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US 2006/0189620 A1Published application
Immunosuppressive effects of pteridine derivatives
OwnerMark Jozef Waer, Piet Andre Herdewijn +1inventors
InventorsMark Jozef Waer, Piet Andre Herdewijn, Wolfgang Pfleiderer
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Abstract
This invention relates to a group of trisubstituted and tetrasubstituted pteridine derivatives, their pharmaceutically acceptable salts, N-oxides, solvates, dihydro- and tetrahydroderivatives and enantiomers, possessing unexpectedly desirable pharmaceutical properties, in particular which are highly active immunosuppressive agents, and as such are useful in the treatment in transplant rejection and/or in the treatment of certain inflammatory diseases. These compounds are also useful in preventing or treating cardiovascular disorders, allergic conditions, disorders of the central nervous system and cell proliferative disorders.
Claims11
A compound of the formula (Ia), (Ib) or (Ic),
- R1 is hydrogen, C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl, wherein R1 is unsubstituted or substituted with at least one substituent chosen from R6,
- R2 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, or heteroaryalkyl wherein R2 is unsubstituted or substituted with at least one substituent chosen from R6,
- R2 is C2-C20-alkenyl, C2-C20-alkynyl, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, or heteroaryalkyl wherein R2 is unsubstituted or substituted with at least one substituent chosen from R6,
- or R1 and R2, together with the nitrogen atom bearing them, form a 3-8-membered ring which may optionally comprises 0, 1 or 2 further heteroatoms chosen from N, O, and S, and wherein said 3-8-membered ring is unsubstituted or substituted by at least one substituent chosen from R6,
- R3 is hydrogen, —CO-alkyl, —CO-alkylaryl, —CO-alkylheteroaryl, —CO-aryl, or —CO-heteroaryl,
- R4 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl, —CO—O-alkyl, —CO—O-aryl, —CO—O-heteroaryl, —CO-alkyl, —CO-aryl or —CO-heteroaryl wherein R4 is unsubstituted or substituted with at least one substituent chosen from R7,
- R4 is C2-C20-alkenyl, C2-C20-alkynyl, cycloalkyl with three to eight ring carbon atoms, cycloalkenyl with three to eight ring carbon atoms, cycloalkylalkyl with five to six ring carbon atoms, heteroaryl, alkylheteroaryl, heteroarylalkyl, —CO—O-alkyl, —CO—O-aryl, —CO—O-heteroaryl, —C—O-aryl or —CO-heteroaryl wherein R4′ is unsubstituted or substituted with at least one substituent chosen from R7,
- R5 is hydrogen, —CO-alkyl, —CO-alkylaryl, —CO-alkylheteroaryl, —CO-aryl, or CO-heteroaryl,
- R6 is —F, —OH, —O-(C1-C10)alkyl, —O-phenyl, —O—CO—(C1-C10)alkyl, —O—CO-aryl, —O—CO-heteroaryl, —NR8R9, oxo, phenyl, —CO—(C1-C5)-alkyl, —CF3, —CN, —CONR8R9, —COOH, —CO—O—C1-C5)-alkyl, —CO—O-aryl, —CO—O-heteroaryl, —S(O)n—(C1-C5)-alkyl, —SO2NR8R9,
- R7 is —F, —OH, —O—(C1-C10)-alkyl, —O-phenyl, —O—CO—(C1-C10)-alkyl, O—CO—O-aryl, O—CO—O-heteroaryl, —NR8R9, oxo, phenyl, —CO—(C1-C5)-alkyl, —CF3, —CN, —CONR8R9, —COOH, —CO—O—(C1-C5)alkyl, —CO—O-aryl, —S(O)n—(C1-C5)alkyl, —SO2—NR8R9,
- R8 is hydrogen or C1-C20-alkyl, and
- R9 is hydrogen, C1-C20-alkyl, aryl, or heteroaryl,
- wherein aryl groups are carbocyclic aryl groups, wherein heteroaryl groups are 5- to 7-membered unsaturated heterocycles comprising 1-4 heteroatoms chosen from O, N, and S,
- or a physiologically acceptable salt, hydrate, or ester thereof, in any stereoisomeric or tautomeric form.
11 more elements
A pteridine derivative having the formula:
- wherein X represents a group with the formula NZ and wherein:
- R1 is aryl or arylalkyl;
- Z is selected from the group consisting of hydrogen, aryl and arylalkyl;
- R2 is amino;
- R4 is hydrogen;
- and
- R3 is selected from the group consisting of aryl optionally substituted with one or more substituents selected from the group consisting of halogen and C1-7 alkoxy;
- aromatic substituents substituted with an aliphatic spacer between the pteridine ring and the aromatic substituent, whereby said aliphatic spacer is a saturated or unsaturated aliphatic chain of 1 to 4 carbon atoms which may be halogenated or hydroxylated;
- and aliphatic chains of 2 to 7 carbon atoms optionally containing one or more functions selected from the group consisting of hydroxyl, ether and substituted or unsubstituted amino.
- and/or a pharmaceutically acceptable addition salt thereof and/or a stereoisomer thereof.
7 more elements
Dependencies are inferred from the claim text.