Synthetic cyclic peptides and methods of preparation and use thereof

Patent metadata

Field	Value
Publication number	US-12043674-B2
Application number	US-202117502506-A
Country	US
Kind code	B2
Filing date	Oct 15, 2021
Priority date	Oct 15, 2020
Publication date	Jul 23, 2024
Grant date	Jul 23, 2024

Abstract

The present invention relates, in part, to novel compounds comprising 4-imidazolidinone-fused cyclic peptides and compositions thereof. The present invention also relates to methods of generating said compounds and compositions thereof as well as methods of inhibiting protein-protein interaction using said compounds or compositions thereof. In another aspect, the present invention relates, in part, to methods of treating or preventing a various diseases or disorders using said compounds or compositions thereof.

First claim

What is claimed is:

1. A compound comprising 4-imidazolidinone-fused cyclic peptide, wherein the compound is a compound having the structure of

or a derivative, prodrug, pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof,
wherein each occurrence of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, alkoxy, amino, aminoalkyl, carbonyl, carboxyl, carboxylic acid, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heterocycloalkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, ester, urea, thiourea, thiol, thioalkyl, thioxo, sulfanyl, sulfinyl, sulfonyl, phosphino, ═O, nitrile, isonitrile, cyano, carbamate, guanidine, guanidine alkyl, amino acid, and any combination thereof;
wherein R 1 and R 2 are optionally fused or joined to form a ring;

each occurrence of X a and X b is independently selected from the group consisting of C, —CR 10 , N, P, P═O, S═O, and any combination thereof;
wherein each occurrence of R 10 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, hydroxylalkyl, alkoxy, amino, aminoalkyl, carbonyl, carboxyl, carboxylic acid, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heterocycloalkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, acyl, ester, urea, thiourea, thiol, thioalkyl, thioxo, sulfanyl, sulfinyl, sulfonyl, phosphino, nitrile, isonitrile, cyano, carbamate, guanidine, guanidine alkyl, amino acid, and any combination thereof;

m is an integer from 1 to 5;
n is an integer from 1 to 20;
o is an integer from 0 to 10;
x is an integer from 0 to 10;
y is an integer selected from the group consisting of 0 and 1; and
z is an integer from 0 to 10.

2. The compound of claim 1 , wherein each occurrence of amino acid a and amino acid b is independently selected from the group consisting of a natural amino acid, unnatural amino acid, D-amino acid, L-amino acid, functionalized natural amino acid, functionalized unnatural amino acid, functionalized D-amino acid, functionalized L-amino acid, and any combination thereof.

3. The compound of claim 1 , wherein the compound having the structure of Formula (I) is a compound having the structure selected from the group consisting of

or a derivative, prodrug, pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof, and

or a derivative, prodrug, pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof,
wherein each occurrence of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino,

 amino acid, and any combination thereof;
wherein R 1 and R 2 are optionally fused or joined to form a ring;

each occurrence of X a and X b is independently selected from the group consisting of C, —CR 10 , N, P, P═O, S═O, and any combination thereof;
wherein each occurrence of R 10 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, hydroxylalkyl, alkoxy, amino, aminoalkyl, carbonyl, carboxyl, carboxylic acid, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heterocycloalkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, acyl, ester, urea, thiourea, thiol, thioalkyl, thioxo, sulfanyl, sulfinyl, sulfonyl, phosphino, nitrile, isonitrile, cyano, carbamate, guanidine, guanidine alkyl, amino acid, and any combination thereof;

m is an integer from 1 to 5;
n is an integer from 1 to 20;
o is an integer from 0 to 10;
x is an integer from 0 to 10;
y is an integer selected from the group consisting of 0 and 1; and
z is an integer from 0 to 10.

4. The compound of claim 1 , wherein
each occurrence of R 1 , R 2 , R 4 , R 6 , and R 9 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, alkoxy, amino, aminoalkyl, carbonyl, carboxyl, carboxylic acid, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heterocycloalkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, ester, urea, thiourea, thiol, thioalkyl, thioxo, sulfanyl, sulfinyl, sulfonyl, phosphino, ═O, nitrile, isonitrile, cyano, carbamate, guanidine, guanidine alkyl, amino acid, and any combination thereof;
wherein R 1 and R 2 are optionally fused or joined to form a ring;

R 3 is selected from the group consisting of hydrogen, deuterium, alkyl, and any combination thereof;
each occurrence of R 5 and R 7 is independently selected from the group consisting of hydrogen and deuterium;
R 8 is amino;
each occurrence of X a and X b is independently selected from the group consisting of C and —CR 10 ;
wherein each occurrence of R 10 is independently selected from the group consisting of hydrogen and deuterium;

m is an integer from 1 to 5;
n is an integer from 1 to 10;
o is an integer selected from the group consisting of 0 and 1;
x is an integer selected from the group consisting of 0 and 1;
y is an integer selected from the group consisting of 0 and 1; and
z is an integer selected from the group consisting of 0, 1, and 2.

5. The compound of claim 1 , wherein (Amino Acid a ) n is selected from the group consisting of an amino acid sequence as set forth in SEQ ID NOs: 1-12.

6. The compound of claim 1 , wherein o is an integer 0.

7. The compound of claim 1 , wherein R 2 is hydrogen.

8. The compound of claim 1 , wherein R 1 and R 2 are fused or joined to form a ring.

9. The compound of claim 8 , wherein the compound having the structure of Formula (I) is a compound having the structure of

or a derivative, prodrug, pharmaceutically acceptable salt, solvate, isomer, or tautomer thereof,
wherein each occurrence of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, alkoxy, amino, aminoalkyl, carbonyl, carboxyl, carboxylic acid, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heterocycloalkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, ester, urea, thiourea, thiol, thioalkyl, thioxo, sulfanyl, sulfinyl, sulfonyl, phosphino, ═O, nitrile, isonitrile, cyano, carbamate, guanidine, guanidine alkyl, amino acid, and any combination thereof;
each occurrence of X a and X b is independently selected from the group consisting of C, —CR 10 , N, P, P═O, S═O, and any combination thereof;
wherein each occurrence of R 10 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, hydroxylalkyl, alkoxy, amino, aminoalkyl, carbonyl, carboxyl, carboxylic acid, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocyclo

Assignees

• Univ Auburn

Inventors

• Raj Monika
• Adebomi Victor

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• C07K5/123 Primary

  Tripeptides · CPC title

• C07K5/1016 Primary

  and aromatic or cycloaliphatic · CPC title