Proteasome inhibitors

Patent metadata

Field	Value
Publication number	US-11999803-B2
Application number	US-202318169158-A
Country	US
Kind code	B2
Filing date	Feb 14, 2023
Priority date	Aug 6, 2018
Publication date	Jun 4, 2024
Grant date	Jun 4, 2024

Abstract

Unique compounds useful for inhibiting a proteasome in a cell, pharmaceutical compositions and methods of their use are provided herein.

First claim

As such, the following are representitive claims:

1. A method of treating Alzheimer's disease in a subject, comprising: administering to the subject an effective amount of a pharmaceutical composition containing a compound, a pharmaceutically acceptable salt, or a solvate thereof, of the formula:

wherein
(a) X and Y are independently selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —O—, —CH 2 O—, —NH—, —CH 2 NH—, —N(CH 3 )—, —CH 2 N(CH 3 )—, —C(═O)—, —CH 2 C(═O)—, —C 6 H 4 —, —CH 2 —(C 6 H 4 )—, —(C 6 H 4 )-F 1-4 -, —CH 2 —C 6 H 4 -(F) 1-4 -, -pyrazole-, -imidazole-, -thiazole-, -oxazole-, -morpholine-, -pyridine-, -piperazine-, and -pyrrole-;
(b) W is —CH 2 —, —CH 2 OCH 2 —, —CH 2 CH 2 O—, or —CH 2 CH 2 OCH 2 CH 2 —;
(c) n is 1, 2, 3, 4, 5, 6, 7, or 8;
(d) R 0 is H, OH, F, CH 3 , or OCH 3 ;
(e) R 1 is selected from the group consisting of:
(i)

wherein R is H, CH 3 , isopropyl, t-butyl, methoxymethyl (MOM), menthoxyethoxy methyl (MEM), or (CH 2 )nCH 3 wherein n is 1, 2, or 3;
(ii)

wherein X, Y, and Z are independently selected from the group consisting of H, CH, N, CH 3 , and CH 2 CH 3 ;
(iii)

wherein X and Y are independently selected from the group consisting of H, CH 3 , and (CH 2 )nCH 3 wherein n is 1, 2, or 3;
(iv)

wherein X is CH 2 or C═O; and R is H, CH 3 , N(CH 3 ) 2 , or Fn, wherein n is 0, 1, 2, 3, 4, or 5;
(v)

(vi)

(v)

wherein X is CH or N; Y is CH 2 , O, or N-R, wherein R is H, CH 3 or COCH 3 ; and n is 0, 1, or 2;
(vi)

wherein X, Y, and Z are independently selected from the group consisting of CH, CH 2 , N, NH, and O; and W is CH 2 or CH 2 CH 2 ;
(vii)

(viii)

wherein R is CH 3 , CH 2 CH 2 Ph-Fn, or CH 2 PhFn, wherein n is 0, 1, 2, 3, 4, or 5;
(ix)

wherein X, Y, and Z are independently selected from N and CH, and n is 0, 1, 2, or 3;
(f) R 2 , R 3 and R 4 are independently selected from the group consisting of:
(i) Gly, Ala, Pro, Leu, Ile, Phe, Tyr, Val, Ser, methyloxySerine, homoPhe, norVal, or norLeu;
(ii)

wherein X and Y are independently selected from the group consisting of H, CH 3 , and CH 2 CH 3 ; R and Z are independently selected from the group consisting of H, OH, OCH 3 , OCH 2 CH 3 , Ph, and OPh; and n is 1, 2, or 3;
(iii)

wherein X is cyclopropyl, cyclopentyl, or cyclohexyl, and n is 1, 2, or 3;
(iv)

wherein X and Y are independently selected from the group consisting of H, CH 3 , CO(CH 3 ), and CO2Bzl, and n is 1, 2, or 3;
(v)

wherein R is H, CH 3 , or (F) 1-3 , and n is 1, 2, or 3;
(vi)

wherein X and Y are independently selected from the group consisting of H, Fn, Cl, CH 3 , OCH 3 , OHCOCH 3 , NH 2 , NH(CH 3 ) and NHFmoc, and n is 1, 2, or 3;
(vii)

wherein X, Y, and Z are independently selected from CH and N, and n is 1, 2, or 3;
(viii)

wherein X and Y are independently selected from the group consisting of H, CH 3 , and COCH 3 , and n is 1, 2, 3, or 4;
(ix)

wherein X is H, Fn, CH 3 , or OCH 3 ; Y is H or OH, and n is 1, 2, 3, 4, or 5;
(x)

wherein X and Y are independently selected from the group consisting of H, Fn, CH 3 OCH 3 , OH, COCH 3 ; and n is 1, 2, 3, 4, or 5;
(xi)

(xii)

wherein n is 0, 1, 2, 3, 4, or 5;
(xii)

wherein X, Y, and Z are independently selected from the group consisting of CH, CH 2 , N, NH, N(CH 3 ), and O, and n is 1, 2, or 3;
(xiv)

wherein R is H, CH 3 , or Fn, wherein n is 0, 1, 2, or 3;
(xv)

and
(xvi)

wherein R is H, Fn, or (CH 3 )n; wherein n is 0, 1, 2, 3, or 4 and
(g) A is selected from:
(i)

wherein
R 5 is selected from the group consisting of: H, CH 3 , (CH 2 ) 1-3 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH(CH 3 ) 2 , CH 2 OH, CH 2 OCH 3 , CH 2 (C 6 H 5 ), CH 2 CH 2 (C 6 H 5 ), and CH 2 (C 6 H 4 )—OH, and X is selected from the group consisting of CH 2 , NH, and N(CH 3 ); (ii)

wherein X, Y, and Z are independently selected from the group consisting of CH, CH 2 , C═O, N, NH, O, S, and N-R, R is H, OH, (F) 1-4 , CH 3 , OCH 3 , CH 2 OCH 3 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(C═O)CH 3 , phenyl, phenyl(F) 1=4 , pyrazole, imidazole, thiazole, oxazole, morpholine, pyridine, piperazine, or pyrrole, and n is 2, 3, 4, or 5.

2. The method of claim 1 , wherein the compound has a formula selected from the group consisting of:

Assignees

• Univ Kentucky Res Found

Inventors

• Kim Kyung Bo

Classifications

• C07K5/123 Primary

  Tripeptides · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07K5/126

  Tetrapeptides · CPC title

• C07K5/06165 Primary

  and Pro-amino acid; Derivatives thereof · CPC title

• 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