Organic compounds as proantigens for natural killer T cells

Patent metadata

Field	Value
Publication number	US-9586985-B2
Application number	US-201314417487-A
Country	US
Kind code	B2
Filing date	Jul 26, 2013
Priority date	Jul 26, 2012
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

This invention relates to sphingoglycolipid analogs, compositions comprising these compounds, processes for preparing the compounds, and methods of treating or preventing diseases or conditions using the compounds, such as diseases or conditions relating to infection, atopic disorders, autoimmune disease, diabetes or cancer.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
R′ is H or glycosyl, provided that if R′ is glycosyl then R 2 and R 3 are both OH and R 4 is CH 2 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 and R 4 is CH 2 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 and R 4 is CH 2 OH;
R 4 is CH 3 , CH 2 OH, CH 2 OCOR 11 , CH 2 OR 10 , CH 2 OR 11 , CH 2 OSO 3 H, CH 2 SH, CH 2 SR 11 , CH 2 SOR 11 , CH 2 SO 2 R 11 , CH 2 PO 3 H 2 , CH 2 OP(O)(OH) 2 , CH 2 OP(O)(OH)(OH 11 ), CH 2 OP(O)(OR 11 ) 2 , CO 2 H, CH 2 NHCOR 11 , CH 2 NHCO 2 R 11 , CH 2 NHCONH 2 , CH 2 NHCONHR 11 , CH 2 NHCON(R 11 ) 2 , CH 2 N(R 11 ) 2 , CH 2 NHSO 2 R 11 ; provided that if R 4 is other than CH 2 OH, then R 1 is H and R 2 and R 3 are OH;
R 5 is H;
or R 5 is a radical of formula (i):

wherein Y is a radical of formula:

each E 1 , the same or different, is independently selected from the group consisting of H, alkyl, alkoxy, halogen, nitroaryl; or, together with the ring to which it is attached, forms a fused bicyclic aryl group;
p is an integer from 1 to 4;
t is an integer from 1 to 2;
Alk 1 is C 1 -C 4 straight chain alkyl;
wherein when Y is a radical of formula (a) or (b) then Z is:

or wherein when Y is a radical of formula (c), (d), (e), (f) or (j) then Z is:

u is 1 or 2;
each A 1 , the same or different, is independently selected from the group consisting of:
alkyl which may be optionally substituted with one or more substituents selected from the group consisting of (OCH 2 CH 2 ) m OMe, NHC(O)OR 14 , alkoxyimino, oxo, halogen, alkoxy, NHCOCH 2 (OCH 2 CH 2 ) m OMe,

alkenyl which may be optionally substituted with one or more substituents selected from the group consisting of (OCH 2 CH 2 ) m OMe, alkoxyimino, oxo, halogen and alkoxy;
aryl which may be optionally substituted with one or more substituents selected from the group consisting of (OCH 2 CH 2 ) m OMe, alkyl, alkoxy, dialkylamino, nitro, halogen; or
aralkyl which may be optionally substituted with one or more substituents selected from the group consisting of (OCH 2 CH 2 ) m OMe, alkoxyimino, oxo, halogen, alkyl, alkoxy, dialkylamino and nitro;
m is an integer from 10 to 1500;
E 2 and A 2 are each independently selected from H and A 1 ;
A 4 is selected from the group consisting of H, methyl, CH 2 CH 2 CH 2 NHC(═NH)NH 2 , CH 2 C(═O)NH 2 , CH 2 C(═O)OH, CH 2 SH, CH 2 CH 2 C(═O)OH, CH 2 CH 2 C(═O)NH 2 , CH 2 (CH 2 ) 3 NH 2 , CH 2 CH 2 SCH 3 , CH 2 OH,

or A 4 , together with the carbon to which it is attached and the nitrogen adjacent to that carbon, forms a pyrrolidine ring;
A 5 is H or benzyloxycarbonyl;
R 6 is OR 12 , OH or H;
R 7 is OR 12 , OH or H; provided that at least one of R 6 and R 7 is OR 12 ; wherein when R 6 is OR 12 , R 7 is H, R 8 is C 1 -C 15 alkyl and X is O, then 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 11 is lower alkyl, lower alkenyl or aralkyl;
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;
R 14 is an optionally substituted alkyl, aryl or aralkyl group;
X is O, CH 2 or S;
n is 1 when X is O or S; or n is 0 or 1 when X is CH 2 ;
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; R 4 is CH 2 OH, CH 2 OR 10 or CH 2 OR 11 ; and:
R 6 is OH and R 7 is OR 12 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 OR 12 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);
wherein 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; R 4 is CH 2 OH, CH 2 OR 10 , CH 2 OR 11 or CO 2 H; and:
R 6 is OH and R 7 is OR 12 and the stereochemistry at carbon atoms 2, 3 and 4 is (2S, 3S, 4R); or
R 6 is OR 12 and R 7 is H and the stereochemistry at the carbon atoms 2 and 3 is (2S, 3S);
or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 which is a compound of formula (Ia):

wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , Y, Z, A 1 , A 2 , A 4 , A 5 , E 1 , E 2 , Alk 1 , p, t, m, u and n are all as defined in claim 1 .

3. A compound as claimed in claim 1 wherein the stereochemistry of the 6-membered sugar ring of formula (I) is α-D-galacto.

4. A compound as claimed in claim 1 wherein X is O.

5. A compound as claimed in 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 OR 12 and the stereochemistry at carbon atoms 2, 3 and 4 is (2S, 3S, 4R).

6. A compound as claimed in 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 OR 12 and the stereochemistry at carbon atoms 2, 3 and 4 is (2S, 3S, 4R).

7. A compound as claimed in claim 1 wherein X is O, R 6 is OR 12 , 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 carbon atoms 2, 3 is (2S, 3S).

8. A compound as claimed in claim 1 wherein R 1 is H.

9. A compound as claimed in claim 1 wherein R 2 is OH.

10. A compound as claimed in claim 1 wherei

Assignees

• Callaghan Innovation Res Ltd
• Victoria Link Ltd

Inventors

• Compton Benjamin Jason
• Hayman Colin Malcolm
• Hermans Ian Francis
• Larsen David Samuel
• Painter Gavin Frank
• Anderson Regan J

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/08

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