Fatty acid compound, preparation method therefor and use therefor

Patent metadata

Field	Value
Publication number	US-10414713-B2
Application number	US-201716075528-A
Country	US
Kind code	B2
Filing date	Feb 20, 2017
Priority date	Feb 25, 2016
Publication date	Sep 17, 2019
Grant date	Sep 17, 2019

Abstract

The present invention relates to a class of fatty acid compounds, a preparation method thereof and use thereof. The fatty acid compounds have the structure of the formula I, which has the ability to activate APMK and inhibit the glucose output in mouse primary hepatocytes. The fatty acid compounds can be used in preparing a medicament for the treatment of obesity or diabetes.

First claim

The invention claimed is:

1. A fatty acid compound of formula II, or a pharmaceutically acceptable salt thereof:

wherein R 1 and R 2 are each independently H, C1˜C4 alkyl or phenyl;
R 3 , R 4 , R 5 , and R 6 are each independently C1˜C4 alkyl or phenyl;
alternatively, R 5 and R 6 together with their adjacent carbon atoms form a C3˜C7 cycloalkyl group, or together with their adjacent carbon atom form a C3˜C7 cycloalkenyl group,
alternatively, R 3 and R 4 together with their adjacent carbon atoms form a C3˜C7 cycloalkyl group, or together with their adjacent carbon atoms form a C3˜C7 cycloalkenyl group;
m, n are each independently 1, 2, 3, 4, 5 or 6,
the double bond is either cis or trans.

2. The fatty acid compound of formula II according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the said fatty acid compound is selected from:

3. A method for preparing the fatty acid compound of formula II according to claim 1 , wherein the method comprises the following steps:

(1) reacting substituted ethyl acetate A1 with dibromoalkane A2 in the presence of lithium diisopropylamide and an organic solvent to obtain intermediate A3; under the same conditions, replacing A1 with

 and reacting with A2 to give A4;
(2) reacting A3 and A4 with tosylmethyl isocyanide in the presence of NaH, tetrabutylammonium iodide, and dimethyl sulfoxide to obtain compound A5;
(3) reacting A5 with concentrated hydrochloric acid to obtain A6;
(4) conducting a hydrolysis reaction of A6 under alkaline conditions, and then acidulating with dilute hydrochloric acid to obtain A7;
(5) further reducing A7 with sodium borohydride to obtain A8;
(6) refluxing a toluene solution of A8 and the catalyst p-toluenesulfonic acid to obtain a compound A9 or A10;
wherein the definitions of R 3 , R 4 , R 5 , R 6 , n and m are the same as described in claim 1 .

4. A method for preparing the fatty acid compound of formula II according to claim 1 , wherein the method comprises the following steps:

(1) condensing A15 with A16 or A17 in the presence of lithium diisopropylamide to obtain intermediate A18;
(2) conducting a hydrogenation reaction of A18 to obtain intermediate A19;
(3) conducting a hydrolysis reaction of A19 under alkaline conditions, and then acidulating with dilute hydrochloric acid to obtain A20;
wherein the definitions of R 3 , R 4 , R 5 , R 6 , n and m are the same as described in claim 1 .

5. The method for preparing the fatty acid compound of formula II according to claim 4 , wherein A15 is prepared using the following steps:

(1) reacting 1-alkynyl-alcohol compound A21 in the presence of pyridine p-toluenesulfonate and 2-tetrahydropyran to give intermediate A23; reacting 1-hydroxy-bromo compound A22 in the presence of pyridine p-toluenesulfonate and 2-tetrahydropyran to obtained intermediate A24;
(2) condensing A23 with A24 in the presence of n-butyllithium and HMPA to give intermediate A25;
(3) deprotection of A25 in the presence of p-toluenesulfonic acid and an organic solvent to obtain intermediate A26;
(4) reacting A26 with carbon tetrabromide and triphenylphosphine to give A15.

6. A method for preparing the fatty acid compound of formula II according to claim 1 , wherein the method comprises the following steps:

(1) reacting intermediate A18 with bis(pinacolato)diboron catalyzed by Tetrakis(triphenylphosphine)platinum to form intermediate A26;
(2) conducting a coupling reaction with A26 and iodide R 1 I or R 2 I to give intermediate A27;
(3) conducting a hydrolysis reaction of A27 under alkaline conditions, and then acidulating with dilute hydrochloric acid to obtain the compound represented by the formula II;
wherein, the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m and n are the same as described in claim 1 .

7. A method for treating obesity or diabetes, comprising the step of administering to a subject in need of such treatment an effective amount of the fatty acid compound or pharmaceutically acceptable salts thereof according to claim 1 .

8. A pharmaceutical composition for treating obesity or diabetes, comprising:
one or more compounds selected from the group consisting of the fatty acid compound and pharmaceutically acceptable salts thereof according to claim 1 as an active ingredient; and
one or more pharmaceutically acceptable carrier.

9. The method for preparing the fatty acid compound of formula II according to claim 4 , wherein A15 is prepared using the following steps:

(1) reacting sodium acetylide A11 with bromo A12 in DMF to obtain intermediate A13;
(2) condensing alkynyl compound A13 and brominated compound A2 in the presence of n-butyl lithium and hexamethylphosphoric triamide to give intermediate A14;
(3) refluxing intermediate A14 with lithium bromide in an organic solvent to give A15.

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Nan Fajun
• Li Jia
• Li Jingya
• Zhang Mei
• Xie Zhifu
• Wang Jingtao
• Guo Dongdong

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07C61/22

  having a carboxyl group bound to a six-membered ring · CPC title

• C07C61/20

  having a carboxyl group bound to a five-membered ring · CPC title

• C07C61/16

  Unsaturated compounds · CPC title