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US 2006/0135786 A1Published application
Methods and compositions for modulating sphingosine-1-phosphate (S1P) receptor activity
AssigneePraecis Phamaceuticals, Inc.
InventorsAshis Saha, Malcolm Kavarana, Ghotas Evindar, Alexander Satz, Barry Morgan
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Abstract
The present invention relates to compounds which modulate the activity of the S1P1 receptor, the use of these compounds for treating conditions associated with signaling through the S1P1 receptor, and pharmaceutical compositions comprising these compounds.
Claims26
A compound of Formula IV:
- wherein:
- L is alkoxy, a covalent bond, substituted or unsubstituted alkyl, alkylcarbonyl, thioether, alkylsulfonyl, alkylcarbonylamino, alkylaminocarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, or substituted or unsubstituted heteroaryl;
- Z and A are each independently substituted or unsubstituted aryl, wherein Z and A may be linked by a covalent bond, substituted or unsubstituted alkyl, NH, alkyloxy, O, thioether, S, aminocarbonyl, carbonylamino, carbonyloxy, or oxycarbonyl;
- R1, R2, R5 and R12 are each independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted aryl, straight chain or branched C1-C6-alkyl, straight chain or branched C1-C6-alkoxy, straight chain or branched halo-C1-C6-alkyl, straight chain or branched halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, hydroxyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, C1-C6-alkyl-SO2 or N(R)R′, wherein R and R′ are each independently hydrogen, straight chain or branched C1-C6-alkyl, straight chain or branched C1-C6-alkoxy, straight chain or branched halo-C1-C6-alkyl, straight chain or branched halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, hydroxyl-C1-C6-alkyl, carboxy-C1-C6-alkyl or C1-C6-alkyl-SO2;
- Q is —CH2NR—, —CH2NR(CO)—, —NH(CO)—, —(CO)NH—, —(CO)—, —O—, —S—, —SO—, —SO2—, —NRSO2—, —SO2—NR— or heteroaryl, where R is hydrogen or straight chain or branched C1-C6-alkyl;
- R6 is —OH, —CO2R9, —CH2═CH(CO)OR9, —OPO2R10R11, —OPO3R10R11, —CH2PO3R10R11, —OPO2(S)R10R11 or —C(Y)(X)PO3R10R11, where X is hydroxyl or halide and Y is H or halide;
- or analogues of other carboxylate, phosphate or phosphonate isosteres not limited to those shown below;
- R9 is H, straight chain or branched C1-C6-alkyl, or a substituted or unsubstituted aryl group;
- R10 and R11 are each independently H, straight chain or branched C1-C6-alkyl, a substituted or unsubstituted aryl group or selected from, but not limited to, the prodrugs listed below:
- R7 is H, C1-C6-alkyl, hydroxy-C1-C6-alkyl, aryl, or together with R8 form a C2-C5-alkylene or a C2-C5-alkenylene group;
- R8 is H or C1-C6-alkyl;
- and
- m and n are each, independently, an integer from 0 to 3;
- provided that when R4 is C4-C20-alkyl, at least one of R1, R2, R3 and R5 is not hydrogen;
- and when R3 is C4-C20-alkyl, at least one of R1, R2, R4 and R5 is not hydrogen;
- and pharmaceutically acceptable salts thereof.
13 more elements
A method for treating a sphingosine 1-phosphate associated disorder in a subject, comprising administering to said subject an effective amount of a compound of formula (IV), such that said subject is treated for said sphingosine 1-phosphate associated disorder, wherein said compound of formula (IV) is:
- wherein:
- L is alkoxy, a covalent bond, substituted or unsubstituted alkyl, alkylcarbonyl, thioether, alkylsulfonyl, alkylcarbonylamino, alkylaminocarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, or substituted or unsubstituted heteroaryl;
- Z and A are each independently substituted or unsubstituted aryl, wherein Z and A may be linked by a covalent bond, substituted or unsubstituted alkyl, NH, alkyloxy, O, thioether, S, aminocarbonyl, carbonylamino, carbonyloxy, or oxycarbonyl;
- R1, R2, R5 and R12 are each independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted aryl, straight chain or branched C1-C6-alkyl, straight chain or branched C1-C6-alkoxy, straight chain or branched halo-C1-C6-alkyl, straight chain or branched halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, hydroxyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, C1-C6-alkyl-SO2 or N(R)R′, wherein R and R′ are each independently hydrogen, straight chain or branched C1-C6-alkyl, straight chain or branched C1-C6-alkoxy, straight chain or branched halo-C1-C6-alkyl, straight chain or branched halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, hydroxyl-C1-C6-alkyl, carboxy-C1-C6-alkyl or C1-C6-alkyl-SO2;
- Q is —CH2NR—, —CH2NR(CO)—, —NH(CO)—, —(CO)NH—, —(CO)—, —O—, —S—, —SO—, —SO2—, —NRSO2—, —SO2—NR— or heteroaryl, where R is hydrogen or straight chain or branched C1-C6-alkyl;
- R6 is —OH, —CO2R9, —CH2═CH(CO)OR9, —OPO2R10R11, —OPO3R10R11, —CH2PO3R10R11, —OPO2(S)R10R11 or —C(Y)(X)PO3R10R11, where X is hydroxyl or halide and Y is H or halide;
- or analogues of other carboxylate, phosphate or phosphonate isosteres not limited to those shown below;
- R9 is H, straight chain or branched C1-C6-alkyl, or a substituted or unsubstituted aryl group;
- R10 and R11 are each independently H, straight chain or branched C1-C6-alkyl, a substituted or unsubstituted aryl group or selected from, but not limited to, the prodrugs listed below:
- R7 is H, C1-C6-alkyl, hydroxy-C1-C6-alkyl, aryl, or together with R8 form a C2-C5-alkylene or a C2-C5-alkenylene group;
- R8 is H or C1-C6-alkyl;
- and
- m and n are each, independently, an integer from 0 to 3;
- provided that when R4 is C4-C20-alkyl, at least one of R1, R2, R3 and R5 is not hydrogen;
- and when R3 is C4-C20-alkyl, at least one of R1, R2, R4 and R5 is not hydrogen;
- and pharmaceutically acceptable salts thereof.
13 more elements
Dependencies are inferred from the claim text.