Method for synthesis of 9-cis-beta-carotene and formulations thereof

Patent metadata

Field	Value
Publication number	US-2019367451-A1
Application number	US-201716303604-A
Country	US
Kind code	A1
Filing date	May 21, 2017
Priority date	May 25, 2016
Publication date	Dec 5, 2019
Grant date	—

Abstract

The present invention relates to a method for total chemical synthesis of 9-cis-β-carotene (9CBC), and further provides stable formulations thereof.

First claim

1 . A formulation comprising an active agent, a thickening/solidifying agent, and an antioxidant, wherein said active agent is 9-cis-β-carotene (9CBC) or a derivative thereof of the formula C:

wherein R 2 is H or methyl; X is (—C═C—C—) n optionally substituted with one or more methyl groups; and n is an integer of 0-16.

2 . The formulation of claim 1 , wherein said thickening/solidifying agent comprises a lecithin or a PEGylated derivative thereof; a lecithin-like substance; a medium chain triglyceride or a mixture thereof; a povidone; a polysorbate; or sorbitol.

3 . The formulation of claim 2 , wherein said thickening/solidifying agent comprises a lecithin or a PEGylated derivative thereof, a lecithin-based product, or a povidone.

4 . The formulation of claim 3 , wherein said lecithin is egg lecithin or soybean lecithin; or said lecithin-based product is L-α-lecithin, granular (Acros Organics™), Phospholipon® 50, Phospholipon® 75, Phospholipon® 85G, Phospholipon® 90G, Phospholipon® 80H, Phospholipon® 90H, Phospholipon® E25, Phospholipon® E35, Phospholipon® E, Phospholipon® LPC20, Phospholipon® LPC25, or Phospholipon® LPC65.

5 . The formulation of claim 2 , wherein said lecithin-like substance is egg yolk; said medium chain triglyceride is miglyol, miglyol 810, or a mixture thereof; or said polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

6 . The formulation of claim 1 , wherein said antioxidant is a thiol; a sulphoximine; a metal chelator; sodium bisulfite; sodium metabisulfite; a vitamin; a phenol; a benzoate; uric acid; mannose; propyl gallate; a selenium; a stilbene; a carotenoid; or a mixture thereof.

7 . The formulation of claim 6 , wherein said antioxidant is a phenol selected from the group consisting of BHT, butylhydroxyanisole, ubiquinol, nordihydroguaiaretic acid, and trihydroxybutyrophenone; a carotenoid selected from the group consisting of α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, astaxanthin, and lycopene; or a mixture thereof.

8 . The formulation of claim 7 , wherein said antioxidant is BHT, a carotenoid, or a mixture thereof.

9 . The formulation of claim 1 , wherein said thickening/solidifying agent comprises a lecithin or a PEGylated derivative thereof, a lecithin-based product, or a povidone; and said antioxidant is BHT, butylhydroxyanisole, ubiquinol, nordihydroguaiaretic acid, trihydroxybutyrophenone, α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, astaxanthin, lycopene, or a mixture thereof.

10 . The formulation of claim 9 , wherein said lecithin is egg lecithin or soybean lecithin; said lecithin-based product is L-α-lecithin, granular (Acros Organics™), Phospholipon® 50, Phospholipon® 75, Phospholipon® 85G, Phospholipon® 90G, Phospholipon® 80H, Phospholipon® 90H, Phospholipon® E25, Phospholipon® E35, Phospholipon® E, Phospholipon® LPC20, Phospholipon® LPC25, or Phospholipon® LPC65; or said antioxidant is BHT, a carotenoid, or a mixture thereof.

11 . The formulation of claim 9 , wherein said thickening/solidifying agent comprises egg lecithin or soybean lecithin; and said antioxidant is BHT, α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, astaxanthin, lycopene, or a mixture thereof.

12 . The formulation of claim 11 , wherein said thickening/solidifying agent comprises egg lecithin or soybean lecithin; and said antioxidant is BHT.

13 . The formulation of claim 9 , wherein the weight ratio between said thickening/solidifying agent and said antioxidant or mixture thereof in said formulation is in a range of 100:1 to 1:100, respectively.

14 . The formulation of claim 1 , wherein said active agent is 9CBC.

15 . The formulation of claim 14 , comprising 9CBC, a soybean lecithin and BHT, at a weight ratio of about 1:10:5, respectively.

16 . The formulation of claim 1 , which is chemically stable for at least 72 hours under inert conditions.

17 . The formulation of claim 1 , in the form of a solid, semi-solid, gel, or paste.

18 . The formulation of claim 17 , formulated for oral administration.

19 . (canceled)

20 . A method for the synthesis of 9-cis β-carotene (9CBC) or a derivative thereof, said method comprising:
(i) reducing 4-methyl-6-(2,6,6-trimethylcyclohex-1-en-1-yl)-5,6-dihydro-2H-pyran-2-one, herein identified compound 3, and opening the ring of the lactol obtained with complete retention of the double bond configuration, to thereby obtain (2Z,4E)-3-methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-2,4-dienal, herein identified compound 5;
(ii) subjecting the (2Z,4E)-3-methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-2,4-dienal to Horner-Emmons reaction to obtain a 9-cis retinyl ester, herein identified compound 6;
(iii) reducing the 9-cis retinyl ester to obtain 9-cis retinol, herein identified compound 7; and
(iv) converting the 9-cis retinol to its triphenylphosphonium salt, herein identified compound 8, and subjecting said triphenylphosphonium salt to Wittig reaction with a compound of the formula A:

wherein R 2 is H or methyl; X is (—C═C—C—) n optionally substituted with one or more methyl groups; and n is an integer of 0-16, in the presence of a strong base, to thereby obtain said 9CBC or derivative thereof.

21 . The method of claim 20 , wherein:
(i) the reduction in step (i) is carried out with diisobutylaluminum hydride (DIBAL-H); or (ii) opening the ring of the lactol in step (i) is carried out in the presence of a strong acid; or (iii) the Horner-Emmons reaction in step (ii) is carried out with triethyl 3-methyl-4-phosphono-2-butenoate to obtain 9-cis retinyl ethyl ester; or (iv) converting the 9-cis retinol to its triphenylphosphonium salt in step (iv) is carried out with triphenylphosphine; or (v) said compound of the formula A is all-trans retinal, to obtain 9CBC.

22 - 25 . (canceled)

26 . The method of any one of claim 20 , wherein said 4-methyl-6-(2,6,6-trimethylcyclohex-1-en-1-yl)-5,6-dihydro-2H-pyran-2-one is synthesized by a method carried out as depicted in Scheme 1 and comprising reacting β-cyclocitral, herein identified compound 1, with a compound of the formula B:

wherein R 1 is (C 1 -C 8 )alkyl or (C 6 -C 10 )aryl, in the presence of metallic Zn, in a Reformatsky reaction.

27 . The method of claim 26 , wherein said β-cyclocitral is reacted with a compound of the formula B wherein R 1 is ethyl.

28 . 9-cis-β-carotene (9CBC) or a derivative thereof, synthesized according to the method of claim 20 , wherein said derivative is of the formula C:

wherein R 2 is H or methyl; X is (—C═C—C—) n optionally substituted with one or more methyl groups; and n is an integer of 0-16.

29 . The formulation of claim 6 , wherein said thiol is selected from the group consisting of aurothioglucose, dihydrolipoic acid, propylthiouracil, thioredoxin, glutathione (GSH), L-cysteine, N-acetylcysteine (NAC), cystine, cystamine, and thiodipropionic acid; said sulphoximine is selected from the group

Assignees

• Univ Ramot

Inventors

• Gazit Ehud
• Buzhansky Ludmila
• Ioffe Michael
• Sayer Alon

Classifications

• A61K47/24

  containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids · CPC title

• A61K31/015

  carbocyclic · CPC title

• C07C67/44

  by oxidation-reduction of aldehydes, e.g. Tishchenko reaction · CPC title

• A61K47/14

  Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters · CPC title

• C07C403/24 Primary

  having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene · CPC title