Tripeptide boronic acid or boronic ester, preparative method and use thereof

• US 9,421,237 B2
• Filed: 05/17/2010
• Issued: 08/23/2016
• Est. Priority Date: 06/19/2009
• Status: Expired due to Fees

• Current Assignee: Peking University
• Original Assignee: Peking University
• Inventors: Li, Runtao, Cui, Jingrong, Zhu, Yongqiang, Yao, Shuyang, Ge, Zemei, Cheng, Tieming
• Primary Examiner(s): Ha, Julie
• Assistant Examiner(s): Hellman, Kristina M
• Application Number:
  US13/379,142
• Publication Number:
  US 20120135921A1
• Time in Patent Office: 2,290 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 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 Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07K 5/08 Tripeptides
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp

Abstract

The present invention discloses proteasome inhibitors of tripeptide boronic acids or boronic esters represented by Formula (I), preparative method and use thereof. The proteasome inhibitors are therapeutical agents for treating malignant tumor, various nervous system degenerative diseases, muscle cachexia or diabetes, wherein the malignant tumor is leukemia, gastric cancer, hepatocarcinoma or nasopharyngeal carcinoma.

Claims

1. A tripeptide boronic acid compound represented by the following general formula (I):

2. The compound according to claim 1, wherein the R₃ group is isobutyl.

3. The compound according to claim 1 wherein the compound is selected from the group consisting of:

Pinanediol N-pyrazineformyl-L-phenylalanyl-L-tyrosyl-L-leucine borate;

Pinanediol N-pyrazineformyl-L-phenylalanyl-L-naphthylalanyl-L-leucine borate;

Pinanediol N-pyrazineformyl-L-phenylalanyl-L-tryptophyl-L-leucine borate;

Pinanediol N-pyrazineformyl-L-phenylalanyl-L-leucyl-L-leucine borate;

N-pyrazineformyl-L-phenylalanyl-L-tyrosyl-L-leucine boronic acid;

N-pyrazineformyl-L-phenylalanyl-L-naphthylalanyl-L-leucine boronic acid;

N-pyrazineformyl-L-phenylalanyl-L-tryptophyl-L-leucine boronic acid; and

N-pyrazineformyl-L-phenylalanyl-L-leucyl-L-leucine boronic acid.

4. A pharmaceutical composition containing a therapeutically-effective amount of a tripeptide boronic acid according to any one of claims 1, 2 and 3 as an active ingredient, and optionally one or more kinds of pharmaceutical carrier(s).

5. The pharmaceutical composition according to claim 4, wherein the content of the active ingredient in the pharmaceutical composition is 0.5%-99%, and the content of the pharmaceutical carrier(s) is 1%-99.5%.

6. The pharmaceutical composition according to claim 5, wherein the composition is formulated into a form for oral administration or a form for parenteral administration, and the form for parenteral administration includes the forms for injection administration, topical administration, inhalation administration, rectal administration or implantable administration.

7. The pharmaceutical composition according to claim 6, wherein the form for oral administration is tablets, capsules, granules or liquid preparations suitable for oral administration, or sustained-release or quantitative release form;

and the form for injection administration is injections, freeze-dried powder injections or solutions suitable for infusion.

8. The pharmaceutical composition according to claim 4 for use in preparation of a proteasome inhibitor.

9. A tripeptide boronic acid compound represented by the following general formula (I):

10. The compound according to claim 9, wherein the R3 group is isobutyl.

11. The compound according to claim 10 wherein the compound is selected from the group consisting of:

Pinanediol N-pyrazineformyl-L-naphthylalanyl-L-phenylalanyl-L-leucine borate;

Pinanediol N-pyrazineformyl-L-tyrosyl-L-phenylalanyl-L-leucine borate;

Pinanediol N-pyrazineformyl-L-leucyl-L-phenylalanyl-L-leucine borate;

Pinanediol N-pyrazineformyl-L-leucyl-L-naphthylalanyl-L-leucine borate;

Pinanediol N-pyrazineformyl-L-naphthylalanyl-L-naphthylalanyl-L-leucine borate;

Pinanediol N-pyrazineformyl-L-tryptophyl-L-phenylalanyl-L-leucine borate;

Pinanediol N-pyrazineformyl-L-leucyl-L-leucyl-L-leucine borate;

Pinanediol N-pyrazineformyl-L-naphthylalanyl-L-leucyl-L-leucine borate;

N-pyrazineformyl-L-naphthylalanyl-L-phenylalanyl-L-leucine boronic acid;

N-pyrazineformyl-L-tyrosyl-L-phenylalanyl-L-leucine boronic acid;

N-pyrazineformyl-L-leucyl-L-phenylalanyl-L-leucine boronic acid;

N-pyrazineformyl-L-leucyl-L-naphthylalanyl-L-leucine boronic acid;

N-pyrazineformyl-L-naphthylalanyl-L-naphthylalanyl-L-leucine boronic acid;

N-pyrazineformyl-L-tryptophyl-L-phenylalanyl-L-leucine boronic acid;

N-pyrazineformyl-L-leucyl-L-leucyl-L-leucine boronic acid; and

N-pyrazineformyl-L-naphthylalanyl-L-leucyl-L-leucine boronic acid.

12. A pharmaceutical composition containing a therapeutically-effective amount of a tripeptide boronic acid according to claim 9 as an active ingredient, and optionally one or more kinds of pharmaceutical carrier(s).

13. The pharmaceutical composition according to claim 12, wherein the content of the active ingredient in the pharmaceutical composition is 0.5%-99%, and the content of the pharmaceutical carrier(s) is 1%-99.5%.

14. The pharmaceutical composition according to claim 13, wherein the composition is formulated into a form for oral administration or a form for parenteral administration, and the form for parenteral administration includes the forms for injection administration, topical administration, inhalation administration, rectal administration or implantable administration.

15. The pharmaceutical composition according to claim 14, wherein the form for oral administration is tablets, capsules, granules or liquid preparations suitable for oral administration, or sustained-release or quantitative release form;

and the form for injection administration is injections, freeze-dried powder injections or solutions suitable for infusion.

16. The pharmaceutical composition according to claim 12 for use in preparation of a proteasome inhibitor.