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US 6,602,849 B1Granted
Cyclic somatostatin analogs
AssigneeSociete de Conseils de Recherche et d'Applications Scientifiques, S.A.S.
InventorThomas D. Gordon
Life of this patent
Estimating the term…
Abstract
The present invention is directed to cyclic derivatives containing an imidazole cis amide bond mimetic which bind selectively to somatostatin receptor subtypes and the use thereof in treating conditions which can be treated by eliciting an agonist or antagonist effect from the somatostatin subtype receptors. This invention is also directed to methods for making the compounds of the instant invention.
Claims25
A compound of the formula (I),
- or a pharmaceutically acceptable salt thereof,
- wherein,
- Y and Z for each occurrence are each independently a D- or L-natural or unnatural α-amino acid;
- n for each occurrence is independently 0 to 50, provided that both n cannot be 0 at the same time;
- m is 0 or an integer from 1 to 10;
- a is H or R1;
- b is OH, —OR1 or —NR9R9;
- or a is taken together with b to form an amide bond;
- R1 is independently H, (C1-C4)alkyl or aryl-(C1-C4)alkyl;
- R2 is H or an optionally substituted moiety selected from the group consisting of (C1-C4)alkyl, phenyl, phenyl-(C1-C4)alkyl and heterocyclyl-(C1-C4)alkyl;
- where the optionally substituted moiety is optionally substituted by one or more substituents each independently selected from the group consisting of (C1-C4)alkyl, (C3—C8)cycloalkyl, —O—R6, —S(O)q—R7, —N(R9R9), —NHCO—R6, —NHSO2R9, —CO2R9, —CONR9R9 and —SO2NR9R9, where q is 0, 1, 2 or 3;
- R3 and R4 are each independently H, halo or an optionally substituted moiety selected from the group consisting of (C1-C4)alkyl, (C3-C8)cycloalkyl, aryl and aryl-(C1-C4)alkyl;
- where the optionally substituted moiety is optionally substituted by one or more substituents selected from the group consisting of OH, (C1-C4)alkyl, (C1-C4)alkoxy, aryloxy, aryl-(C1-C4)alkoxy, —NR9R9, COOH, —CONR9R9 and halo;
- or R3 and R4 are taken together with the carbons to which they are attached to form optionally substituted aryl, where the aryl is optionally substituted by one or more substituents each independently selected from the group consisting of OH, (C1-C4)alkyl, (C1-C4)alkoxy, aryloxy, aryl-(C1-C4)alkoxy, —NR9R9, COOR5, —CONR9R9 and halo;
- R5 for each occurrence is independently H, or an optionally substituted moiety selected from the group consisting of (C1-C4)alkyl and aryl-(C1-C4)alkyl, where the optionally substituted moiety is optionally substituted by one or more substituents each independently selected from the group consisting of (C1-C4)alkyl, OH, (C1-C4)alkoxy, aryloxy, NO2, aryl-(C1-C4)alkoxy, —NR9R9, COOH, —CONR9R9 and halo;
- R6 for each occurrence is independently selected from the group consisting of H, (C1-C4)alkyl, (C1-C4)alkoxy, aryl-(C1-C4)alkyl and aryl-(C1-C4)alkoxy;
- R7 is H when q is 3 or, R7 for each occurrence is independently selected from the group consisting of (C1-C4)alkyl, aryl and aryl-(C1-C4)alkyl when q is 0, 1 or 2;
- and
- R9 for each occurrence is independently selected from the group consisting of H, NO2, (C1-C4)alkyl, aryl and aryl-(C1-C4)alkyl.
16 more elements
A compound of the formula (II),
- or a pharmaceutically acceptable salt thereof,
- wherein,
- Y and Z for each occurrence are each independently a D- or L-natural or unnatural α-amino acid;
- m is 0 or an integer from 1 to 10;
- n for each occurrence is independently 0 to 6;
- R1 for each occurrence is independently H, (C1-C4)alkyl or aryl-(C1-C4)alkyl;
- R2 is H or an optionally substituted moiety selected from the group consisting of (C1-C4)alkyl, phenyl, phenyl-(C1-C4)alkyl and heterocyclyl-(C1-C4)alkyl, where the optionally substituted moiety is optionally substituted by one or more substituents each independently selected from the group consisting of (C1-C4)alkyl, cycloalkyl, —O—R6, —S(O)q—R7, —N(R9R9), —NHCO—R6, —NHSO2R9, —CO2R9, —CONR9R9 and —SO2NR9R9, where q is 0, 1, 2 or 3;
- R3 and R4 are each independently H, halo or an optionally substituted moiety selected from the group consisting of (C1-C4)alkyl, cycloalkyl, aryl and aryl-(C1-C4)alkyl;
- where the optionally substituted moiety is optionally substituted by one or more substituents selected from the group consisting of OH, (C1-C4)alkyl, (C1-C4)alkoxy, aryloxy, aryl-(C1-C4)alkoxy, —NR9R9, COOH, —CONR9R9 and halo;
- or R3 and R4 are taken together with the carbons to which they are attached to form optionally substituted aryl, where the aryl is optionally substituted by one or more substituents each independently selected from the group consisting of OH, (C1-C4)alkyl, (C1-C4)alkoxy, aryloxy, aryl-(C1-C4)alkoxy, —NR9R9, COOR5, —CONR9R9 and halo;
- R5 for each occurrence is independently H, or an optionally substituted moiety selected from the group consisting of (C1-C4)alkyl and aryl-(C1-C4)alkyl, where the optionally substituted moiety is optionally substituted by one or more substituents each independently selected from the group consisting of (C1-C4)alkyl, OH, (C1-C4)alkoxy, aryloxy, NO2, aryl-(C1-C4)alkoxy, —NR9R9, COOH, —CONR9R9 and halo;
- R6 for each occurrence is independently selected from the group consisting of H, (C1-C4)alkyl, (C1-C4)alkoxy, aryl-(C1-C4)alkyl and aryl-(C1-C4)alkoxy;
- R7 is H when q is 3, or R7 for each occurrence is independently selected from the group consisting of (C1-C4)alkyl, aryl and aryl-(C1-C4)alkyl when q is 0, 1 or 2;
- and
- R9 for each occurrence is independently selected from the group consisting of H, NO2, (C1-C4)alkyl, aryl and aryl-(C1-C4)alkyl,
- X1 is a natural or unnatural D- or L-α-amino acid, where when X1 is Phe, NaI, Trp, Tyr, PaI or His the aromatic ring thereof is optionally substituted on carbon or nitrogen by R6 or when X1 is Ser or Thr, the side chain oxygen is optionally substituted by one or more R1;
- X2 is or L-Trp, N-methyl-D-Trp or N-methyl-L-Trp;
- X3 is Lys, α-N-methyl-Lys or ε-N-(C1-C4)alkyl-Lys or ε-N-[aryl-(C1-C4)alkyl]-Lys;
- X4 is a natural or unnatural D- or L-α-amino acid where when X4 is Phe, NaI, Trp, Tyr or His, the aromatic ring thereof is optionally substituted on carbon or nitrogen by R8 or when X4 is Ser, Tyr or Thr, the side chain oxygen may be substituted with one or more R1.
16 more elements
Dependencies are inferred from the claim text.