Process for the manufacture of ajoene derivatives

Patent metadata

Field	Value
Publication number	US-10603289-B2
Application number	US-201815980471-A
Country	US
Kind code	B2
Filing date	May 15, 2018
Priority date	Dec 8, 2010
Publication date	Mar 31, 2020
Grant date	Mar 31, 2020

Abstract

The present invention relates to the compound (E,Z)-ajoene of formula (1) for use in treatment of bacterial infections. Another aspect of the present invention is a composition comprising (E,Z)-ajoene of formula (1) and at least one antibiotic. Yet another aspect of the invention relates to a method for manufacturing (E,Z) ajoene of formula (1) wherein the conformation of the internal C═C— bond can be either E or Z or a mixture thereof, said method comprising reacting allicin of formula (3) with an acid in the presence of a solvent to provide (E,Z ajoene) of formula (1) as defined above. Yet another aspect of the invention is (E,Z)-ajoene of formula 1 obtainable by the method described above.

First claim

The invention claimed is:

1. A method for inhibiting virulence of a bacteria in a mammal in need thereof, comprising:
a) selecting a mammal having an infection caused by a biofilm forming bacteria, wherein the bacteria is Pseudomonas aeruginosa ; and
b) administering to the selected mammal a therapeutically effective amount of ajoene formula (I):

2. The method of claim 1 , wherein the bacterial infection is a pulmonary infection.

3. The method of claim 1 , wherein the bacterial infection is present in a chronic wound of the selected mammal.

4. The method of claim 1 , wherein the ajoene has a concentration of around 10 to 80 ug/ml.

5. The method of claim 1 , wherein the dose of ajoene administered to the selected mammal is 25 ug/g body weight.

6. The method of claim 1 , wherein the ajoene is a mixture of an E-isomer and a Z-isomer.

7. The method of claim 6 , wherein ratio of the E- and Z-isomers in the mixture is 20:1 to 1:10.

8. The method of claim 1 , wherein the selected mammal has an immune deficiency and the selected mammal is a human, pet or livestock.

9. The method according to claim 8 , wherein the immune deficiency is an immuno-compromising disease or the selected mammal is taking an immuno-suppressant medication.

10. The method of claim 1 , wherein the selected mammal is a cystic fibrosis patient.

11. The method of claim 1 , further comprising providing at least one antibiotic selected from the group consisting of aminoglycosides, ansamycins, carbacephem, carbapenems, cephalosporins, glycopeptides, macrolides, monobactams, penicillins, polypeptides, quinolones, sulfonamides, and tetracyclines.

12. The method according to claim 11 , wherein the antibiotic is an aminoglycoside.

13. The method according to claim 12 , wherein the antibiotic is selected from the group consisting of Ampicillin, Bacampicillin, Carbenicillin Indanyl, Mezlocillin, Piperacillin, Ticarcillin, Amoxicillin-Clavulanic Acid, Ampicillin-Sulbactam, Benzylpenicillin, Cloxacillin, Dicloxacillin, Methicillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin Tazobactam, Ticarcillin Clavulanic Acid, Nafcillin, Cefadroxil, Cefazolin, Cephalexin, Cephalothin, Cephapirin, Cephradine, Cefaclor, Cefamandol, Cefonicid, Cefotetan, Cefoxitin, Cefprozil, Ceftmetazole, Cefuroxime, Loracarbef, Cefdinir, Ceftibuten, Cefoperazone, Cefixime, Cefotaxime, Cefpodoxime proxetil, Ceftazidime, Ceftizoxime, Ceftriaxone, Cefepime, Azithromycin, Clarithromycin, Clindamycin, Dirithromycin, Erythromycin, Lincomycin, Troleandomycin, Cinoxacin, Ciprofloxacin, Enoxacin, Gatifloxacin, Grepafloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Sparfloxacin, Trovafloxacin, Oxolinic acid, Gemifloxacin, Perfloxacin, Imipenem-Cilastatin, Meropenem, Aztreonam, Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Streptomycin, Tobramycin, Paromomycin, Teicoplanin, Vancomycin, Demeclocycline, Doxycycline, Methacycline, Minocycline, Oxytetracycline, Tetracycline, Chlortetracycline, Mafenide, Silver Sulfadiazine, Sulfacetamide, Sulfadiazine, Sulfamethoxazole, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole, Sulfamethizole, Rifampin, Rifabutin, Rifampin, Rifapentine, Linezolid, Quinopristin Dalfopristin, Bacitracin, Chloramphenicol, Fosfomycin, Isoniazid, Methenamine, Metronidazol, Mupirocin, Nitrofurantoin, Nitrofurazone, Novobiocin, Polymyxin, Spectinomycin, Trimethoprim, Colistin, Cycloserine, Capreomycin, Ethionamide, Pyrazinamide, Para-aminosalicyclic acid, and Erythromycin ethylsuccinate.

14. The method of claim 13 , wherein the antibiotic is tobramycin.

15. The method of claim 1 , further comprising inhibiting or reducing biofilm formation by the bacteria via the administering of the therapeutically effective amount of ajoene formula (I).

16. The method of claim 1 , further comprising administering the therapeutically effective amount of ajoene formula (I) in a pharmaceutical composition including at least 95% ajoene formula (I) with an E:Z isomer ratio of 1:2-1:6.

17. A method for inhibiting virulence of a bacteria in a mammal in need thereof, comprising:
a) selecting a mammal having an infection caused by a biofilm forming bacteria, wherein the bacteria is Pseudomonas aeruginosa ; and
b) administering to the selected mammal a therapeutically effective amount of a garlic extract purified to 95% to 99.5% ajoene formula (I):

18. The method of claim 17 , wherein the garlic extract includes 0.5% to 5% garlic extract components other than ajoene formula (I).

Assignees

• Univ Danmarks Tekniske

Inventors

• Bjarnsholt Thomas
• Høiby Niels
• Jensen Peter Østrup
• Phipps Richard
• Shanmugham Meenakshi Sundaram
• Alhede Maria
• Hultqvist Louise Dahl
• Jakobsen Tim Holm
• Tanner David
• Larsen Thomas Ostenfeld
• Givskov Michael

Classifications

• C07C319/22

  of hydropolysulfides or polysulfides · CPC title

• A61K31/7036

  having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61M16/0683

  Holding devices therefor · CPC title

• A61K31/105 Primary

  Persulfides (thiuram disulfides A61K31/145; thiosulfonic acids A61K31/185) · CPC title