Phospholipid analogues

Patent metadata

Field	Value
Publication number	US-10954255-B2
Application number	US-201816635883-A
Country	US
Kind code	B2
Filing date	Jul 27, 2018
Priority date	Aug 3, 2017
Publication date	Mar 23, 2021
Grant date	Mar 23, 2021

Abstract

The present invention relates to a compound having a structure according to formula (I) or a salt thereof, wherein: R 1 is a branched or linear alkyl, acyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, or hydroxy-alkinyl residue comprising 6 to 30 carbon atoms, R 2 is selected from the group consisting of: a) an alkyl residue comprising 1 to 10 carbon atoms and comprising a terminal or cyclic quaternary ammonium, b) an alkyl residue comprising 1 to 10 carbon atoms and comprising a terminal amino group and/or 1 to 3 hydroxyl groups, c) an amino acid residue, d) a five or six carbon sugar and e) H, R 3 is a residue selected from the group consisting of an alkyl, alkenyl, prostanyl-dialkyl, furanyl-dialkyl, cyclobutyl-dialkyl, cycloalkyl and aryl group of 2 to 40 carbon atoms length and comprising at least one keto group, epoxy group, aldehyde group, peroxy group, hydroperoxy group, hydroxyl group or a free carboxyl group, L1 is selected from the group consisting of O, NH, S, CH 2 , (aa), (bb), (cc), (dd), (ee), (ff), (gg), (hh), (ii), (jj), (kk), (ll), (mm), or (nn), L2 is an amide group or an ether group, X and Z are independently O, S or CH 2 , and Y is selected from the group consisting of O and S.

First claim

The invention claimed is:

1. A compound having a structure according to formula (I)

or a salt thereof, wherein
R 1 is a branched or linear alkyl, acyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, or hydroxy-alkinyl residue comprising 6 to 30 carbon atoms,
R 2 is selected from the group consisting of
a) an alkyl residue comprising 1 to 10 carbon atoms and comprising a terminal or cyclic quaternary ammonium,
b) an alkyl residue comprising 1 to 10 carbon atoms and comprising a terminal amino group and/or 1 to 3 hydroxyl groups,
c) an amino acid residue,
d) a five or six carbon sugar and
e) H,
R 3 is a residue selected from the group consisting of an alkyl, alkenyl, prostanyl-dialkyl, furanyl-dialkyl, cyclobutyl-dialkyl, cycloalkyl and aryl group of 2 to 40 carbon atoms length and comprising at least one keto group, epoxy group, aldehyde group, peroxy group, hydroperoxy group, hydroxyl group or a free carboxyl group,
L1 is O,
L2 is an amide group,
X and Z are independently O, S or CH 2 , and
Y is selected from the group consisting of O and S.

2. The compound according to claim 1 , wherein R 1 is a residue selected from the group consisting of hexyl residue, heptyl residue, octyl residue, nonyl residue, decyl residue, undecyl residue, dodecyl residue, tetradecyl residue, hexadecyl residue and octadecyl residue.

3. The compound according to claim 1 , wherein R 2 is a choline residue.

4. The compound according to claim 1 , wherein R 2 is inositol, glycerol, ethanolamine, serine or H.

5. The compound according to claim 1 , wherein R 3 is an oxylipin selected from the group consisting of prostaglandins, isoprostanes, lipoxins, resolvins, protectins and maresins, monohydroxy-, dihydroxy-, trihydroxy-, tetrahydroxy fatty acid residues with epoxy-, keto-, hydroperoxy-, hydroxyl- or prostane groups independent of regio- and stereo-position of substituents within their structures.

6. The compound according to claim 1 , wherein R 3 is selected from the group consisting of prostacyclins, prostaglandins, isoprostanes, lipoxins, maresins, resolvins and protectins.

7. The compound according to claim 1 , wherein R 3 is a prostaglandin selected from the group consisting of prostaglandin E2, prostaglandin A2, prostaglandin F2α, prostaglandin B2, prostaglandin C2, prostaglandin D2, prostaglandin J2, 15-deoxy-Δ12,14-prostaglandin J2, deoxyprostaglandin D2, deoxyprostaglandin E2, deoxyprostaglandin A2, 15-keto-prostaglandin F2α, 15-keto-prostaglandin E2, and epoxyprostaglandin E2.

8. The compound according to claim 1 , wherein R 3 is an isoprostane selected from the group consisting of isoprostaglandin E2, isoprostaglandin A2, isoprostaglandin F2α, isoprostaglandin B2, isoprostaglandin C2, isoprostaglandin D2, isoprostaglandin J2, deoxyisoprostaglandin D2, deoxyisoprostaglandin E2, deoxyisoprostaglandin A2, deoxyisoprostaglandin J2, 15-keto-isoprostaglandin F2 α, 15-keto-isoprostaglandin E2 and epoxyisoprostaglandin E2.

9. The compound according to claim 1 , wherein R 3 is a lipoxin selected from the group consisting of lipoxin A4, lipoxin B4 and 15(R)-lipoxin A4.

10. The compound according to claim 1 , wherein R 3 is a maresin selected from the group consisting of maresin 1 and maresin 2.

11. The compound according to claim 1 , wherein R 3 is a resolvin selected from the group consisting of resolvin E1, resolvin T1, resolvin D1 and resolvin D2.

12. The compound according to claim 1 , wherein R 3 is a protectin selected from the group consisting of protectin PDX and protectin D1.

13. The compound according to claim 1 , wherein R 3 is a prostacyclin selected from the group consisting of 5-{(E)-(1S,5S,6R,7R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]-bicyclo[3.3.0]octan-3-ylidene}pentanyl (iloprost), 5-cis-iloprost, 5-cis-15(R)-iloprost, 15(R)-iloprost, 15-keto-iloprost, carbaprostacyclin, 5-cis-carbaprostacyclin, 13,14-dehydro-15-cyclohexyl, carbaprostacyclin, 5Z-[3aR,3-difluorohexahydro-5R-hydroxy-4R-[3R-hydroxy-4S-methyl-1E-nonen-6aS-ynyl]-2H-cyclopenta[b]furan-2-ylidene]-pentanoyl (16(R)-AFP07), 5Z-[(3aR,4R,5R,6aS)-3,3-difluorohexahydro-5-hydroxy-4-[(1E,3S,4S)-3-hydroxy-4-methyl-1-nonen-6-ynyl]-2H-cyclopenta[b]furan-2-ylidene]-pentanoyl (AFP07), treprostinil, cicaprost, beraprost, ciprostene and 15(R)-prostaglandin I 2 .

14. The compound according to claim 1 , wherein R 3 is a compound selected from the group consisting of 10-hydroxydecanyl, 12-hydroxydodecanyl, 15-hydroxyeicosatetraenyl, 12-hydroxy eicosatetraenyl, 8-hydroxyeicosatetraenyl, 9-hydroxyeicosatetrenyl, D,L-threo-9,10,16-trixydroxyhexadecanyl (aleuritic acid residue), (R)-12-hydroxy-cis-9-octadecanyl (12-hydroxyoleic acid residue or ricinoleic acid).

15. The compound according to claim 1 , wherein X, Y and Z are O.

16. The compound according to claim 1 , wherein the compound is selected from the group consisting of

17. A pharmaceutical composition comprising a compound according to claim 1 .

18. A method for treating an inflammatory disease or disorder or a disease or disorder associated with Toll-like receptor 2 (TLR2) and/or Toll-like receptor 4 (TLR4) and/or NFkB inflammatory cascade comprising the administration of a compound according to claim 1 to a mammal in need thereof.

19. The method according to claim 18 , wherein the mammal is a human.

20. The method according to claim 18 , wherein the inflammatory disease or disorder associated with Toll-like receptor 2 (TLR2) and/or Toll-like receptor 4 (TLR4) is Gram-negative sepsis, Gram-positive sepsis, or mixed-type sepsis.

Assignees

• Karl Franzens Univ Graz
• Univ Chicago

Inventors

• Birukov Konstantin
• Birukova Anna
• Bochkov Valery
• Oskolkova Olga

Classifications

• C07F9/106

  Adducts, complexes, salts of phosphatides · CPC title

• C07F9/10

  Phosphatides, e.g. lecithin · CPC title

• A61P25/16 Primary

  Anti-Parkinson drugs · CPC title

• C07F9/572

  Five-membered rings · CPC title

• C07F9/117 Primary

  with cycloaliphatic alcohols · CPC title