WO2013007792A1 - Novel th2 polarizing compounds - Google Patents

Abstract

The present invention relates to a pharmaceutical composition, particularly to a pharmaceutical composition for use in the treatment and/or prevention of immune-mediated diseases which are characterized by a Th1 environment such as autoimmune diseases, wherein said pharmaceutical composition comprises a compound of formula (I) as defined herein. The present invention also relates to the use of a compound according to formula (I) as defined herein for activating the production of at least one Th2 polarizing cytokine in NKT cells.

Description

Munich, 12 July 2012 Our reference: T 7705 / DB

Thurgauische Stiftung fur Wissenschaft und Forschung

c/o Amt fur Mittel- und Hochschulen

Grabenstrasse 11

8510 Frauenfeld

Switzerland

Novel Th2 polarizing compounds

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising a compound according to formula (I) as defined herein. A pharmaceutical composition according to the present invention may particularly be used for the treatment and/or prevention of immune-mediated diseases which are characterized by a Thl environment such as autoimmune diseases. Further, the present invention relates to the use of a compound according to formula (I) as defined herein for activating the production of at least one Th2 polarizing cytokine in natural killer T (NKT) cells.

BACKGROUND OF THE INVENTION

The cytokine environment is one of the most important parameters in balancing an immune response. Thus, depending on the cytokine profile, a cell-mediated immune response (Thl) or a humoral immune response (Th2) may be initiated. A potent source of early cytokines is the NKT cell population (1). NKT cells are also known as Type I NKT lymphocytes and are characterized by the expression of a T cell receptor that recognizes glycolipid antigens presented in complex with CD Id (2). CD Id corresponds to a non-polymorphic MHC class I like molecule and is present inter alia on antigen-presenting cells. Upon stimulation with the glycolipid a-galactosylceramide (referred to as "a-GalCer" or "Reference A" in the following), a derivative of a marine sponge, NKT cells produce a variety of both T helper (Th) 1 and Th2 cytokines (3-5). Due to their ability to produce cytokines polarizing the immune response, NKT cells are of interest as modulators of arising or ongoing immune responses. Accordingly, several compounds capable of stimulating NKT cells are used in immunotherapy research as agents influencing the cytokine release from NKT cells (6-8). A benchmark CD Id ligand is a-GalCer (9). a-GalCer has been extensively studied over the past years and was shown to be able to influence the bias of immune responses (10) and to have immune- stimulatory functions in anti tumor responses (8) or in infectious diseases (7). It seems that autoimmune diseases may be positively influenced by a-GalCer as well (11, 12). However, most likely due to the rather undefined cytokine profile elicited by a-GalCer which results in the release of both Thl and Th2 cytokines, a-GalCer appears to result in undesired effects as well, as described for arthritis models and experimental colitis (13, 14).

Another widely known CD Id ligand is the a-GalCer analogue OCH (also referred to as "reference C" in the following) which shows a more defined cytokine pattern (15). It mainly activates the production of IL-4 and, contrary to a-GalCer, apparently promotes a Th2 environment. OCH has been shown to be preventive against experimental autoimmune encephalomyelitis (EAE). However, OCH clearly still induces the production of a quite substantial amount of the Thl cytokine IFN-γ (15). The Thl response is mainly driven and characterized by the production of IFN-γ which results in the cell-mediated immune response, whereas a Th2 response is mainly characterized by the release of IL-4 which results in the activation of B-cells leading to the humoral immune response. A large number of immune-mediated diseases, particularly autoimmune disease, are characterized by a Thl environment and appear to be driven by Thl polarization, respectively.

Thus, there is still a need for novel compounds capable of modulating NKT cells such that a more precise Th2 cytokine profile is achieved which likely results in a more pronounced shift of the immune response towards a Th2 environment. Such compounds may particularly be used in the treatment of immune-mediated diseases, especially in the treatment of autoimmune diseases which are characterized by a Thl environment. OBJECTS AND SUMMARY OF THE INVENTION

The inventors of the present invention surprisingly found that compounds of formula (I) as defined herein are capable of eliciting a clearly defined cytokine profile resulting in a Th2 environment. In accordance with this finding, compounds of the present invention are highly effective against diseases characterized by a Thl environment, as shown by the inventors in mouse models for such diseases.

The present invention discloses a compound of formula (I) and preferred

embodiments thereof as defined in the following:

wherein

Z¹ is selected from C and CH;

Z² is selected from CR_A, CHR_A, N, NR_A, O and S;

Z³ is selected from CR_A and CHR_A;

Z⁴ is selected from CR_A and CHR_A;

Z⁵ is selected from CR_A, CHR_A, N, NR_A, O and S;

m is 1 or 2 to form a 5-membered or 6-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic;

R_A is either Ri or independently selected from the group consisting of H, halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl; with the proviso that at least one Ri substituent is present in the 5-membered or 6-membered carbocycle or heterocycle;

Ri is a 6-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide, phenyl and trifluoromethyl; or a C5-C25 alkyl, which is optionally branched and further substituted with one or more substituent(s) selected from oxo, hydroxyl and amino;

Y is either absent to form a direct bond between NH and Z¹; or selected from the group consisting of -C(0)(CH₂)_n-, -S0₂(CH₂)_n-, -C(0)0(CH₂)_n-, -C(0)NH(CH₂)_n- and -C(0)N((CH₂)pCH3)(CH₂)n-, wherein n is an integer from 0 to 10 and wherein p is an integer from 0 to 9;

R₂ is selected from the group consisting of -CH₂(CH₂)_QCH₃, -CH(OH)(CH₂)_QCH₃, -CH(OH)(CH₂)_QCH(CH₃)₂, -CH=CH(CH₂)_QCH₃, and

-CH(OH)(CH₂)_QCH(CH₃)CH₂CH₃, wherein q is an integer from 5 to 17;

X is O or -CH₂-;

R₃ and R4 are independently selected from the group consisting of H, amino, hydroxyl, amino alkyl and alkoxy;

R₅ is selected from the group consisting of H, amino, hydroxyl, aminoalkyl, alkoxy, a-glucose, β-glucose, a-galactose and β-galactose; and

5 is selected from the group consisting of H, amino, hydroxyl, aminoalkyl, alkoxy, C I -C I O alkyl and -CH₂OH.

In a preferred embodiment, Z¹ is C; Z² is selected from CR_A, N, NR_A, O and S; Z³ is CR_A; Z⁴ is CR_A; Z⁵ is selected from CR_A, N, NR_A, O and S; and m is 1 or 2 to form a 5-membered or 6-membered carbocycle or heterocycle which is aromatic.

In another preferred embodiment, Z¹ is C; Z² is selected from CR_A, N, NR_A, O and S; Z³ is CR_A; Z⁴ is CR_A; Z⁵ is selected from CR_A, N, NR_A, O and S; and m is 2 to form a 6-membered carbocycle or heterocycle which is aromatic.

In a further preferred embodiment, Z¹ is selected from C and CH; Z² is selected from CR_A, CHR_A, N, NR_A, O and S; Z³ is selected from CR_A and CHR_A; Z⁴ is selected from CR_A and CHR_A; Z⁵ is selected from CR_A, CHR_A, N, NR_A, O and S; and m is 2 to form a 6-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic.

In another preferred embodiment, Z¹ is selected from C and CH; Z² is selected from CR_A and CHR_A; Z³ is selected from CR_A and CHR_A; Z⁴ is selected from CR_A and CHR_A; Z⁵ is selected from CR_A and CHR_A; and m is 2 to form a 6-membered carbocycle which is saturated or unsaturated or aromatic.

In yet another preferred embodiment, Z¹ is C; Z² is CR_A; Z³ is CR_A; Z⁴ is CR_A; Z⁵ is CR_A; and m is 2 to form a 6-membered carbocycle which is aromatic.

In another preferred embodiment, Z¹ is selected from C and CH; Z² is selected from CR_A, CHR_a, N, NR_A, O and S; Z³ is selected from CR_A and CHR_A; Z⁴ is selected from CR_A and CHR_A; Z⁵ is selected from CR_A, CHR_A, N, NR_A, O and S; and m is 1 to form a 5-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic.

In yet another preferred embodiment, Z¹ is selected from C and CH; Z² is selected from N, NR_A, O and S; Z³ is selected from CR_A and CHR_A; Z⁴ is selected from CR_A and CHR_A; Z⁵ is selected from CR_A, CHR_a, N, NR_A, O and S; and m is 1 to form a 5-membered heterocycle which is saturated or unsaturated or aromatic.

In still another preferred embodiment, Z¹ is selected from C and CH; Z² is selected from CR_A, CHR_a, N, NR_A, O and S; Z³ is selected from CR_A and CHR_A; Z⁴ is selected from CR_A and CHR_A; Z⁵ is selected from N, NR_A, O and S; and m is 1 to form a 5-membered heterocycle which is saturated or unsaturated or aromatic.

In another preferred embodiment, Z¹ is selected from C and CH; Z² is selected from N, NR_A, O and S; Z³ is selected from CR_A and CHR_A; Z⁴ is selected from CR_A and CHR_A; Z⁵ is selected from N, NR_A, O and S; and m is 1 to form a 5-membered heterocycle which is saturated or unsaturated or aromatic.

In another preferred embodiment, Z¹ is C; Z² is selected from N, NR_A, O and S; Z³ is CR_A; Z⁴ is CR_A; Z⁵ is selected from CR_A, N, NR_A, O and S; and m is 1 to form a 5- membered heterocycle which is aromatic. In still preferred embodiment relating to the compound of formula (I), Z¹ is C; Z² is selected from CR_A, N, NR_A, O and S; Z³ is CR_A; Z⁴ is CR_A; Z⁵ is selected from N, NR_A, O and S; and m is 1 to form a 5-membered heterocycle which is aromatic.

In another preferred embodiment, Z¹ is C; Z² is selected from N, NR_A, O and S; Z³ is CR_A; Z⁴ is CR_A; Z⁵ is selected from N, NR_A, O and S; and m is 1 to form a 5- membered heterocycle which is aromatic. In a preferred embodiment, R_A is either Ri or independently selected from the group consisting of H, halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl; with the proviso that one Ri substituent is present in the 5- membered or 6-membered carbocycle or heterocycle.

In a preferred embodiment, R_A is either Ri or independently selected from the group consisting of H, halogen, amino, hydroxyl, C1-C3 alkyl, -NH(C1-C3 alkyl), -0(C1- C3 alkyl), carboxylic acid and trifluoromethyl; with the proviso that one Ri substituent is present in the 5-membered or 6-membered carbocycle or heterocycle.

In another preferred embodiment, R_A is either Ri or H; with the proviso that one Ri substituent is present in the 5-membered or 6-membered carbocycle or heterocycle.

If one Ri substituent is present in the 5-membered carbocycle or heterocycle, it can be preferred that said carbocycle or heterocycle is substituted with Ri at the following position:

If one Ri substituent is present in the 6-membered carbocycle or heterocycle, it can be preferred that said carbocycle or heterocycle is substituted with Ri at the following position:

In another preferred embodiment, Ri is a 6-membered carbocycle which is aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl.

In a preferred embodiment, Ri is a 6-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide, phenyl and trifluoromethyl. Preferably, said 6-membered heterocycle is aromatic. Further, it can be preferred that said 6-membered heterocycle comprises at least one nitrogen-atom, preferably one or two nitrogen- atoms. It may also be preferred that said 6-membered heterocycle is aromatic and comprises at least one nitrogen-atom, preferably one or two nitrogen-atoms. Most preferably, said 6-membered heterocycle is selected from the group consisting of pyridine, pyrazine, pyrimidine, pyridazine, 1 ,2,3-triazine, 1 ,2,4-triazine and 1 ,3,5- triazine. In a preferred embodiment, Ri is a 6-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl.

In a particularly preferred embodiment, Ri is a 6-membered carbocycle which is saturated or unsaturated or aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide, phenyl and trifluoromethyl.

In another preferred embodiment, Ri is a 6-membered carbocycle which is saturated or unsaturated or aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl. In another preferred embodiment, Ri is a 6-membered carbocycle which is aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, C1-C3 alkyl, -NH(C1-C6 alkyl), -0(C1-C3 alkyl), carboxylic acid, phenyl and trifluoromethyl. In another preferred embodiment, Ri is a 6-membered carbocycle which is aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, C1-C3 alkyl, -NH(C1-C6 alkyl), -0(C1-C3 alkyl), carboxylic acid, and trifluoromethyl. In another preferred embodiment, Ri is a 6-membered carbocycle which is aromatic and which is optionally substituted with one or more -O(C 10-C20 alkyl), preferably with one -O(C 10-C20 alkyl). In another preferred embodiment, Ri is a 6-membered carbocycle which is aromatic and which is substituted with one phenyl.

In another preferred embodiment, Ri is a 6-membered unsubstituted carbocycle which is aromatic.

In another preferred embodiment, Z¹ is selected from C and CH; Z² is selected from CRA and CHR_A; Z³ is selected from CRA and CHR_A; Z⁴ is selected from CRA and CHRA; Z⁵ is selected from CRA and CHRA; m is 2 to form a 6-membered carbocycle which is saturated or unsaturated or aromatic; and Ri is a 6-membered carbocycle which is aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl. It can further be preferred in this respect that Y is selected from the group consisting of -C(0)(CH₂)_N-, -S0₂(CH₂)_N- and

-C(0)NH(CH₂)_N-, wherein n is an integer from 0 to 10.

In another preferred embodiment, Z¹ is selected from C and CH; Z² is selected from CRA, CHR_a and N; Z³ is selected from CRA and CHR_A; Z⁴ is selected from CRA and CHR_A; Z⁵ is selected from CRA, CHR_a and N; m is 2 to form a 6-membered heterocycle which is saturated or unsaturated or aromatic; and Ri is a 6-membered carbocycle which is aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide, phenyl and trifluoromethyl. It can further be preferred in this respect that Y is selected from the group consisting of -C(0)(CH₂)_N-, -S0₂(CH₂)_N- and -C(0)NH(CH₂)_N-, wherein n is an integer from 0 to 6.

In another preferred embodiment, Z¹ is selected from C and CH; Z² is selected from CRA, CHR_a and N; Z³ is selected from CRA and CHR_A; Z⁴ is selected from CRA and CHR_A; Z⁵ is selected from CRA, CHR_a and N; m is 2 to form a 6-membered heterocycle which is saturated or unsaturated or aromatic; and Ri is a 6-membered carbocycle which is aromatic and which is substituted with one or more phenyls. It can further be preferred in this respect that Y is absent.

In yet another preferred embodiment, Z¹ is C; Z² is CRA; Z³ is CRA; Z⁴ is CRA; Z⁵ is CRA; m is 2 to form a 6-membered carbocycle which is aromatic; and Ri is a 6- membered carbocycle which is aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl.

In yet another preferred embodiment, Ri is a C5-C25 alkyl, preferably a C 10-C20 alkyl, more preferably a C 15-C 1 8 alkyl, which is optionally substituted with one or more substituent(s) selected from oxo, hydroxyl and amino.

In still another preferred embodiment, Ri is an unsubstituted C5-C25 alkyl, preferably an unsubstituted C 10-C20 alkyl, more preferably an unsubstituted C I S- C I S alkyl.

In another preferred embodiment, Z¹ is selected from C and CH; Z² is selected from N, NRA, O and S; Z³ is selected from CRA and CHR_A; Z⁴ is selected from CRA and CHR_A; Z⁵ is selected from N, NR_A, O and S ; m is 1 to form a 5 -membered heterocycle which is saturated or unsaturated or aromatic; and Ri is a C5-C25 alkyl, preferably a C 10-C20 alkyl, more preferably a C 15-C 18 alkyl, which is optionally substituted with one or more substituent(s) selected from oxo, hydroxyl and amino. It can further be preferred in this respect that Y is absent to form a direct bond between NH and Z¹. In another preferred embodiment, Z¹ is C; Z² is selected from N, NR_A, O and S; Z³ is CR_A; Z⁴ is CR_A; Z⁵ is selected from N, NR_A, O and S ; m is 1 to form a 5 -membered heterocycle which is aromatic; and Ri is a C5-C25 alkyl, preferably a C10-C20 alkyl, more preferably a C15-C18 alkyl, which is optionally substituted with one or more substituent(s) selected from oxo, hydroxyl and amino.

In another preferred embodiment, Z¹ is C; Z² is selected from CR_A, N, NR_A, O and S; Z³ is CR_A; Z⁴ is CR_A; Z⁵ is selected from N, NR_A, O and S; m is 1 to form a 5- membered heterocycle which is aromatic; and Ri is a 6-membered heterocycle which is saturated or unsaturated or aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl.

In another preferred embodiment, Y is either absent to form a direct bond between NH and Z¹ or selected from the group consisting of -C(0)(CH₂)_n-, -S0₂(CH₂)_n-,

-C(0)0(CH₂)„-, -C(0)NH(CH₂)_n- and -C(0)N((CH₂)_pCH₃)(CH₂)_n-, wherein n is an integer from 0 to 6 and wherein p is an integer from 0 to 9.

In still another preferred embodiment, Y is absent or selected from the group consisting of -C(0)(CH₂)_n-, -S0₂(CH₂)_n-, -C(0)0(CH₂)_n- and -C(0)NH(CH₂)_n-, wherein n is an integer from 0 to 10, preferably an integer from 2 to 8, more preferably an integer from 3 to 7, and most preferably 4.

In still another preferred embodiment, Y is absent or selected from the group consisting of -C(0)(CH₂)_n-, -S0₂(CH₂)_n-, -C(0)0(CH₂)_n- and -C(0)NH(CH₂)_n-, wherein n is an integer from 0 to 10, preferably an integer from 0 to 6, more preferably an integer from 3 to 6, and most preferably 4.

In another preferred embodiment, Y is absent to form a direct bond between NH and Z¹.

In yet another preferred embodiment, Y is selected from the group consisting of -C(0)(CH₂)_n-, -S0₂(CH₂)_n-, -C(0)0(CH₂)_n-, -C(0)NH(CH₂)_n- and

-C(0)N((CH₂)_pCH₃)(CH₂)_n-, wherein n is an integer from 0 to 10 and wherein p is an integer from 0 to 9. It can also be preferred that Y is selected from the group consisting of -C(0)(CH₂)_n-, -S0₂(CH₂)_n- and -C(0)NH(CH₂)_n-, wherein n is an integer from 0 to 10. It can further be preferred in this respect that n is an integer from 2 to 8, more preferably an integer from 3 to 7, and most preferably 4. It can further be preferred that p is 0.

In still another preferred embodiment, Y is -C(0)(CH₂)_n-, wherein n is an integer from 0 to 10, preferably an integer from 2 to 8, more preferably an integer from 3 to 7, and most preferably 4. In yet another preferred embodiment, R₂ is selected from the group consisting of -CH₂(CH₂)_qCH₃, -CH(OH)(CH₂)_qCH₃, -CH(OH)(CH₂)_qCH(CH₃)₂,

-CH=CH(CH₂)_qCH₃, and -CH(OH)(CH₂)_qCH(CH₃)CH₂CH₃, wherein q is an integer from 5 to 17, preferably from 8 to 16, more preferably from 10 to 15, and most preferably 13.

In another preferred embodiment, R₂ is -CH(OH)(CH₂)_qCH_3i wherein q is an integer from 5 to 17, preferably from 8 to 16, more preferably from 10 to 15, and most preferably 13.

In another particularly preferred embodiment, X is -CH₂- In still another preferred embodiment, R₃ and R4 are independently selected from the group consisting of H, amino and hydroxyl, wherein R₃ and R4 are preferably hydroxyl.

In yet another preferred embodiment, R5 is in the following configuration:

In yet another preferred embodiment, R5 is selected from the group consisting of H, amino, hydroxyl, amino alkyl and alkoxy. Preferably, R₅ is hydroxyl or alkoxy, and most preferably, R₅ is hydroxyl.

In still another preferred embodiment, R^ is -CH₂OH.

It can further be preferred that R^ is CI -C IO alkyl, wherein R^ as -CH₃ is particularly preferred. In an alternative embodiment, R^ may also be selected from the group consisting of H, amino, hydroxyl, aminoalkyl, alkoxy, CI -CI O alkyl, -CH₂OH, aryl and heteroaryl.

In yet another preferred embodiment, R₃, R4 and R₅ are hydroxyl and R6 is -CH₂OH.

In yet another preferred embodiment, the compound is selected from 5 - (biphenyl - 4 - yl) - N - ((3S,4S,5S) - 4,5 - dihydroxy - l-((2i?,3i?,4i?,5i?,6i?)-3,4,5- trihydroxy - 6 - (hydroxymethyl) tetrahydro-2H-pyran-2-yl) nonadecan - 3 - yl) pentanamide;

(2R,3R,4R,5R,6R) - 2 - ((3S,4S,5S) - 3 - (4 - heptadecylthiazol-2-ylamino) -4,5- dihydroxynonadecyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; and (2R,3R,4R,5R,6R) - 2 - ((35,45,55) - 3 - (4 - (4 - (dodecyloxy) phenyl) thiazol-2- ylamino) -4,5-dihydroxynonadecyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5- triol.

In a first aspect, the present invention is concerned with a pharmaceutical composition comprising a compound of formula (I) as defined above (including all preferred embodiments as defined above) or a pharmaceutically acceptable salt thereof.

In a preferred embodiment relating to the first aspect of the invention, the pharmaceutical composition comprises microspheres in order to achieve sustained release of said compound. Preferably, said microspheres comprise poly(lactide-co- glycolide)(PLGA).

In a preferred embodiment relating to the first aspect of the invention, the pharmaceutical composition comprises said compound as the only pharmaceutically active agent. In yet another preferred embodiment relating to the first aspect of the invention, the pharmaceutical composition comprises at least one further pharmaceutically active agent.

In a second aspect, the present invention is concerned with a pharmaceutical composition comprising a compound of formula (I) as defined above (including all preferred embodiments as defined above) or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of an immune-mediated disease characterized by a Thl polarization, wherein said disease is selected from inflammatory bowel disease including ulcerative colitis and Crohn's disease, type 1 diabetes, multiple sclerosis, arthritis including rheumatoid arthritis, allogeneic transplantation reactions including graft-versus-host disease, type IV allergies, systemic lupus erythematosus, systemic sclerosis, encephalomyelitis, chronic articular rheumatism, Sjoegren's syndrome, primary biliary cirrhosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, myasthenia gravis, sympathetic ophthalmia, Goodpasture's syndrome (e.g. glomerular nephritis), pernicious anemia and Hashimoto's disease.

In a preferred embodiment relating to the second aspect of the invention, said disease is selected from ulcerative colitis, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, type IV allergies and graft-versus-host disease.

In a third aspect, the present invention is concerned with a method for activating the production of at least one Th2 polarizing cytokine in NKT cells comprising contacting said NKT cells with a compound of formula (I) as defined above

(including all preferred embodiments as defined above) or a pharmaceutically acceptable salt thereof.

In a preferred embodiment relating to the third aspect of the invention, said method is carried out in vitro.

In another preferred embodiment relating to the third aspect of the invention, said at least one Th2 polarizing cytokine is IL-4.

In another preferred embodiment relating to the third aspect of the invention, said production is characterized by the absence of Thl polarizing cytokines, particularly by the absence of IFN-γ. DESCRIPTION OF THE FIGURES

Figure 1 depicts the serum levels of the cytokines IL-4 and IFN-γ over at time course of 50 h after injection of 2 μg of either Compound A or Reference A. The

compounds were injected intravenously into mice (n=3), blood samples were taken at the indicated time points and the cytokine levels were analyzed (see example section for further details).

Figure 2 depicts the serum levels of the cytokines IL-4 and IFN-γ over at time course of 48 h after injection of 2 μg of Compound A, Reference A or Reference C. The compounds were injected intravenously into mice (n=3), blood samples were taken at the indicated time points and the cytokine levels were analyzed (see example section for further details). Note that no IFN-γ levels were detectable 2 h after injection of Compound A.

Figure 3 depicts the serum levels of cytokine IL-4 at 2 h after injection of 2 μg of Compound A, Compound B, Reference A, Reference B or Reference C (left side). On the right side, figure 3 depicts the serum levels of cytokine IFN-γ at 24 h after injection of 2 μg of Compound A, Compound B, Reference A, Reference B or Reference C. Compounds were injected intravenously into mice (n=3), blood samples were taken at the indicated time points and the cytokine levels were analyzed (see example section for further details).

Figure 4 depicts the GATA-3 and T-bet mRNA levels in colitic mice treated either with Compound A or a control (vehicle only). Mice (n=9) were treated with 2,2 % DSS for a period of five days. On day four, mice were treated with 2 μg Compound A or the vehicle alone. At day 8, splenocytes were isolated and magnetically sorted for CD4⁺ lymphocytes. Expression levels of GATA-3 and T-bet mRNA were assessed by real-time PCR using SYBR GREEN technology. Mean values were normalized for 18S rRNA and are given in fold upregulation compared to a naive mouse. Differences between groups were assessed by an unpaired students t-test (p=0,0106) (see example section for further details).

Figure 5 depicts the body weight loss in % of mice in a DSS-induced colitis over a time course of 20 days. Mice were treated with 2,2 % DSS for a period of five days. On day four, mice were treated either with 2 μg of Compound A, Reference C, or control (vehicle only). The body weight was assessed at indicated time points and body weight loss was calculated (see example section for further details). Figure 6 depicts the EAE-score as indication of the severity of the EAE-symptoms over a period of 30 days for untreated mice and mice treated with Compound A, Reference A or Reference C. For the induction of EAE, mice were treated with 200 μg of MOG35-55 peptide s.c. in 200 μΐ phosphate buffered saline:CFA (1 : 1) and 200 ng pertussis toxin i.v.. After two days, the injection of pertussis toxin was repeated. Treatment of mice with the indicated compounds started at day 6 and lasted up to day 20 as indicated by the red triangles in the graph. Mice were scored daily for the EAE score as described in the example section.

Figure 7 depicts the blood glucose levels (A) and the increase in blood glucose (B) in a mouse diabetes model (low-dose streptozotocin induced diabetes). (A) Mice (n=15) were treated daily with 40 mg streptozotocin / kg bodyweight i.p. for a period of five days. On day four, mice were treated either with 2 μg of soluble Compound A in PBS, 2 μg of PLGA-microsphere encapsulated Compound A or DMSO in PBS (vehicle). Blood glucose levels were measured at indicated time points. Differences between groups were assessed by one-way analyses of variance (day 7: p=0,0071; day 11 : p=0.0025) (B) Increase of blood glucose levels was calculated for the same mice as in (A) for day 7 and day 9. Differences between groups were assessed by one-way analyses of variance (day 7: p=0,0082). Figure 8 depicts the ear swelling of mice as measure of DNFB induced contact hypersensitivity. Mice (n=13) were sensitized at the left ear with 5 μΐ of a 1% DNFB in acetone:olive oil (4: 1) mixture on day 0. Five days later, mice were challenged at the right ear with 5 μΐ of 1 % DNFB. Immediately after the challenge, mice were treated with Compound A (soluble or encapsulated) or control (vehicle).

Subsequently, the ear swelling, compared to the naive ear at day 0, was measured after 24 hours. Differences between groups were assessed by one-way analyses of variance (p=0,0222). Figure 9 shows the body weight loss in % of either wt or CDl ^/_ mice in the DSS- induced colitis (A), wherein the mice were either treated with 2 μg of Compound A or control (vehicle only). Figure 9B depicts the EAE-score over a period of 15 days for CDl ^/_ mice treated with Compound A or vehicle. DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention inter alia succeeded in identifying new compounds which stimulate NKT cells such that substantial amounts of IL-4 are produced and released by said cells, whereas at best only marginal levels (if detectable levels at all) of IFN-γ are produced and released by said cells. The cytokine profile induced by said compounds thus corresponds to a clearly and nicely defined Th2 profile, and said compounds are highly efficient when treating or preventing particularly autoimmune diseases. Before some of the embodiments of the present invention are described in more detail, the following definitions are introduced.

1. Definitions As used in the specification and the claims, the singular forms of "a" and "an" also include the corresponding plurals unless the context clearly dictates otherwise.

The term "about" in the context of the present invention denotes an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±10% and preferably ±5%.

It needs to be understood that the term "comprising" is not limiting. For the purposes of the present invention, the term "consisting of is considered to be a preferred embodiment of the term "comprising of. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group which preferably consists of these embodiments only. The term "halogen" includes fluoride, bromide, chloride or iodide.

In general, the number of carbon atoms present in a given group is designated "Cx- Cy" where x and y are the lower and upper limits, respectively. For example, a group designated as "CI -CIO" contains from 1 to 10 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents. General examples of alkyl groups include methyl, propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl. The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Cl- C6 indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. If there is no indication of carbon atoms of the alkyl, the term "alkyl" refers to a Cl- C15 alkyl, preferably a CI -CIO alkyl, and more preferably to a C1-C4 alkyl. For example, the term "C1-C3 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1-3 carbon atoms. Examples of a C1-C3 alkyl group include, but are not limited to, methyl, ethyl, propyl and isopropyl. For example, the term "C6-C10 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 6-10 carbon atoms. Examples of a C6-C10 alkyl group include, but are not limited to, hexyl, octyl and decyl.

The term "heterocycle" refers to a cyclic structure comprising carbon atoms and at least one heteroatom. The term "heteroatom" preferably refers to nitrogen, sulfur and oxygen atoms. A heterocycle may generally contain different heteroatoms. For the present invention, nitrogen as heteroatom may be preferred. Further, for the present invention, it can be preferred that a heterocycle comprises one or two heteroatoms. The term "amino" represents -NH₂, the term "hydroxyl" is -OH, "carboxylic acid" is -C(0)OH, "sulfonic acid" is -S(0)₂OH and "oxo" is -0-.

The term "aminoalkyl" refers to -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)₂. The term "alkoxy" refers to -0(C1-C6 alkyl). The term "carboxyester" refers to -C(0)0(C1- C6 alkyl). The term "carboxamide" refers to -C(0)NH- or -C(0)N(C1-C6 alkyl)-. The term "carbamate" refers to -OC(0)NH- or -OC(0)N(Cl-C6 alkyl)-. The term "sulfonamide" refers to -S(0)₂NH-, or -S(0)₂N(C 1 -C6 alkyl)-. All of the above definitions apply if the term is not specifically defined otherwise (e.g. -0(C1-C3 alkyl)).

"Carbon branching" or "branched alkyl" means that one or more alkyl groups such as methyl, ethyl or propyl, replace one or both hydrogens in a -CH₂- group of a linear alkyl chain.

"α/β-glucose" and "α/β-galactose" are used herein as common in the field, wherein the bond between R₅ optionally corresponding to α/β-glucose or α/β-galactose and the C atom of the glucose/galactose moiety of formula (I) and R₅ is preferably a (1-4) bond.

The definition "with the proviso that at least one Ri substituent is present in the 5- membered or 6-membered carbocycle or heterocycle" means that at least one RA is Ri . If "one Ri substituent is present in the 5-membered or 6-membered carbocycle or heterocycle", this means that one of the R_A-substituents present in the carbocycle or heterocycle is Ri . The remaining R_A-substituents are then selected from the group as defined above.

The invention disclosed herein is meant to encompass all pharmaceutically acceptable salts of the disclosed compounds. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, Ν,Ν'- dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, fumarate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like.

"Pharmaceutically active agent" as used herein means that a compound is potent of modulating a response in a human or animal being in vivo. When reference is made to a compound as "the only pharmaceutically active agent", this is meant to describe that the activity of a corresponding pharmaceutical composition is due to said active agent only.

The term "pharmaceutically acceptable excipient" as used herein refers to

compounds commonly comprised in pharmaceutical compositions, which are known to the skilled person. Such compounds or excipients are exemplary listed under 2. below. In view of the definition "pharmaceutically active agent" as given above, a pharmaceutically acceptable excipient can be defined as being pharmaceutically inactive.

In the following, the pharmaceutical compositions according to the present invention are described in more detail.

2. Pharmaceutical compositions according to the present invention

A pharmaceutical composition according to the present invention may be formulated for oral, buccal, nasal, rectal, topical, transdermal or parenteral application.

Parenteral application is preferred and includes intravenous, intramuscular or subcutaneous administration. The compound according to formula (I) should be applied in pharmaceutically effective amounts, for example in the amounts as set out herein below.

A pharmaceutical composition of the present invention may also be designated as formulation or dosage form. A compound of formula (I) may also be designated in the following as (pharmaceutically) active agent or active compound.

Pharmaceutical compositions may be solid or liquid dosage forms or may have an intermediate, e.g. gel-like character depending inter alia on the route of

administration.

In general, the inventive dosage forms can comprise various pharmaceutically acceptable excipients which will be selected depending on which functionality is to be achieved for the dosage form. A "pharmaceutically acceptable excipient" in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, release-modifying materials, carrier materials, diluents, binding agents and other adjuvants. Typical pharmaceutically acceptable excipients include substances like sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents.

The term "carrier" denotes pharmaceutically acceptable organic or inorganic carrier substances with which the active ingredient is combined to facilitate the application. Suitable pharmaceutically acceptable carriers include, for instance, water, salt solutions, alcohols, oils, preferably vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid

monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl- cellulose, polyvinylpyrrolidone and the like. The pharmaceutical compositions can be sterilized and if desired, mixed with auxiliary agents, like lubricants,

preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.

If desired, the bioavailability of the compound of formula (I) can be enhanced by micronisation of suitable formulations and the compound of formula (I) using conventional techniques such as grinding, milling and spray-drying in the presence of suitable excipients or agents such as polymers, phospholipids or surfactants. In this respect, it can be particularly preferred to use poly(lactide-co-glycolide) (PLGA), particularly to produce microspheres. Such preparations may results in a depot effect, i.e. the release of the compound of formula (I) over an extended period of time from the preparations.

If liquid dosage forms are considered for the present invention, these can include pharmaceutically acceptable emulsions, solutions, suspensions and syrups containing inert diluents commonly used in the art such as water. These dosage forms may contain e.g. microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and sweeteners/flavouring agents. For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Pharmaceutical formulations for parenteral administration are particularly preferred and include aqueous solutions of the compounds of formula (I) in water-soluble form. Additionally, suspensions of the compounds of formula (I) may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium

carboxymethyl cellulose, sorbitol, or dextran.

Particularly preferred dosage forms are injectable preparations of a compound of formula (I). Thus, sterile injectable aqueous or oleaginous suspensions can for example be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluant or solvent. Among the acceptable vehicles and solvents that can be used are water and isotonic sodium chloride solution. Sterile oils are also conventionally used as solvent or suspending medium. It can be preferred to use specific solvents in order to achieve a high solubility of the compound of formula (I). In this respect, it can be advantageous to include cremophore EL^® or the like to an aqueous solution. A possible solvents is e.g. a solvent comprising 20% cremophore EL^® and 80% water. It can be preferred to use a solvent comprising 10% cremophore EL^®, 10% DMSO and 80% water. Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g. mixing the compound with a suitable non-irritating excipient such as cocoa butter, synthetic triglycerides and polyethylene glycols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the compound according to formula (I) from said suppositories.

For administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g.,

dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

Oral dosage forms may be liquid or solid and include e.g. tablets, troches, pills, capsules, powders, effervescent formulations, dragees and granules. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The oral dosage forms may be formulated to ensure an immediate release of the compound of formula (I) or a sustained release of the compound of formula (I). A solid dosage form may comprise a film coating. For example, the inventive dosage form may be in the form of a so-called film tablet. A capsule of the invention may be a two-piece hard gelatin capsule, a two-piece hydroxypropylmethylcellulose capsule, a two-piece capsule made of vegetable or plant-based cellulose or a two-piece capsule made of polysaccharide.

The dosage form according to the invention may be formulated for topical application. Suitable pharmaceutical application forms for such an application may be a topical nasal spray, sublingual administration forms and controlled and/or sustained release skin patches. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compositions may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. The methods can include the step of bringing the compounds into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. Liquid dose units are vials or ampoules. Solid dose units are tablets, capsules and suppositories.

As regards human patients, the compound of formula (I) may be administered to a patient in an amount of about 0.001 mg to about 100 mg per day, preferably of about 0.01 mg to about 10 mg per day, more preferably of about 0.1 mg to about 5 mg per day.

3. Area of application

As mentioned above, there are several immune-mediated diseases, particularly autoimmune diseases, which are characterized by a Thl environment. Said diseases are thus mediated by T-cells which attack and destroy the body's own cells (so called "autoimmune tissue destruction"). Using the compounds according to the present invention which are capable of inducing a very pronounced Th2 environment, it is possible to counter the T-cell mediated response and to shift the Thl environment present in said diseases towards a Th2 environment. Thus, the Thl immune response based on T-cells can be suppressed (but not the complete immune response) by compounds according to the present invention and shifted towards the humoral response. The term "Thl environment" is interchangeably used with "Thl response" or "Thl bias" and indicates that the immune response is T cell-mediated response. A major Thl cytokine is IFN-γ. Accordingly, the term "Th 2 environment" is used

interchangeably with "Th2 response" or "Th2 bias" and indicates that the immune response is a humoral, antibody-mediated response. A major Thl cytokine is IL-4.

Generally, the compounds of the present invention may be used in order to treat and /or prevent an immune-mediated disease mediated by T cells. Some of the major T- cell mediated immune-diseases are briefly described in the following. Type 1 diabetes (also referred to as "insulin-dependent diabetes mellitus", "IDDM") is inter alia characterized by the loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas. The beta cells are attacked by the body's own T-cells (Thl response) such that the disease corresponds to an autoimmune disease. Further details can be found in (16) and (17), also with respect to mouse models used for IDDM.

Multiple sclerosis (MS) is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination. MS in an autoimmune disease, wherein the immune system including T-cells attacks the nervous system (18). EAE can serve as model for MS and it could be shown that EAE is suppressed by Reference C as used herein (15).

Some forms of arthritis and particularly rheumatoid arthritis (RA) are autoimmune diseases characterized by the persistent inflammation, in rheumatoid arthritis of joints resulting in progressive destruction of cartilage and bone. It is believed that Thl cells exacerbate the disease. Further details can be found in (19), also with respect to mouse models used for RA. The two major forms of inflammatory-bowel disease ("IBD") are Crohn's disease, in which the bowel becomes inflamed, and ulcerative colitis, both of which are regarded as autoimmune diseases. It is assumed that T-cells dominate the immune response (20). The subtype of allergies termed„type IV allergy" (or "contact allergies") corresponds to a hypersensitivity reaction induced by the activation of allergen- specific T cells.

Immune responses during allogeneic transplantations induced by the tissue/cells of a donor and/or the tissue/cells of a recipient can create severe problems during transplantations, particularly if T cells are involved in the response. Thus, the T cells of the recipient may attack the transplanted region. On the other hand, graft-versus- host disease (GVHD) is also a common complication of allogeneic transplantation (e.g. bone marrow transplantation) in which immune cells in the transplanted region (e.g. the marrow) recognize the recipient as "foreign". Accordingly, T cells of the transplanted region attack the recipient.

Compared to the best characterized compounds described in the prior art (see particularly Reference A [11, 12, 13] and Reference C [15, 19]), the compounds according to the present invention appear to be superior in several disease models, likely due to their more clearly defined Th2 cytokine profile.

The term "treatment" indicates that an immune mediated disease as discussed above has been diagnosed and the symptoms associated therewith can be abolished or at least alleviated by administration of a pharmaceutical composition comprising a compound of formula (I) according to the present invention.

The term "prevention" means that there is an increased risk in a patient of suffering from an immune mediated disease, which can be prevented or attenuated by administration of a pharmaceutical composition comprising a compound of formula (I) according to the present invention; thus, the administration of such a composition prevents a development or reduces the likelihood of development of such diseases or at least alleviates the extent and/or frequency to which these diseases develop.

When the term "disease" is used in the present invention, it preferably refers to a disease in a human or animal being.

4. Alternative formulations

The subject matter of the present invention may also be referred to as follows:

Method of administering to a subject in need thereof an effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof as defined above (including the preferred embodiments).

Method of treating and/or preventing an immune-mediated disease characterized by a Thl polarization by administering to a subject in need thereof an effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof as defined above (including the preferred embodiments). Method of treating and/or preventing an autoimmune disease by administering to a subject in need thereof an effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof as defined above (including the preferred embodiments).

Method of treating and/or preventing an immune-mediated disease selected from the group consisting of inflammatory bowel disease including ulcerative colitis and Crohn's disease, type 1 diabetes, multiple sclerosis, arthritis including rheumatoid arthritis, allogeneic transplantation reactions including graft-versus-host disease, type IV allergies, systemic lupus erythematosus, systemic sclerosis, encephalomyelitis, chronic articular rheumatism, Sjoegren's syndrome, primary biliary cirrhosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, myasthenia gravis, sympathetic ophthalmia, Goodpasture's syndrome (e.g. glomerular nephritis), pernicious anemia and Hashimoto's disease by administering to a subject in need thereof an effective amount of a compound according to formula (I) or a

pharmaceutically acceptable salt thereof as defined above (including the preferred embodiments). Method of activating the production of at least one Th2 polarizing cytokine in NKT cells, preferably IL-4, in a subject in need thereof by administering to said subject an effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof as defined above (including the preferred embodiments). Method of shifting the immune response towards a Th2 environment in a subject in need thereof by administering to said subject an effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof as defined above (including the preferred embodiments). In the following, examples of embodiments of the present invention are outlined. However, said examples should not be construed as limiting the scope of the present invention. 5. Examples

5.1. Synthesis of exemplary compounds according to the present invention

The following general synthesis route was used in order to synthesize e.g. Compound A (or Reference D) as set out in Tables 1 and 2 below:

Scheme 1 Reagents and conditions: (i) 2, Me₃Al, CH₂C1₂ then HCl/MeOH, 72%; (ii) Boc₂0, Et₃N, 96%; (iii) rc-BuLi, Boc₂0, 90%; (iv) TFAA, UHP; (v) KOH, EtOH, (89%o, 2 steps), 9: 1 dr (separable); (vi) HCl/dioxane; (vii) a) Carboxylic acid, b) isocyanate, c) sulfonyl chloride, d) carbonic anhydride; (viii) H₂, Pd(OH)₂/C, MeOH/CH₂Cl₂.

As depicted in scheme 1 , treatment of N-tert-butanesulfmyl imine 1 with

alkenylzirconocene 2 and trimethylaluminum provided, upon in-situ deprotection, allylic amine 3. Bis Boc-protection via a 2-step protocol provided 4. With 4 in hand, a diastereoselective epoxidation - regioselective carbamate epoxide opening - hydrolysis yielded a 9: 1 separable mixture of amino diol 5. This synthetic route allowed for a multi-gram preparation of 5. Deprotection of the Boc group of 5 with HC1 in dioxane followed by coupling to a carboxylic acid, isocyanate or sulfonyl chloride provided desired N-acyl derivatives in high yield.

Thus, carboxylic acid 6 as depicted below was used as coupling reagent using EDCI and DMAP in order to synthesize Compound A. For synthesis of Reference D, isocyanate 7 was used as coupling reagent using Et₃N.

Starting from 1 and 5, the skilled person knows how to arrive at compounds of the present invention, inter alia by choosing suitable starting compounds and suitable carboxylic acids, isocyanatas or sulfonyls as coupling reagents.

The following general synthesis route was used in order to synthesize e.g.

Compounds B and C as set out below:

Scheme 2. Reagents and conditions: (i) HCl, dioxane; (ii) Fmoc-thioisocyanate, Et₃N; (iii) diethylamine, THF (78%, 3 steps); (iv) a-bromo ketone, EtOH; (v) BC1₃, -78°C.

Thus, as generally depicted in scheme 2, treatment of 5 with HCl generated the HCl salt that was subsequently coupled with Fmoc-thioisocyanate, followed by Fmoc deprotection to yield thiourea 8 in 78% yield over the three steps. Conversion of thiourea 8 to desired thiazole scaffold was accomplished via treatment with a-bromo ketones followed by global deprotection of the benzyl ethers.

Using the a-bromo ketones 9 and 10 as depicted below, Compounds B and C according to the present invention were synthesized in high yields (88% for Compound B and 83% for Compound C).

Starting from 5 and 8, the skilled person knows how to arrive at compounds of the present invention, inter alia by choosing suitable starting compounds and suitable a- bromo ketones as coupling reagents. 5.2. Detailed synthesis protocols for compounds mentioned in 5.1.

All reactions were performed under an N₂ atmosphere and all glassware was dried in an oven at 140 °C for 2 h prior to use. Reactions carried out at -78 °C employed a C0₂ / acetone bath. THF and Et₂0 was distilled over sodium / benzophenone ketyl, Et₃N was distilled from CaH₂, and CH₂C1₂ and toluene were purified using an alumina filtration system. Reactions were monitored by TLC analysis (EM Science pre-coated silica gel 60 F₂₅4 plates, 250 μιη layer thickness) and visualization was accomplished with a 254 nm UV light and by staining with a PMA solution (5 g of phosphomolybdic acid in 100 mL of 95% EtOH), p- anisaldehyde solution (2.5 mL of /?-anisaldehyde, 2 mL of AcOH, and 3.5 mL of cone. H₂SO₄ in 100 mL of 95% EtOH), Vaughn's reagent (4.8 g of

(ΝΗ₄)₆Μθ7θ24·4 H₂0 and 0.2 g of Ce(S0₄)₂ in 100 mL of a 3.5 N H₂S0₄ solution) or a KMn0₄ solution (1.5 g of KMn0₄ and 1.5 g of K₂C0₃ in 100 mL of a 0.1%) NaOH solution). Flash chromatography on S1O₂ was used to purify the crude reaction mixtures. Melting points were determined using a Laboratory

Devices Mel-Temp II. Infrared spectra were determined on a Nicolet Avatar 360 FT-IR spectrometer. 1H and ¹³C NMR spectra were obtained on a Bruker Avance 300 instrument in CDC1₃ unless otherwise noted. Chemical shifts were reported in parts per million with the residual solvent peak used as an internal standard. 1H NMR spectra are tabulated as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), number of protons, and coupling constant(s). ¹³C NMR spectra were run at 76 MHz using a proton- decoupled pulse sequence with a di of 3 sec, and are tabulated by observed peak. Mass spectra were obtained on a Micromass Autospec double focusing

instrument. (R,£)-2-Methyl- V-(3-((2R,3S,4R,5S,6R)-3,4,5-tris (benzyloxy)-6- (benzyloxymethyl)tetrahydro-2H-pyran-2-yl)propylidene)propane-2- sulflnamide (1). To a solution of the aldehyde prepared according to (21) (2.18 g, 3.75 mmol) in CH₂C1₂ (30 mL) was added MgS0₄ (2.53 g, 21.0 mmol), (R)-2- methylpropane-2-sulfinamide (500 mg, 4.13 mmol), and PPTS (104 mg, 0.410 mmol). The resulting suspension was stirred at rt for 24 h, filtered through Celite^®, and concentrated in vacuo. The residue was purified by chromatography on Si0₂ (4:6, EtOAc:hexanes) to yield 2.40 g (94%) of 1 as a colorless oil: [α]ο - 32.3 (c 1.1 , CH₂C1₂); IR (neat) 3063, 3030, 2921 , 1622, 1454, 1 185 cm^"1 ; 1H

NMR δ 8.08 (t, 1 H, J = 4.1 Hz), 7.40-7.15 (m, 20 H), 4.79-4.41 (m, 8 H), 4.05- 3.95 (m, 3 H), 3.89-3.79 (m, 1 H), 3.79-3.70 (m, 2 H), 3.70-3.61 (m, 1 H), 2.70- 2.52 (m, 1 H), 2.50-2.36 (m, 1 H), 2.04- 1.80 (m, 2 H); ¹³C NMR δ 168.7, 138.1 , 138.0, 137.9, 137.8, 128.0, 128.0, 127.9, 127.6, 127.5, 127.4, 127.2, 127.2, 127.1 , 76.2, 73.8, 72.8, 72.8, 72.6, 72.1 , 69.9, 67.1 , 56.0, 32.1 , 22.9, 21.9; ESIMS m/z 706 ([M+Na]⁺, 100), 684 ([M+H]⁺, 20); HRMS (ESI) m/z calcd for

C₄iH₄₉N0₆SNa (M+Na) 706.3178, found 706.3201.

(S,_JE)-l-((2R,3S,4R,5S,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl) tetrahydro-2H-pyran-2-yl) nonadec-4-en-3-amine (3). To a solution of 1 - hexadecyne (979 mg, 4.40 mmol) in CH₂C1₂ (20 mL) was added zirconocene hydrochloride (1.13 g, 4.40 mmol) and the resulting suspension was stirred at rt for 5 min. The yellow solution was cooled to 0 °C and treated with AlMe₃ (2.20 mL, 4.40 mmol, 2.0 M in CH₂C1₂) and a solution of imine 1 (2.01 g, 2.92 mmol) in CH₂C1₂ (10 mL). The reaction mixture was stirred at rt for 5 h, quenched with 25 mL of MeOH and 10 mL of 3 M HC1 were added and stirred at rt for 1 h. The solution was diluted with EtOAc, washed with NaHC0₃, dried (MgS0₄) and concentrated in vacuo. The residue was purified by chromatography on Si0₂ (3 :7, MeOH:CH₂Cl₂) to yield 1.69 g (72%) of 3 as a colorless oil: [<x]_D +28.5 (c 0.9, CH₂C1₂); IR (neat) 3063, 3030, 2927, 2853, 1454, 1097 cm^"1 ; 1H NMR δ 7.50-7.10 (m, 20 H), 5.51 (dt, 1 H, J = 15.1 , 6.5 Hz), 5.32 (dd, 1 H, J = 15.3, 7.2 Hz), 4.80-4.41 (m, 8 H), 4.02-3.90 (m, 3 H), 3.85-3.75 (m, 2 H), 3.75-3.70 (m, 1 H), 3.64 (dd, 1 H, J = 10.2, 4.5 Hz), 3.24 (app q, 1 H, J = 6.6 Hz), 2.05-1.90 (m, 2 H), 1.75-1.42 (m, 6 H), 1.42-1.10 (m, 24 H), 0.89 (t, 3 H, J = 6.3 Hz); ¹³C NMR δ 138.6, 138.4, 138.2, 134.2, 130.7, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.4, 76.7, 74.3, 73.2, 73.2, 73.0, 72.9, 71.9, 67.6, 53.6, 33.9, 32.3, 31.9, 29.6, 29.6, 29.5, 29.3, 29.3, 29.2, 22.6, 14.1 ; ESIMS m/z 805 ([M+H]⁺, 100); HRMS (ESI) m/z calcd for C₅₃H₇₄N0₅ (M+H) 804.5567, found 804.5587.

[(S_9J-i)-l-((2R,3S,4R,5S,6R)-3,4,5-Tris(benzyloxy)-6- (benzyloxymethyl)tetrahydro-2H-pyran-2-yl)nonadec-4-en-3-yl]-bis carbamic acid terf-butyl ester (4). To a solution of allylic amine 3 (1.50 g, 2.25 mmol) and Et₃N (627 μί, 4.50 mmol) in CH₂CI₂ (25 mL) was added a solution of B0C2O (515 mg, 2.36 mmol) and DMAP (27.5 mg, 0.225 mmol) and the mixture was stirred at rt for 1 h. The reaction was filtered through a pad of S1O2 and concentrated to yield 1.95 g (96%) of mono-boc carbamate as a colorless solid which was carried on without further purification. To a solution of the crude carbamate (1.95 g, 2.16 mmol) in THF (25 mL) at -78 °C was added n-BuLi (1.66 mL, 2.16 mmol, 1.3 M in hexanes) and the yellow solution was stirred at -78 °C for 30 min. To this solution was then added B0C2O (565 mg, 2.59 mmol) and the resulting solution was warmed to rt and stirred for 1 h. The reaction was quenched with sat. aq. NH₄C1, extracted with EtOAc, organic layer separated, dried (MgS0₄), concentrated and purified by chromatography on S1O2 (1.5 :8.5, EtOAc: hexanes) to yield 1.95 g (90%, 86%> over 2 steps) of 4 as a yellow oil:

[a]_D +24.7 (c 1.1 , CHC1₃); IR (neat) 3063, 3030, 2924, 2854, 1740, 1701 , 1454, 1343, 1 1 12 cm^"1 ; 1H NMR δ 7.45-7.10 (m, 20 H), 5.80-5.65 (m, 2 H), 4.90-4.40 (m, 9 H), 4.10-3.95 (m, 3 H), 3.90-3.80 (m, 2 H), 3.80-3.65 (m, 2 H), 2.10-2.05 (m, 2 H), 2.00-1.63 (m, 4 H), 1.60-1.45 (m, 18 H), 1.40-1.25 (m, 24 H), 0.94 (t, 3 H, J = 6.4 Hz); ¹³C NMR δ 153.0, 138.6, 138.3, 133.6, 129.0, 128.2, 127.7, 127.6, 127.5, 127.3, 81.6, 74.5, 73.2, 73.0, 72.9, 71.9, 71.7, 67.7, 59.0, 32.2, 31.8, 29.6, 29.2, 29.1 , 27.9, 27.7, 24.0, 22.6, 14.0; ESIMS m/z 1026 ([M+Na]⁺, 100), 905 ([M-Boc]⁺, 30), 805 ([M-2Boc]⁺, 100); HRMS (ESI) m/z calcd for

(M+Na) 1026.6435, found 1026.6396. tert-Butyl (3S,4S,5R)-4,5-dihydroxy-l-((2R,3S,4R,5S,6R)-3,4,5- tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)nonadecan-3- ylcarbamate (5). To a solution of imide 4 (400 mg, 0.398 mmol) in CH₂CI₂ (25 mL) at -40 °C was added urea hydrogen peroxide (169 mg, 1.79 mmol), dibasic sodium phosphate (283 mg, 1.99 mmol) and trifluoroacetic anhydride (167 mg, 0.796 mmol). The mixture was stirred at -40 °C for 8 h and at rt for 4 h, quenched with sat. aq. NaHC0₃, extracted with CH₂CI₂, dried (MgS0₄) and concentrated in vacuo. HPLC analysis of the crude mixture showed a 9: 1 mixture of diastereomers). To the crude residue was added EtOH (10 mL) and KOH (100 mg, 1.78 mmol) and the reaction mixture was heated at 40 °C for 2 h, extracted with EtOAc, dried (MgS0₄) and concentrated in vacuo. The residue was purified by chromatography on S1O₂ (1 : 1 , EtOAc:hexanes) to yield 298 mg (80%) of 5 and 33.7 mg (9%) of 5' as greasy colorless waxes: 5: [α]ο +27.1 (c 1.0, CH₂CI₂); IR (neat) 3436, 3357, 2921 , 2852, 1682, 1526, 1 108 cm ¹ ; 1H NMR (500 MHz) δ 7.40-7.25 (m, 20 H), 5.12 (d, 1 H, J = 8.3 Hz), 4.78-4.71 (m, 1 H), 4.71-4.61 (m, 3 H), 4.60-4.45 (m, 4 H), 4.08-3.97 (m, 2 H), 3.96-3.92 (m, 1 H), 3.92-3.79 (m, 2 H), 3.78-3.68 (m, 2 H), 3.52 (app d, 2 H, J = 7.1 Hz), 3.43 (app t, 1 H, J = 4.5 Hz), 2.80-2.30 (bs, 2 H), 1.95-1.63 (m, 4 H), 1.61-1.47 (m, 2 H), 1.45 (s, 9 H), 1.39-1.22 (m, 24 H), 0.92 (t, 3 H, J = 6.7 Hz); ¹³C NMR δ 156.6, 138.6, 138.4, 138.2, 128.3, 128.2, 127.9, 127.8, 127.6, 127.6, 127.5, 79.4, 74.7, 73.2, 73.1 , 72.9, 72.0, 68.2, 53.3, 33.2, 31.8, 29.6, 29.3, 28.4, 26.3, 25.9, 23.6, 22.6, 14.0; ESIMS m/z 960 ([M+Na]⁺, 50), 839 ([M-Boc]⁺, 100); HRMS (ESI) m/z calcd for C₅₈H₈₄N0₉ 938.6146, found 938.6176. 5 - (Biphenyl - 4 - yl) - TV - ((3S,4S,5S) - 4,5 - dihydroxy - 1- ((2R,3R,4R,5R,6R)-3,4,5- trihydroxy - 6 - (hydroxymethyl) tetrahydro-2H- pyran-2-yl) nonadecan - 3 - yl) pentanamide (Compound A). To a solution of 5 (1 14 mg, 0.122 mmol) in CH₂C1₂ (2 niL) at rt was added HC1 (1.00 niL, 4.00 mmol, 4.0 M in dioxane) and the reaction mixture was stirred at rt for 2 h, concentrated, and the crude amine salt carried on without further purification. To the crude amine salt in CHCI3 (2 mL) was added Et₃N (3.0 eq, 51.0 μΐ,, 0.366 mmol), biphenyl propionic acid (1.2 eq, 37.1 mg, 0.146 mmol), DMAP (.05 eq, 0.745 mg, 0.00610 mmol) and EDCI (1.1 eq, 25.7 mg, 0.134 mmol) and the reaction mixture was stirred at rt for 5 h. The reaction was quenched with sat. aq. NH₄CI, extracted with CH₂C1₂ (2x), washed with brine, dried (MgS0₄), filtered and concentrated. The crude residue was purified by chromatography on Si0₂ (40% EtOAc/hexanes) to yield 97.4 mg (79% over 2 steps) as a colorless waxy solid. To a solution of coupled product (97.4 mg, 0.0906 mmol) in CHCl₃/MeOH (3 : 1 , 4 mL) was added Pd(OH)₂/C (10 mg) and the reaction mixture was stirred under and atmosphere of H₂ for 2 h. The reaction mixture was filtered though a pad of Celite, concentrated and the crude residue purified by chromatography on Si0₂ (20% MeOH/CHCl₃) to yield 62.1 mg, (96%) of Compound A as a colorless waxy solid: [a]_D +18.2 (c 0.10, pyridine); IR (neat) 3444, 3397, 2921 , 2852,

2256, 1739, 1624, 1587, 1548, 1455, 1372, 1 143, 1079 cm^'YH NMR (300 MHz, d₅-Pyridine) δ 8.47 (d, 1 H, J = 9.0 Hz), 7.36-7.27 (m, 2 H), 7.25-7.17 (m, 3 H), 6.80-5.80 (m, 6 H), 5.13 (dd, 1 H, J = 9.6, 9.6 Hz), 4.72 (dd, 1 H, J = 8.7, 5.4 Hz), 4.56-4.43 (m, 3 H), 4.34 (dd, 1 H, J = 1 1.1 , 4.2 Hz), 4.27-4.09 (m, 4 H), 2.80-2.63 (m, 1 H), 2.63-2.54 (m, 1 H), 2.54-2.45 (m, 2 H), 2.45-2.36 (m, 2 H), 2.36-2.08 (m, 3 H), 2.01-1.83 (m, 2 H), 1.83-1.72 (m, 2 H), 1.72-1.59 (m, 1 H), 1.54-1.1 1 (m, 30 H), 0.85 (t, 3 H, J = 5.4 Hz NMR (150 MHz, d₅ pyridine) δ 173.4, 143.3, 128.9, 128.7, 126.1 , 78.5, 77.1 , 73.8, 72.6, 72.2, 70.6, 70.4, 62.8, 52.7, 37.0, 36.1 , 34.5, 32.2, 31.9, 30.4, 30.2, 30.1 , 30.0, 30.0, 29.7, 29.7, 29.6, 29.5, 26.6, 26. ,5, 26.4, 23.0, 22.6, 14.3; ESIMS m/z 675 (5), 702 ([M+Na]⁺, 100), 707 (10), 708 (3); HRMS (ESI) m/z calcd for C₃₉H₆₉N0₈Na (M+Na) 702.4921 , found 702.4881.

1 - ((3S,4S,5R) - 4,5 - Dihydroxy - 1 - ((2R,3R,4R,5R,6R) - 3,4,5 - trihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)nonadecan-3-yl)-3-(4- phenylbutyl) urea (Reference D). To a solution of 5 (100 mg, 0.107 mmol) in CH₂C1₂ (1.5 mL) at rt was added HC1 (0.750 mL, 3.00 mmol, 4.0 M in dioxane) and the reaction mixture was stirred at rt for 2 h, concentrated, and the crude amine salt carried on without further purification. To the crude amine salt in acetonitrile (2.5 mL) and diethyl ether (1.5 mL) was added Et₃N (3.0 eq, 44.7 μί, 0.321 mmol) and 4-phenylbutyl isocyanate (1.0 eq, 18.3 μί, 0.109 mmol), and the reaction mixture was stirred at rt for 6 h. The reaction was quenched with H₂0, extracted with CH₂CI₂ (2x), washed with brine, dried (MgS0₄), filtered and concentrated. The crude residue was carried on without further purification. To a solution of crude urea in CHCl₃/MeOH (3 : 1 , 4 mL) was added Pd(OH)₂/C (10 mg) and the reaction mixture was stirred under and atmosphere of ¾ for 2 h. The reaction mixture was filtered though a pad of Celite, concentrated and the crude residue purified by chromatography on S1O₂ (20% MeOH/CHCl₃) to yield 51.7 mg, (74%)) of Reference D as a colorless waxy solid: [α]ο +15.2 (c 0.17, pyridine); IR (neat) 3329, 2922, 2853, 1627, 1561 , 1454, 1248, 1071 cm^"VH

NMR (300 MHz, d₅-Pyridine) δ 7.33-7.23 (m, 2 H), 7.22-7.1 1 (m, 3 H), 6.74 (d, 1

H, J = 8.7 Hz), 6.65 (dd, 1 H, J = 5.4, 5.4 Hz), 6.50-5.10 (bs, 6 H), 4.92 (dd, 1 H, J = 7.5, 7.5 Hz), 4.70 (dd, 1 H, 8.7, 5.4 Hz), 4.62-4.51 (m, 2 H), 4.51-4.45 (m, 1 H), 4.33 (dd, 1 H, J = 1 1.4, 4.2 Hz), 4.28-4.09 (m, 4 H), 3.53-3.22 (m, 2 H), 2.65- 2.54 (m, 2 H), 2.54-2.45 (m, 2 H), 2.41-2.20 (m, 3 H), 1.98-1.77 (m, 2 H), 1.72-

I .48 (m, 3 H), 1.45-1.09 (m, 24 H), 0.85 (t, 3 H, J = 6.9 Hz); ¹³C NMR (76 MHz, d₅-Pyridine) δ 160.2, 142.9, 128.9, 128.7, 126.1 , 79.0, 76.9, 74.1 , 72.8, 72.2, 70.6, 70.5, 62.7, 53.5, 40.4, 35.8, 35.1 , 32.2, 30.7, 30.4, 30.2, 30.1 , 30.0, 30.0, 29.6, 29.2, 26.7, 26.6, 23.0, 22.6, 14.3; ESIMS m/z 675 ([M+Na]⁺, 100), 676 (8); HRMS (ESI) m/z calcd for C₃₆H₆₄N₂0₈Na (M+Na) 675.4560, found 675.4512. 1 - ((3S,4S,5S) - 4,5 - Dihydroxy - 1 - ((2R,3S,4R,5S,6R) -3,4,5- tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)nonadecan-3- yl)thiourea (8). To a solution of 5 (100 mg, 0.107 mmol) in CH₂C1₂ (1.5 mL) at rt was added HC1 (0.75 mL, 3.00 mmol, 4.0 M in dioxane) and the reaction mixture was stirred at rt for 2 h, concentrated, and the crude amine salt carried on without further purification. To the crude amine salt in THF (4.0 mL) was added Et₃N (3.0 eq, 44.7 μί, 0.321 mmol) and Fmoc isothiocyanate (1.0 eq, 30.1 mg, 0.107 mmol), and the reaction mixture was stirred at rt for 6 h. The reaction mixture was treated with Et₂NH (10 eq, 1 1 1 μί, 1.07 mmol) and stirred at rt for 2 h. The reaction was quenched with sat. aq. NH₄C1, extracted with CH₂C1₂ (2x), washed with brine, dried (MgS0₄), filtered and concentrated. The crude residue was purified by chromatography on Si0₂ (40% EtOAc/hexanes) to yield 74.9 mg (78%) of thiourea 8 as a yellow solid.

(2R,3R,4R,5R,6R) - 2 - ((3S,4S,55) - 3 - (4 - Heptadecylthiazol-2-ylamino) - 4,5-dihydroxynonadecyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound B). To a solution of crude thiourea (75.7 mg, 0.0844 mmol) in EtOH (1 mL) was added bromo ketone 9 (30.5 mg, 0.0844 mmol) and the reaction mixture was heated at 60 °C for 4 h. The reaction mixture was concentrated and the crude solid carried on without further purification. To a solution of crude thiazole in CH₂C1₂ (2 mL) at -78 °C was added BC1₃ (1.0 M in hexanes, 10 eq, 0.844 mmol, 0.844 mL) and the reaction mixture stirred at -78 °C for 30 min. The reaction mixture was quenched at this temperature with sat. aq. NH₄C1, extracted with CHC1₃ (2x), washed with brine, dried (MgS0₄), filtered and concentrated. The crude residue was purified by chromatography on Si0₂ (20%> MeOH/CHCl₃) to provide 59.4 mg (88%) of Compound B as a light yellow waxy solid: [<x]_D +17.7 (c 0.12, pyridine); IR (neat) 3330, 2918, 2850, 1557, 1519, 1467, 1075 cm^"VH NMR (600 MHz, d₅-pyridine) δ 8.59 (dd, 1 H, J = 8.4, 3.0 Hz), 6.23 (s, 1 H), 6.20-5.60 (bs, 6 H), 4.95-4.86 (m, 1 H), 4.74-4.68 (m, 1 H), 4.57-4.47 (m, 3 H), 4.42-4.32 (m, 2 H), 4.29-4.18 (m, 3 H), 2.79-2.71 (m, 1 H), 2.71-2.62 (m, 3 H), 2.50-2.40 (m, 1 H), 2.40-2.30 (m, 2 H), 1.98-1.86 (m, 2 H), 1.85-1.76 (m, 2 H), 1.73-1.61 (m, 1 H), 1.52-1.17 (m, 50 H), 0.89 (t, 3 H, J = 7.2 Hz), 0.88 (t, 3 H, J = 7.2 Hz); ¹³C NMR (150 MHz, d₅-pyridine) δ 170.5, 154.2, 99.8, 78.2, 77.7, 74.3, 73.2, 72.7, 71.2, 70.9, 63.3, 59.5, 35.6, 32.9, 32.7, 30.9, 30.7, 30.6, 30.5, 30.4, 30.3, 30.2, 29.8, 27.0, 26.6, 23.5, 23.3, 14.8; EIMS m/z 781 (30), 782 (30), 800 ([M+H]⁺, 100); HRMS (EI) m/z calcd for C₄5H₈₆N₂0₇S 799.6234, found 799.6198. (2R,3R,4R,5R,6R) - 2 - ((3S,4S,55) - 3 - (4 - (4 - (Dodecyloxy) phenyl) thiazol- 2-ylamino) -4,5-dihydroxynonadecyl)-6-(hydroxymethyl) tetrahydro-2H- pyran-3,4,5-triol (Compound C). To a solution of crude thiourea (75.7 mg, 0.0844 mmol) in EtOH (1 mL) was added bromo ketone 10 (32.4 mg, 0.0844 mmol) and the reaction mixture was heated at 60 °C for 4 h. The reaction mixture was concentrated and the crude solid carried on without further purification. To a solution of crude thiazole in CH₂CI₂ (2 mL) at -78 °C was added BCI₃ (1.0 M in hexanes, 10 eq, 0.844 mmol, 0.844 mL) and the reaction mixture stirred at -78 °C for 30 min. The reaction mixture was quenched at this temperature with sat. aq. NH₄C1, extracted with CHC1₃ (2x), washed with brine, dried (MgS0₄), filtered and concentrated. The crude residue was purified by chromatography on Si0₂

(20% MeOH/CHCl₃) to provide 57.5 mg (83%, 2 steps) of Compound C as a light yellow waxy solid: [<x]_D +20.2 (c 0.10, pyridine); IR (neat) 3348, 2922, 2853, 1688, 1606, 1467, 1251 , 1076 cm^"VH NMR (600 MHz, CDCl₃/MeOD) δ 7.61- 7.57 (m, 2 H), 6.89-6.84 (m, 2 H), 6.48 (s, 1 H), 3.98-3.92 (m, 3 H), 3.91-3.82 (m, 3 H), 3.79 (dd, 1 H, J = 12.6, 8.4 Hz), 3.70-3.65 (m, 2 H), 3.61 (dd, 1 H, J = 9.6, 3.6 Hz), 3.57 (dd, 1 H, J = 7.8, 3.6 Hz), 3.50 (ddd, 1 H, J = 9.0, 2.4, 2.4 Hz), 1.93-1.86 (m, 1 H), 1.86-1.72 (m, 4 H), 1.71-1.62 (m, 2 H), 1.56-1.47 (m, 1 H), 1.47-1.41 (m, 2 H), 1.40-1.17 (m, 40 H), 0.85 (t, 3 H, J = 7.2 Hz), 0.85 (t, 3 H, J = 7.2 Hz); ¹³C NMR (150 MHz, CDCl₃/MeOD) δ 169.1, 158.1 , 149.6, 127.0, 126.3, 113.6, 97.7, 77.4, 77.0, 76.6, 76.5, 74.8, 71.7, 71.4, 69.9, 68.5, 67.2, 60.8, 57.3, 28.9, 28.9, 28.8, 28.8, 28.8, 28.6, 28.5, 28.5, 28.5, 25.2, 25.0, 24.6, 21.8, 21.0, 12.8. HRMS (EI) m/z calcd for C₄6H₈oN₂0₈S 821.2103, found 821.2098.

5.3. Table 1 : Compounds according to the present invention

The following compounds according to the present invention are synthesized according to the general scheme depicted under 5.1. above:

5.4. Table 2: Reference compounds

5.5. Cytokine profiles induced by compounds according to the present invention and reference compounds

As outlined above, glyco lipids stimulate the production of cytokines from NKT cells. Depending inter alia on the cytokine environment, an immune response is triggered; several cytokines could be identified which bias the immune response towards Thl or Th2. Thus, higher levels of IFN-γ are associated with a Thl -polarization, whereas IL-4 is a Th2 cytokine. In their first experiments, the inventors set out to characterize the cytokine pattern induced by compounds according to the present invention vs. reference compounds. To this aim, the compounds were injected into mice and the cytokine levels of IL-4 and INF- γ were determined over a time course of 48 h. The following experimental setup was used:

Protocol: 2 μg of each compound were injected into mice intravenously. Prior to the injection, the compounds were dissolved in DMSO (0,5 mg/ml) and diluted in PBS to a final concentration of 10 μg/ml. At the indicated time points, blood samples were taken followed by the determination of IL-4 and IFN-γ concentrations by ELISA.

Mice: C57BL/6 mice (H-2b) were originally purchased from Charles River

Laboratories. All mice were kept in a specific pathogen- free facility and used age and sex matched at 6-10 wk of age. Animal experiments were approved by the review board of the Regierungsprasidium Freiburg, Germany.

ELISA: For the IFN-γ and IL-4 cytokine determination, the corresponding BD- ELISA Kit (BD OptElATM, BD Bioscience) was used, following the manufacturer's instructions. Absorbance at 450-570 nm was measured using a SpectrafluorPlus plate reader (Tecan). As can be derived from figure 1, Compound A induced an initial burst of IL-4 release (upper graph) peaking at 2 hours post injection. Compared to reference A, Compound A yielded lower quantities of IL-4. In both cases, the IL-4 levels decreased after a few hours. After injection of Compound A, there was no release of IFN-γ (lower graph) in comparison to reference A, where a robust production of IFN-γ was detected (which peaked 24 hours after injection and was still detectable after 48 hours). Thus, Compound A shows a clear Th2 polarizing cytokine pattern, characterized by substantial amounts of early IL-4 in the absence of IFN-γ.

Reference C has been described as Th2 polarizing glyco lipid (15). Thus, the inventors included reference C into an assay as described above. As can be derived from figure 2, the results described above for Compound A and reference A could be confirmed. Thus, in response to Compound A, IL-4 could be detected (upper graph), whereas no IFN-γ was present in the serum (lower graph). Reference C, however, clearly induced the production of IFN-γ as well (lower graph).

Figure 3 depicts the IL-4 levels two hours post injection (left graph) of several compounds. As can be derived from figures 1 and 2, this time point corresponds to the peak in IL-4 levels. Since the IFN-γ peaks can be found 24 hours post injection, the right graph of figure 3 depicts the IFN-γ levels at 24 hours post injection of several compounds. The results of figure 3 again confirm the IL-4 and IFN-γ levels detected upon injection of Compound A and reference A. Further, it can be derived that Compound B according to the present invention also results in a desired cytokine pattern whereas reference B results in a Thl biasing cytokine pattern (as expected). Reference D is inactive and does not result in the production of substantial amounts of either IL-4 or IFN-γ.

Thus, compared to the known and characterized Reference A (9) and Reference B (22), Compounds A and B according to the present invention also induce the production of IL-4. However, upon injection of Compounds A and B of the present invention, there is no induction of IFN-γ at all. In summary, Compounds A and B are clearly Th2 -polarizing according to the cytokine pattern induced by said two compounds.

5.6. Expression analysis of the T-bet and the GATA-3 genes in colitic mice

As outlined above, naive T helper cells can differentiate into Thl and Th2 cells, each with distinct functions and cytokine profiles. Among other factors, a Thl -specific T box transcription factor (T-bet) positively influences a Thl polarization since T-bet controls and induces the expression of the Thl -cytokine IFN-γ. Further, it could be shown that T-bet represses the opposing Th2 program (23). Trans-acting T-cell- specific transcription factor GATA-3 on the other hand has been shown to be implicated in the promotion of IL-4 production, among other cytokines (24).

In order to support their above finding on the Th2 -polarizing effects of Compounds A and B, the inventors used a mouse model in order to analyze the expression of the two transcription factors upon administration of Compound A. The following experimental setup was used:

Protocol: Colitis was induced in mice by feeding mice a DSS solution for five days. Weight loss was monitored until day 8. On day four, mice were treated with either 2 μg Compound A or with vehicle. At day 8, the weight loss was determined and the splenocytes of the mice were subsequently sorted for CD4⁺ lymphocytes, followed by R A isolation. A real-time RT-PCR analysis was carried out in order to determine the expression levels of T-bet and GATA-3.

DSS-induced colitis: Mice (see 5.5. above) were treated with a 2,2 % solution of dextrane sulfate sodium salt (DSS, MP Biomedicals, Solon, Ohio, USA) ad libitum via the drinking water for five days. On day four, mice were inoculated with 2 μg of Compound A dissolved in PBS i.v.. Control groups were treated with the

corresponding volumes of DMSO in PBS (vehicle). The percentage of body weight loss was calculated as following: (((body weight at day x) X 100)) / (body weight at day 0))- 100.

Quantitative real-time RT-PCR: Real-time RT-PCR was used to quantify

transcription factor expression levels in CD4⁺ mouse splenocytes. Total RNA was extracted from magnetically sorted (CD4 T cell isolation kit, mouse; Miltenyi Biotec) CD4⁺ splenocytes using a NucleoSpin® RNA II extraction kit (Macherey- Nagel). 1 μg of total RNA was reverse-transcribed using oligo(dT) primers or 18S rRNA RT primers (5 '-GAGCTGGAATTACCGCT-3 ' , SEQ ID No. 1) and the reverse transcription system (Promega). Quantitative PCR was performed with the LightCycler® instrument (Roche Applied Science) using the LightCycler® Fast Start DNA Master SYBR Green I reaction mix (Roche Applied Science) with the following primers: GATA-3 specific forward (5 '-CTGGAGGAGGAACGCTAATG- 3', SEQ ID No. 2); GATA-3 specific reverse (5'-AGATGTGGCTCAGGGATGAC- 3', SEQ ID No. 3) and T-bet specific forward (5 '-GGACCCAACTGTCAACTGCT- 3', SEQ ID No. 4); T-bet specific reverse (5'- AACTGTGTTCCCGAGGTGTC-3', SEQ ID No. 5). Mouse 18S was used as a reference gene with the following primers: 18S rRNA forward (5 '-GAGGTAGTGACGAAAAATAACAAT-3 ', SEQ ID No. 6) and 18S rRNA reverse (5^*-TTGCCCTCCAATGGATCCT-3^*, SEQ ID No. 7).

Primers were purchased from Microsynth (Balgach, CH).

As can be derived from figure 4, the expression of T-bet in the Compound A treated group is significantly reduced compared to the vehicle treated group, whereas the GATA-3 levels are not affected. Further, on day 8, the average weight loss of the vehicle treated groups ranged between 13,5 % to 14,5 %, whereas the Compound A treated groups showed a decreased weight loss of about 8 % to 8,5 %. Summing up, the results clearly indicate a shift Thl vs. Th2 differentiation by Compound A in favor of Th2. 5.7. DSS-induced colitis in mice as model for chronic inflammation in the colon

Further to the effect on the expression of T-bet and GATA-3, the inventors were interested in the effect of compounds according to the present invention on the course of DSS induced colitis in mice. The following experimental setup was used:

Protocol: Colitis was induced in mice by feeding mice a DSS solution for five days. Weight loss was monitored until day 17. On day four, mice were treated with 2 μg Compound A, 2 μg Reference C, or vehicle (PBS+DMSO). The body weight and the survival of the mice were monitored over a period of 17 days. Further details on the experimental setup can be found in 5.7.

Figure 5 clearly indicates that the survival rate of mice treated with Compound A or Reference C corresponds to 100% whereas all mice treated with vehicle fail to survive the experiment. Further, figure 5 indicates that the efficacy of Compound A is at least comparable to Reference C. Thus, a single injection of Compound A applied early after onset of the DSS-induced colitis resulted in the survival of all mice in this group. Further, it could be demonstrated that the length of the colon is clearly increased in the Compound A-treated group compared to the vehicle-treated group indicating a decrease in the inflammation (data not shown).

5.8. Experimental autoimmune encephalomyelitis (EAE) as model for a Thl driven autoimmune disease EAE corresponds to a prototype autoimmune disease mediated by Thl cells and is well established as experimental model in mice (general model of brain

inflammation, in particular for multiple sclerosis and encephalomyelitis including acute disseminated encephalomyelitis). EAE can be used to assess the Th2 biasing effect of a substance since a Th2 polarizing substance can suppress EAE. The inventors set out to test the efficacy of Compound A of the present invention in comparison to Reference A and Reference C in the EAE model. The following general experimental setup was used wherein details can be found in (15):

Protocol: For the induction of EAE, mice were treated with 200 μg of MOG35-55 peptide s.c. in 200 μΐ phosphate buffered saline:CFA (1 : 1) and 200 ng pertussis toxin i.v.. After two days, the injection of pertussis toxin was repeated. Treatment of mice with the indicated compounds started at day 6 and lasted up to day 20 as indicated by the red triangles in the graph. Mice were scored daily for their EAE score as follows:

0 No detectable signs of EAE

0,5 distal limp tail

1 complete limp tail

1,5 limp tail and hind limb weakness

2 Unilateral partial hind limb paralysis

2,5 bilateral partial hind limb paralysis

3 complete bilateral hind limb paralysis

3,5 complete bilateral hind limb paralysis and partial forelimb paralysis

4 Morbibund (mouse completely paralyzed).

Figure 6 indicates that Compound A according to the present invention with a peak EAE score of only about 0.5 is clearly superior over the Reference compounds

[including Reference C corresponding to "OCH" as the most efficient compound in (15)]. This strongly indicates a positive effect of compounds according to the present invention in human autoimmune diseases such as multiple sclerosis. 5.9. Low-dose streptozotocin induced diabetes in mice as model for diabetes

A further example of a Thl driven autoimmune disease is diabetes, particularly type 1 diabetes characterized by the destruction of the insulin-producing cells in the pancreas. Thus, a potential therapeutic activity of compounds according to the present invention on diabetes was tested by the inventors in a mouse model. The following experimental setup was used:

Protocol: Male mice were treated daily with 40 mg/kg streptozotocin (STZ; Sigma) in freshly prepared Na-Citrate buffer (0,1M) i.p. for 5 days. On day four, mice were injected with 2 μg Compound A either encapsulated into PLGA-microspheres (sac.) or dissolved in PBS (i.v.). Control groups were treated with the corresponding volumes of DMSO in PBS. Blood glucose levels were monitored using a blood glucose analyzer (Contour, Bayer). Increase in blood glucose level on day 7 and day 9 was calculated as follows: (blood glucose level on day x) - (blood glucose level on day 0).

The PLGA microspheres were prepared from 14 kDa poly(D,L-lactide-co-glycolide) (PLGA) 50:50 carrying hydroxyl- and carboxyl-end groups (Resomer RG502H, Boehringer Ingelheim, Ingelheim, Germany) by spray drying. Briefly, 50 mg ovalbumin (Grade V, Sigma) and 5 mg CpG oligodeoxynucleotides with a phosphothioate backbone (CpG-ODN 1826, Microsynth, Balgach, Switzerland) or 0,5 mg polyLC (Calbiochem, VWR, Dietikon, Switzerland) (MS polyLC) were dissolved in 0.5 ml 0.1M NaHC0₃ (aqueous phase) and mixed with 1 g of PLGA dissolved in 20 ml of dichloromethane (organic phase). Optionally 0.5mg Compound A was dissolved in 160 μΐ methanol / chloroform (MS-a-C-diPheGalCer) and mixed with 1 g of PLGA dissolved in 20 ml of dichloromethane. The two phases were subsequently emulsified by ultrasonication (Hielscher, UP200 H, Ampl. 40%) for 10 s on ice. The obtained dispersion was immediately spray-dried (Bvichi, Mini Spray- Dryer 191) at a flow rate of 2 ml/min and inlet/outlet temperatures of 40/37 °C. The obtained MS were washed out of the spray-dryer's cyclone with 0.05 % Synperonic (Synperonic®F68, Serva Electrophoresis GmbH, Heidelberg, Germany), collected on a cellulose acetate membrane filter and dried under reduced pressure (20 mbar) for 18 h at room temperature. PLGA-MS were stored at 4°C. Immediately before use MS were dispersed in PBS by ultrasonication for 30 sec. Figure 7A shows a kinetic of the blood glucose levels in mg glucose per dl blood, whereas figure 7B shows the increase of blood glucose at day 7 and day 9. In line with the disease models described above, early treatment with Compound A resulted in a significant reduction in the susceptibility to develop diabetes. It appears that an application of Compound A in the encapsulated form is slightly more beneficial at later time points compared to a i.v. application in the dissolved state. In summary, Compound A also showed a positive effect on the glucose levels in a diabetes model. 5.10. DNFB-induced contact hypersensitivity as model for a contact

hypersensitivity

A further example of a Thl driven reaction if contact hypersensitivity (CHS). Thus, a potential therapeutic activity of compounds according to the present invention was tested by the inventors in a mouse model as described in (25). The following experimental setup was used:

Protocol: Mice were sensitized with 5 μΐ of a 1 % solution of 2,4- dinitrofluorobenzene (DNFB; Sigma) in acetone:olive oil (4:1) epicutanously on the left ear. Five days later, the right ear was challenged with 5 μΐ of a 1 % solution DNFB in acetone:olive oil (4: 1) and the mice were immediately treated with 2 μg Compound A either encapsulated into PLGA-microspheres (sac.) or dissolved in PBS (i.v.). Control groups were treated with the corresponding volumes of DMSO in PBS. 24 h after the challenge, ear swelling was assessed. Further details of the assay can be found in (25).

Figure 8 shows that the administration of Compound A resulted in a significant reduction of the ear swelling and thus in a decrease of the contact hypersensitivity. It appears that an application of Compound A in the dissolved form is slightly more beneficial compared to an encapsulated form. In summary, Compound A also showed a positive effect on contact hypersensitivity as a model for e.g. type IV allergies.

5.11. The effect on EAE and DSS-induced colitis is dependent on CD 1 d

In order to determine whether the observed effects are dependent on CD Id, similar experiments to the experiments described above under 5.7 and 5.8 were carried out in CD l ^" mice.

In the DSS-induced colitis model (Figure 9A), colitis was elicited in C57BL/6 (wt) and CDl ^/_ mice with DSS. On day 4, both groups were treated with 2 μg Compound A in PBS i.v. or with DMSO in PBS (vehicle). Only wt-mice receiving Compound A recovered, whereas mice of all other groups had to be sacrificed due to excessive weight loss. As can be derived from Figure 9B (EAE), there is no difference in the disease scores between CDl ^/_ mice treated with Compound A and vehicle. These results clearly suggest that the effect of Compound A relies on the presentation of the compound by CD Id.

Further preferred embodiments of the present invention relate to:

1. A pharmaceutical composition comprising a compound of formula (I):

(I) wherein

Z¹ is selected from C and CH;

Z² is selected from CR_A, CHR_A, N, NR_A, O and S;

Z³ is selected from CR_A and CHR_A;

Z⁴ is selected from CR_A and CHR_A;

Z⁵ is selected from CR_A, CHR_A, N, NR_A, O and S;

m is 1 or 2 to form a 5-membered or 6-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic;

R_A is either Ri or independently selected from the group consisting of H, halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl; with the proviso that at least one Ri substituent is present in the 5-membered or 6-membered carbocycle or heterocycle;

Ri is a 6-membered carbocycle which is saturated or unsaturated or aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and

trifluoromethyl; or a C5-C25 alkyl, which is optionally branched and further substituted with one or more substituent(s) selected from oxo, hydroxyl and amino; Y is either absent to form a direct bond between NH and Z¹; or selected from the group consisting of -C(0)(CH₂)_n-, -S0₂(CH₂)_n-, -C(0)0(CH₂)_n-, -C(0)NH(CH₂)_n- and -C(0)N((CH₂)_pCH₃)(CH₂)_n-, wherein n is an integer from 0 to 10 and wherein p is an integer from 0 to 9;

R₂ is selected from the group consisting of -CH₂(CH₂)_qCH₃, -CH(OH)(CH₂)_qCH₃, -CH(OH)(CH₂)_qCH(CH₃)₂, -CH=CH(CH₂)_qCH₃, and

-CH(OH)(CH₂)_qCH(CH₃)CH₂CH₃, wherein q is an integer from 5 to 17;

X is O or -CH₂-;

R₃ and R4 are independently selected from the group consisting of H, amino, hydroxyl, aminoalkyl and alkoxy; R₅ is selected from the group consisting of H, amino, hydroxyl, aminoalkyl, alkoxy, a-glucose, β-glucose, a-galactose and β-galactose; and

R6 is selected from the group consisting of H, amino, hydroxyl, aminoalkyl, alkoxy, Cl-C lO alkyl and -CH₂OH;

or a pharmaceutically acceptable salt thereof.

2. Pharmaceutical composition according to 1 , wherein Z¹ is C; Z² is selected from CR_A, N, NR_a, O and S; Z³ is CR_A; Z⁴ is CR_A; Z⁵ is selected from CRA, N, NR_A, O and S; and m is 1 or 2 to form a 5 -membered or 6-membered carbocycle or heterocycle which is aromatic.

3. Pharmaceutical composition according to 1 or 2, wherein Z¹ is C; Z² is CRA; Z³ is CRA; Z⁴ is CRA; Z⁵ is CRA; and m is 2 to form a 6-membered carbocycle which is aromatic.

4. Pharmaceutical composition according to 1 or 2, wherein

Z¹ is C; Z² is selected from N, NR_A, O and S; Z³ is CR_A;

Z⁴ is CRA; Z⁵ is selected from N, NRA, O and S; and m is 1 to form a 5 -membered heterocycle which is aromatic.

5. Pharmaceutical composition according to any of 1 to 5, wherein RA is either Ri or independently selected from the group consisting of H, halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl; with the proviso that one Ri substituent is present in the 5 -membered or 6-membered carbocycle or

heterocycle.

6. Pharmaceutical composition according to any of 1 to 5, wherein Ri is a 6- membered carbocycle which is aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl.

7. Pharmaceutical composition according to any of 1 to 5, wherein Ri is a C5- C25 alkyl, preferably a C10-C20 alkyl, more preferably a C15-C18 alkyl, which is optionally substituted with one or more substituent(s) selected from oxo, hydroxyl and amino.

8. Pharmaceutical composition according to any of 1 to 7, wherein Y is absent or selected from the group consisting of -C(0)(CH₂)„-, -S0₂(CH₂)„-, -C(0)0(CH₂)_n- and -C(0)NH(CH₂)_n-, wherein n is an integer from 0 to 10, preferably an integer from 2 to 8, more preferably an integer from 3 to 7, and most preferably 4.

9. Pharmaceutical composition according to any of 1 to 8, wherein R₂ is -CH(OH)(CH₂)_qCH_3i wherein q is an integer from 5 to 17, preferably from 8 to 16, more preferably from 10 to 15, and most preferably 13.

10. Pharmaceutical composition according to any of 1 to 9, wherein X is -CH₂-. 11. Pharmaceutical composition according to any of 1 to 10, wherein R₃ and R4 are hydroxyl.

12. Pharmaceutical composition according to any of 1 to 11, wherein R^ is -CH₂OH.

13. Pharmaceutical composition according to any of 1 to 12, wherein said composition comprises said compound as the only pharmaceutically active agent.

14. Pharmaceutical composition according to any of 1 to 13, wherein said composition is for use in the treatment and/or prevention of an immune-mediated disease characterized by a Thl polarization, wherein said disease is selected from inflammatory bowel disease including ulcerative colitis and Crohn's disease, type 1 diabetes, multiple sclerosis, arthritis including rheumatoid arthritis, allogeneic transplantation reactions including graft-versus-host disease, type IV allergies, systemic lupus erythematosus, systemic sclerosis, encephalomyelitis, chronic articular rheumatism, Sjoegren's syndrome, primary biliary cirrhosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, myasthenia gravis, sympathetic ophthalmia, Goodpasture's syndrome (e.g. glomerular nephritis), pernicious anemia and Hashimoto's disease.

15. A method for activating the production of at least one Th2 polarizing cytokine in NKT cells in vitro comprising contacting said NKT cells with a compound of formula (I)

(I)

wherein

Z¹ is selected from C and CH;

Z² is selected from CR_A, CHR_A, N, NR_A, O and S;

Z³ is selected from CR_A and CHR_A;

Z⁴ is selected from CR_A and CHR_A;

Z⁵ is selected from CR_A, CHR_A, N, NR_A, O and S;

m is 1 or 2 to form a 5-membered or 6-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic;

R_A is either Ri or independently selected from the group consisting of H, halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl; with the proviso that at least one Ri substituent is present in the 5-membered or 6-membered carbocycle or heterocycle;

Ri is a 6-membered carbocycle which is saturated or unsaturated or aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and

trifluoromethyl; or a C5-C25 alkyl, which is optionally branched and further substituted with one or more substituent(s) selected from oxo, hydroxyl and amino; Y is either absent to form a direct bond between NH and Z¹; or selected from the group consisting of -C(0)(CH₂)_n-, -S0₂(CH₂)_n-, -C(0)0(CH₂)_n-, -C(0)NH(CH₂)_n- and -C(0)N((CH₂)_pCH₃)(CH₂)_n-, wherein n is an integer from 0 to 10 and wherein p is an integer from 0 to 9;

R₂ is selected from the group consisting of -CH₂(CH₂)_qCH₃, -CH(OH)(CH₂)_qCH₃, -CH(OH)(CH₂)_qCH(CH₃)₂, -CH=CH(CH₂)_qCH₃, and

-CH(OH)(CH₂)_qCH(CH₃)CH₂CH₃, wherein q is an integer from 5 to 17;

X is O or -CH₂-;

R₃ and R4 are independently selected from the group consisting of H, amino, hydroxyl, aminoalkyl and alkoxy;

R₅ is selected from the group consisting of H, amino, hydroxyl, aminoalkyl, alkoxy, a-glucose, β-glucose, a-galactose and β-galactose; and

5 is selected from the group consisting of H, amino, hydroxyl, aminoalkyl, alkoxy,

CI -CIO alkyl and -CH₂OH;

or a pharmaceutically acceptable salt thereof. Table of references:

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glycosylceramides. Science 278: 1626-1629.

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178:2827-2834.

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Yamamura, and K. Chayama. 2005. Single dose of OCH improves mucosal T helper type 1/T helper type 2 cytokine balance and prevents experimental colitis in the presence of valphal4 natural killer T cells in mice. Inflamm Bowel Dis 11 :35-41.

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8. Fujii, S., K. Shimizu, M. Kronenberg, and R.M. Steinman. 2002. Prolonged IFN-gamma-producing NKT response induced with alpha- galactosylceramide-loaded DCs. Nat Immunol 3:867-874.

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11. Pal, E., T. Tabira, T. Kawano, M. Taniguchi, S. Miyake, and T. Yamamura.

2001. Costimulation-dependent modulation of experimental autoimmune encephalomyelitis by ligand stimulation of V alpha 14 NK T cells. J Immunol 166:662-668.

12. Naumov, Y.N., K.S. Bahjat, R. Gausling, R. Abraham, M.A. Exley, Y.

Koezuka, S.B. Balk, J.L. Strominger, M. Clare-Salzer, and S.B. Wilson. 2001. Activation of CD ld-restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets. Proc Natl Acad Sci USA 98: 13838-13843. 13. Kim, H.Y., H.J. Kim, H.S. Min, S. Kim, W.S. Park, S.H. Park, and D.H. Chung. 2005. NKT cells promote antibody- induced joint inflammation by suppressing transforming growth factor betal production. J Exp Med 201 :41- 47.

14. Ronet, C, S. Darche, M. Leite de Moraes, S. Miyake, T. Yamamura, J.A.

Louis, L.H. Kasper, and D. Buzoni-Gatel. 2005. NKT cells are critical for the initiation of an inflammatory bowel response against Toxoplasma gondii. J Immunol 175:899-908.

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166:3749-3756.

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1221-1231.

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1. Prepared according to the following literature procedure: C. Palomo, M.

Oiarbide, A. Landa, M. C. Gonzalez-Rego, J. M. Garcia, A. Gonzalez, J. M. Odriozola, M. Martin-Pastor, A. Linden, J. Am. Chem. Soc. 2002, 124, 8637 2. Figueroa-Perez, S., and R.R. Schmidt. 2000. Total synthesis of alpha- galactosyl cerebroside. Carbohydr Res 328:95-102.

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novel transcription factor, T-bet, directs Thl lineage commitment. Cell 100:655-669.

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4 deficient mice at a late phase of the elicitation reaction. Scand J Immunol 45:308-314.

Claims

1. A pharmaceutical composition comprising a compound of formula (I):

wherein

Z¹ is selected from C and CH;

Z² is selected from CR_A, CHR_A, N, NR_A, O and S;

Z³ is selected from CR_A and CHR_A;

Z⁴ is selected from CR_A and CHR_A;

Z⁵ is selected from CR_A, CHR_A, N, NR_A, O and S;

m is 1 or 2 to form a 5-membered or 6-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic;

R_A is either Ri or independently selected from the group consisting of H, halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl; with the proviso that at least one Ri substituent is present in the 5-membered or 6-membered carbocycle or heterocycle;

Ri is a 6-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide, phenyl and trifluoromethyl;

Y is either absent to form a direct bond between NH and Z¹; or selected from the group consisting of -C(0)(CH₂)_n-, -S0₂(CH₂)_n-, -C(0)0(CH₂)_n-, -C(0)NH(CH₂)_n- and -C(0)N((CH₂)_pCH₃)(CH₂)_n-, wherein n is an integer from 0 to 10 and wherein p is an integer from 0 to 9; - 2 -

R₂ is selected from the group consisting of -CH₂(CH₂)_qCH₃, -CH(OH)(CH₂)_qCH₃, -CH(OH)(CH₂)_qCH(CH₃)₂, -CH=CH(CH₂)_qCH₃, and

-CH(OH)(CH₂)_qCH(CH₃)CH₂CH₃, wherein q is an integer from 5 to 17;

X is -CH₂-;

R₃ and R4 are independently selected from the group consisting of H, amino, hydroxyl, amino alkyl and alkoxy;

R₅ is selected from the group consisting of H, amino, hydroxyl, aminoalkyl, alkoxy, a-glucose, β-glucose, a-galactose and β-galactose; and

5 is selected from the group consisting of H, amino, hydroxyl, aminoalkyl, alkoxy, C 1 -C 10 alkyl and -CH₂OH;

or a pharmaceutically acceptable salt thereof.

2. Pharmaceutical composition according to claim 1 , wherein Z¹ is C; Z² is selected from CR_A, N, NR_A, O and S; Z³ is CR_A; Z⁴ is CR_A; Z⁵ is selected from CR_A, N, NR_A, O and S; and m is 1 or 2 to form a 5-membered or 6-membered carbocycle or heterocycle which is aromatic.

3. Pharmaceutical composition according to claim 1 or 2, wherein Z¹ is C; Z² is CR_A; Z³ is CR_A; Z⁴ is CR_A; Z⁵ is CR_A; and m is 2 to form a 6-membered carbocycle which is aromatic.

4. Pharmaceutical composition according to claim 1 or 2, wherein

Z¹ is C; Z² is selected from N, NR_A, O and S; Z³ is CR_A;

Z⁴ is CR_A; Z⁵ is selected from N, NR_A, O and S; and m is 1 to form a 5-membered heterocycle which is aromatic.

5. Pharmaceutical composition according to any of the preceding claims, wherein R_A is either Ri or independently selected from the group consisting of H, halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl; with the - 3 -

proviso that one Ri substituent is present in the 5-membered or 6-membered carbocycle or heterocycle.

6. Pharmaceutical composition according to any of the preceding claims, wherein Ri is a 6-membered carbocycle or heterocycle which is aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide, phenyl and trifluoromethyl.

7. Pharmaceutical composition according to any one of claims 1 to 5, wherein Ri is a 6-membered carbocycle which is saturated or unsaturated or aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and

trifluoromethyl.

8. Pharmaceutical composition according to any of the preceding claims, wherein Y is absent or selected from the group consisting of -C(0)(CH₂)_n-,

-S0₂(CH₂)„-, -C(0)0(CH₂)_n- and -C(0)NH(CH₂)_n-, wherein n is an integer from 0 to 10, preferably an integer from 0 to 6, more preferably an integer from 3 to 6, and most preferably 4.

9. Pharmaceutical composition according to any of the preceding claims, wherein R₂ is -CH(OH)(CH₂)_qCH_3i wherein q is an integer from 5 to 17, preferably from 8 to 16, more preferably from 10 to 15, and most preferably 13.

10. Pharmaceutical composition according to any of the preceding claims, wherein R₃ and R4 are hydroxyl.

1 1. Pharmaceutical composition according to any of the preceding claims, wherein R^ is -CH₂OH. - 4 -

12. Pharmaceutical composition according to any of the preceding claims, wherein said composition comprises microspheres in order to achieve sustained release of said compound.

13. Pharmaceutical composition according to claim 12, wherein said

microspheres comprise poly(lactide-co-glycolide) (PLGA).

14. Pharmaceutical composition according to any of the preceding claims, wherein said composition comprises said compound as the only pharmaceutically active agent.

15. Pharmaceutical composition according to any of the preceding claims, wherein said composition is for use in the treatment and/or prevention of an immune- mediated disease characterized by a Thl polarization, wherein said disease is selected from inflammatory bowel disease including ulcerative colitis and Crohn's disease, type 1 diabetes, multiple sclerosis, arthritis including rheumatoid arthritis, allogeneic transplantation reactions including graft-versus-host disease, type IV allergies, systemic lupus erythematosus, systemic sclerosis, encephalomyelitis, chronic articular rheumatism, Sjoegren's syndrome, primary biliary cirrhosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, myasthenia gravis, sympathetic ophthalmia, Goodpasture's syndrome (e.g. glomerular nephritis), pernicious anemia and Hashimoto's disease.

16. A method for activating the production of at least one Th2 polarizing cytokine in NKT cells in vitro comprising contacting said NKT cells with a compound of formula (I) - 5 -

wherein

Z¹ is selected from C and CH;

Z² is selected from CR_A, CHR_A, N, NR_A, O and S;

Z³ is selected from CR_A and CHR_A;

Z⁴ is selected from CR_A and CHR_A;

Z⁵ is selected from CR_A, CHR_A, N, NR_A, O and S;

m is 1 or 2 to form a 5-membered or 6-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic;

R_A is either Ri or independently selected from the group consisting of H, halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide and trifluoromethyl; with the proviso that at least one Ri substituent is present in the 5-membered or 6-membered carbocycle or heterocycle;

Ri is a 6-membered carbocycle or heterocycle which is saturated or unsaturated or aromatic and which is optionally substituted with one or more substituents selected from the group consisting of halogen, amino, hydroxyl, alkyl, aminoalkyl, alkoxy, carboxylic acid, carboxyester, carboxamide, carbamate, sulfonic acid, sulfonamide, phenyl and trifluoromethyl;

Y is either absent to form a direct bond between NH and Z¹; or selected from the group consisting of -C(0)(CH₂)_n-, -S0₂(CH₂)_n-, -C(0)0(CH₂)_n-, -C(0)NH(CH₂)_n- and -C(0)N((CH₂)_pCH₃)(CH₂)_n-, wherein n is an integer from 0 to 10 and wherein p is an integer from 0 to 9; - 6 -

R₂ is selected from the group consisting of -CH₂(CH₂)_qCH₃, -CH(OH)(CH₂)_qCH₃, -CH(OH)(CH₂)_qCH(CH₃)₂, -CH=CH(CH₂)_qCH₃, and

-CH(OH)(CH₂)_qCH(CH₃)CH₂CH₃, wherein q is an integer from 5 to 17;

X is -CH₂-;

R₃ and R4 are independently selected from the group consisting of H, amino, hydroxyl, amino alkyl and alkoxy;

R₅ is selected from the group consisting of H, amino, hydroxyl, aminoalkyl, alkoxy, a-glucose, β-glucose, a-galactose and β-galactose; and

5 is selected from the group consisting of H, amino, hydroxyl, aminoalkyl, alkoxy, C 1 -C 10 alkyl and -CH₂OH;

or a pharmaceutically acceptable salt thereof.