WO2010029048A1 - 1, 2, 5-thiadiazole derivatives useful as immune potentiators - Google Patents
1, 2, 5-thiadiazole derivatives useful as immune potentiators Download PDFInfo
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- WO2010029048A1 WO2010029048A1 PCT/EP2009/061580 EP2009061580W WO2010029048A1 WO 2010029048 A1 WO2010029048 A1 WO 2010029048A1 EP 2009061580 W EP2009061580 W EP 2009061580W WO 2010029048 A1 WO2010029048 A1 WO 2010029048A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
Definitions
- the reaction is carried out according to conventional procedures for the chemistry of amides, preferably using a suitable peptide coupling reagent such as TBTU, 2-(1 H)- benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate in the presence of N-hydroxybenzotriazole in a suitable solvent.
- a suitable peptide coupling reagent such as TBTU, 2-(1 H)- benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate
- compositions containing a compound of formula (I) or a salt thereof in admixture with a pharmaceutically acceptable carrier are a further object of the present invention.
- the compounds of formula (I) as well as pharmaceutical compositions containing them can be used also in combination with vaccines, as adjuvants.
- the immune potentiator activity of the compounds of formula (I) has been tested in vitro and in vivo.
- the experiments carried out to exploit DC properties showed that the compounds of formula (I) are capable of positively influence DC functionality, therefore usable as adjuvants.
- the compounds object of the present invention are a class of small molecules, easy to synthesize at very low cost.
- the compounds of formula (I) are able to activate
- the compounds of formula (I) favour the production of molecules that create an environment unfavourable for the maintenance and propagation of allergic responses, their administration during the manifestation of an allergic reaction can be envisaged to reduce the symptoms.
- the compounds of formula (I), object of the present invention are a class of small molecules with immune potentiator effects able to favour the development of immune responses considered to be protective against viral or bacterial infections. This particular property can be exploited to improve the efficacy of currently used vaccine formulations and to produce new vaccine formulations. In order to better illustrate the present invention without limiting it, the following examples are now given.
- OVA ovalbumin
- Immature D1 cells were cultured in Iscove's modified Dulbecco's medium (Sigma Chemical Co., Saint Louis, MO) supplemented with 10% FCS (Invitrogen Life Technologies, Carlsbad, CA) and 30% R1 medium, i.e. granulocyte-macrophage colony-stimulating factor-transfected NIH-3T3 fibroblast conditioned medium. Before stimulation, loosely adherent D1 cells were detached using 2 mM EDTA and washed once. The cells were then plated at a density of 1 x 106 cells/ml in 35 mm Petri dishes. NK cell purifica tion .
- NK cells were positively selected from splenocytes. 108 cells were stained with biotinylated anti-pan-NK-cell (DX5) antibody (20 ⁇ g/ml), washed and incubated with streptavidin MicroBeads (Miltenyi Biotech, Bergisch Gladbach, Germany). Cells were then positively selected with MS columns, according to the manufacturer's recommendations. NK cells were used when more than 95% were NK1.1 positive.
- DC activation and NK-DC co-cultures D1 cells were resuspended in IMDM complete medium plated in 24 well plates (2.5x10 5 cells/well). Cells were treated with the molecule. In some cases, after 0.5 hours NK cells (5x10 5 cells/well) were added directly to the culture. 18 hours after DC activation, clarified supernatants were tested for IL2 or IFN ⁇ production. Mice immunization.
- mice were immunized at day 0 and at day 15 with 2 sc injections (50 ⁇ l each site). Total amount of antigen: 20 ⁇ g Ovalbumin. Compound X: 250 ⁇ g or 25 ⁇ g per mouse. IgGI and lgG2a serum levels.
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Abstract
Compounds of Formula (I) wherein R1, R2, R3 and R4 have the meanings reported in the description, are useful as immune potentiators. They can be used as adjuvants for vaccines.
Description
1,2,5-THIADIAZOLE DERIVATIVES USEFUL AS IMMUNE POTENTIATORS
Description
The present invention relates to adjuvants, in particular immune potentiators, and to their uses in pharmaceutical compositions, especially as adjuvants for vaccines. More particularly, the present invention relates to organic compounds useful as immune potentiators to improve the efficacy of prophylactic and/or therapeutic vaccination in the treatment of infectious diseases, inflammatory diseases, autoimmune diseases, tumours, and allergies. Adjuvants are substances able to help the development of efficient adaptive immune responses and the generation of effective immunological memory. They are believed to exert their effects preferentially on dendritic cells (DCs), critical controllers of both innate and adaptive immune responses (Banchereau et al., Annu Rev Immunol, 2000, 18, 767-811 ), by positively influencing their activation process. DCs are able to sense the presence of a pathogen through particular receptors called Pattern Recognition Receptors (PRRs), among which Toll like receptors (TLRs) are the best characterized. The signalling transmitted by these receptors is crucial for DC activation and, consequently, the generation of immune responses suitable for the type of infection (Medzhitov et al., Cell, 1997, 91 , 295-298). Adjuvants can be divided in two classes, delivery systems and immune potentiators, based on their mechanism of action. Immune potentiators activate innate immunity directly or through PRRs, whereas delivery systems may concentrate and display antigens in repetitive patterns, target vaccine antigens to antigen presenting cells and help colocalize antigens and immune potentiators. Thus both delivery systems and immune potentiators can serve to augment antigen-specific immune responses in vivo.
Among the adjuvants routinely used in vaccines the most widely used is the one based on aluminium salt precipitates called alum. Alum efficiency is suboptimal since it is not able to induce Th1 responses (it induces Th2 skewed responses) required for the development of protective immunity to most of viral and bacterial infections.
The other types of adjuvants routinely used in experimental animals and increasingly in man, are emulsion adjuvants. MF59 is an emulsion adjuvant authorized in Europe. Like alum, it induces suboptimal immune responses, being unable to favour the development of Th1 responses. Finally there are combination adjuvants, such as AS04 and AS02 that have been tested in multiple clinical trials. AS02 is included in the formulation of the new malaria vaccine that although reduces the risk of infection by only 30% compared with a control vaccine is far better than any previous result. Given the limited efficacy of the diverse authorized adjuvants the identification of new adjuvant formulations, possibly able to induce Th1 immune responses often required in resolving infectious diseases, could be useful for the development of efficacious vaccines. We have now found a class of compounds which show immune potentiator effect and are useful as adjuvant for vaccines.
Therefore, object of the present invention are compounds of formula
Ri, R2 and R3 independently represent a group selected among OR5, SR5, SO2R5, halogen, CN, COOR5, CF3 and CH2R6;
R4 and R5 independently represent hydrogen or a linear or branched CrC3 alkyl group;
R6 is a group selected among OR5, SR5, SO2R5, halogen, CN, COOR5, and CF3; and pharmaceutically acceptable salts thereof.
The compounds of formula I have immune potentiator activity and are useful in eliciting immune response against viral and bacterial infections. This activity is useful to improve the efficacy of vaccines and to develop new vaccines.
Preferred compounds of formula I are compounds wherein R1, R2 and R3 independently represent a group selected among OR5, CF3 and CH2Re; R4 and R5 independently represent hydrogen or methyl; and Re is CN.
Particularly preferred compounds of formula I are compounds wherein R1 is CF3, R2 is methoxy, R3 is CH2R6, R4 is hydrogen and Re is CN.
The compounds of formula I can be prepared according to the following synthetic scheme 1.
Scheme 1
wherein R1, R2, R3 and R4 have the already reported meanings; R is a C1-C3 alkyl group, preferably a methyl group; X and W are suitable leaving groups and P1 is a protecting group.
- A -
The cyclic sulfamide 1 is reacted with a suitable benzyl derivative 2 in the presence of a base, for example an alkali metal carbonate. Pi is a protecting group which can be easily removed in the subsequent step of the synthesis, preferably a f.butyl group. The benzyl derivative 2 is preferably a halide (X = halogen), still more preferably a bromide or chloride.
After removal of the protecting group according to conventional procedures, the resultant intermediate 4 is reacted with a compound of formula 5 under the normal Mitsunobu conditions. Particularly suitable compounds of formula 5 are those wherein W is hydroxy and R is methyl.
After basic hydrolysis of the resultant ester 6 to obtain the acid intermediate 7, the subsequent reaction with a suitable aniline derivative 8 affords the compounds of formula (I), object of the present invention. The reaction is carried out according to conventional procedures for the chemistry of amides, preferably using a suitable peptide coupling reagent such as TBTU, 2-(1 H)- benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate in the presence of N-hydroxybenzotriazole in a suitable solvent.
For their use in therapy the compounds of formula (I) can be formulated in conventional pharmaceutical compositions such as tablets, capsules and solutions. Therefore, pharmaceutical compositions containing a compound of formula (I) or a salt thereof in admixture with a pharmaceutically acceptable carrier are a further object of the present invention.
The compounds of formula (I) as well as pharmaceutical compositions containing them can be used also in combination with vaccines, as adjuvants. The immune potentiator activity of the compounds of formula (I) has been tested in vitro and in vivo.
It has been observed that DCs stimulated with different compounds known to be associated in vivo with the development of Th1 responses produce IL-2 (Granucci et al., 2003, J Immunol, 170, 5075-5081 ). Thus IL-2 production by DCs can be
exploited to identify immune potentiators able to induce TM responses.
The experiments carried out on a representative compound of formula (I) showed its ability to induce IL-2 production by DCs. It has been described that only Toll like receptor (TLR) agonists able to induce Th1 immune responses, and not TLR agonists known to induce Th2 responses render
DCs capable of activating Natural Killer (NK) cells in terms of IFN-γ production
(Zanoni et al., 2005, J Immunol, 175, 286-292). DCs were stimulated with a representative compound of formula (I) and co-cultured with NK cells. The amount of IFN-Y produced by NK cells was measured in the supernatant 24 hours later, showing that activated DCs were able to elicit IFN-γ production from NK cells.
Also in vivo experiments carried out on immunized mice showed the efficacy of a representative compound of formula (I) to increase lgG2a production.
Since lgG2a production is associated with Th1 responses, we can conclude that the compounds of formula (I), object of the present invention, are immune potentiators capable to help the development of Th1 responses.
The experiments carried out to exploit DC properties showed that the compounds of formula (I) are capable of positively influence DC functionality, therefore usable as adjuvants. The compounds object of the present invention are a class of small molecules, easy to synthesize at very low cost. The compounds of formula (I) are able to activate
DCs in vitro in terms of inflammatory cytokine production and possibly to strengthen adaptive immune responses in vivo.
The use of the compounds of formula (I) in addition to the currently used vaccines could strongly improve their efficacy. For instance, the influenza vaccine presently used in the USA does not contain adjuvants. Since the compounds of formula (I) are able to skew immune responses toward TM , the addition of these molecules to the current influenza vaccine could strongly improve its efficacy.
The improvement of the vaccine efficacy could be established at different levels:
improvement in the protection; reduction of the antigen doses; single dose vs double or triple dose administration.
The compounds of formula (I) can also be used in the formulation of vaccines against allergies. These pathologies are mediated by aberrant immune responses against usually innocuous antigens (allergens). Forcing the development of Th1 adaptive immune responses against a given allergen can inhibit these aberrant allergic responses. Since the compounds of formula (I) favour the development of Th1 responses, they can be exploited to cure allergies through appropriate vaccinations.
Moreover, as the compounds of formula (I) favour the production of molecules that create an environment unfavourable for the maintenance and propagation of allergic responses, their administration during the manifestation of an allergic reaction can be envisaged to reduce the symptoms. The compounds of formula (I), object of the present invention, are a class of small molecules with immune potentiator effects able to favour the development of immune responses considered to be protective against viral or bacterial infections. This particular property can be exploited to improve the efficacy of currently used vaccine formulations and to produce new vaccine formulations. In order to better illustrate the present invention without limiting it, the following examples are now given.
Example 1 Preparation of compound X
Compound X [(I) - Ri=CF3, R2=OCH3, R3=CH2CN, R4=H]
A solution of 5-methoxy-2-[5[(4-trifluoromethylphenyl)methyl]-(1 ,2,5-thiadiazolidin- 1 ,1-dioxide-2-yl]methyl]benzoic acid (145 mg, 0.35mmol), 4-cianomethyl-aniline (56 mg, 0.42mmol), N-hydroxybenzotriazole (57mg, 0.42mmol), TBTU (135 mg, 0.42mmol), and triethylamine (0.146 ml, 1.05 mmol,) in dichloromethane (4ml) and DMF (1 ml) was stirred at 400C for 18 hours. After this time, water (4ml) was added and the crude was extracted with dichloromethane (4ml x 2). The combined organic layers were concentrated in vacuum and the crude was purified by Varian Mega Bond Elut (Sl) eluting with dichloromethane/methanol=95/5 mobile phase to give compound X (82 mg, 0.19 mmoles) in a 42% yield as a white solid. [M+1]+ = 559.56
1H-NMR (CDCI3): 3.10 (m, 2H); 3.38 (m, 2H); 3.77 (m, 2H); 3.85 (s, 3H); 4.25 (m, 2H); 4.45 (m, 2H); 6.9 - 8.0 (m, 12H). The starting acid was prepared from 2-f.butyl-1 ,2,5-thiadiazolidine-1 ,1-dioxide (described in Chem. Ber. 1978 111 1915-1921 ) following a procedure similar to that described in J. Med. Chem. 1994 37 (19) 3023-3032 and illustrated in the following scheme 2.
Scheme 2
70% yield
Compound d, 2-hydroxymethyl-5-methoxybenzoic acid methyl ester, is described in TETRAHEDRON 49(4) 929 1993; 4-cianomethyl-aniline is commercially available. Compound f was obtained after flash chromatography and used as such in the preparation of compound X.
Example 2
IL-2 production from DCs The ability of compound X to induce IL-2 production by DCs was tested as follows. D1 cells (Winzler et al., 1997, J Exp Med, 185, 317-328) were incubated with compound X (10 μM) for 24 hours and IL-2 measured in the supernatant. As shown in figure 1 compound X was able to elicit IL-2 production by D1 cells. D1 cells were activated in presence of the compound X (10μM) and the amount of IL-2 secreted in the supernatant was measured 24 hours later by ELISA. NT, untreated D1 ; X, D1
treated with compound X; LPS, D1 treated with LPS (1 μg/ml). DCs were stimulated with compound X and co-cultured with NK cells. The amount of IFN-y produced by NK cells was measured in the supernatant 24 hours later. Compound X-activated DCs were able to elicit IFN-γ production from NK cells.
As shown in figure 2, compound X was able to make DCs capable of activating NK cells. D1 cells were activated in presence of compound X. Two hours later NK cells were added to the culture and the amount of IFN-γ produced by NK cells was measured 24 hours later by ELISA. LPS, D1 stimulated with LPS; NT, untreated D1 ; compound X, DCs treated with compound X (10μM).
Example 3
Induction of Th1 responses in vivo
BALB/c mice were immunized with ovalbumine (OVA) using the following immunizations combinations: OVA alone, OVA plus complete Freund adjuvant (CFA), OVA plus incomplete Freund adjuvant (IFA), OVA plus compound X, OVA plus compound X and IFA. CFA was used as positive control as one of the most potent adjuvant while IFA was used as delivery system. Two immunizations were performed: the first one at day 0 and the second one at day 15. Compound X was able to strongly increase lgG2a production in vivo in these immunization conditions. As shown in figure 3, compound X induced Th1 skewing in vivo. Mice were immunized with ovalbumin (OVA) at day 0 and 15 at the indicated conditions: OVA alone, OVA plus compound X (10 mg/kg), OVA plus incomplete Freund's adjuvand (IFA), OVA plus complete Freund's adjuvant (CFA), OVA plus IFA and compound X (10mg/kg). The amounts of anti-OVA antibodies produced in vivo were measured by ELISA at day 15 and 30. Material and Methods Mice and reagents.
BALB/c mice were purchased from Harlan Italy. ELISA kits for IL2 and IFN-γ were purchased from R&D Systems. TLR-grade LPS was purchased from Alexis.
D1 cell culture.
Immature D1 cells were cultured in Iscove's modified Dulbecco's medium (Sigma Chemical Co., Saint Louis, MO) supplemented with 10% FCS (Invitrogen Life Technologies, Carlsbad, CA) and 30% R1 medium, i.e. granulocyte-macrophage colony-stimulating factor-transfected NIH-3T3 fibroblast conditioned medium. Before stimulation, loosely adherent D1 cells were detached using 2 mM EDTA and washed once. The cells were then plated at a density of 1 x 106 cells/ml in 35 mm Petri dishes. NK cell purifica tion .
NK cells were positively selected from splenocytes. 108 cells were stained with biotinylated anti-pan-NK-cell (DX5) antibody (20μg/ml), washed and incubated with streptavidin MicroBeads (Miltenyi Biotech, Bergisch Gladbach, Germany). Cells were then positively selected with MS columns, according to the manufacturer's recommendations. NK cells were used when more than 95% were NK1.1 positive. DC activation and NK-DC co-cultures. D1 cells were resuspended in IMDM complete medium plated in 24 well plates (2.5x105 cells/well). Cells were treated with the molecule. In some cases, after 0.5 hours NK cells (5x105 cells/well) were added directly to the culture. 18 hours after DC activation, clarified supernatants were tested for IL2 or IFNγ production. Mice immunization.
BALB/c mice were immunized at day 0 and at day 15 with 2 sc injections (50μl each site). Total amount of antigen: 20μg Ovalbumin. Compound X: 250μg or 25μg per mouse. IgGI and lgG2a serum levels.
To assess the amount of circulating IgGI and lgG2a protein, blood samples were taken from the animals and classic indirect ELISA tests were performed. In brief: 96 well maxysorp immunoplates (NUNC) were coated overnight at 4°C with OVA (20μg/ml), then blocked, with PBS/BSA 3%, for at least two hours at room
temperature. Afterwards, serial dilution of the samples (in PBS/BSA 0.5%) were transferred into the wells and incubated overnight at 4°C. Biotinilated anti-mouse IgGI or lgG2a antibody was, then, added and incubated for 2 hours at 37°C and followed with 20 min incubation with streptavidin-HRP conjugated (RT). Developing substrate (TMB, from SIGMA) was finally added for 20 min (RT) and reaction stopped with H2SO4 2N. Plates were read using a Hewlett Packard reader. All steps were interpolated with appropriate washing using tap water.
Claims
1 ) A compound of formula
Ri, R2 and R3 independently represent a group selected among OR5, SR5, SO2R5, halogen, CN, COOR5, CF3 and CH2R6;
R4 and R5 independently represent hydrogen or a linear or branched CrC3 alkyl group; R6 is a group selected among OR5, SR5, SO2R5, halogen, CN, COOR5, and CF3; and pharmaceutically acceptable salts thereof.
2) A compound according to claim 1 wherein R1, R2 and R3 independently represent a group selected among OR5, CF3 and CH2R6; R4 and R5 independently represent hydrogen or methyl; and R6 is CN. 3) A compound according to claim 2 wherein R1 is CF3, R2 is methoxy, R3 is CH2R6,
R4 is hydrogen and R6 is CN.
4) A process for the preparation of a compound according to claim 1 which comprises the reaction of an acid intermediate of formula
5) A process according to claim 4 wherein the reaction is carried out using a suitable peptide coupling reagent.
6) A process according to claim 5 wherein the reaction is carried out using 2-(1 H)- benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate in the presence of
N-hydroxybenzotriazole in a suitable solvent.
7) A pharmaceutical composition containing a compound of formula (I) or a salt thereof in admixture with a pharmaceutically acceptable carrier.
8) The use of a compound of formula (I) in combination with vaccines, as adjuvant. 9) The use of a compound of formula (I) as immune potentiator.
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| EP08163973 | 2008-09-09 | ||
| EP08163973.4 | 2008-09-09 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105121404A (en) * | 2013-03-15 | 2015-12-02 | 豪夫迈·罗氏有限公司 | Arylsulfonamide and sulfamic acid derivatives as RORc modulators |
| CN106661009A (en) * | 2014-04-28 | 2017-05-10 | 江苏康缘药业股份有限公司 | Anti-enterovirus 71 thiadiazolidine derivative |
| CN113851716A (en) * | 2021-09-24 | 2021-12-28 | 珠海市赛纬电子材料股份有限公司 | Non-aqueous electrolyte and lithium ion battery thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1566380A1 (en) * | 2002-11-22 | 2005-08-24 | Mitsubishi Pharma Corporation | Isoquinoline compounds and medicinal use thereof |
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2009
- 2009-09-07 WO PCT/EP2009/061580 patent/WO2010029048A1/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1566380A1 (en) * | 2002-11-22 | 2005-08-24 | Mitsubishi Pharma Corporation | Isoquinoline compounds and medicinal use thereof |
Non-Patent Citations (1)
| Title |
|---|
| DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2007, FUKUSHIMA, HIROSHI ET AL: "Preparation of imidazolidinone derivatives as 11.beta.-HSD1 inhibitors", XP002559376, retrieved from STN Database accession no. 2007:1110441 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105121404A (en) * | 2013-03-15 | 2015-12-02 | 豪夫迈·罗氏有限公司 | Arylsulfonamide and sulfamic acid derivatives as RORc modulators |
| CN106661009A (en) * | 2014-04-28 | 2017-05-10 | 江苏康缘药业股份有限公司 | Anti-enterovirus 71 thiadiazolidine derivative |
| JP2017513914A (en) * | 2014-04-28 | 2017-06-01 | ジアンス カニョン ファーマシューティカル カンパニー リミテッド | Anti-enterovirus 71 thiadiazolidine derivative |
| US9988361B2 (en) * | 2014-04-28 | 2018-06-05 | Jiangsu Kanion Pharmaceutical Co., Ltd. | Anti-enterovirus 71 thiadiazolidine derivative |
| CN113851716A (en) * | 2021-09-24 | 2021-12-28 | 珠海市赛纬电子材料股份有限公司 | Non-aqueous electrolyte and lithium ion battery thereof |
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