Cyclic peptides multimers targeting α4β7 integrin

A method of treating ulcerative colitis or Crohn's disease in a patient, comprising administering to the patient a therapeutically effective amount of a multimer selected from the group consisting of a homodimer, a homotrimer and a homotetramer, the multimer comprising two, three or four compounds covalently linked together by a linker selected from the group consisting of an amide linker, an amine linker and a mixed amide/amine linker, the compounds being identical and having the formula (I):

• or a pharmaceutically acceptable salt thereof, wherein
• R1 is H, C1-C6 alkyl, aryl, heteroaryl, alkenyl, or heterocycle, all of which are optionally substituted at one or more substitutable positions with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, aryloxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ether, thioether, thioalkoxy, phosphino, and —NRaRb, where Ra and Rb are independently selected from C1-C6 alkyl, aryl or benzyl,
• and where the one or more substituents is not alkyl when R1 is C1-C6 alkyl;
• R2 and R3 are each independently an amino acid side chain of a proteinogenic or a non-proteinogenic alpha-amino acid,
• or R2 and R3 are covalently linked to each other to form a ring;
• R4 and R5 are each independently H, C1-C6 alkyl, aryl, heteroaryl, alkenyl, heterocycle, acids of the formula —C(O)OH, esters of the formula —C(O)OR* wherein R* is selected from alkyl and aryl, amides of the formula —C(O)NR ** R *** , wherein R ** and R *** are independently selected from H, alkyl and aryl;
• —CH2C(O)R, wherein R is selected from —OH, —C1-C6 alkyl, aryl, —C1-C6 alkyl-aryl, or —NRaRb, where Ra and Rb are independently selected from H, C1-C6 alkyl, aryl or —C1-C6 alkyl-aryl;
• or —C(O)Rc, wherein Rc is selected from C1-C6 alkyl, aryl or —C1-C6 alkyl-aryl, or —C1-C6 alkyl-ORd, wherein Rd is a suitable protecting group or OH group;
• all of which are optionally substituted at one or more substitutable positions with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, aryloxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ether, thioether, thioalkoxy, phosphino, and —NRaRb, where Ra and Rb are independently selected from C1-C6 alkyl, aryl or benzyl;
• and where the one or more substituents is not alkyl when R4 and/or R5 is C1-C6 alkyl;
• or R2 or R3 are covalently linked to R1 to form a cyclic secondary amine, and/or to R4 or R5 to form a ring, or R4 and R5 are covalently linked to each other to form a ring;
• R6 is H, C1-C6 alkyl, benzyl, alkenyl, C1-C6 alkyloxy, aryl, heteroaryl, heterocycle, —C(O)R **** , wherein R *** is independently selected from alkyl, aryl, heteroaryl, amino, aminoalkyl, aminoaryl, aminoheteroaryl, alkoxy, aryloxy, heteroaryloxy;
• —CH2C(O)R, or —C(O) Rc;
• all of which are optionally substituted at one or more substitutable positions with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, aryloxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ether, thioether, thioalkoxy, phosphino, and —NRaRb, where Ra and Rb are independently selected from C1-C6 alkyl, aryl or benzyl;
• and where the one or more substituents is not alkyl when R6 is C1-C6 alkyl;
• or along with R7 or R8, a cyclic side chain of a proteinogenic or a non-proteinogenic amino acid having, the N-terminus thereof being the N-R6, wherein the proteinogenic or non-proteinogenic amino acid is optionally substituted with a substituent selected from the group consisting of hydroxyl, cyano, alkoxy, aryloxy, vinyl, alkenyl, alkynyl, formyl, haloalkyl, halide, aryl, heteroaryl, amide, acyl, ether, thioether, thioalkoxy, phosphino, and —NRaRb, where Ra and Rb are independently selected from C1-C6 alkyl, aryl or benzyl;
• R7 and R8 are independently selected from the amino acid side chains of a proteinogenic or a non-proteinogenic alpha-amino acid having the N-terminus thereof being the N-R6, or form a cyclic side chain with R6;
• stereocentres 1*, 2* and 3* are each independently selected from R and S;
• n is 1, 2, 3, or 4 and where n is 2-4, each R7 and each R8 are independent of each other;
• and
• wherein Z is an amino terminus of an amino acid;
• —C═O— adjacent L is the carboxy terminus of an amino acid;
• and L along with Z and —C═O— is a peptide having the following formula:
• Xy—Xz—X1—X2—X3
• wherein Xy and Xz are each independently a proteinogenic or non-proteinogenic amino acid, or Xz is absent;
• X1 is Leucine or tert-butyl-Ala;
• X2 is Asp;
• and
• X3 is an amino acid selected from the group consisting of Val, Thr, Ile, Thr(OBn), Thr(OMe), Thr (OEt), Pen, MeThr, alloThr, Abu, and allolle;
• wherein the compounds are linked together at a nitrogen atom associated with Xy;
• or a pharmaceutically acceptable salt thereof.