Proteasome inhibitors

Patent metadata

Field	Value
Publication number	US-11345724-B2
Application number	US-201716305693-A
Country	US
Kind code	B2
Filing date	Jun 6, 2017
Priority date	Jun 6, 2016
Publication date	May 31, 2022
Grant date	May 31, 2022

Abstract

The present invention relates to a compound of formula (I), wherein X is C═O, C═S or B—OH; Y is an electrophile and Z is a leaving group, or Y═Z is an electrophile; R 1 comprises or consists of (a) (i) a first group binding to a proteolytic site of a proteasome, the first group being bound to X; and (ii) optionally a second group enhancing delivery; or (b) a group binding between subunits β1 and β2 of a proteasome; R 2 and R 3 are independently selected from H, methyl, methoxy, ethyl, ethenyl, ethynyl and cyano, wherein methyl and ethyl may be substituted with OH or halogen.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
X is C═O, C═S or B—OH;
Y is an electrophile and Z is a leaving group, or Y═Z is an electrophile;
R 1 is a peptidic group, wherein said peptidic group consists of three α-amino acids and wherein
(a) the N-terminal amino acid is selected from Ser(OMe), Leu, Phe and Ala; the middle amino acid is selected from Ser(OMe), Leu, Phe and Ala; and/or the C-terminal amino acid is attached to X and is a truncated amino acid residue that lacks a carbonyl group, wherein the truncated amino acid residue is based upon an amino acid selected from Phe, Tyr, Leu, Ser(OMe) and Ala; or
(b) said peptidic group consists of Ser(OMe)-Ser(OMe)-Phe, Leu-Leu-Tyr or Ala-Ala-Ala
R 2 and R 3 are independently selected from H, methyl, methoxy, ethyl, ethenyl, ethynyl and cyano, wherein methyl and ethyl may be substituted with OH or halogen.

2. The compound of claim 1 , wherein Y═Z is
(a) CH═O, CH 2 —I, CH 2 —Br, CH 2 —Cl, CH 2 —OPO(OH) 2 , CH 2 -OTs, CO—NHS or CH═CH 2 , wherein OTs is p-toluene sulfonyloxy and NHS is N-oxy-succinimide; or
(b) O—I, O—Br, O—Cl, S—I, S—Br or S—I.

3. The compound of claim 1 , wherein R 2 and R 3 are identical.

4. The compound of claim 1 , wherein X is C═O and Y═Z is CH═O or CO—NHS.

5. A method of inhibiting a proteasome, said method comprising bringing into contact a proteasome and a compound as defined in claim 1 .

6. A method of treating, ameliorating or preventing cancer, an autoimmune disease, muscular dystrophy, emphysema, or cachexia accompanying cancer or AIDS, comprising administering a compound as defined in claim 1 to a subject in need thereof.

7. The method of claim 6 , wherein
(a) said cancer is a lymphoid malignancy, wherein the lymphoid malignancy is multiple myeloma (MM) or non-Hodgkin lymphoma, wherein the non-Hodgkin lymphoma is a B-cell lymphoma selected from mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Waldenström macroglobulinaemia; or
(b) said autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, Sjörgen's syndrome or scleroderma.

8. The compound of claim 3 , wherein R 2 and R 3 are selected from methyl, methoxy, and —CH 2 OH.

Assignees

• Max Planck Gesellschaft

Inventors

• Chari Ashwin
• Stark Holger
• Schrader Jil
• Henneberg Fabian

Classifications

• C07K5/0806

  the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala · CPC title

• A61K38/03

  Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof · CPC title

• A61K38/005

  Enzyme inhibitors (protease inhibitors A61K38/55) · CPC title

• C07K5/0808

  the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu · CPC title

• C07K5/0202 Primary

  containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids · CPC title