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(Biphenyl-3 ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4-Thiophen-2-yl benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4-Thiophen-2-yl-3 trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4'-Fluoro biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4' 15 Trifluoromethoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4 [1-(3'-Trifluoromethoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 1-{4-[I-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-azetidine-3 carboxylic acid, 1-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzyl} pyrrolidine-3-carboxylic acid, 1-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino) 20 ethyl]-benzyl}-piperidine-3-carboxylic acid, 3-{4-[1-(3'-Mcthoxy-biphenyl-4 ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 2-Hydroxy-3-{4-[1-(2 trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1 (4'-Methyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4 Phenyl-thiophen-2-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 1-{4-[1 25 (Biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-pyrrolidine-3-carboxylic acid, 3-{4-[1-(4 Furan-3-yl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4-Thiophen-3-yl 3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4 Thiophen-3-yl-2-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 2 Fluoro-3-{4-[I-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino} 30 propionic acid, 3-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyll benzylamino}-butyric acid, 3-{4-[1-(5-Phenyl-thiophen-2-yhnethoxyimino)-ethyl] 9 WO 2004/103306 PCT/US2004/015603 benzylamino}-propionic acid, 3-{4-[1-(4-Cyclohexyl-benzyloxyimino)-ethyl] benzylamino}-propionic acid, 3-{4-[1-(3-Fluoro-biphenyl-4-ylmethoxyimino)-ethyl] benzylamino}-propionic acid, 3-{4-[1-(4'-Fluoro-2-trifluoromethyl-biphenyl-4 ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4'-Methyl-2 5 trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1 (4-Furan-2-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4 [1-(2'-Fluoro-2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-(4-{1-[4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-benzyloxyimino]-ethyl} benzylamino)-propionic acid, 3-{4-[1-(4-Furan-3-yl-3-trifluoromethyl-benzyloxyimino) 10 ethyl] -benzylamino} -propionic acid, 3-{4-[1-(4-Pyridin-3-yl-benzyloxyimino)-ethyl] benzylamino}-propionic acid, 3-{4-[1-(4-Pyridin-4-yl-benzyloxyimino)-ethyl] benzylamino}-propionic acid, 3-{4-[1-(2-Fluoro-biphenyl-4-ylmethoxyimino)-ethyl] benzylamino}-propionic acid, 3-({2-Methoxy-6-[1-(2-trifluoromethyl-biphenyl-4 ylmethoxyimino)-ethyl)-pyridin-3-ylmethyl}-amino)-propionic acid, 3-{4-[1-(4-Cyclohexyl 15 3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionic acid, 3-{4-[1-(4 Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{2 Bromo-4-[1-(4-cyclohexyl-3-trifluoromethyl-bcnzyloxyimino)-ethyl]-benzylamino} propionic acid, 3-{4-[1-(4-Cyclopentyl-3-trifluoromethyl-benzyloxyimino)-ethyl] benzylamino}-propionic acid, 3-{2-Chloro-4-[1-(4-cyclohexyl-3-trifluoromethyl 20 benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-({6-[1-(4-Cyclohexyl-3 trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionic acid, 3-({5 [1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-thiophen-2-ylmethyl}-amino) propionic acid, 3-({5-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-2 ylmethyl}-amino)-propionic acid, 3-({5-[1-(4-Cyclohexyl-3-trifluoromethyl 25 benzyloxyimino)-ethyl]-furan-2-ylmethyl}-amino)-propionic acid, 3-({2-[1-(4-Cyclohexyl 3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-4-ylmethyl}-amino)-propionic acid, 3-{4 [1-(4-Cyclohexyl-3-fluoro-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{2 Chloro-4- [1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl] -benzylamino) propionic acid, 1-{6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl 30 pyridin-3-ylmethyl}-azetidine-3-carboxylic acid, 3-{2-Ethyl-4-[1-(4-piperidin-1-yl-3 trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4 10 WO 2004/103306 PCT/US2004/015603 Cyclohexyl-3-methyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionic acid, 3-(4 [1-(3-Chloro-4-cyclohexyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionic acid, 3 {4-[1-(4-Cyclohexyl-3-methoxy-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionic acid, 1-{4-[1-(4-Cyclohexyl-3-methoxy-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine 5 3-carboxylic acid, 3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2 methyl-benzylamino} -propionic acid, 1- {4-[1-(4-Cyclohexyl-3-trifluoromethyl benzyloxyimino)-ethyl]-2-methyl-benzyl}-azetidine-3-carboxylic acid, 3-{4-[1-(4 Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-cyclopropyl-benzylamino} propionic acid, 1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2 10 cyclopropyl-benzyl}-azetidine-3-carboxylic acid, 3-{2-Ethyl-4-[1-(2-trifluoromethyl biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 1-{4-[-(4-Cyclohexyl-3 ethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid, 1-{4-[1-(4 Cyclohexyl-3-methyl-benzyloxyimino)-ethyl] -2-ethyl-benzyl} -azetidine-3-carboxylic acid, 1-{2-Chloro-4-[1-(4-cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-benzyl}-azetidine-3 15 carboxylic acid, 3-{2-Chloro-4-[1-(4-cyclohexyl-3-ethyl-benzyloxyimino)-ethyl] benzylamino} -propionic acid, 3- {4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino) ethyl] -2-fluoro-benzylamino} -propionic acid, 1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl benzyloxyimino)-ethyl]-2-fluoro-benzyl}-azetidine-3-carboxylic acid, 3-{6-[1-(4 Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl} 20 propionic acid, 3-{6-[1-(4-Cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-3,4-dihydro-1H isoquinolin-2-yl}-propionic acid, 3-{4-[1-(2-Trifluoromethyl-biphenyl-4-yl) ethylideneaminooxymethyl]-benzylamino}-propionic acid, 3-{4-[1-(4-Cyclohexyl-3 trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-benzylamino}-propionic acid, 3-{4-[1 (4-Cyclohexyl-3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-2-ethyl 25 benzylamino}-propionic acid, 1-{4-[I-(4-Cyclohexyl-3-trifluoromethyl-phenyl) ethylideneaminooxymethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid and 1-{4-[1-(4 Cyclohexyl-3-ethyl-phenyl)-ethylideneaminooxymethyl]-2-ethyl-benzyl}-azetidine-3 carboxylic acid. Further, preferred compounds are also shown in the examples and table 1, infra. 30 The invention provides forms of the compound that have the hydroxyl or amine group present in a protected form; these function as prodrugs. Prodrugs are compounds that 11 WO 2004/103306 PCT/US2004/015603 are converted into an active drug form after administration, through one or more chemical or biochemical transformations. Forms of the compounds of the present invention that are readily converted into the claimed compound under physiological conditions are prodrugs of the claimed compounds and are within the scope of the present invention. Examples of 5 prodrugs include forms where a hydroxyl group is acylated to form a relatively labile ester such as an acetate ester, and forms where an amine group is acylated with the carboxylate group of glycine or an L-amino acid such as shrine, forming an amide bond that is particularly susceptible to hydrolysis by common metabolic enzymes. Compounds of Formula Ia or Ib can exist in free form or in salt form, e.g. addition 10 salts with inorganic or organic acids. Where hydroxyl groups are present, these groups can also be present in salt form, e.g. an ammonium salt or salts with metals such as lithium, sodium, potassium, calcium, zinc or magnesium, or a mixture thereof. Compounds of Formula Ia or Ib and their salts in hydrate or solvate form are also part of the invention. When the compounds of Formula Ia or Ib have asymmetric centers in the molecule, 15 various optical isomers are obtained. The present invention also encompasses enantiomers, racemates, diastereoisomers and mixtures thereof. Moreover, when the compounds of Formula Ia or Ib include geometric isomers, the present invention embraces cis-compounds, trans-compounds and mixtures thereof. Similar considerations apply in relation to starting materials exhibiting asymmetric carbon atoms or unsaturated bonds as mentioned above. 20 Methods and Pharmaceutical Compositions for Treating Immunomodulatory Conditions The compounds of Formula Ia or Ib in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. lymphocyte recirculation modulating properties, for example, as indicated by the in vitro and in vivo tests of Example 25 6 and are therefore indicated for therapy. Compounds of Formula Ia or Ib preferably show an EC 50 in the range of 1 x 10~" to I x 10' M, preferably less than 50nM. The compounds exhibit selectivity for one or more EDG/SlP receptors, preferably EDG-1/SIP-1. EDG 1/S1P-I selective modulators of the present invention can be identified by assaying a compound's binding to EDG-1/S1P-1 and one or more of the other EDG/SlP receptors (e.g., 30 EDG-3/S1P-3, EDG-5/SlP-2, EDG-6/S1P-4, and EDG-8/SIP-5). An EDG-1/S1P-1 selective modulator usually has an EC50 for the EDG-1/SlP-1 receptor in the range of 1 x 12 WO 2004/103306 PCT/US2004/015603 10-" to 1 x 10 M, preferably less than 50 nM, more preferably less than 5 nM. It also has an EC50 for one or more of the other EDG/S1P receptors that is at least 5, 10, 25, 50, 100, 500, or 1000 fold higher than its EC50 for EDG-1/S1P-1. Thus, some of the EDG-1/SIP-1 modulatory compounds will have an EC50 for EDG-1/SIP-1 that is less than 5 nM while 5 their EC50 for one or more of the other EDG/SlP receptors are at least 100 nM or higher. Other than assaying binding activity to the EDG/S 1 P receptors, EDG- 1/S1P-I selective agents can also be identified by examining a test agent's ability to modify a cellular process or activity mediated by an EDG/S1P receptor. The compounds of Formula Ia or lb are, therefore, useful in the treatment and/or 10 prevention of diseases or disorders mediated by lymphocytes interactions, for example in transplantation, such as acute or chronic rejection of cell, tissue or organ allo- or xenografts or delayed graft function, graft versus host disease, autoimmune diseases, e.g. rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or II and the disorders associated therewith, vasculitis, 15 pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic rhinitis/conjunctivitis, allergic contact dermatitis, inflammatory diseases optionally with underlying aberrant reactions, e.g. inflammatory bowel disease, Crohn's disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory 20 glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, ischemia/reperfusion injury, e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, traumatic shock, T cell lymphomas or T cell 25 leukemias, infectious diseases, e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, chronic bacterial infection, or senile dementia. Examples of cell, tissue or solid organ transplants include e.g. pancreatic islets, stem cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus. For the 30 above uses the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. 13 WO 2004/103306 PCT/US2004/015603 Furthermore, the compounds of Formula Ia or Ib are useful in cancer chemotherapy, particularly for cancer chemotherapy of solid tumors, e.g. breast cancer, or as an anti-angiogenic agent. The required dosage will of course vary depending on the mode of administration, 5 the particular condition to be treated and the effect desired. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral 10 administration comprise from ca. I to 50 mg active ingredient. The compounds of Formula Ia or Ib can be administered by any conventional route, in particular enterally, for example, orally, e.g. in the form of tablets or capsules, or parenterally, for example, in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form. 15 Pharmaceutical compositions comprising a compound of Formula Ia or Ib in free form or in pharmaceutically acceptable salt form in association with at least one pharmaceutical acceptable carrier or diluent can be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. The compounds of Formula Ia or lb can be administered in free form or in 20 pharmaceutically acceptable salt form, for example, as indicated above. Such salts can be prepared in a conventional manner and exhibit the same order of activity as the free compounds. In accordance with the foregoing the present invention further provides: 1.1 A method for preventing or treating disorders or diseases mediated by 25 lymphocytes, e.g. such as indicated above, in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound of Formula Ia or Ib or a pharmaceutically acceptable salt thereof; 1.2 A method for preventing or treating acute or chronic transplant rejection or T cell mediated inflammatory or autoimmune diseases, e.g. as indicated above, in a subject in 30 need of such treatment, which method comprises administering to said subject an effective amount of a compound of Formula Ia or lb or a pharmaceutically acceptable salt thereof; 14 WO 2004/103306 PCT/US2004/015603 1.3 A method for inhibiting or controlling deregulated angiogenesis, e.g. sphingosine- 1-phosphate (Si P) mediated angiogenesis, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of Formula Ia or Ib or a pharmaceutically acceptable salt thereof 5 1.4 A method for preventing or treating diseases mediated by a neo-angiogenesis process or associated with deregulated angiogenesis in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of Formula Ia or Ib or a pharmaceutically acceptable salt thereof. 2. A compound of Formula la or Ib, in free form or in a pharmaceutically 10 acceptable salt form for use as a pharmaceutical, e.g. in any of the methods as indicated under 1.1 to 1.4 above. 3. A pharmaceutical composition, e.g. for use in any of the methods as in 1.1 to 1.4 above comprising a compound of Formula Ia or Ib in free form or pharmaceutically acceptable salt form in association with a pharmaceutically acceptable diluent or carrier 15 therefor. 4. A compound of Formula Ia or Ib or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for use in any of the method as in 1.1 to 1.4 above. The compounds of Formula Ia or Ib may be administered as the sole active 20 ingredient or in conjunction with, e.g. as an adjuvant to, other drugs e.g. immunosuppressive or immunomodulating agents or other anti-inflammatory agents, e.g. for the treatment or prevention of allo- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders, or a chemotherapeutic agent, e.g. a malignant cell anti-proliferative agent. For example the compounds of Formula Ia or Ib may be used in combination with a calcineurin 25 inhibitor, e.g. cyclosporin A or FK 506; a mTOR inhibitor, e.g. rapamycin, 40-0-(2 hydroxyethyl)-rapamycin, CC1779, ABT578 or AP23573; an ascomycin having immunosuppressive properties, e.g. ABT-281, ASM981, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, 30 analogue or derivative thereof; immunosuppressive monoclonal antibodies, e.g. monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, 15 WO 2004/103306 PCT/US2004/015603 CD40. CD45, CD58, CD80, CD86 or their ligands; other immunomodulatory compounds, e.g. a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4Ig (for ex. designated ATCC 5 68629) or a mutant thereof, e.g. LEA29Y ; adhesion molecule inhibitors, e.g. LFA-i antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or a chemotherapeutic agent. By the tern "chemotherapeutic agent" is meant any chemotherapeutic agent and it includes but is not limited to, 10 1. an aromatase inhibitor, ii. an anti-estrogen, an anti-androgen (especially in the case of prostate cancer) or a gonadorelin agonist, iii. a topoisomerase I inhibitor or a topoisomerase II inhibitor, iv. a microtubule active agent, an alkylating agent, an antineoplastic antimetabolite 15 or a platin compound, v. a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid phosphatase activity, a further anti-angiogenic compound or a compound which induces cell differentiation processes, vi. a bradykinin 1 receptor or an angiotensin II antagonist, 20 vii. a cyclooxygenase inhibitor, a bisphosphonate, a histone deacetylase inhibitor, a heparanase inhibitor (prevents heparan sulphate degradation), e.g. PI-88, a biological response modifier, preferably a lymphokine or interferons, e.g. interferon 0, an ubiquitination inhibitor, or an inhibitor which blocks anti-apoptotic pathways, viii. an inhibitor of Ras oncogenic isoforms, e.g. H-Ras, K-Ras or N-Ras, or a 25 farnesyl transferase inhibitor, e.g. L-744,832 or DK8G557, ix. a telomerase inhibitor, e.g. telomestatin, x. a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase inhibitor, e.g. bengamide or a derivative thereof, or a proteosome inhibitor, e.g. PS-341, and/or 30 xi. a mTOR inhibitor. 16 WO 2004/103306 PCT/US2004/015603 The term "aromatase inhibitor" as used herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testo sterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atainestane, exemestane and formestane and, in particular, non-steroids, 5 especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g. breast tumors. The term "anti-estrogen" as used herein relates to a compound which antagonizes 10 the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. A combination of the invention comprising a chemotherapeutic agent which is an anti-estrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g. breast tumors. The term "anti-androgen" as used herein relates to any substance which is capable 15 of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide. The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. The term "topoisomerase I inhibitor" as used herein includes, but is not limited to 20 topotecan, irinotecan, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound Al in W099/17804). The term "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines 25 etoposide and teniposide. The term "microtubule active agent" relates to microtubule stabilizing and microtubule destabilizing agents including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolides and epothilones and 30 derivatives thereof, e.g. epothilone B or a derivative thereof. 17 WO 2004/103306 PCT/US2004/015603 The term "alkylating agent" as used herein includes, but is not limited to busulfan, chlorambucil, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or GliadelTm). The term "antineoplastic antimetabolite" includes, but is not limited to 5 5 fluorouracil, capecitabine, gemcitabine, cytarabine, fludarabine, thioguanine, methotrexate and edatrexate. The term "platin compound" as used herein includes, but is not limited to carboplatin, cis-platin and oxaliplatin. The term "compounds targeting/decreasing a protein or lipid kinase activity or 10 further anti-angiogenic compounds" as used herein includes, but is not limited to protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g. compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers), the vascular endothelial growth factor family of receptor tyrosine kinases 15 (VEGFR), the platelet-derived growth factor-receptors (PDGFR), the fibroblast growth factor-receptors (FGFR), the insulin-like growth factor receptor 1 (IGF- IR), the Trk receptor tyrosine kinase family, the Axl receptor tyrosine kinase family, the Ret receptor tyrosine kinase, the Kit/SCFR receptor tyrosine kinase, members of the c-Abl family and their gene fusion products (e.g. BCR-Abl), members of the protein kinase C (PKC) and Raf family of 20 serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK or PI(3) kinase family, or of the PI(3)-kinase-related kinase family, and/or members of the cyclin-dependent kinase family (CDK) and anti-angiogenic compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition. Compounds which target, decrease or inhibit the activity of VEGFR are especially 25 compounds, proteins or antibodies which inhibit the VEGF receptor tyrosine kinase, inhibit a VEGF receptor or bind to VEGF, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 98/35958, e.g. 1-(4 chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g. the succinate, in WO 00/27820, e.g. a N-aryl(thio) anthranilic acid amide derivative e.g. 30 2-[(4-pyridyl)methyl]amino-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide or 2-[(1 oxido-4-pyridyl)methyl]amino-N-[3-trifluoromethylphenyl]benzamide, or in WO 00/09495, 18 WO 2004/103306 PCT/US2004/015603 WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; those as described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218, by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp. 14765-14770, Dec. 1996, by Z. Zhu et al in Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti et al in Toxicologic Pathology, Vol. 27, no. 1, pp 14-21, 5 1999; in WO 00/37502 and WO 94/10202; Angiostatin
    TM
    , described by M. S. O'Reilly et al, Cell 79, 1994, 315-328; Endostatin
    TM
    , described by M. S. O'Reilly et al, Cell 88, 1997, 277 285; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF antibodies or anti-VEGF receptor antibodies,e.g. RhuMab. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, 10 multispecific antibodies formed from at least 2 intact antibodies, and antibody fragments so long as they exhibit the desired biological activity. Compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and 15 ErbB4 or bind to EGF or EGF related ligands, or which have a dual inhibiting effect on the ErbB and VEGF receptor kinase and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g. the compound of ex. 39, or 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 20 97/38983 and, especially, WO 96/30347 (e.g. compound known as CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g. compound ZM105180) or PCT/EP02/08780; e.g. trastuzumab (HerpetinR), cetuximab, Iressa, OSI-774, CI-1033, EKB 569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3. Compounds which target, decrease or inhibit the activity of PDGFR are especially 25 compounds which inhibit the PDGF receptor, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib. Compounds which target, decrease or inhibit the activity of c-AbI family members and their gene fusion products are, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib; PD180970; AG957; or NSC 680410. 30 Compounds which target, decrease or inhibit the activity of protein kinase C, Raf, MEK, SRC, JAK, FAK and PDK family members, or PI(3) kinase or PI(3) kinase-related 19 WO 2004/103306 PCT/US2004/015603 family members, and/or members of the cyclin-dependent kinase family (CDK) are especially those staurosporine derivatives disclosed in EP 0 296 110, e.g. midostaurin; examples of further compounds include e.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; or 5 LY333531/LY379196. Further anti-angiogenic compounds are e.g. thalidomide (THALOMID) and TNP 470. Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are, e.g. inhibitors of phosphatase 1, phosphatase 2A, PTEN or CDC25, e.g. 10 okadaic acid or a derivative thereof. Compounds which induce cell differentiation processes are, e.g. retinoic acid, X-, y- or 8-tocopherol or cc-, y- or 8-tocotrienol. The term cyclooxygenase inhibitor as used herein includes, but is not limited to, e.g. celecoxib (CelebrexR), rofecoxib (VioxxR), etoricoxib, valdecoxib or a 5-alkyl-2 15 arylaminophenylacetic acid, e.g. 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid. The term "histone deacetylase inhibitor" as used herein includes, but is not limited to MS-27-275, SAHA, pyroxamide, FR-901228 or valproic acid. The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. 20 The term "matrix metalloproteinase inhibitor" as used herein includes, but is not limited to collagen peptidomimetic and non-petidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, prinomastat, BMS-279251, BAY 12-9566, TAA211 or AAJ996. The term "mTOR inhibitor" as used herein includes, but is not limited to 25 rapamycin (sirolimus) or a derivative thereof, e.g. 32-deoxorapamycin, 16-pent-2-ynyloxy 32-deoxorapamycin, 16-pent-2-ynyloxy-32(S)-dihydro-rapamycin, 16-pent-2-ynyloxy 32(S)-dihydro-40-0-(2-hydroxyethyl)-rapamycin and, more preferably, 40-0-(2-hydroxy ethyl)-rapamycin. Further examples of rapamycin derivatives include e.g. CC1779 or 40- [3 hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin or a pharmaceutically 30 acceptable salt thereof, as disclosed in USP 5,362,718, ABT578 or 40-(tetrazolyl) 20 WO 2004/103306 PCT/US2004/015603 rapamycin, particularly 40-epi-(tetrazolyl)-rapamycin, e.g. as disclosed in WO 99/15530, or rapalogs as disclosed e.g. in WO 98/02441 and WO01/14387, e.g. AP23573. Where the compounds of Formula Ia or Ib are administered in conjunction with other immunosuppressive / immunomodulatory, anti-inflammatory or chemotherapeutic 5 therapy, dosages of the co-administered immunosuppressant, immunomodulatory, anti inflammatory or chemotherapeutic compound will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a calcineurin inhibitor, on the specific drug employed, on the condition being treated and so forth. In accordance with the foregoing the present invention provides in a yet further 10 aspect: 5. A method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective non-toxic amount of a compound of Formula Ia or Ib and at least a second drug substance, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic drug, e.g. as indicated above. 15 6. A pharmaceutical combination, e.g. a kit, comprising a) a first agent which is a compound of Formula Ia or Ib as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic drug, e.g. as disclosed above. The kit may comprise instructions for its administration. 20 The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product that results 25 from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of Formula Ia or Tb and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of Formula Ia 30 or lb and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such 21 WO 2004/103306 PCT/US2004/015603 administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients. 5 Methods for Preparing Compounds of the Invention The present invention also includes processes for the preparation of immunomodulatory compounds of the invention. In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted 10 participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991. Compounds of Formula Ia, in which A is R 5 OC(O)- and R 3 and R 4 are hydrogen, can be prepared by proceeding as in the following reaction scheme: 15
    R
    5 0 Z O (3) 0 O Y>..N .W. N 1) Et 3 N, MeOH 'A' R O''R mR5O Z Y NO', R 2) NaBH 4 2 R2 (2) (Ia) in which W, Y, Z, R 1 , R 2 , and R 5 are as defined for Formula Ta above. Compounds of Formula I can be prepared by reacting a compound of formula 2 with a compound of 20 formula 3 in the presence of a suitable solvent (e.g. methanol, and the like), a suitable base (e.g. triethylamine, and the like) and a suitable reducing agent (e.g. sodium borohydride). The reaction proceeds at a temperature of about 0 to about 60*C and can take up to about 48 hours to complete. 25 Compounds of Formula Ib, in which A is RSOC(O)- and R 3 and R 4 are hydrogen, can be prepared by proceeding as in the following reaction scheme: 22 WO 2004/103306 PCT/US2004/015603
    R
    5 0 Z o R 4
    R
    3 R2.. .
    (3) A R 0 Y, W .ON R 1) Et3N, MeOH Z N R 1 2) NaBH 4 (4) (Ib) in which W, Y, Z, R 1 , R 2 , and R 5 are as defined for Formula lb above. Compounds of Formula I can be prepared by reacting a compound of formula 4 with a compound of 5 formula 3 in the presence of a suitable solvent (e.g. methanol, and the like), a suitable base (e.g. triethylamine, and the like) and a suitable reducing agent (e.g. sodium borohydride). The reaction proceeds at a temperature of about 0 to about 60 0 C and can take up to about 48 hours to complete. 10 Additional Processes for Preparing Compounds of the Invention: A compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the 15 free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates. The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For 20 example a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.). 25 Compounds of the invention in unoxidized form can be prepared from N-oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, 23 WO 2004/103306 PCT/US2004/015603 tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 0 C. Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), 5 Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like). Protected derivatives of the compounds of the invention can be made by means 10 known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T W. Greene, "Protecting Groups in Organic Chemistry", 3 rd edition, John Wiley and Sons, Inc., 1999. Compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of 15 the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol. Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to 20 forma pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can 25 be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography, or preferable, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of 30 compounds from the their racemic mixture can be found in Jean Jacques, Andre Collet, 24 WO 2004/103306 PCT/US2004/015603 Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981. In summary, the compounds of Formula Ia or lb can be made by a process, which involves: 5 (a) reacting a compound of formula 2 or 4 with a compound of formula 3; and (b) optionally converting a compound of the invention into a pharmaceutically acceptable salt; (c) optionally converting a salt form of a compound of the invention to a non-salt form; 10 (d) optionally converting an unoxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide; (e) optionally converting an N-oxide form of a compound of the invention to its unoxidized form; (f) optionally resolving an individual isomer of a compound of the invention from 15 a mixture of isomers; (g) optionally converting a non-derivatized compound of the invention into a pharmaceutically acceptable prodrug derivative; and (h) optionally converting a prodrug derivative of a compound of the invention to its non-derivatized form. 20 Insofar as the production of the starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter. One of skill in the art will appreciate that the above transformations are only representative of methods for preparation of the compounds of the present invention, and 25 that other well known methods can similarly be used. EXAMPLES The following examples provide detailed descriptions of the preparation of representative compounds and are offered to illustrate, but not to limit the present invention. 25 WO 2004/103306 PCT/US2004/015603 Example 1 3- {44 1 -(2-Trifluoromethyl-biphenyl-4-ylmethoxvimino)-ethyll -benzylamino}-propionic acid 0 HO N H N,
    CF
    3 5 To a solution of 1-(4-hydroxymethyl-phenyl)-ethanone (1 eq) in methanol is added O-(4-chloro-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed by the addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 5 hours. After concentrated, the residue is purified by column chromatography (30% EtOAc in hexane) to 10 give 1-(4-hydroxymethyl-phenyl)-ethanone O-(4-chloro-3-trifluoromethyl-benzyl)-oxime as an oil [MS: (ES*) 358.1 (M+1)*]. A mixture of 1-(4-hydroxymethyl-phenyl)-ethanone O-(4-chloro-3-trifluoromethyl benzyl)-oxime (1 eq), phenyl boronic acid (1.5 eq), Pd(OAc) 2 (0.03 eq), phosphine ligand (0.06 eq) and KF (3 eq) in dry THF is heated at 100 0 C in microwave for 30 minutes. The 15 resulting mixture is diluted with EtOAc and washed with brine. The organic layer is dried over Na 2
    SO
    4 . After concentration, the residue is purified by column chromatography (30% EtOAc in hexane) to give 1-(4-hydroxymethyl-phenyl)-ethanone O-(2-trifluoromethyl biphenyl-4-ylmethyl)-oxime as a white solid [MS: (ES*) 400.1 (M+1)+]. To a suspension of MnO 2 (10 eq) in dioxane is added 1-(4-hydroxymethyl-phenyl) 20 ethanone O-(2-trifluoromethyl-biphenyl-4-ylmethyl)-oxime (1 eq). The resulting mixture is refluxed for 10 minutes. After filtration and concentration, the residue is dissolved in MeOH and treated with p-alanine (2 eq) and Et 3 N (1.5 eq). The resulting mixture is heated at 50 0 C for 30 minutes. After cooling to room temperature, NaBH 4 (3 eq) is added in portions. Purification by preparative LCMS results in 3- {4- [1-(2-trifluoromethyl-biphenyl-4 25 ylmethoxyimino)-ethyl]-benzylamino}-propionic acid; 'H NMR (400 MHz, CD 3 0D) 6 2.28 (s, 3H), 2.75 (t, J= 6.8 Hz, 2H), 3.26 (t, J= 6.8 Hz, 2H), 4.22 (s, 2H), 5.30 (s, 2H), 7.26 7.77 (in, 12H). MS: (ES+): 471.1 (M+1)*. 26 WO 2004/103306 PCT/US2004/015603 Example 2 3-{4-F1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxvimino)-ethyll-2-ethyl-benzylamino} propionic acid 0 HO N H I N,
    CF
    3 5 A mixture of 4-amino-3-ethyl-benzonitrile (5 mmol) and water (10 mL) is placed in a flask equipped with a magnetic stirrer and a thermometer probe. Concentrated hydrochloric acid (1.2 mL) is added slowly. After most of the solid is dissolved, ice (20 g) is added and the temperature is kept at 0*C using an ice-salt bath. To the stirred mixture is added a solution of sodium nitrite (5 mmol) in water (2.5 mL), dropwise. The mixture is 10 stirred at 0"C for 30 minutes. A solution of hydrated sodium acetate in water is added to adjust the pH to neutral. In a separate flask, a mixture of formaldoxime trimer hydrochloride (7.5 mmol), hydrated cupric sulfate (0.52 mmol), sodium sulfite (0.15 mmol) and a solution of sodium acetate (20 mmol) is prepared, and is cooled to 0 0 C. 15 The mixture of the diazonium salt is slowly added to the above mixture. After addition, the mixture is stirred at 0"C for 1.5 hours, treated with concentrated hydrochloric acid (4.4 mL) and heated to reflux overnight. The mixture is cooled to room temperature, and extracted with ethyl acetate. The combined ethyl acetate layers are washed with a saturated aqueous NaHCO 3 , brine, dried 20 over MgSO 4 , and concentrated to give dark oil. 3-Ethyl-4-formyl-benzonitrile is isolated by column chromatography (EtOAc/Hexane gradient). To a solution of 3-ethyl-4-formyl-benzonitrile (1.7 mmol) in ethanol (10 mL) at 0 0 C is added NaBH 4 (1.7 mmol). The mixture is stirred at 0 0 C for 0.5 hour, 5% citric acid (5 mL) is added and the solvent is removed under reduced pressure. The mixture is dissolved 25 in EtOAc (50 mL), washed with saturated aqueous NaHCO 3 , and brine. The separated organic layer is dried over MgSO 4 , filtered and concentrated. 3-Ethyl-4-hydroxymethyl benzonitrile is purified by column chromatography. 27 WO 2004/103306 PCT/US2004/015603 To a solution of 3-ethyl-4-hydroxymethyl-benzonitrile (1.21 mmol) in dry THF under N 2 is added methyl magnesium bromide (3.63 mmol, 3.0 M in diethyl ether). The mixture is heated to reflux overnight. The mixture is cooled, concentrated HC (10 mL) is added and the mixture is extracted with EtOAc. The combined EtOAc layers are washed 5 with saturated aqueous NaHCO 3 and brine. The organic layer is separated, dried over MgSO 4 , filtered and concentrated. The crude product 1-(3-ethyl-4-hydroxymethyl-phenyl) ethanone is carried to the next step without further purification. To a solution of 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone (1 eq) in methanol is added O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed by the 10 addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 12 hours. After concentration, the residue is purified by column chromatography (30% EtOAc in hexane) to give 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone O-(4-cyclohexyl-3 trifluoromethyl-benzyl)-oxime as an oil [MS: (ES*) 434.2 (M+1)*]. To a suspension of MnO 2 (10 eq) in dioxane is added 1-(3-ethyl-4-hydroxymethyl 15 phenyl)-ethanone O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime (1 eq). The resulting mixture is refluxed for 10 minutes. After filtration and concentration, the residue is dissolved in MeOH and treated with p-alanine (2 eq) and Et 3 N (1.5 eq). The resulting mixture is heated at 50 0 C for 30 minutes. After cooling to room temperature, NaBH 4 (3 eq) is added in portions. Purification by preparative LCMS results in 3-{4-[1-(4-cyclohexyl-3 20 trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionic acid; 'H NMR (400 MHz, CD 3 0D) 3 1.25 (t, 3H), 1.45 (m, 5H), 1.85 (in, 5H), 2.28 (s, 3H), 2.79 (m, 4H), 2.95 (in, 1H), 3.36 (t, 2H), 4.31 (s, 2H), 5.26 (s, 2H) 7.42-7.68 (m, 6H). MS: (ES+): 505.3 (M+1)+. 25 28 WO 2004/103306 PCT/US2004/015603 Example 3 1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxvimino)-ethyll-2-ethyl-benzyl)-azetidine 3-carboxylic acid fN HO N N'O
    CF
    3 0K 5 To a suspension of MnO 2 (10 eq) in dioxane is added 1-(3-ethyl-4-hydroxymethyl phenyl)-ethanone O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime (1 eq). The resulting mixture is refluxed for 10 minutes. After filtration and concentration, the residue is dissolved in MeOH and treated with azetidine-3-carboxylic acid (2 eq) and Et 3 N (1.5 eq). 10 The resulting mixture is heated at 50 0 C for 30 minutes. After cooling to room temperature, NaBH 3 CN (3 eq) is added in portions. Purification by preparative LCMS results in 1-{4-[1 (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl} -azetidine-3 carboxylic acid; 'H NMR (400 MHz, CD 3 0D) 8 1.24 (t, 3H), 1.30-1.60 (in, 5H), 1.74-1.92 (in, 5H), 2.28 (s, 3H), 2.79 (q, 2H), 2.92 (in, 1H), 3.68 (in, IH), 4.32 (m, 4H), 4.51 (s, 2H) 15 5.22 (s, 2H), 7.38 (d, 1H), 7.50-7.68 (in, 5H). MS: (ES+): 517.3 (M+1)+. Example 4 3-({2-Chloro-6-[ 1-(4-cyclohexyl-3-trifluoromethyl-benzyloxvimino)-ethyll-pyridin-3 vlmethyll-amino)-propionic acid 0 HO N HCI N N O
    CF
    3 20 To a solution of 1-(6-chloro-5-methyl-pyridin-2-yl)-ethanone (1 eq) in CC1 4 is added NBS (1 eq) and BPO (0.1 eq). The mixture is refluxed for 12 hours. After concentration, 1-(5-bromomethyl-6-chloro-pyridin-2-yl)-ethanone is isolated by flash column chromatography. MS: (ES*): 247.9 (M+1)+. 29 WO 2004/103306 PCT/US2004/015603 To a solution of 3-amino-propionic acid tert-butyl ester hydrochloride (1.5 eq) in DMF is added NaH (3.5 eq). The resulting mixture is stirred at room temperature for 15 minutes and a solution of 1-(5-bromomethyl-6-chloro-pyridin-2-yl)-ethanone (1 eq) in DMF is then added. After stirring for 3 hours, it is partitioned with 20% EtOAc/hexane and H 2 0. 5 The organic layer is washed with brine and dried. After concentration, 3-[(6-acetyl-2 chloro-pyridin-3-ylmethyl)-amino]-propionic acid tert-butyl ester is isolated by flash column chromatography. MS: (ES t ): 313.1 (M+1)*. To a solution of 3-[(6-acetyl-2-chloro-pyridin-3-ylmethyl)-amino]-propionic acid tert-butyl ester (1 eq) in methanol is added 0-(4-chloro-3-trifluoromethyl-benzyl) 10 hydroxylamine (1 eq) followed by the addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 5 hours. After concentration, the residue is purified by column chromatography to give 3-({2-chloro-6-[1-(4-cyclohexyl-3-trifluoromethyl benzyloxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionic acid tert-butyl ester. MS: (ES*) 568.3 (M+ I)+. The tert-butyl group is subsequently removed by treatment with 15 TFA/DCM (1/1) at room temperature. The final compound 3-({2-chloro-6-[1-(4 cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethyl} -amino)-propionic acid is purified by preparative LCMS. 'H NMR (400 MHz, CD 3 0D) 8 1.28-1.60 (m, 5H), 1.71-1.92 (in, 5H), 2.30 (s, 3H), 2.79 (t, 2H), 2.90 (in, 1H), 3.38 (t, 2H), 4.42 (s, 2H), 5.29 (s, 2H), 7.38 (d, 1H), 7.50-7.68 (m, 3H), 7.94 (s, 2H). MS: (ES+): 512.2 (M+1)*. 20 Example 5 3-(f{6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxvimino)-ethyl]-2-ethyl-pyridin-3 ylmethyll-amino)-propionic acid 0 HO N H N, CF3 25 A mixture of 3-[(6-acetyl-2-chloro-pyridin-3-ylmethyl)-amino]-propionic acid tert butyl ester (1 eq), tributyl-vinyltin (1.2 eq), Pd(PPh 3
    )
    4 (0.05 eq), and LiC1 (3 eq) in dioxane is heated at 100 0 C for 12 hours. The reaction mixture is diluted with EtOAc and stirred 30 WO 2004/103306 PCT/US2004/015603 together with aqueous KF for 10 minutes. It is then filtered through celite and the organic layer is washed with brine. After concentration, the residue is purified by flash column chromatography to give 3-[(6-cetyl-2-vinyl-pyridin-3-ylmethyl)-amino]-propionic acid tert butyl ester. MS: (ES*): 305.2 (M+1)*. 5 The above compound is dissolved in EtOH and hydrogenated in the presence of 10% Pd-C. After filtration and concentration, the crude product 3-[(6-acetyl-2-ethyl-pyridin 3-ylmethyl)-amino]-propionic acid tert-butyl ester is used directly in the next step without further purification. To a solution of 3-[(6-acetyl-2-ethyl-pyridin-3-ylmethyl)-amino]-propionic acid 10 tert-butyl ester (1 eq) in methanol is added O-(4-chloro-3-trifluoromethyl-benzyl) hydroxylamine (1 eq) followed by the addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 5 hours. After concentration, the residue is purified by column chromatography to give 3-({6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) ethyl]-2-ethyl-pyridin-3 -ylmethyl} -amino)-propionic acid tert-butyl ester. MS: (ES*) 562.3 15 (M+1)*. The tert-butyl group is subsequently removed by treatment with TFA/DCM (1/1) at room temperature. The final compound 3-({6-[I-(4-cyclohexyl-3-trifluoromethyl benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl)-amino)-propionic acid is purified by preparative LCMS. 'H NMR (400 MHz, CD 3 0D) 8 1.30-1.62 (m, 8H), 1.72-1.91 (in, 5H), 2.36 (s, 3H), 2.78 (t, 2H), 2.94 (in, 311), 3.37 (t, 211), 4.42 (s, 2H), 5.29 (s, 2H), 7.51-7.80 (m, 20 5H). MS: (ES*): 506.3 (M+1)+. By repeating the procedure described in the above examples, using appropriate starting materials, the following compounds of Formula Ia or lb can be synthesized (Table 1). 25 TABLE 1 Physical Compound Structure Data MS ES (M+1) 31 WO 2004/103306 PCT/US2004/015603 Physical Compound Structure MS ES (M+1) NO OH 7 O N O417.2 - N 0 OH 'NN f__ OH O N__ OO 415.2 OH 11 OH 443.2 O,'N 1 H ... 389.2 O-N' /N OH 142 FC OH 471.2 13N H /93 OH OH 14 / . H 471 .2
    F
    3 CQ
    /_O
    32 WO 2004/103306 PCT/US2004/015603 Physical Compound Structure MS ES (M+1)
    CF
    3 OH 15 H O 471.2 1N N 4 MeO OH 16 O N H 433.2 N N 17 01403.2 9N H NO OH 18 / Os 409.2 H N 0 OH 3CF 3 19 01 'N 1 477.2 x N 0 OH 20 01 N~ 421.1 OH 33 WO 2004/103306 PCT/US2004/015603 Physical Compound Structure DSES (M+1)
    F
    3 CO 21 O 487.2 N 0 OH
    F
    3 CO 22 FC N 487.2 NO OH 23 ON 483.1 OH
    CF
    3 24 O N O 497.2 N OH -~ CF 3 25 0 N 511.2 OH 34 WO 2004/103306 PCT/US2004/015603 Physical Compound Structure MS ES (M+1) OH 26 N H 433.2 MeN O CF3 27 01 N H OH 31.9 OH 28 N O OH 3N N O 417.2 / N 0 OH /S _;- 01 NN OH 30 01 N 429.2 OH 35 WO 2004/103306 PCT/US2004/015603 Physical Compound Structure MS ES (M+1) 31 0 H 393.2 H O ~- N 0 OH sc: CF 3 32 N 477.2 N 0 OH
    CF
    3 33 0 N 477.2 N 0 OH - Q F 3 34 0 N N F 489.2 N -N 0 OH
    CF
    3 35 0 ' H 485.2 H H 3N OH 36 WO 2004/103306 PCT/US2004/015603 Physical Compound Structure MS ES (M+1) 36 N H 409.2 N OH 37 O N H409.2 37- NN NO OH 38 N H N 0 OH CF3 39 / N 489.2 H N 0 OH 37 WO 2004/103306 PCT/US2004/015603 Physical Compound Structure MS ES (M+I1)
    CF
    3 40 0H 485.2 NN 0 OH 41 AN 461.2 H S N 0 OH
    CF
    3 42 F / ON 489.2 H ,- N O OH
    CF
    3 43 01 N- 479.2 IH - N 0 OH 38 WO 2004/103306 PCT/US2004/015603 Physical Compound Structure MS ES (M+1) F F,
    CF
    3 44 N H 507.2 N OH N 0 OH 46 0 404.2 47N O-N H 404.2 48 O N 421.2 OH 46 N 0 OH 0 HO N 49 H 0 N CF 3 502.2 39 WO 2004/103306 PCT/US2004/015603 Physical Compound Structure MS ES (M+1) 0
    CF
    3 50 NO O 505.3 H
    N-
    0 / 0
    CF
    3 51 /-N HO N- 0 / 477.2 O0/
    CF
    3 52 HO O 555.1 HO- Br N- 0 53o O
    CF
    3 53 N OO 463.2 0
    CF
    3 54 HO O 511.2 HO CI
    N-
    0 / O0/
    CF
    3 55 HOOH N 478.2 HO N- 0 /G HO H C 56 S 483.2 0
    N-
    0 / 0
    CF
    3 HO
    NO
    0 H / 478.2 HO~ H
    CF
    3 58 0' 0 467.2 59 HO N O 478.2 40 60 IN l 427. ,O H
    N-
    0 /O 427. 40 WO 2004/103306 PCT/US2004/015603 Physical Compound Structure MS ES (M+1) 61 HO O 512.2 HO NO CF3 62 o 518.3 0 HO N 63 HO N 0
    CF
    3 506.3 0 HO N "N 64 N- N 451.3 0 HO N 65 H N' CI 471.2 0
    CH
    3 )7N N_ 66 HO H N'-0 467.3
    OCH
    3 N N/ 67 HO N 479.3 0 ~ CF 3 68 HO N N 491.3 41 WO 2004/103306 PCTIUS2004/015603 Physical Compound Structure MS ES (M+1)
    CF
    3 69 HO N N 503.2 0 ,0 03. 70 HO HN'-' N-.
    0 517.3
    CF
    3 1 HO 529.3 71 HO 0 HO N 72 H N 0 CF 3 499.2 F-N 73 HO NNO 1 477.3 0 74 HO N N 463.3 75 HO N N-O 483.2 76 HO N O, 471.2 0 FN
    N-CF
    3 77 HO FN 7 HN 0 495.2 42 WO 2004/103306 PCTIUS2004/015603 Physical Compound Structure MS ES (M+1)
    CF
    3 78 HO NF N 507.2 79 HO 0 N 503.2 80 HO N 463.3 81 HoN OHN 0 /-ONCF 3 82 HO" H O N 0 CF 3 83 HO N O N 'I
    CF
    3 84 HO N O N 85 HO N N HO 0 Example 6 Compounds of Formula Ia or Ib Exhibit Biological Activity 43 WO 2004/103306 PCT/US2004/015603 A. In vitro: GPCR activation assay measuring GTP [y- 35 S1 binding to membranes prepared from CHO cells expressing human EDG receptors EDG-1 (SIPi) GTP [y- 35 S] binding assay: Homogenized membranes are prepared from CHO cell clones stably expressing a human EDG-l N-terminal c-myc tag. Cells are 5 grown in suspension in two 850 cm 2 roller bottles for three or fours days before harvesting. The cells are centrifuged down, washed once with cold PBS, and resuspended in 20 ml of Buffer A (20 mM HEPES, pH 7.4, 10 mM EDTA, EDTA-free complete protease inhibitor cocktail [1 tablet/25 ml]). The cell suspension is homogenized on ice, using a Polytron homogenizer at 30000 rpm at three intervals of 15 seconds each. The homogenate is first 10 centrifuged at 2000 rpm on a tabletop low speed centrifuge for 10 minutes. The supernatant, after passing through a cell strainer, is then re-centrifuged at 50,000 x g for 25 minutes at 4*C. The pellet is resuspended into buffer B (15% glycerol, 20 mM HEPES, pH 7.4, 0.1 mM EDTA, EDTA-free complete protease inhibitor cocktail [1 tablet/10 ml]). Protein concentration of the prep is determined using the BCA Protein Assay kit (Pierce) using BSA 15 as standard. The membranes are aliquoted and kept frozen at -80*C. Solutions of test compounds ranging from 10mM to 0.01nM are prepared in DMSO. SIP is diluted in 4% BSA solution as positive controls. The desired amount of membrane prep is diluted with ice-cold assay buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl 2 , 0.1% Fatty acid-free BSA, 5 pM GDP) and vortexed well. 2 pl or 20 less of compound is distributed into each well of a round-bottom 96-well polystyrene assay plate, followed by addition of 100 pl of diluted membranes (3-10 pg/well) and kept on ice until the addition of hot GTPyS. [ 35 S]-GTPyS is diluted 1:1000 (v/v) with cold assay buffer and 100 pl is added into each well. The reaction is carried out at room temperature for 90 minutes before the membranes are harvested onto Perkin-Elmer Unifilter* GF/B-96 filter 25 plate using a Packard Filtermate Harvester. After several washes with wash buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgC 2 ), and a rinse with 95% ethanol, the filter is dried in a 37'C oven for 30 minutes. MicroScint-20 is added and the plate sealed for scintillation counting on TopCount. EC50 values are obtained by fitting the GTP [y- 35 S] binding curves (raw data) with the dose response curve-fitting tool of GraphPad Prism. Six 30 or twelve different concentrations are used to generate a concentration response curve (using three data points per concentration). 44 WO 2004/103306 PCT/US2004/015603 EDG-3,-5,-6 and -8 GTP [y- 35 S] binding assays are carried out in a comparable manner to the EDG-1 GTP [y- 35 S] binding assay using membranes from CHO cells stably expressing c-terminal c-myc tagged or untagged receptors. For each membrane preparation, titration experiments are first run with Si P control to determine the optimal amount of 5 membranes to be added per assay well. Compounds of the invention were tested according to the above assay and were observed to exhibit selectivity for the EDG- 1 receptor. For example, 3-{4-Fl-( 4 -cvclohexyl-3-trifluoromethyl-benzloxvimino)-ethyll-2-ethyl benzylaminol-propionic acid (example 2) has an EC 50 of 0.8 nM in the above assay and is at least 1000 fold selective for EDG-1 compared to one or more of the other receptors 10 including EDG-3, EDG-5, EDG-6 and EDG-8. Similarly, 1-{4-fl-(4-Cyclohexyl-3 trifluoromethyl-benzyloxvimino)-ethyll-2-ethyl-benzyl}-azetidine-3-carboxylic acid (example 3) has an EC 5 0 of 0.2 nM in the above assay and is at least 1000 fold selective for EDG- I compared to one or more of the other receptors including EDG-3, EDG-5, EDG-6 and EDG-8. 15 B. In vitro: FLIPR calcium flux assay Compounds of the invention are tested for agonist activity on EDG-1, EDG-3, EDG-5, and EDG-6 with a FLIPR calcium flux assay. Briefly, CHO cells expressing an EDG receptor are maintained in F-12K medium (ATCC), containing 5% FBS, with 500ug/ml of G418. Prior to the assay, the cells are plated in 384 black clear bottom plates at the density of 20 10,000 cells/well/25pL in the medium of F-12K containing 1% FBS. The second day, the cells are washed three times (25 1./each) with washing buffer. About 25 pl of dye are added to each well and incubated for 1 hour at 37"C and 5% CO 2 . The cells are then washed four times with washing buffer (25 pl./each). The calcium flux is assayed after adding 25 [1 of SEQ2871 solution to each well of cells. The same assay is performed with cells expressing 25 each of the different EDG receptors. Titration in the FLIPR calcium flux assay is recorded over a 3-minute interval, and quantitated as maximal peak height percentage response relative to EDG- 1 activation. 45 WO 2004/103306 PCT/US2004/015603 C. In vivo: Screenin2 Assays for measurement of blood lymphocyte depletion and assessment of heart effect Measurement of circulating lymphocytes: Compounds are dissolved in DMSO and diluted to obtain a final concentration of 4% DMSO (v/v, final concentration) and then 5 further diluted in a constant volume of Tween80 25%/H20, v/v. Tween80 25%/H20 (200 pl), 4% DMSO, and FTY720 (10pg) are included as negative and positive controls, respectively. Mice (C57bl/6 male, 6-10 week-old) are administered 250-300 pL of compound solution orally by gavages under short isoflurane anesthesia. Blood is collected from the retro-orbital sinus 6 and 24 hours after drug 10 administration under short isoflurane anesthesia. Whole blood samples are subjected to hematology analysis. Peripheral lymphocyte counts are determined using an automated analyzer. Subpopulations of peripheral blood lymphocytes are stained by fluorochrome conjugated specific antibodies and analyzed using a fluorescent activating cell sorter (Facscalibur). Two mice are used to assess the lymphocyte depletion activity of each 15 compound screened. The result is an ED 50 , which is defined as the effective dose required displaying 50 % of blood lymphocyte depletion. Compounds of the invention were tested according to the above assay and were preferably found to exhibit an ED 5 o of less than 1mg/kg, more preferably an ED 50 of less than 0.5 mg/kg. For example, 3-{4-[1-(4 cyclohexyl-3-trifluoromethyl-benzyloxvimino)-ethyll-2-ethyl-benzylaminol-propionic acid 20 (example 2) exhibits an ED50 of 0.07 mg/kg. Further, 1-{4-[1-(4-Cyclohexyl-3 trifluoromethyl-benzyloxvimino)-ethyll-2-ethyl-benzyll-azetidine-3-carboxylic acid (example 3) exhibits and ED50 of 0.1 mg/kg. Assessment of Heart Effect: The effects of compounds on cardiac function are 25 monitored using the AnonyMOUSE ECG screening system. Electrocardiograms are recorded in conscious mice (C57bl/6 male, 6-10 week-old) before and after compound administration. ECG signals are then processed and analyzed using the e-MOUSE software. 90 jtg of compound further diluted in 200pl water, 15% DMSO are injected IP. Four mice are used to assess the heart effect of each compound. 46 WO 2004/103306 PCT/US2004/015603 D: In vivo: Anti-an2iogenic Activity Porous chambers containing (i) sphingosine-1-phosphate (5 pM/chamber) or (ii) human VEGF (1 pg/chamber) in 0.5 ml of 0.8% w/v agar (containing heparin, 20 U/ml) are implanted subcutaneously in the flank of mice. SlP or VEGF induces the growth of 5 vascularized tissue around the chamber. This response is dose-dependent and can be quantified by measuring the weight and blood content of the tissue. Mice are treated once a day orally or intravenously with a compound of Formula Ia or Ib starting 4-6 hours before implantation of the chambers and continuing for 4 days. The animals are sacrificed for measurement of the vascularized tissues 24 hours after the last dose. The weight and blood 10 content of the vascularized tissues around the chamber is determined. Animals treated with a compound of Formula Ia or Ib show reduced weight and/or blood content of the vascularized tissues compared to animals treated with vehicle alone. Compounds of Formula Ia or Ib are anti-angiogenic when administered at a dose of about 0.3 to about 3mg/kg. E: In vitro: Antitumor Activity 15 A mouse breast cancer cell line originally isolated from mammary carcinomas is used, e.g. JygMC(A). The cell number is adjusted to 5x10 5 for plating in fresh medium before the procedure. Cells are incubated with fresh medium containing 2.5mM of thymidine without FCS for 12 hours and then washed twice with PBS, followed by addition of fresh medium with 10% FCS and additionally incubated for another 12 hours. Thereafter the cells 20 are incubated with fresh medium containing 2.5mM of thymidine without FCS for 12 hours. To release the cells from the block, the cells are washed twice with PBS and replated in fresh medium with 10% FCS. After synchronization, the cells are incubated with or without various concentrations of a compound of Formula Ia or Ib for 3, 6, 9, 12, 18 or 24 hours. The cells are harvested after treatment with 0.2% EDTA, fixed with ice-cold 70% ethanol 25 solution, hydrolyzed with 250ptg/ml of RNaseA (type 1-A: Sigma Chem. Co.) at 37*C for 30 minutes and stained with propidium iodide at 10mg/ml for 20 minutes. After the incubation period, the number of cells is determined both by counting cells in a Coulter counter and by the SRB colorimetric assay. Under these conditions compounds of Formula Ia or Ib inhibit the proliferation of the tumor cells at concentrations ranging from 10-" to 10-6 M. 30 47 WO 2004/103306 PCT/US2004/015603 It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and understanding of this application and scope of the appended claims. All publications, 5 patents, and patent applications cited herein are hereby incorporated by reference for all purposes. 48
    权利要求:
    Claims (12)
    [1] 1. A compound selected from Formula Ia and Ib: R 4 R 3 R 4 R 3 A 'v A R
    [2] 2 Z Y R2 Z YW' O N R 1 5 Ia N'O' R1lb in which: A is chosen from -C(O)OR 5 , -OP(O)(OR) 2 , -P(O)(OR) 2 , -S(O) 2 0R 5 , P(O)(Rs)OR 5 and 1H-tetrazol-5-yl; wherein each R 5 is independently chosen from hydrogen and CI 6 alkyl; 10 W is chosen from a bond, Ci- 3 alkylene, C 2 - 3 alkenylene; Y is chosen from C 6 .ioaryl and C 2 . 9 heteroaryl; wherein any aryl or heteroaryl of Y can be optionally substituted with 1 to 3 radicals chosen from halo, hydroxy, nitro, C 1 6 alkyl, C 1- 6 alkoxy, halo-substituted C I.alkyl and halo-substituted C 1 6 alkoxy; Z is chosen from: 49 WO 2004/103306 PCT/US2004/015603 *' N * N *** N N A6 A. R o * ' N N N F F R OH R 6 F 00 %NM * HOro,,"* HOA * ,,N^ *, * N AsA6 and 2 wherein the left and right asterisks of Z indicate the point of attachment between C(R 3 )(R4)- and A of Formula Ia or Ib, respectively; R 6 is chosen from hydrogen and C 1 . 5 6 alkyl; and Ji and J 2 are independently methylene or a heteroatom chosen from S, 0 and NR 5 ; wherein R 5 is chosen from hydrogen and C- 6 alkyl; and any alkylene of Z can be further substituted by one to three radicals chosen from halo, hydroxy, Ci- 6 alkyl; or R6 can be attached to a carbon atom of Y to form a 5-7 member ring; Ri is chosen from C 6 -oaryl and C 2 - 9 heteroaryl; wherein any aryl or heteroaryl 10 of R, is optionally substituted by a radical chosen from C6o-oarylCo. 4 alkyl, C 2 - 9 heteroarylCo. 4 alkyl, C 3 .scycloalkylCa. 4 alkyl, C 3 .sheterocycloalkylCo. 4 alkyl or C 1 . 6 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R 1 can be optionally substituted by one to five radicals chosen from halo, CI. 6 alkyl, CI. 6 alkoxy, halo-substituted-CI- 6 alkyl and halo substituted-Ci- 6 alkoxy; and any alkyl group of R 1 can optionally have a methylene replaced 15 by an atom or group chosen from -S-, -S(O)-, -S(0) 2 -, -NRs- and -0-; wherein R 5 is chosen from hydrogen or C 1 . 6 alkyl; R2 is chosen from hydrogen, C 1 . 6 alkyl, C 2 - 6 alkenyl, C 2 . 6 alkynyl and halo substituted CI 16 alkyl; 50 WO 2004/103306 PCT/US2004/015603 R3 and R 4 are independently chosen from hydrogen, CI. 6 alkyl, halo, hydroxy, C 1 . 6 alkoxy, halo-substituted C 1 - 6 alkyl and halo-substituted C 1 . 6 alkoxy; and the pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof. 5 2. The compound of claim 1 in which R, is phenyl, naphthyl or thienyl optionally substituted by C 6 -ioarylCo. 4 alkyl, C 2 - 9 heteroarylCo_4alkyl, C3.scycloalkylCo_4alkyl, C 3 . sheterocycloalkylCo. 4 alkyl or CI- 6 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R, can be optionally substituted by one to five radicals chosen from halo, C 1 . 6 alkyl, Ci- 6 alkoxy, halo-substituted-C 1 - 6 alkyl and halo-substituted-C 1 . 6 alkoxy; 10 and any alkyl group of R1 can optionally have a methylene replaced by an atom or group chosen from -S-, -S(O)-, -S(O) 2 -, -NRs- and -0-; wherein R5 is hydrogen or CI. 6 alkyl.
    [3] 3. The compound of claim 1 in which Y is chosen from: */ * ;* * ; N NN D 0, N 0* 1 and 15/ wherein R 7 is hydrogen or C 1 . 6 alkyl; and the left and right asterisks of Y indicate the point of attachment a) either between -C(R 2 )=NOWRI and the -CR 3 R 4 -, or between -CR 3 R 4 - and C(R 2 )=NOWR 1 of Formula Ia, respectively, or b) either between -CR 3 R 4 - and W or 20 between W and -CR 3 R 4 - of Formula Lb, respectively; wherein any aryl or heteroaryl of Y can be optionally substituted with 1 to 3 radicals chosen from halo, hydroxy, nitro, Ci. 6 alkyl, Ci-6alkoxy, halo-substituted C 1 . 6 alkyl and halo-substituted C 1 . 6 alkoxy. 51 WO 2004/103306 PCT/US2004/015603
    [4] 4. The compound of claim 1 in which R 1 is chosen from: R 8 .r-S0 R9 I- > and R9 *R R 8 5 wherein the asterisk is the point of attachment of R 1 with W; R8 is C 6 -oarylCo. 4 alkyl, C2. 9 heteroarylCo.4alkyl, C 3 .scycloalkylCo.4alkyl, C 3 .sheterocycloalkylCo.4alkyl or C 1 6 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl group of R 8 can be optionally substituted by one to three radicals chosen from halo, C 1 6 alkyl, C 1 6 alkoxy, halo 10 substituted-C 1 . 6 alkyl and halo-substituted-C 1 - 6 alkoxy; and any alkyl group of R 8 can optionally have a methylene replaced by an atom or group chosen from -S-, -S(O)-, S(0) 2 -, -NR5- and -0-; wherein R 5 is hydrogen or CI. 6 alkyl; and R 9 is chosen from halo, CI 6 alkyl, C 1 _ 6 alkoxy, halo-substituted-C 1 - 6 alkyl and halo-substituted-CI. 6 alkoxy. 15
    [5] 5. The compound of claim 1 in which A is -C(O)OH; Z is chosen from: *N * * Nf *-N ** N N *N R 6 OH R 6 F wherein the left and right asterisks of Z indicate the point of attachment between 20 C(R 3 )(R4)- and A of Formula Ia or Ib, respectively; R 6 is chosen from hydrogen and C 1 . 6 alkyl; and R 3 and R 4 are both hydrogen.
    [6] 6. The compound of claim 5 in which Y is chosen from phenyl, pyridinyl, thienyl and furanyl; wherein any phenyl, pyridinyl, thienyl or furanyl of Y is optionally 25 substituted with 1 to 3 radicals chosen from methyl, ethyl, cyclopropyl, chloro, bromo, fluoro and methoxy; or where Y is phenyl, R 6 can be attached to a carbon atom of Y to form 3,4-dihydro-1H-isoquinolin-2-yl. 52 WO 2004/103306 PCT/US2004/015603
    [7] 7. The compound of claim 6 in which W is a bond or methylene; Ri is chosen from: R< S "-0 R 9 R9- and R 9 R R 8 5 wherein R 8 is chosen from phenyl, cyclohexyl, thienyl, 3,3-dimethyl-butyl, pyridinyl, cyclopentyl and piperidinyl; wherein R can be optionally substituted by 1 to 3 radicals chosen from trifluoromethyl, methoxy, fluoro, triflouromethoxy and methyl; and R 9 is chosen from trifluoromethyl, fluoro, methyl, chloro, methoxy and ethyl. 10
    [8] 8. The compound of claim 6 chosen from: 3-{4-[1-(2-Trifluoromethyl-biphenyl 4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4-Cyclohexyl-3 trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionic acid, 1-{4-[1-(4 Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3 15 carboxylic acid, 3-({2-Chloro-6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl] pyridin-3-ylmethyl}-amino)-propionic acid, 3-({6-[1-(4-Cyclohexyl-3-trifluoromethyl benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl} -amino)-propionic acid, 3-{4-[1 (Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 4-{4-[1-(Biphenyl-4 ylmethoxyimino)-ethyl]-benzylamino}-butyric acid, 1-{4-[1-(Biphenyl-4-ylmethoxyimino) 20 ethyl]-benzyl} -azetidine-3-carboxylic acid, 1-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl] benzyl}-piperidine-3-carboxylic acid, {4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl] benzylamino} -acetic acid, 3-{4-[1-(Biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino} cyclopentanecarboxylic acid, 3-{4-[1-(4'-Trifluoromethyl-biphenyl-4-ylmethoxyimino) ethyl]-benzylamino } -propionic acid, 3-{4-[1-(5-Phenyl-furan-2-ylmethoxyimino)-ethyl] 25 benzylamino}-propionic acid, 3-{4-[1-(3'-Trifluoromethyl-biphenyl-4-ylmethoxyimino) ethyl]-benzylamino } -propionic acid, 3-{4-[1-(3-Trifluoromethyl-biphenyl-4 ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4'-Methoxy-biphenyl-4 ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(Biphenyl-3 ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4-Thiophen-2-yl 30 benzyloxyimino)-ethyl]-benzylamino)-propionic acid, 3-{4-[1-(4-Thiophen-2-yl-3 53 WO 2004/103306 PCT/US2004/015603 trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4'-Fluoro biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4' Trifluoromethoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4 [1-(3'-Trifluoromethoxy-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 5 1-{4-[I-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-azetidine-3 carboxylic acid, 1-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzyl} pyrrolidine-3-carboxylic acid, 1-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino) ethyl]-benzyl} -piperidine-3-carboxylic acid, 3-{4-[1-(3'-Methoxy-biphenyl-4 ylmethoxyimino)-ethyl]-benzylamino} -propionic acid, 2-Hydroxy-3- {4-[1-(2 10 trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl-benzylamino}-propionic acid, 3-{4-[1 (4'-Methyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4 Phenyl-thiophen-2-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 1-{4-[1 (Biphenyl-4-ylmethoxyimino)-ethyl]-benzyl}-pyrrolidine-3-carboxylic acid, 3-{4-[1-(4 Furan-3-yl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4-Thiophen-3-yl 15 3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4 Thiophen-3-yl-2-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 2 Fluoro-3-{4-[1-(2-trifluoromethyl-biphenyl-4-ymethoxyimino)-ethyl]-benzylamino) propionic acid, 3-{4-[1-(2-Trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl] benzylamino}-butyric acid, 3-{4-[1-(5-Phenyl-thiophen-2-ylmethoxyimino)-ethyl] 20 benzylamino}-propionic acid, 3-{4-[1-(4-Cyclohexyl-benzyloxyimino)-ethyl] benzylamino}-propionic acid, 3-{4-[1-(3-Fluoro-biphenyl-4-ylmethoxyimino)-ethyl] benzylamino}-propionic acid, 3-{4-[I-(4'-Fluoro-2-trifluoromethyl-biphenyl-4 ylmethoxyimino)-ethyl]-benzylamino} -propionic acid, 3- {4-[I-(4'-Methyl-2 trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4-[1 25 (4-Furan-2-yl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{4 [1-(2'-Fluoro-2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid, 3-(4-{1- [4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-benzyloxyimino]-ethyl} benzylamino)-propionic acid, 3-{4-[1-(4-Furan-3-yl-3-trifluoromethyl-benzyloxyimino) ethyl]-benzylamino}-propionic acid, 3-{4-[1-(4-Pyridin-3-yl-benzyloxyimino)-ethyl] 30 benzylamino}-propionic acid, 3-{4-[1-(4-Pyridin-4-yl-benzyloxyimino)-ethyl] benzylamino}-propionic acid, 3-{4-[1-(2-Fluoro-biphenyl-4-ylmethoxyimino)-ethyl] 54 WO 2004/103306 PCT/US2004/015603 benzylamino}-propionic acid, 3-({2-Methoxy-6-[1-(2-trifluoromethyl-biphenyl-4 ylmethoxyimino)-ethyl]-pyridin-3-ylmethyl}-amino)-propionic acid, 3-{4-[1-(4-Cyclohexyl 3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionic acid, 3-{4-[1-(4 Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{2 5 Bromo-4-[I-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino} propionic acid, 3-{4-[1-(4-Cyclopentyl-3-trifluoromethyl-benzyloxyimino)-ethyl] benzylamino}-propionic acid, 3-{2-Chloro-4-[I-(4-cyclohexyl-3-trifluoromethyl benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-({6-[1-(4-Cyclohexyl-3 trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-3-ylmethy1}-amino)-propionic acid, 3-({5 10 [1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-thiophen-2-ylmethyl -amino) propionic acid, 3-({5-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin- 2 ylmethyl}-amino)-propionic acid, 3-({5-[1-(4-Cyclohexyl-3-trifluoromethyl benzyloxyimino)-ethyl]-furan-2-ylmethyl}-amino)-propionic acid, 3-({2-[1-(4-Cyclohexyl 3-trifluoromethyl-benzyloxyimino)-ethyl]-pyridin-4-ylmethyl}-amino)-propionic acid, 3-(4 15 [1-(4-Cyclohexyl-3-fluoro-benzyloxyimino)-ethyl]-benzylamino}-propionic acid, 3-{2 Chloro-4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-benzylamino} propionic acid, 1- {6-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]- 2 -ethyl pyridin-3-ylmethyl}-azetidine-3-carboxylic acid, 3-{2-Ethyl-4-[1-(4-piperidin-1-yl-3 trifluoromethyl-benzyloxyimino)-ethyl]-benzylamifno}-propionic acid, 3-{4-[1-(4 20 Cyclohexyl-3-methyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionic acid, 3-(4 [1-(3-Chloro-4-cyclohexyl-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionic acid, 3 {4-[I-(4-Cyclohexyl-3-methoxy-benzyloxyimino)-ethyl]-2-ethyl-benzylamino}-propionic acid, 1-{4-[1-(4-Cyclohexyl-3-methoxy-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine 3-carboxylic acid, 3-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]- 2 25 methyl-benzylamino}-propionic acid, 1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl benzyloxyimino)-ethyl]-2-methyl-benzyl}-azetidine-3-carboxylic acid, 3-{4-[1-(4 Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-cyclopropyl-benzylamino} propionic acid, 1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]- 2 cyclopropyl-benzyl}-azetidine-3-carboxylic acid, 3-{2-Ethyl-4-[1-(2-trifluoromethyl 30 biphenyl-4-ylmethoxyimino)-ethyl]-benzylaminol}-propionic acid, 1-{4-[1-(4-Cyclohexyl-3 ethyl-benzyloxyimino)-ethyll-2-ethyl-benzyl}-azetidine-3-carboxylic acid, 1-{4-[1-(4 55 WO 2004/103306 PCT/US2004/015603 Cyclohexyl-3-methyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid, 1-{2-Chloro-4-[1-(4-cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-benzyl}-azetidine-3 carboxylic acid, 3-{2-Chloro-4-[1-(4-cyclohexyl-3-ethyl-benzyloxyimino)-ethyl] benzylamino}-propionic acid, 3-{4-[1-( 4 -Cyclohexyl-3-trifluoromethyl-benzyloxyimino) 5 ethyl] -2-fluoro-benzylamino} -propionic acid, 1-{4-[1-(4-Cyclohexyl-3-trifloromethyl benzyloxyimino)-ethyl]-2-fluoro-benzyl}-azetidine-3-carboxylic acid, 3-{6-[1-(4 Cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl) propionic acid, 3-{6-[1-(4-Cyclohexyl-3-ethyl-benzyloxyimino)-ethyl]-3,4-dihydro-1H isoquinolin-2-yi}-propionic acid, 3-{4-[1-(2-Trifluoromethyl-biphenyl-4-yl) 10 ethylideneaminooxymethyl]-benzylamino)-propionic acid, 3-{4-[1-(4-Cyclohexyl-3 trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-benzylamino}-propionic acid, 3-{4-[1 (4-Cyclohexyl-3-trifluoromethyl-phenyl)-ethylideneaminooxymethyl]-2-ethyl benzylamino}-propionic acid, 1-{4-[1-(4-Cyclohexyl-3-trifluoromethyl-phenyl) ethylideneaminooxymethyl]-2-ethyl-benzyl)-azetidine-3-carboxylic acid and 1-{4-[1-(4 15 Cyclohexyl-3-ethyl-phenyl)-ethylideneaminooxymethyl]-2-ethyl-benzyl}-azetidine-3 carboxylic acid.
    [9] 9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 in combination with a pharmaceutically acceptable 20 excipient.
    [10] 10. A method for treating a disease in an animal in which alteration of EDG/S 1P receptor mediated signal transduction can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which method comprises administering to 25 the animal a therapeutically effective amount of a compound of Claim 1.
    [11] 11. A method for preventing or treating disorders or diseases mediated by lymphocytes, for preventing or treating acute or chronic transplant rejection or T-cell mediated inflammatory or autoimmune diseases, for inhibiting or controlling deregulated 30 angiogenesis, or for preventing or treating diseases mediated by a neo-angiogenesis process or associated with deregulated angiogenesis in a subject comprising administering to the 56 WO 2004/103306 PCT/US2004/015603 subject in need thereof an effective amount of a compound of claims 1, or a pharmaceutically acceptable salt thereof.
    [12] 12. The use of a compound of claim 1 in the manufacture of a medicament for 5 treating a disease in an animal in which alteration of EDG/S 1 P receptor mediated signal transduction contributes to the pathology and/or symptomology of the disease. 57
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    法律状态:
    2008-08-07| MK5| Application lapsed section 142(2)(e) - patent request and compl. specification not accepted|
    优先权:
    申请号 | 申请日 | 专利标题
    US47193103P| true| 2003-05-19|2003-05-19||
    US60/471,931||2003-05-19||
    US56196804P| true| 2004-04-14|2004-04-14||
    US60/561,968||2004-04-14||
    PCT/US2004/015603|WO2004103306A2|2003-05-19|2004-05-19|Immunosuppressant compounds and compositions|AU2008203087A| AU2008203087A1|2003-05-19|2008-07-11|Immunosuppressant compounds and compositions|
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