Sphingoglycolipid analogues

Patent metadata

Field	Value
Publication number	US-9717790-B2
Application number	US-201414897601-A
Country	US
Kind code	B2
Filing date	Jun 10, 2014
Priority date	Jun 10, 2013
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

The invention relates to sphingoglycolipid analogues which are useful in treating or preventing diseases and conditions such as those relating to infection, atopic disorders, autoimmune diseases or cancer.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
Z is S, S—S, SO or SO 2 ;
D is selected from the group consisting of:
hydrogen, halogen, hydroxyl, cyano, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, a radical of formula D1, a radical of formula D2 and a radical of formula D3;

wherein R 32 is selected from the group consisting of: an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group and an optionally substituted aryl group; R 33 is halogen; m is an integer from 2 to 10, and wherein in D2 denotes an optional double bond;
provided that if D is halogen then Z is not S or S—S and provided that if D is cyano then Z is not S—S, SO or SO 2 and provided that if D is hydroxyl then Z is not S, S—S or SO;
R 1 is H or glycosyl, provided that if R 1 is glycosyl then R 2 and R 3 are both OH;
R 2 is selected from the group consisting of H, OH, F and OR 10 ; provided that if R 2 is H, F or OR 10 , then R 1 is H, R 3 is OH;
R 3 is selected from the group consisting of H, OH, F and OR 10 ; provided that if R 3 is H, F or OR 10 , then R 1 is H, R 2 is OH;
R 6 is OH or H;
R 7 is OH or H; wherein when R 7 is H, R 8 is C 1 -C 15 alkyl and X is O, denotes an optional double bond linking the carbon adjacent to R 7 with the carbon adjacent to R 8 ;
R 8 is H or C 1 -C 15 alkyl having a straight or branched carbon chain, wherein the carbon chain optionally incorporates one or more double bonds, one or more triple bonds, one or more oxygen atoms and/or a terminal or non-terminal optionally substituted aryl group;
R 10 is glycosyl;
R 12 is C 6 -C 30 acyl having a straight or branched carbon chain optionally substituted with one or more hydroxy groups at positions 2 and/or 3 of the acyl group and/or an optionally substituted chain terminating aryl group and which optionally incorporates one or more double bonds, one or more triple bonds, and/or one or more optionally substituted arylene groups and wherein the carbon chain is optionally substituted with one or more deuterium atoms; wherein the optional substituents on the aryl and arylene groups may be selected from halogen, cyano, dialkylamino, C 1 -C 6 amide, nitro, C 1 -C 6 alkoxy, C 1 -C 6 acyloxy and C 1 -C 6 thioalkyl;
X is O, CH 2 or S; wherein,
when X is CH 2 then the following must all be true: the stereochemistry of the 6-membered sugar ring in formula (I) is α-D-galacto; R 1 is H; R 2 and R 3 are both OH; and:
either R 6 is OH and R 7 is OH and the stereochemistry at carbon atoms 2, 3 and 4 is (2S, 3S, 4R), (2S, 3S, 4S), (2R, 3S, 4S), (2R, 3S, 4R) or (2S, 3R, 4S); or R 6 is OH and R 7 is H, and R 8 is C 13 H 27 and the stereochemistry at carbon atoms 2 and 3 is (2S, 3S); or
when X is S then the following must all be true: the stereochemistry of the 6-membered sugar ring in formula (I) is α-D-galacto; R 1 is H; R 2 and R 3 are both OH; and:
either R 6 is OH and R 7 is OH and the stereochemistry at carbon atoms 2, 3 and 4 is (2S, 3S, 4R); or R 6 is OH and R 7 is H and the stereochemistry at the carbon atoms 2 and 3 is (2S, 3S);
n is 1 when X is O or S; or n is 0 or 1 when X is CH 2 ;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 which is a compound of formula (Ia)

wherein X, Z, D, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 10 , R 12 , R 32 and n are all as defined in claim 1 .

3. The compound of claim 1 wherein X is O.

4. The compound of claim 1 wherein n in formula (I) is 1, the stereochemistry of the 6-membered sugar ring of formula (I) is α-D-galacto, R 6 is OH, R 7 is OH and the stereochemistry at carbon atoms 2, 3 and 4 is (2S, 3S, 4R).

5. The compound of claim 1 wherein n in formula (I) is 0, the stereochemistry of the 6-membered sugar ring of formula (I) is α-D-galacto, R 6 is OH, R 7 is OH and the stereochemistry at carbon atoms 2, 3 and 4 is (2S, 3S, 4R).

6. The compound of claim 1 wherein X is O, R 6 is OH, R 7 is H, R 8 is C 1 -C 15 alkyl and is a double bond linking the carbon adjacent to R 7 with the carbon adjacent to R 8 and the stereochemistry at the carbon atoms 2, 3 is (2S, 3S).

7. The compound of claim 1 wherein D is an alkyl group.

8. The compound of claim 1 wherein D is hydrogen.

9. The compound of claim 1 which is a compound of formula (I.2), (I.3) or (I.4)

wherein X, Z, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 10 , R 12 , R 32 , R 33 and n are all as defined in claim 1 .

10. The compound of claim 1 wherein R 12 is a C 26 -acyl group.

11. A compound of formula (IV)

wherein X, Z, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 10 , R 12 , R 32 , R 33 and n are all as defined in claim 1 ; and wherein denotes an optional double bond;
or a pharmaceutically acceptable salt thereof.

12. A compound of formula (V)

wherein X, Z, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 10 , R 12 and n are all as defined in claim 1 ;
or a pharmaceutically acceptable salt thereof.

13. The compound of claim 11 wherein R 12 is a C 26 acyl group.

14. The compound of claim 12 wherein R 12 is a C 26 -acyl group.

15. The compound of claim 1 , selected from the group consisting of:

16. The compound of claim 1 wherein R 8 is C 1 -C 15 alkyl having a straight or branched carbon chain, wherein the carbon chain optionally incorporates one or more double bonds, one or more triple bonds, one or more oxygen atoms and/or a terminal or non-terminal optionally substituted aryl group.

17. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 1 , and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17 which is a vaccine optionally comprising an antigen.

19. A method of modifying an immune response in a patient, comprising administering to the patient either (i) the compo

Assignees

• Victoria Link Ltd

Inventors

• Anderson Regan James
• Compton Benjamin Jason
• Hayman Colin Malcolm
• Hermans Ian Francis
• Johnston Karen Anne
• Larsen David Samuel
• Painter Gavin Frank

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title