Cycloheptapeptide agents for treatment of cancer and obesity diseases

Patent metadata

Field	Value
Publication number	US-9963485-B2
Application number	US-201615293516-A
Country	US
Kind code	B2
Filing date	Oct 14, 2016
Priority date	Oct 16, 2012
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

New anticancer and anti-obesity agents based on cyclic peptide compounds are isolated from the stem barks of Maytenus variabilis (Loes.) C. Y. Cheng (Celastraceae). The invention also includes its preparation and application method for treating cancer and obesity diseases.

First claim

What is claimed is:

1. A method for use in the treatment or delay of progression of cancer or obesity in a subject in needs thereof by administering an effective dosage of a composition comprising a compound according to formula (II):

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen and a moiety comprising 1 to 30 plural valence atoms selected from carbon, nitrogen, oxygen and sulphur;
at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is a cyclic group;
while one of R 1 and R 2 , R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 or R 13 and R 14 is hydrogen, halogen, hydrocarbyl, alkoxy or cyclic group, the other one of R 1 and R 2 , R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 or R 13 and R 14 is independently selected from R 15 ;
R 15 is independently selected from hydrogen, and hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R 16 , —(CH 2 ) k -heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 16 , —OR 17 , —C(O)R 18 , —C(O)N(R 17 )R 18 , —C(O)OR 17 , —OC(O)R 17 , —S(O) 2 R 17 , —S(O) 2 N(R 17 )R 18 , —N(R 17 )R 18 , —N(R 17 )N(R 17 )R 18 , —N(R 17 )C(O)R 18 and —N(R 17 )S(O) 2 R 18 ;
R 16 is independently selected from halogen, —OR 17 , —C(O)R 18 , —C(O)N(R 17 )R 18 , —C(O)OR 17 , —OC(O)R 18 , —N(R 17 )R 18 and —N(R 17 )C(O)R 18 ;
R 17 and R 18 are each independently hydrogen or selected from hydrocarbyl;
Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently selected from nitrogen with substitution of an L 1 , L 2 , L 3 , L 4 , L 5 or L 6 group, wherein L 1 , L 2 , L 3 , L 4 , L 5 and L 6 are each independently selected from R 15 , —C(O)R 15 or —C(O)OR 15 ;
Z is selected from oxygen, nitrogen with substitution of an L 7 group, hydrocarbyl, or alkoxy;
L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 are each independently selected from R 15 , —C(O)R 15 or —C(O)OR 15 ;
or an enantiomer thereof;
or a pharmaceutically acceptable salt or pro-drug thereof,
wherein said cancer comprising colon cancer, breast cancer, prostate cancer, lung cancer, melanoma, leukemia, cervical and oral epidermoid cancer.

2. The method according to claim 1 , wherein said composition comprising a compound having formula (I):

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen and a moiety comprising 1 to 30 plural valence atoms selected from carbon, nitrogen, oxygen and sulphur;
at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 is a cyclic group;
while one of R 1 and R 2 , R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 or R 13 and R 14 is hydrogen, halogen, hydrocarbyl, alkoxy or cyclic group, the other one of R 1 and R 2 , R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 or R 13 and R 14 is independently selected from R 15 ;
R 15 is independently selected from hydrogen, and hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R 16 , —(CH 2 ) k -heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R 16 , —OR 17 , —C(O)R 18 , —C(O)N(R 17 )R 18 , —C(O)OR 17 , —OC(O)R 17 , —S(O) 2 R 17 , —S(O) 2 N(R 17 )R 18 , —N(R 17 )R 18 , —N(R 17 )N(R 17 )R 18 , —N(R 17 )C(O)R 18 and —N(R 17 )S(O) 2 R 18 ;
R 16 is independently selected from halogen, —OR 17 , —C(O)R 18 , —C(O)N(R 17 )R 18 , —C(O)OR 17 , —OC(O)R 18 , —N(R 17 )R 18 and —N(R 17 )C(O)R 18 ;
R 17 and R 18 are each independently hydrogen or selected from hydrocarbyl;
L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 are each independently selected from R 15 , —C(O)R 15 or —C(O)OR 15 ;
or an enantiomer thereof;
or a pharmaceutically acceptable salt or pro-drug thereof.

3. The method of claim 1 , wherein said compound is an optically pure stereoisomer.

4. The method of claim 1 , wherein said compound is an enantiomer.

5. The method of claim 1 , wherein said compound is a racemate.

6. The method of claim 1 , wherein said compound is a diastereomer.

7. The method of claim 1 , wherein said compound is a tautomer.

8. The method according to claim 2 is selected from compound MV-A, compound MV-B, compound MV-C or compound MV-D:

or a pharmaceutically acceptable salt or prodrug thereof.

9. The method of claim 1 , wherein said subject is a human.

10. The method according to claim 1 , wherein the effective dosage is at least 0.0041 mg/kg per patient body weight.

11. The method according to claim 1 , wherein the effective dosage is at least 0.0081 mg/kg per patient body weight.

12. The method according to claim 1 , wherein the effective dosage is at least 0.0162 mg/kg per patient body weight.

13. The method according to claim 1 , wherein the effective dosage is at least 0.0324 mg/kg per patient body weight.

14. The method according to claim 1 , wherein the effective dosage is at least 0.0649 mg/kg per patient body weight.

15. The method according to claim 1 , wherein the effective dosage is at least 0.0405 mg/kg per patient body weight.

16. The method according to claim 1 , wherein the effective dosage is at least 0.0811 mg/kg per patient body weight.

17. The method according to claim 1 , wherein the effective dosage is at least 0.162 mg/kg per patient body weight.

Assignees

• Univ Hong Kong Baptist Univ

Inventors

• Zhang Hongjie

Classifications

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · 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

• C07C2601/02

  with a three-membered ring · CPC title

• C07C229/04

  the carbon skeleton being acyclic and saturated · CPC title

• C07K11/02

  cyclic, e.g. valinomycins {; Derivatives thereof} · CPC title