BR112019022686B1 - Use of functionalized saccharide compounds for the treatment of an inflammatory disease. - Google Patents

Abstract

The present invention relates to functionalized saccharides as anti-inflammatory agents acting on inflammatory mechanisms in mammals, in particular anti-inflammatory agents acting on the expression of at least one cytokine by suppressing or inhibiting the expression of at least one cytokine, wherein said cytokine is selected from the group consisting of pro-inflammatory cytokines, anti-inflammatory cytokines and chemokines.

Description

FIELD OF THE INVENTION

[001] The present invention relates to functionalized saccharide compounds as anti-inflammatory agents that act on inflammatory mechanisms in mammals.

BACKGROUND OF THE INVENTION

[002] Inflammation is a complex biological response of the immune system to protect the body against harmful substances, injury, and tissue destruction. The inflammatory response can be triggered by physical, chemical, and infectious agents such as bacteria, viruses, and other pathogenic microorganisms. The goal of inflammation is to eliminate the initial cause of damage, clear damaged cells and tissue, and initiate tissue repair.

[003] Inflammation can be acute or chronic. Acute inflammation refers to the body's immune system's initial response to harmful stimuli. Chronic inflammation is a form of prolonged inflammation that results in the recruitment of macrophages and T-lymphocytes. Macrophages are large phagocytic white blood cells and, along with T-lymphocytes, known for producing cytokines and enzymes, they cause more lasting damage to cells. While it is necessary for the body to have a properly functioning immune system, it is so important to keep these inflammatory mechanisms under control that chronic inflammation can give rise to a variety of pathologies and even cancer.

[004] Inflammation is not, however, a synonym for infection. Infection refers merely to the interaction of a microorganism's invasion with the body's inflammatory response to that invasion. Inflammation, on the other hand, describes the inflammatory mechanism that occurs independently of the causative agent. Nevertheless, in the health field, inflammation, or a specific organ inflammation denoted with the suffix -itis, is often referred to as an infection because microbial invasion is commonly observed in correlation with inflammation. However, it is important to distinguish between the two, since many pathological conditions involve inflammatory processes that are triggered by microbial or viral invasion, and vice versa; not all microbial or viral infections will result in inflammation.

[005] Confusion between infection and inflammation is especially prevalent in gastritis, or the presence of inflammation in the stomach. Many clinicians consider chronic gastritis equivalent to Helicobacter pylori (H. pylori) infection. However, numerous other causes for the condition are known. Furthermore, gastric pathology can also be persistent even after successful eradication of H. pylori. In the American Journal of Gastroenterology, Genta et al. very recently reported that in up to 20% of patients who received a gastric biopsy, a diagnosis of Helicobacter-negative gastritis was made. Given its common occurrence, Borkman et al. published a proposal in the New England Journal of Medicine to consider Helicobacter-negative gastritis as a separate clinical entity. Known causes of gastric inflammation without bacterial infection, particularly H. pylori infection, include:

[006](i) viral infection (Cytomegalovirus, Herpes simplex)

[007](ii) chemical or reactive inflammation caused by reflux of bile and pancreatic juice into the stomach or by exogenous substances such as NSAIDs (non-steroidal anti-inflammatory drugs), ASA (acetylsalicylic acid), alcohol or chemotherapeutic agents

[008](iii) autoimmune inflammation characterized by the presence of antibodies against parietal cells

[009](iv) post-radiation and eosinophilic inflammation

[010](v) inflammation in the course of collagenosis

[011](vi) inflammation in the course of Crohn's disease

[012](vii) inflammation in the course of sarcoidosis

[013](viii) stress-induced inflammation

[014](ix) Non-gastric H. pylori species Helicobacter (NHPH) in humans, of which H. suis is the most predominant. It is associated with chronic gastritis, gastric ulcer and other gastric pathological changes in both animals and humans (G. Zhang et al., Vet Res (2016) 47:101, p. 1 l. 1-3).

[015](x) idiopathic: all cases of gastritis where no causal factor can be identified.

[016] In addition to the problem of Helicobacter-negative gastritis, the recurrence of gastric ulcers, even after successful eradication of Helicobacter species, remains a challenge in human medicine as well as in livestock. In the case of swine, for example, although treated pigs may recover, ulcer recurrence is a common problem. Ulcer recurrence will result in animal discomfort and loss of appetite with weight loss and economic implications as a result. But also in human medicine, the recurrence of gastric ulcers represents a significant impact on health. Currently, those suffering from chronic gastritis and/or gastric ulcers are dependent on the long-term use of proton pump inhibitors (PPIs) to block acid formation in the stomach. This long-term use is known to have many side effects and confers an increased risk of chronic kidney disease, renal failure, and an increased risk of cardiovascular events.

[017]Alternatively, instead of blocking acid production in the stomach, gastric ulcers and gastritis are treated by directly targeting Helicobacter pylori bacteria.

[018]Furthermore, the use of NSAIDs is contraindicated for alleviating gastric inflammation, as these drugs are known to be a risk factor for gastric pathology.

[019]In view of the above, there is a need for anti-inflammatory agents that can overcome the disadvantages of current anti-inflammatory treatments such as the many side effects, i.e., an increased risk of chronic kidney disease, renal failure, an increased risk of cardiovascular events and the like, limited scope of application, failure to adhere to treatment and that can overcome the problem of ulcer recurrence, in particular gastric ulcers.

SUMMARY OF THE INVENTION

[020]The applicant has now surprisingly found that it is possible to provide anti-inflammatory agents that meet the needs mentioned above.

[021] It is an object of the present invention to provide an alternative anti-inflammatory agent instead of NSAIDs to suppress inflammation in the stomach of mammals suffering from gastritis, gastric ulcers or those at risk of developing them.

[022] It is an object of the present invention to provide an alternative to the long-term use of proton pump inhibitors (PPIs) in individuals suffering from gastric ulcer and chronic gastritis.

[023] It is an object of the present invention to provide an anti-inflammatory agent that can act on the inflammatory mechanisms underlying gastric ulcer and gastritis in mammals.

[024]The present invention relates to compounds for use as an anti-inflammatory agent acting on inflammatory mechanisms in mammals [anti-inflammatory compound (C), hereinafter], wherein said anti-inflammatory compound (C) is at least one of the compounds according to general formulas (I), (II), (III) or (IV), or the pharmaceutically acceptable salt, solvate, isomer or pharmaceutically acceptable mixture thereof: in which

[025]- each of R1 is independently selected from -OH or -N(R1a)(R1b) wherein each of R1a and R1b, independently of each other and in each occurrence, are selected from the group consisting of H, an amino protecting group, aryl, heteroaryl, aliphatic and a heteroaliphatic group,

[026]- each of R2, R4, R5, R11 and R12, independently of each other and in each occurrence, are selected from the group consisting of H, -ORz, -N(Rz)2, aryl, heteroaryl, aliphatic and a heteroaliphatic group, wherein Rz is independently selected from the group consisting of H, a hydroxyl protecting group, an amino protecting group, aryl, heteroaryl, aliphatic, heteroaliphatic and a carbohydrate moiety,

[027] - each of R3 is independently selected from the group consisting of H, -OH, -NH2, -SH, ORw, -NH(Rw), -N(Rw)2, -SRw, -O(C=O)Rw, -NH(C=O)Rw, -O(C=NH)Rw, -NH(C=NH)Rw, -S(C=NH)Rw, -NH(C=S)Rw, -S(C=O)Rw, -O(C=S)Rw, -S(=S)Rw, aryl, heteroaryl, aliphatic and a heteroaliphatic group, wherein Rw is selected from the group consisting of a carbohydrate moiety, aryl, heteroaryl, aliphatic, and heteroaliphatic group, ,,

[028]- each of R6, R14 and R15, independently of each other and in each occurrence, are selected from the group consisting of H, hydroxyl protecting group, aryl, heteroaryl, aliphatic, heteroaliphatic group and carbohydrate moiety,

[029]- each of R7 is independently selected from the group consisting of H, C(=O)N(Rz’)2, -C(=O)ORz’, a hydroxyl protecting group, aryl, heteroaryl, aliphatic, heteroaliphatic group and carbohydrate moiety, wherein Rz’ is independently selected from the group consisting of H, a hydroxyl protecting group, an amino protecting group, aryl, heteroaryl, aliphatic, and a heteroaliphatic group,

[030]- each of R10 is independently selected from the group consisting of -C(=O)N(Rl)(Rp),-C(=O)ORk, and -CH2ORk wherein Rl and Rp are, independently of each other and in each occurrence, selected from the group consisting of H, an amino protecting group, aryl, heteroaryl, aliphatic, heteroaliphatic group and a carbohydrate moiety, wherein Rk is independently selected from the group consisting of H, a hydroxyl protecting group, aryl, heteroaryl, aliphatic, heteroaliphatic group and a carbohydrate moiety,

[031]- each of R13 is independently selected from the group consisting of -OH and -N(Ro’’)(Rm’’), wherein Ro’’ and Rm’’, independently of each other and in each occurrence, are selected from the group consisting of H, -C(=O)Rh, an amino protecting group, aryl, heteroaryl, aliphatic and heteroaliphatic group, wherein Rh is selected from the group consisting of a carbohydrate moiety, aryl, heteroaryl, aliphatic and heteroaliphatic group,

[032]- each of (R°) and (Rm), independently of each other and in each occurrence, are selected from the group consisting of H, -C(=O)Rw', an amino, aryl, heteroaryl, aliphatic and heteroaliphatic protecting group, wherein Rw' is selected from the group consisting of a carbohydrate, aryl, heteroaryl, aliphatic and heteroaliphatic moiety;

[033]- each of (Rs) and (Rt), independently of each other and in each occurrence, are selected from the group consisting of H, -C(=O)Rw", an amino, aryl, heteroaryl, aliphatic and heteroaliphatic protecting group, wherein Rw" is selected from the group consisting of a carbohydrate, aryl, heteroaryl, aliphatic and heteroaliphatic moiety;

[034]- each of R6a and R6a', independently of each other and in each occurrence, are selected from H or -OH, preferably R6a is H and R6a' is -OH;

[035] - one of Rc is independently selected from the group consisting of H, halogen, heteroaryl, - ORq, -N(Rq)2, -SRq, NO2, -NC, -CN, -N3, -N(Rq)=NRq, -CHO, -C(=O)Rq, -C(=S)Rq, C(=NRq)Rq, -C(=O)ORq, -C(=NRq)ORq, -C(=NRq)N(Rq)2, -C(=O)N(Rq)2, -C(=S)ORq, -C(=O)SRq, -C(=S)SRq, -P(=O)(ORq)2, -S(=O)(ORq), -S(=0)2(ORq), -P(=O)N(Rq)2, -P(=O)2N(Rq)2, -C(=O)NR’S(=O)2Rq, -S(=O)N(Rq)2 and - S(=O)2N(Rq)2, wherein each Rq is independently selected from the group consisting of H, aliphatic, heteroaliphatic, aryl, heteroaryl, and a hydroxyl protecting group,

[036]- each of Ri is independently selected from the group consisting of H, a hydroxyl protecting group, aliphatic, heteroaliphatic, aryl, and heteroaryl,

[037]- each lipid is independently selected from H or an aliphatic C1-30 moiety, wherein 0 to 10 methylene units are optionally substituted with -O-, -NRx-, -S-, -C(=O)-, -C(=NRx)-, -S(=O)-, -S(=O)2-, -N=N-, -C=N-, -C(Ry)=C(Ry’)-, -N-O-, an arylene, or a heteroarylene moiety, wherein each of Rx is independently selected from the group consisting of H, aliphatic, heteroaliphatic, aryl, heteroaryl, or an amino protecting group, and wherein each of Ry and Ry’, independently of each other and in each occurrence, are selected from the group consisting of H, aliphatic, heteroaliphatic, aryl and heteroaryl group.

[038]The present invention also relates to a pharmaceutical composition for use as an anti-inflammatory agent acting on inflammatory mechanisms in mammals comprising a carrier and, as the active ingredient, an effective amount of the anti-inflammatory compound (C) as defined in any of the embodiments presented herein.

[039]The present invention also relates to a process for preparing said pharmaceutical composition.

[040]The present invention also relates to the anti-inflammatory compound (C), as defined in any of the embodiments presented herein, for use as a medicament.

[041]The present invention also relates to a pharmaceutical composition comprising a vehicle and, as an active ingredient, an effective amount of the anti-inflammatory compound (C) as defined in any of the embodiments presented herein, for use as a medicament.

[042]The present invention also relates to the anti-inflammatory compound (C), as defined in any of the embodiments presented herein, for use in the treatment of inflammatory diseases or inflammatory-related diseases.

[043]The present invention also relates to the anti-inflammatory compound (C), as defined in any of the embodiments presented herein, for use in the treatment of a disease mediated by at least one cytokine.

[044]The present invention also relates to an in vivo method of suppressing or inhibiting inflammatory responses by using the anti-inflammatory compound (C), as defined in any of the embodiments presented herein.

[045]The present invention also relates to a method of suppressing or inhibiting the expression of at least one cytokine in a mammal.

[046]The present invention also relates to a method of treating inflammatory diseases related to cytokine expression levels in mammals.

ANTI-INFLAMMATORY COMPOUND (C) AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

[047]It is further understood that all definitions and preferences as described for the anti-inflammatory compound (C) above apply equally to this embodiment and all additional embodiments, as described below.

[048]As used above and below, the following definitions apply unless otherwise noted.

[049]The term "aliphatic" includes both straight, non-aromatic, saturated and unsaturated (i.e., unbranched) hydrocarbon chains, branched, cyclic and acyclic hydrocarbon chains having 1 to 30 carbon atoms, which are optionally substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid or alkoxy. According to certain embodiments, as used herein, aliphatic CF-G defines an aliphatic CF-G group having carbon atoms F to G, for example, aliphatic C1-12 defines an aliphatic group containing 12 carbon atoms, aliphatic C1-10 defines an aliphatic group containing 1 to 10 carbon atoms.

[050]As will be appreciated by one skilled in the art, "aliphatic" is intended here to include, but is not limited to, alkyl, alkenyl, and alkynyl moieties. As used herein, the terms "alkyl," "alkenyl," and "alkynyl" have the broader meaning generally understood in the art, and may include a moiety that is linear, branched, cyclic (cycloalkyl, cycloalkenyl, cycloalkynyl), or a combination thereof.

[051]The term "alkyl", alone or in combination, means an alkane-derived radical, which may be a straight-chain alkyl, branched-chain alkyl, or cyclic alkyl, containing from 1 to 30 carbon atoms, unless otherwise specified. The straight-chain or branched alkyl group is attached at any point available to produce a stable compound. Alkyl also includes a straight-chain or branched alkyl group that contains or is interrupted by a cycloalkyl moiety. According to certain embodiments, CA-B alkyl defines a straight or branched alkyl radical having A to B carbon atoms, for example, C1-15 alkyl defines a straight or branched alkyl radical having 1 to 15 carbon atoms, C1-12 alkyl defines a straight or branched alkyl radical having 1 to 12 carbon atoms, C1-6 alkyl defines a straight or branched alkyl radical having 1 to 6 carbon atoms such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl. According to certain embodiments, a CC-D cyclic alkyl defines a cyclic alkyl radical having C to D carbon atoms, for example, C3-6 cyclic alkyl.

[052]The term "alkenyl", alone or in combination, means a straight or branched hydrocarbon containing 1–30 carbon atoms, unless otherwise specified, and at least one carbon-to-carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl, and the like. Alkenyl also includes a straight or branched alkenyl group that contains or is interrupted by a cycloalkyl moiety. Carbon-to-carbon double bonds may be contained within a cycloalkyl moiety or within a straight or branched moiety. According to certain embodiments, C1-I alkenyl defines a straight or branched alkenyl radical having from H to I carbon atoms, for example, C1-6 alkenyl defines a straight or branched alkenyl radical having from 1 to 6 carbon atoms.

[053]The term "alkynyl" alone or in combination means a straight, branched or cyclic hydrocarbon containing 1 to 30 carbon atoms containing at least one carbon-to-carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl and the like.

[054]As used herein, the term "heteroaliphatic" refers to an aliphatic moiety, as defined herein, which includes both straight-chain, non-aromatic, saturated and unsaturated (i.e., unbranched), branched, acyclic, cyclic (i.e., heterocyclic) or polycyclic hydrocarbons having 1 to 30 carbon atoms, unless otherwise specified, which are optionally substituted with one or more groups, including but not limited to alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy and which contain one or more heteroatoms such as sulfur, nitrogen, phosphorus, or silicon atoms, for example, in place of carbon atoms. In certain embodiments, the heteroaliphatic moieties are replaced by independent substitution of one or more of the hydrogen atoms therein with one or more substituents. As will be appreciated by one skilled in the art, "heteroaliphatic" is intended here to include heteroalkyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. Thus, as used herein, the term "heteroalkyl" includes straight-chain, branched, and cyclic alkyl groups containing one or more heteroatoms such as oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, for example, in place of carbon atoms. An analogous convention applies to other generic terms such as "heteroalkenyl," "heteroalkynyl," and the like. Furthermore, as used herein, the terms "heteroalkyl," "heteroalkenyl," "heteroalkynyl," and the like encompass both substituted and unsubstituted groups.

[055]As used herein, the term "aryl", alone or in combination, means any carbon-based aromatic group including, but not limited to, phenyl, tolyl, xylyl, cumenyl, naphthyl, anthracenyl, etc., optionally carbocyclic fused with a cycloalkyl or heterocyclyl of preferably 5-7, more preferably 5-6, ring elements and/or optionally substituted with 1 to 5 groups or substituent. An aryl may be optionally substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy whereby the substituent is attached at one point to the aryl or whereby the substituent is attached at two points to the aryl to form a bicyclic system, for example, benzodioxol, benzodioxane, benzimidazole.

[056]The term "heteroaryl", alone or in combination, means a monocyclic aromatic ring structure containing 5 or 6 atoms in the ring, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, heteroatoms independently selected from the O, S, and N groups, and optionally substituted with 1 to 5 groups or substituents including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the attachment point of the heteroaryl ring structure such that a stable aromatic ring is retained. More specifically, the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, benzothiophenyl, dibenzofuran, and benzodiazepin-2-one-5-yl, and the like.

[057]According to a particular embodiment of the present invention, the lipid is an unsaturated C4-20 hydrocarbon chain, in which 1 to 10 methylene units are substituted by -C(Ry)=C(Ry')- wherein each of Ry and Ry', independently of each other and in each occurrence, are selected from the group consisting of H, aliphatic, heteroaliphatic, aryl, or heteroaryl; and wherein said hydrocarbon chain is optionally substituted with a C1-6 alkyl, a C3-6 cyclic alkyl, a C1-6 alkenyl or hydroxyl group, preferably the lipid is a C4-20 hydrocarbon chain, wherein 1 to 5 methylene units are substituted by -C(Ry)=C(Ry')- wherein each of Ry and Ry', independently of each other and in each occurrence, are selected from the group consisting of H, C1-6 alkyl and C1-6 alkenyl and wherein said hydrocarbon chain is optionally substituted with a C1-6 alkyl, a C3-6 cyclic alkyl, a C1-6 alkenyl or hydroxyl group, more preferably the lipid is chosen from the following formulas:

[058]Even more preferred, the lipid is chosen from the following formulas:

[059]According to a particular embodiment of the present invention, the lipid is a saturated hydrocarbon chain according to the general formula Z:

[060]in which

[061]- each of R9’ and R9’’ are, independently of each other and in each occurrence, selected from the group consisting of H, -OH and C1-6 alkyl,

[062]- each of Rx’ and Rx’’, independently of each other and in each occurrence, are selected from H, a C1-15 alkyl and an aryl wherein said aryl is optionally further replaced by a C1-15 alkyl, and wherein n=4 to 30, and m= 0 or 1.

[063]Preferably, the saturated hydrocarbon chain is chosen from the following formulas:

[064]According to a particular embodiment of the present invention, R1 is independently selected from -OH or -N(R1a)(R1b), wherein each of R1a and R1b, independently of each other and in each instance, are selected from the group consisting of H, C1-20 aliphatic and C1-20 heteroaliphatic group, preferably R1 is OH, NH2, or NH(R1b), wherein R1b is a C1-10 cycloalkyl or C1-10 cycloalkenyl group that is optionally substituted with a halide, hydroxyl or alkoxy, more preferably R1 is -NH(R1b), wherein R1b is of the following formula.

[065]According to a particular embodiment of the present invention, R3 is independently selected from the group consisting of H, -OH and -ORw, wherein Rw is selected from the group consisting of a carbohydrate moiety, wherein said carbohydrate moiety is independently selected from the group consisting of D- and L-monosaccharides, such notably D-erythrose, L-erythrose, D-threose, L-threose, L-erythrulose, D-arabinose, L-arabinose, D-deoxyribose, L-deoxyribose, D-lixose, L-lixose, D-ribose, L-ribose, D-ribulose, L-ribulose, D-xylose, L-xylose, D-xylulose, L-xylulose, D-allose, L-allose, D-altrose, L-altrose, D-galactose, L-galactose, D-glucose, L-glucose, D-gulose, L-gulose, D-idose, L-idose, D-mannose, L-mannose, D-talose, L-talose, D-fructose, L-fructose, D-psicose, L-psicose, D-sorbose, L-sorbose, D-tagatose, L-tagatose, D-fucose, L-fucose, Dramnose and L-rhamnose, disaccharides, such as notably sucrose, lactose, trehalose, and maltose, trisaccharides such as notably acarbose, raffinose, and melezitose, more preferably, R3 is -ORw, wherein Rw is a D-monosaccharide such as notably D-erythrose, D-threose, D-erytrulose, D-arabinose, D-deoxyribose, D-lixose, D-ribose, D-ribulose, D-xylose, D-xylulose, D-allose, D-altrose, D-galactose, D-glucose, D-gulose, D-idose, D-mannose, D-talose, D-fructose, D-psicose, D-sorbose, D-tagatose, D-fucose, and D-rhamnose, even more preferably, R3 is -ORw, wherein Rw is independently selected from the group consisting of D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-iodose, D-galose or D-talose, more preferably, R3 is -ORw, wherein Rw is D-glucose.

[066]According to a particular embodiment of the present invention, each of R2, R4, R5, R11 and R12, independently of each other and in each instance, are selected from the group consisting of H, ORz, a C1-12 aliphatic, a C1-12 heteroaliphatic and a carbohydrate moiety, wherein Rz is selected from the group consisting of H, hydroxyl protecting group, C1-12 aliphatic, C1-12 heteroaliphatic, aryl and heteroaryl, and wherein said carbohydrate moiety is selected from the group consisting of D-monosaccharides such as notably D-erythrose, D-threose, D-erythrulose, D-arabinose, D-deoxyribose, D-lyxose, D-ribose, D-ribulose, D-xylose, D-xylulose, D-allose, D-altrose, D-galactose, D-glucose, D-gulose, D-idose, D-mannose, D-talose, D-fructose, D-psicose, D-sorbose, D-tagatose, D-fucose, and D-rhamnose, preferably each R2, R4, R5, R11, and R12, independently of each other and in each occurrence, are selected from the group consisting of H, ORz, a hydroxyl protecting group, C1-6 alkyl, and a carbohydrate moiety, wherein Rz is selected from the group consisting of H, a hydroxyl protecting group, and C1-6 alkyl, and wherein said carbohydrate moiety is selected from the group consisting of D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-iodose, D-galose, and D-talose, more preferably R2, R4, R11, and R12, independently of each other and in each occurrence. are selected from H or ORz, wherein Rz is selected from H or C1-6 alkyl, more preferably R5 is a C1-6 alkyl, even more preferably R2 is H, R4, R11 and R12 are -OH and R5 is -CH3;

[067]According to a particular embodiment of the present invention, each of R6, R14 and R15, independently of each other and in each instance, are selected from the group consisting of H, hydroxyl protecting group, C1-12 aliphatic and C1-12 heteroaliphatic group, preferably R6, R14 and R15, independently of each other and in each instance, are selected from the group consisting of H or a hydroxyl protecting group, more preferably R6, R14 and R15, independently of each other and in each instance, are H.

[068]According to a particular embodiment of the present invention, R7 is group -C(=O)N(Rz’)2, wherein each of Rz’ is independently selected from the group consisting of H, aryl, heteroaryl and C1-12 alkyl, preferably each of Rz’ is independently selected from H or C1-12 alkyl, more preferably each of Rz’ is independently selected from the group consisting of H, methyl, ethyl and propyl, more preferably each of Rz’ is independently H.

[069] According to a particular embodiment of the present invention, each of R10 is independently selected from -C(=O)N(Rl)(Rp) or -C(=O)ORk, wherein Rl and Rp are, independently of each other and in each instance, selected from the group consisting of H, an amino protecting group, aryl, heteroaryl, C1-12 aliphatic and C1-12 heteroaliphatic group, and wherein Rk is independently selected from the group consisting of H, a hydroxyl protecting group, aryl, heteroaryl, C1-30 aliphatic and C1-30 heteroaliphatic group, preferably each of R10 is independently selected from -C(=O)N(Rl)(Rp) or -C(=O)ORk, wherein Rl and Rp are independently of each other and in each instance, selected from the group consisting of H, an amino protecting group, aryl, heteroaryl and C1-6 alkyl, wherein each of Rk is independently selected from the group consisting of H, a hydroxyl protecting group and C1-6 alkyl, more preferably, each of R10 is independently selected from -C(=O)N(Rl)(Rp) or -C(=O)ORk, wherein R1 and Rp, independently of each other and in each occurrence, are selected from the group consisting of H, an amino protecting group, methyl, ethyl, and propyl, wherein each of Rk is independently selected from the group consisting of H, a hydroxyl protecting group, methyl, ethyl, and propyl, more preferably, R10 is -C(=O)NH2 or -C(=O)OH.

[070] According to a particular embodiment of the present invention, each of R13 is independently selected from the group consisting of -OH and -N(Ro’’)(Rm’’), wherein Ro’’ and Rm’’, independently of each other and in each instance, are selected from the group consisting of H,-C(=O)Rh, an amino protecting group, C1-12 aliphatic and C1-12 heteroaliphatic group, wherein Rh is independently selected from a C1-12 aliphatic or C1-12 heteroaliphatic group, preferably Ro’’ and Rm’, independently of each other and in each instance, are selected from the group consisting of H,-C(=O)Rh and C1-12 alkyl, wherein Rh is C1-12 alkyl, more preferably Ro’’ and Rm’’, independently of each other and in each instance, are selected from the group consisting of H,-C(=O)Rh and C1-6 alkyl, wherein Rh is C1-6 alkyl, more preferably Ro’’ is H and Rm’ is -C(=O)CH3.

[071] According to a particular embodiment of the present invention, each of (Ro) and (Rm), independently of each other and in each instance, is selected from the group consisting of H, -C(=O)Rw’, an amino protecting group, C1-12 aliphatic and C1-12 heteroaliphatic group, wherein Rw’ is independently selected from the group consisting of a C1-12 aliphatic and C1-12 heteroaliphatic group, preferably (Ro) and (Rm), independently of each other and in each instance, are selected from the group consisting of H, -C(=O)Rw’, an amino protecting group and C1-12 alkyl, wherein Rw’ is a C1-12 alkyl, more preferably (Ro) and (Rm), independently of each other and in each instance, are selected from the group consisting of H, -C(=O)Rw’, and C1-6 alkyl, wherein Rw’ is a C1-6 alkyl, more preferably (Ro) is H and (Rm) is -C(=O)CH3.

[072] According to a particular embodiment of the present invention, each of (Rs) and (Rt), independently of each other and in each instance, is selected from the group consisting of H, -C(=O)Rw’’, an amino protecting group, C1-12 aliphatic and C1-12 heteroaliphatic group, wherein Rw’’ is independently selected from a C1-12 aliphatic or C1-12 heteroaliphatic group, preferably (Rs) and (Rt), independently of each other and in each instance, are selected from the group consisting of H, -C(=O)Rw’’, an amino protecting group and C1-12 alkyl, wherein Rw’’ is C1-12 alkyl, more preferably (Rs) and (Rt), independently of each other and in each instance, are selected from the group consisting of H, -C(=O)Rw’’, and C1-6 alkyl, wherein Rw’’ is C1-6 alkyl, more preferably (Rs) is H and (Rt) is -C(=O)CH3.

[073] According to a particular embodiment of the present invention, each Rc is independently selected from the group consisting of H, -C(=O)ORq, -C(=O)SRq, -C(=S)ORq, -C(=O)SRq, -C(=S)SRq, wherein each Rq is independently selected from the group consisting of H, C1-12 alkyl, aryl, heteroaryl and a hydroxyl protecting group, preferably each Rc is independently selected from the group consisting of H, -C(=O)ORq, -C(=O)SRq, and -C(=O)SRq, wherein each Rq is independently selected from the group consisting of H, C1-6 alkyl and a hydroxyl protecting group, more preferably each Rc is independently selected from H or -C(=O)ORq, wherein each Rq is independently selected from the group consisting of H, methyl, ethyl and propyl, more preferably Rc is -C(=O)OH.

[074]According to a particular embodiment of the present invention, each of Ri is independently selected from the group consisting of H, a hydroxyl protecting group, C1-12 aliphatic, C1-12 heteroaliphatic, aryl and heteroaryl, preferably Ri is independently selected from the group consisting of H, a hydroxyl protecting group, C1-12 alkyl, aryl and heteroaryl, more preferably Ri is independently selected from the group consisting of H, a hydroxyl protecting group and C1-6 alkyl, even more preferably Ri is independently selected from the group consisting of H, a hydroxyl protecting group, methyl, ethyl, and propyl, most preferably Ri is H.

[075]The anti-inflammatory compounds (C) of the present invention, as detailed above, have several chiral centers and exist as stereochemically isomeric forms. The term "stereochemically isomeric forms" as used herein defines all possible compounds consisting of the same atoms linked by the same sequence of bonds, but having different three-dimensional structures that are not interchangeable, which the anti-inflammatory compound (C), as specified herein, may possess.

[076] Unless mentioned or indicated otherwise, the clinical designation of the anti-inflammatory compounds (C), as detailed above, encompasses the mixture of all possible stereochemically isomeric forms that said anti-inflammatory compounds (C) may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said anti-inflammatory compounds (C). All stereochemically isomeric forms of the compounds of the present invention, whether in pure form or mixed with each other, are intended to be incorporated within the scope of the present invention.

[077]Preferred anti-inflammatory compounds (C) are compounds according to formula (Ia) [class I anti-inflammatory compounds (C) below] or the pharmaceutically acceptable salt, solvate, isomer or pharmaceutically acceptable mixture thereof, in which

[078] - each of R1 is independently selected from OH, NH2, or NH(R1b), wherein R1b is a C1-10 cycloalkyl or C1-10 cycloalkenyl group that is optionally substituted with a halide, hydroxyl, or alkoxy group, most preferably R1 is -NH(R1b), wherein R1b is of the following formula:

[079]- each of R3 is independently selected from the group consisting of H, -OH and -ORw, where Rw is D-glucose;

[080]- each of R2 and R4, independently of each other and in each occurrence, are selected from H or -OH;

[081]- each of R5 is independently selected from the group consisting of H, -OH and -CH3;

[082]-the lipid is chosen from the following formula Li or formula L2:

[083]More preferably, the anti-inflammatory compound (C) is a mixture of class 1 anti-inflammatory compounds (C), as detailed above.

[084]Non-limiting examples of commercially available anti-inflammatory compounds (C) suitable for the invention include Flavomycin®.

[085]The commercially available Flavomycin® is also commonly known by its synonymous name Bambermycin.

[086]Bambermycin or Flavomycin® is a known complex of compounds, mainly composed of moenomycins A and C, in particular, the main compound is moenomycin A, according to formula (Ib), as detailed below, and the minor compounds are labeled as A12, C1, C3 and C4. Moenomycin A and the minor compounds, labeled as A12, C1, C3 and C4, are compounds according to formula (Ia), as detailed above.

[087]In moenomycin A, according to formula (Ib), as detailed below, and the smaller compounds A12, C1, C3 and C4, the lipid is according to formula L2, R2 is H, R1 is --NH(R1b), where R1b is of the following formula:

[088]In moenomycin A, R3 is ORw, where Rw is D-glucose, R4 is OH and R5 is CH3. In moenomycin A12, R3 is ORw, where Rw is D-glucose, R4 is H and R5 is OH.

[089]In moenomycin C1, R3 is H, R4 is H and R5 is OH. In moenomycin C3, R3 is H, R4 is OH and R5 is CH3. In moenomycin C4, R3 is OH, R4 is OH and R5 is CH3.

[090]Bambermycin or Flavomycin® can be obtained from Streptomyces bambergiensis and Streptomyces ghanaensis, Streptomyces ederensis, Streptomyces geysiriensis and related strains or biosynthesized, thus forming a complex of compounds, as discussed above. Since the complex is not extensively purified, Flavomycin® also contains building blocks and various biosynthesis intermediates.

[091]Bambermycin is also known as flavofosfolipol. Bambermycin, flavofosfolipol and Flavomicina® are used interchangeably herein.

[092]A preferred class I anti-inflammatory compound (C) is notably moenomycin A according to formula (lb), or the pharmaceutically acceptable salt, solvate, isomer or pharmaceutically acceptable mixture thereof:

[093]According to an alternative embodiment of the present invention, anti-inflammatory compounds (C) are compounds according to formula (lla) [class II anti-inflammatory compounds (C), hereafter] or the pharmaceutically acceptable salt, solvate, isomer or pharmaceutically acceptable mixture thereof: in which

[094]- R3 is H or -OH;

[095]- each of R2 and R4, independently of each other and in each occurrence, are selected from H or -OH;

[096]- each of R6a and R6a', independently of each other and in each occurrence, are selected from H or -OH, preferably R6a is H and R6a' is -OH;

[097]- R5 is H, -OH or CH3;

[098]- R13 is -OH or -NHC(=O)CH3

[099]- the lipid is chosen from the following Formula L3, Formula L4 or Formula L5:

[0100]According to an alternative embodiment of the present invention, anti-inflammatory compounds (C) are compounds according to formula (IIIa) [class III anti-inflammatory compounds (C), hereafter] or the pharmaceutically acceptable salt, solvate, isomer or pharmaceutically acceptable mixture thereof: in which

[0101]- each of R4 and R5, independently of each other and in each occurrence, are selected from the group consisting of H, -CH3 and -OH;

[0102]- R7 is independently selected from H or -C(=O)NH2, preferably, R7 is C(=O)NH2;

[0103]- R10 is independently selected from -C(=O)NH2 or -C(=O)OH, preferably, R10 is C(=O)NH2;

[0104]- R13 is independently selected from the group consisting of -OH or -NHC(=O)CH3, preferably R13 is --NHC(=O)CH3

[0105]- the lipid is chosen from the following Formula L6, Formula L7 or Formula L8:

[0106] For therapeutic use, salts of the anti-inflammatory compound (C) of the present invention, as detailed above, are those in which the contraion is pharmaceutically acceptable, which salts may be referred to as pharmaceutically acceptable acid and base addition salts. However, salts of acids and bases that are not pharmaceutically acceptable may also have use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention.

[0107]The pharmaceutically acceptable acid and base addition salts mentioned above comprise the therapeutically active non-toxic acid and base addition salt forms that the anti-inflammatory compounds (C) of the present invention, as detailed above, are capable of forming. The pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with such an appropriate acid in an anion form. Suitable anions include, for example, trifluoroacetate, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, cansiate, carbonate, chloride, citrate, dihydrochloride, edetate, esylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, Tartrate, theoaclate, triethiodide, and the like. The counterion of choice can be introduced using ion exchange resins. Alternatively, these salt forms can be converted into free base form by treatment with an appropriate base.

[0108]Anti-inflammatory compounds (C), as specified herein, containing an acidic proton, may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases in a cationic form. Suitable basic salts comprise those formed with organic cations such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, and the like; and those formed with metallic cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. Conversely, said salt forms may be converted by treatment with an appropriate acid in the free form.

[0109]The term added salt as used above also includes solvates that the anti-inflammatory compound (C), as specified herein, as well as salts thereof, are capable of forming. Such solvates are, for example, hydrates, alcoholates and the like.

[0110]It is generally known that related inflammatory diseases involve a sophisticated cytokine network “system”, such that the functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines.

[0111]As stated, the anti-inflammatory compound (C) of the present invention, as detailed above, acts on inflammatory mechanisms in mammals. Preferably, the anti-inflammatory compound (C) of the present invention, as detailed above, acts on inflammatory mechanisms in non-human mammals. The non-human mammal may be a pig; a ruminant such as notably cattle, horses; a camel; a sheep; a goat; a cat; a dog; or a rodent such as notably a mouse, a rabbit or a rat; preferably, a pig.

[0112]The applicant has now surprisingly found that the anti-inflammatory compound (C) of the present invention, as detailed above, can act on the expression of at least one cytokine by suppressing or inhibiting the expression of at least one cytokine wherein said cytokine is selected from the group consisting of pro-inflammatory cytokines, anti-inflammatory cytokines and chemokines.

[0113] Within the context of the present invention, the expression "at least one cytokine" is intended to denote one or more cytokines. In other words, the anti-inflammatory compound (C) of the present invention can suppress or inhibit the expression of one, two, three or more cytokines at the same time, thereby achieving better therapeutic efficacy with fewer side effects.

[0114]The applicant further verified that by the upsuppression or inhibition of the expression of at least one cytokine by the anti-inflammatory compound (C) of the present invention, a substantial decrease in the infiltration of macrophages, B cells and T cells was observed. Having said that, the anti-inflammatory compound (C) of the present invention shows properties of suppressing or inhibiting inflammation.

[0115]Examples of diseases mediated by cytokines (C) that are treatable by the anti-inflammatory compound (C) of the present invention notably include inflammatory diseases and inflammatory-related diseases.

[0116]Non-limiting examples of inflammatory diseases notably include arthritis, rheumatoid arthritis, an inflammatory bowel disease, psoriasis, multiple sclerosis, systemic lupus erythematosus (SLE), pancreatitis, scleroderma, type 1 diabetes, an inflammatory gastrointestinal disorder, allergic conjunctivitis, glomerulonephritis, Sjögren's syndrome, uveitis, dermatitis, ankylosing spondylitis, and fibromyalgia.

[0117]The term "gastrointestinal inflammatory disorder" is understood to refer to disorders such as acute gastritis, chronic gastritis, the development and recurrence of gastric ulcers, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome and ulcerative colitis.

[0118]Non-limiting examples of related inflammatory diseases notably include a neurodegenerative disorder, congestive heart failure, stroke, aortic valve stenosis, renal failure, allergy, fibrosis, atherosclerosis, a metabolic disease, a cardiovascular disease, a chemotherapy/radiation-related complication, a liver disease, a gastrointestinal disorder, an ophthalmological disease, diabetic retinopathy, a pulmonary disorder, and leprosy.

[0119] Pro-inflammatory cytokines notably include IL-1α, IL-1β, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23,TNF-α, LT, LIF, Oncostatin, and IFN-α, IFN-β, and IFN-ϒ.

[0120]Anti-inflammatory cytokines notably include IL-4, IL-10, IL-11, W-13 and TGF β.

[0121]Chemokines notably include IL-8, Gro-α, MIP-1, MCP-1, ENA-78, and RANTES.

[0122]Unless mentioned or indicated otherwise, the designation of cytokines (C), as detailed above, encompasses the presence of all possible homologous forms, which said anti-inflammatory compounds (C) can suppress. Homology is defined as the relationship between biological structures, proteins, or DNA sequences that are derived from a common ancestor. For example, the term “IL-8” refers to IL-8 and all IL-8 homologs, such as notably IL-8Kc, IL-8MIP, IL-8LIX, and the like.

PHARMACEUTICAL COMPOSITIONS

[0123]The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of the anti-inflammatory compound (C) as defined above and as defined in any of the embodiments presented herein, in particular the anti-inflammatory compound (C) of any of classes (I) to (III), as defined above, and a pharmaceutically acceptable carrier.

[0124]In the rest of the text, the expression "the anti-inflammatory compound (C)" is understood, for the purposes of the present invention, both in the plural and in the singular, meaning that the composition of the invention may comprise one or more than one anti-inflammatory compound (C).

[0125]In yet another aspect, this invention relates to a process for preparing a pharmaceutical composition, as detailed above, comprising intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the anti-inflammatory compound (C), as defined above, and as defined in any of the embodiments presented herein, in particular an anti-inflammatory compound (C) of any of classes (I) to (III), as defined above.

[0126]Therefore, the anti-inflammatory compounds (C) of the present invention, as specified herein, in particular the anti-inflammatory compounds (C) of any of classes (I) to (III), as defined above, can be formulated in various pharmaceutical forms for administration purposes. Suitable compositions include all compositions commonly employed for the systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in the form of the addition salt or metal complex, as the active ingredient, is combined in intimate mixture with a pharmaceutically acceptable vehicle, which vehicle can take a wide variety of forms depending on the desired form of preparation for administration. These pharmaceutical compositions are desirable in suitable unit dosage form, particularly for oral, rectal, percutaneous or parenteral injection administration. For example, in the preparation of compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid vehicles such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.

[0127]Due to their ease of administration, tablets and capsules represent the most advantageous forms of oral dosage unit, in which case solid pharmaceutical vehicles are obviously employed. For parenteral compositions, the vehicle will usually comprise sterile water, at least in large part, although other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the vehicle comprises saline solution, glucose solution, or a mixture of saline solution and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid vehicles, suspending agents, and the like may be employed. Also included are preparations in solid form, which are intended to be converted, shortly before use, into preparations in liquid form. In compositions suitable for percutaneous administration, the vehicle optionally comprises a penetration enhancer and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant detrimental effect on the skin.

[0128]The anti-inflammatory compound (C), as defined above and as defined in any of the embodiments presented herein, in particular the anti-inflammatory compounds (C) of any of classes (I) to (III), as defined above, may also be administered by oral inhalation or insufflation by means of methods and formulations employed in the art for administration by this manner. Thus, in general, the anti-inflammatory compound (C) as specified herein, in particular the anti-inflammatory compounds (C) of any of classes (I) to (III), as defined above, may be administered to the lungs in the form of a solution, a suspension or a dry powder, a solution being preferred. Any system developed for the delivery of solutions, suspensions or dry powders by oral inhalation or insufflation is suitable for the administration of the present compounds.

[0129] It is especially advantageous to formulate the pharmaceutical compositions mentioned above in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used herein refers to physically discrete units suitable as unit dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. Examples of such unit dosage forms are tablets (including graded or coated tablets), capsules, tablets, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.

[0130] It is understood that the term "therapeutically effective amount" generally refers to that amount of the active compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human being that is being sought, in light of the present invention, by a researcher, veterinarian, physician or other clinician, which includes relief of the symptoms of the disease being treated.

[0131] In the present invention, the therapeutically effective amount of the anti-inflammatory compound (C), as defined above, in particular the anti-inflammatory compound (C) of any of classes (I) to (III), as defined above, is intended to refer to an amount sufficient to act prophylactically against, to stabilize or reduce diseases mediated by at least one cytokine selected from the group consisting of pro-inflammatory cytokines, anti-inflammatory cytokines and chemokines, as detailed above, in particular, at least one cytokine selected from the group consisting of IL-8, Gro-α, MIP-1, MCP-1, ENA-78, and RANTES, IL-1α, IL-1β, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23, TNF-α, LT, LIF, Oncostatin, IFN-α, IFN- β, IFN-ϒ, IL-4, IL-10, IL-11, W-13 and TGF β, more preferably the at least one cytokine is selected from the group consisting of IL-8, IL-4, IL-6, IL-10, TNF-α, TNF-β, IL-17, IL-23 and IFN-ϒ, even more preferably the at least one of said cytokine is selected from the group consisting of IL-8, IL-1β and IFN-ϒ.

Anti-inflammatory compounds (C) and pharmaceutical compositions, uses as medicines and in the treatment of diseases

[0132]The present invention relates to an anti-inflammatory compound (C), as defined above, in particular the anti-inflammatory compound (C) of any of classes (I) to (III), as defined above, for use as a medicament.

[0133]The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of the anti-inflammatory compound (C), as defined above and as defined in any of the embodiments presented herein, in particular the anti-inflammatory compound (C) of any of classes (I) to (III), as defined above, and a pharmaceutically acceptable vehicle, for use as a medicament.

[0134]The present invention relates to an anti-inflammatory compound (C), as defined above, in particular an anti-inflammatory compound (C) of any of classes (I) to (III), as defined above, for use in the treatment of selected inflammatory diseases from the group of arthritis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, systemic lupus erythematosus (SLE), pancreatitis, scleroderma, type 1 diabetes, gastrointestinal inflammatory disorder, allergic conjunctivitis, glomerulonephritis, Sjögren's syndrome, uveitis, dermatitis, ankylosing spondylitis, and fibromyalgia, preferably for use in the treatment of gastrointestinal inflammatory disorders such as acute gastritis, chronic gastritis, development and recurrence of gastric ulcers, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome and ulcerative colitis, more preferably for use in Treatment of acute gastritis, chronic gastritis, development and recurrence of gastric ulcers.

[0135]The present invention relates to an anti-inflammatory compound (C), as defined above, in particular an anti-inflammatory compound (C) of any of classes (I) to (III), as defined above, for use in the treatment of selected related inflammatory diseases from the group of a neurodegenerative disorder, congestive heart failure, stroke, aortic valve stenosis, renal failure, allergy, fibrosis, atherosclerosis, a metabolic disease, a cardiovascular disease, a chemotherapy/radiation related complication, a liver disease, a gastrointestinal disorder, an ophthalmological disease, diabetic retinopathy, a pulmonary disorder and leprosy.

[0136]Consequently, the anti-inflammatory compound (C), as defined above, in particular the anti-inflammatory compound (C) of any of the classes (I) to (III), as defined above, and the pharmaceutical composition, as defined above, may be used in the manufacture of a medicament useful for the treatment, prevention or combating of disease or illness associated with the expression of cytokines including inflammatory diseases, as defined above and related inflammatory diseases, as defined above.

[0137]The present invention relates to an anti-inflammatory compound (C), as defined above, in particular an anti-inflammatory compound (C) of any of classes (I) to (III), as defined above, for use in the treatment of a disease mediated by at least one cytokine.

[0138]At least one cytokine is advantageously selected from the group consisting of pro-inflammatory cytokines, anti-inflammatory cytokines and chemokines, as detailed above, preferably at least one cytokine is selected from the group consisting of IL-8, Gro-α, MIP-1, MCP-1, ENA-78, and RANTES, IL-1α, IL-1β, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23, TNF-α, LT, LIF, Oncostatin, IFN-α, IFN-β, IFN-ϒ, IL-4, IL-10, IL-11, W-13 and TGF β, more preferably at least one cytokine is selected from the group consisting of IL-8, IL-4, IL-6, IL-10, TNF-α, TNF-β, IL-17, IL-23 and IFN-ϒ, or even more preferably at least one of said cytokine is selected from the group consisting of IL-8, IL-1β and IFN-ϒ.

[0139]The exact dosage and frequency of administration depends on the particular anti-inflammatory compound (C) as specified herein, used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of the disorder and general physical condition of the particular patient, as well as other medication the individual may be taking, as one skilled in the art well knows. Furthermore, it is evident that said effective daily amount may be decreased or increased depending on the response of the treated individual and/or depending on the assessment of the physician prescribing the compounds of the present invention.

[0140]As stated above, the anti-inflammatory compound (C) of the present invention, as detailed above, can act on inflammatory mechanisms in animals.

[0141]For administration to animals, the anti-inflammatory compound (C), as defined above, in particular an anti-inflammatory compound (C) of any of classes (I) to (III), as defined above, or the pharmaceutical composition thereof, comprising at least one of said anti-inflammatory compound (C) as an active ingredient, may be added to the animal's feed or drinking water, may be administered by spraying, as a probiotic for a lactation barrier, may be administered as a slow-release bolus or by means of a lick stone.

[0142]The effective amount of the anti-inflammatory compound (C), as defined above, in particular the anti-inflammatory compound (C) of any of the classes (I) to (III), as defined above, which specifically suppresses or inhibits the expression of at least one cytokine, as detailed above, for the treatment of animals is advantageously at least 1 ppm, preferably at least 2 ppm, more preferably at least 3 ppm, based on the total weight of the animal feed. On the other hand, the effective amount of the anti-inflammatory compound (C), as defined above, in particular the anti-inflammatory compound (C) of any of the classes (I) to (III), as defined above, composition (C) is advantageously less than 130 ppm, preferably less than 70 ppm, more preferably less than 35 ppm, based on the total weight of the animal feed, the animal in this case being a rodent, notably a mouse. It should be understood that for the purpose of the present invention, the upper limit is not critical and the effective amount depends on the particular species treated. The invention also relates to an animal feed comprising the anti-inflammatory compound (C), as defined above, in particular the anti-inflammatory compound (C) of any of classes (I) to (III), as defined above, or the pharmaceutical composition thereof, comprising said anti-inflammatory compound (C) as an active ingredient.

METHODS FOR TREATING INFLAMMATORY DISEASES USING ANTI-INFLAMMATORY COMPOUNDS (C)

[0143]The present invention relates to an in vivo method of suppressing or inhibiting inflammatory responses by using at least one anti-inflammatory compound (C), as defined above, in particular the anti-inflammatory compound (C) of any of classes (I) to (III), as defined above, and as defined in any of the embodiments presented herein.

[0144]The present invention further relates to a method of suppressing or inhibiting the expression of at least one cytokine in a mammal, said method comprising administering to a mammal in need thereof, an amount of anti-inflammatory compound (C), as defined above and as defined in any of the embodiments presented herein, sufficient to inhibit or suppress at least one cytokine, wherein the cytokine is selected from the group consisting of IL-8, Gro-α, MIP-1, MCP-1, ENA-78, and RANTES, IL-1α, IL-1β, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23, TNF-α, LT, LIF, Oncostatin, IFN-α, IFN-β, IFN-ϒ, IL-4, IL-10, IL-11, W-13 and TGF β, more Preferably, at least one cytokine is selected from the group consisting of IL-8, IL-4, IL-6, IL-10, TNF-α, TNF-β, IL-17, IL-23, and IFN-γ; even more preferably, at least one of said cytokines is selected from the group consisting of IL-8, IL-1β, and IFN-γ.

[0145]The present invention further relates to a method of treating related inflammatory diseases associated with cytokine expression levels in mammals, said method comprising administering to a mammal in need thereof an amount of anti-inflammatory compound (C) as defined above and as defined in any of the embodiments presented herein, sufficient to treat said related inflammatory disease.

[0146]The following examples are merely illustrative of some non-limiting embodiments of the present invention.

EXAMPLES MATERIALS

[0147]a) Experimental Configuration

[0148]Experiments were conducted to evaluate the effects of feed supplementation with Flavomycin® as an anti-inflammatory compound (C) in a mouse model.

[0149] For in vivo experiments, the BALB/c mouse strain was chosen for its association with a more pronounced gastric pathology compared to other mouse strains. The mice were divided into 4 groups of 8 animals each. The 4 groups have the following characteristics:

1) INFECTED + STANDARD DIET: COMPARATIVE EXAMPLE 1

[0150]The group of mice from 'comparative example 1' was intragastrically inoculated twice with 108 viable bacteria of the HS1 Helicobacter suis (H. suis) strain within a 48-hour interval (on day 8 and day 9). On day 17, the mice were fed ad libitum with a control diet (standard diet without Flavomycin®). After 73 days, the mice were euthanized by cervical dislocation under deep anesthesia with isoflurane. A strip of gastric tissue was taken to perform the experimental procedures, as detailed below.

2) INFECTED + DIET SUPPLEMENTED WITH FLAVOMICIN® (AMOUNT OF FLAVOMICIN® < 100 PPM BASED ON THE TOTAL AMOUNT OF FOOD GIVEN): EXAMPLE 1

[0151]The mouse group from 'example 1' was intragastrically inoculated twice with 108 viable bacteria of the HS1 strain (H. suis) within a 48-hour interval (on day 8 and day 9). On day 17, the mice were fed ad libitum with a diet supplemented with Flavomycin® (amount of Flavomycin® <100 ppm based on the total amount of diet). After 73 days, the mice were euthanized by cervical dislocation under deep anesthesia with isoflurane. A strip of gastric tissue was taken to perform the experimental procedures, as detailed below.

3) NON-INFECTED + STANDARD DIET: COMPARATIVE EXAMPLE 2

[0152]The group of mice from 'comparative example 2' did not receive intragastric inoculation and was fed ad libitum with a control ration, a standard diet without Flavomycin®. After 73 days, the mice were euthanized by cervical dislocation under deep anesthesia with isoflurane. A strip of gastric tissue was taken to perform the experimental procedures, as detailed below.

4) NON-INFECTED + DIET SUPPLEMENTED WITH FLAVOMICIN® (AMOUNT OF FLAVOMICIN® < 100 PPM BASED ON THE TOTAL AMOUNT OF FOOD GIVEN): EXAMPLE 2

[0153]The mouse group from 'example 2' did not receive intragastric inoculation and was fed ad libitum with a diet supplemented with Flavomycin® (amount of Flavomycin® <100 ppm based on the total amount of diet). After 73 days, the mice were euthanized by cervical dislocation under deep anesthesia with isoflurane. A strip of gastric tissue was taken to perform the experimental procedures, as detailed below.

[0154]b) Verification of experimental setup - quantification of H. suis

[0155] The presence of H. suis infection was determined by qRT-PCR experiments. The experiments were conducted as detailed below. Table 1 shows that the 'comparative example 1' and 'example 1' groups are successfully infected with H. suis bacteria. The 'comparative example 2' and 'example 2' groups are not infected as shown in Table 1 since no H. suis bacteria were detected in these animals. TABLE 1: DETERMINATION OF THE PRESENCE OF H. SUIS INFECTION BY QRT-PCR EXPERIMENTS, EXPRESSED IN LOG RATIOS OF H. SUIS PER MG OF TISSUE (ABSOLUTE QUANTIFICATION OF NUCLEIC ACID (AMOUNT OF BACTERIAL DNA) PER GIVEN AMOUNT OF SAMPLE (MG OF TISSUE).

METHODS QRT-PCR assay

[0156]1) Quantification of H. suis

[0157]The quantification of H. suis colonization in the stomach was performed based on the publications of Blaecher C. et al. (2013) and O’Rourke J.L. et al. (2004).

[0158]The presence of H. suis DNA in the extracts was determined using an H. suis-specific qRT-PCR with absolute quantification, based on the ureA gene (Blaecher C. et al. (2013)). First, the pattern was generated by amplifying a portion of the ureAB gene cluster (1236 bp) from the H. suis HS5 strain using U430F and U1735R primers (O’Rourke J.L. et al. (2004)). In summary, the PCR amplification reactions involved 1x reaction buffer [67mM Tris/HCl, 16 mM (NH4) 2SO4, 0.45% Triton X-100, 0.2% gelatin], one unit of Taq DNA polymerase (Biotech International), 200 μM of each deoxynucleotide triphosphate, 2 mM MgCl2, 10 pmols of each oligonucleotide primer, and 1 μl of diluted DNA (usually a 1:10 dilution of the original sample containing approximately 20100 ng/μl -1) in a final volume of 50 μl. The cycling conditions were initial denaturation at 94°C for 3 min, followed by 35 cycles of 94°C for 10 s, 52°C for 30 s, and 72°C for 1.5 min, followed by a final extension step at 72°C for 5 min. All reactions were performed using a Perkin Elmer PE2400 thermocycler. PCR products were separated on agarose mini-prescriptions in TAE buffer (40 mM Tris/acetate, 1 mM EDTA) and photographed under UV transillumination after staining with ethidium bromide. PCR products were purified prior to sequencing using Wizard PCR Preps DNA Purification System (Promega) or Centricon-100 filters (Amicon). The amplified DNA was then directly sequenced using the ABI PRISM Ready Reaction DyeDeoxy Terminator Cycle Sequencing kit (PE Applied Biosystems) and the GeneAmp® PCR System 2400 (Perkin Elmer) according to the manufacturers' protocols. Sequencing products were separated on model 377 DNA Sequencer machines and analyzed using programs contained in the legacy package (PE Applied Biosystems). In all cases, both DNA strands were sequenced with contiguous overlaps. After standard generation, 10-fold dilutions were made, starting at 10⁸ PCR amplicons, for each 9 μL of reaction mixture. One microliter of extracted DNA template was added to 9 μL of reaction mixture, consisting of 0.25 μL of both primers located within the 1236 bp fragment (to yield a 150 bp PCR product), 3.5 μL of HPLC water, and 5 μL of SensiMix™ SYBR No-ROX (Bioline Reagents Ltd, London, UK). The sense primer was BF_HsuisF1: 5‘-AAA ACA MAG GCG ATC GCC CTG TA-3‘. The antisense primer was BF_Hsuis R1: 5‘-TTT CTT CGC CAG GTT CAA AGC G-3‘. The annealing temperature was 62 °C. Both standards and samples were run in duplicate on a CFX96™ RT-PCR System with a C1000 Thermal Cycler (Bio-Rad, Hercules, CA, USA). Results are expressed in terms of the absolute quantification of nucleic acid (amount of bacterial DNA) per given sample quantity (mg of tissue).

[0159]2) Cytokine expression levels

[0160] A qRT-PCR to assess cytokine expression levels was performed based on the publications of Flahou B. et al. (2012) and Liu C. et al. (2016). RNA was extracted using the RNeasy Mini Kit® (Qiagen, Hilden, Germany), according to the manufacturer's instructions. The RNA concentrations obtained were measured using a NanoDrop® spectrophotometer (Isogen Life Science, Utrecht, The Netherlands), after which the concentration of all samples obtained from all mice belonging to the 4 groups, as defined above in the experimental setup, was adjusted to 1 μg/μL, followed by cDNA synthesis using the iScript™ cDNA Synthesis Kit (Bio-Rad, California, USA). Expression analysis was then performed for genes encoding host factors involved in inflammation. The maintenance genes PPIa, H2afz, and HPRT were included as reference genes. All primer sequences used are shown in Table 2. The mRNA expression levels of the reference and target genes were quantified using RT-PCR, as previously described (Flahou B. et al. (2012)). Reaction mixtures without template control were included, and all such samples were run in duplicate. Cycle threshold (Ct) values were first normalized to the geometric mean of the Ct values of the reference genes. Modulations were calculated using the ΔΔCT method (72) with mean Ct values from H. suis-negative mice. Finally, for each target gene, the results were expressed as modulations of mRNA expression from H. suis-positive mice relative to mRNA expression levels from H. suis-negative mice. The results are summarized in Tables 3 and 4 below. TABLE 2: PRIMER SEQUENCES USED IN THE RT-PCR METHOD

Immunohistochemistry Experiments - Determination of T Cells, B Cells, Parietal Cells, Necrotic Cells, and Macrophage Infiltration

[0161]Immunohistochemistry was performed based on the publication by Flahou B. et al. (2010). Consecutive 5 μm sections were cut from paraffin-embedded tissues. After rehydration and deparaffinization, heat-induced antigen retrieval was performed in citrate buffer (pH 6.0) using a microwave oven. Slides were incubated with 3% H2O2 in methanol (5 min) and 30% goat serum (30 min) to block endogenous peroxidase activity and nonspecific reactions, respectively. Differentiation between T and B lymphocytes was performed by staining for CD3 and CD20 antigens. CD3 antigens were detected using a polyclonal rabbit anti-CD3 antibody (1/100; DakoCytomation). CD20 antigens were detected using a polyclonal rabbit anti-CD20 antibody (1/100; Thermo Scientific, Fremont, USA). Incubation with primary antibodies targeting CD3 and CD20 was followed by incubation with a biotinylated goat anti-rabbit IgG antibody (1/500; DakoCytomation). After rinsing, sections were incubated with a streptavidin-biotin-HRP complex (DakoCytomation) and staining was developed with diaminobenzidine tetrachloride (DAB) and H2O2. A primary antibody targeting the F4/80 surface marker (1/50; Santa Cruz Biotechnology, Inc., Santa Cruz, USA) was used to highlight mature macrophages. Detection was performed using a rat ABC staining system (Santa Cruz Biotechnology, Inc.). Apoptotic cells were identified by immunohistochemical staining using a rabbit polyclonal antibody directed against active caspase-3 and an HRP-AEC anti-rabbit cell and tissue staining kit (R&D Systems, Minneapolis, USA). Parietal cells were identified by immunohistochemical staining for hydrogen potassium ATPase using a mouse monoclonal antibody (1/200; Abcam Ltd, Cambridge, UK) and a biotinylated goat anti-mouse IgG antibody (1/200; DakoCytomation). Apoptotic cells were identified by immunohistochemical staining using a rabbit polyclonal antibody directed against active caspase-3 and an HRP-AEC anti-rabbit cell and tissue staining kit (R&D Systems, Minneapolis, USA). Parietal cells were identified by immunohistochemical staining for hydrogen and potassium ATPase using a mouse monoclonal antibody (1/200; Abcam Ltd, Cambridge, UK) and a biotinylated goat anti-mouse IgG antibody (1/200; DakoCytomation). Finally, positive cells were counted in five randomly selected high-power fields (magnification: x400). An average count of positive cells was then determined for each mouse. All results are shown in Tables 5, 6, 7, and 8.

RESULTS EXPERIMENT 1

[0162]Measurement of cytokine expression levels in animals infected with H. suis using the qRT-PCR method as detailed above.TABLE 3: RESULTS OF THE QRT-PCR EXPERIMENT TO DETERMINE THE EFFECT OF FLAVOMICIN® SUPPLEMENTATION ON CYTOKINE LEVELS IN ANIMALS INFECTED WITH H. SUIS EXPRESSED AS MODULATION IN MRNA EXPRESSION LEVELS.

[0163]Table 3 shows decreased expression levels of IL-113, IL-8MIP and IFN-γ in infected animals that received a diet supplemented with Flavomycin® (example 1) compared to the control group on a standard diet (comparative example 1).

EXPERIMENT 2

[0164]Measurement of cytokine expression levels in the absence of H. suis infection using the qRT-PCR method as detailed above.TABLE 4: RESULTS OF THE QRT-PCR EXPERIMENT TO DETERMINE THE EFFECT OF FLAVOMICIN® SUPPLEMENTATION ON CYTOKINE LEVELS IN UNINFECTED ANIMALS, EXPRESSED AS MODULATION IN MRNA EXPRESSION LEVELS.

[0165]Table 4 shows decreased IL-113 expression even in the absence of infection. IL-8MIP expression levels remain stable, although there is a slight increase in IFN-γ expression.

EXPERIMENT 3

[0166]The evaluation of the inflammatory response in animals infected with H. suis using immunohistochemistry experiments, as detailed above. TABLE 5: RESULTS OF IMMUNOHISTOCHEMICAL EXPERIMENTS TO DETERMINE THE EFFECT OF SUPPLEMENTATION WITH FLAVOMICIN® ON THE NUMBER OF INFILTRATING T CELLS, B CELLS AND MACROPHAGES IN ANIMALS INFECTED WITH H. SUIS, EXPRESSED AS THE AVERAGE NUMBER OF POSITIVE CELLS COUNTED.

[0167]Table 5 shows a strong reduction in the number of infiltrating T cells, B cells and macrophages in mice infected with H. suis and treated with Flavomycin® (example 1) compared to the comparative example 1.

EXPERIMENT 4

[0168]The assessment of the inflammatory response in the absence of H. suis infection by the use of immunohistochemistry experiments, as detailed above.

[0169]TABLE 6: RESULTS OF IMMUNOHISTOCHEMICAL EXPERIMENTS TO DETERMINE THE EFFECT OF SUPPLEMENTATION WITH FLAVOMICIN® ON THE NUMBER OF INFILTRATING T CELLS, B CELLS AND MACROPHAGES IN UNINFECTED ANIMALS, EXPRESSED AS THE AVERAGE NUMBER OF POSITIVE CELLS COUNTED.

[0170]Table 6 shows an anti-inflammatory effect of Flavomycin® for the group of uninfected mice that received a supplemented diet (example 2) compared to the comparative example 2. In particular, a decrease in T cells and macrophages was observed.

[0171]Taking the results of experiments 3 and 4 together, Flavomicina® showed to have an anti-inflammatory capacity independent of an infection with H. suis.

EXPERIMENT 5

[0172] Physiological evaluation of animals infected with H. suis using immunohistochemistry experiments, as detailed above. TABLE 7: RESULTS OF IMMUNOHISTOCHEMICAL EXPERIMENTS TO DETERMINE THE EFFECT OF SUPPLEMENTATION WITH FLAVOMICIN® ON THE NUMBER OF NECROTIC AND PARIETAL CELLS IN ANIMALS INFECTED WITH H. SUIS, EXPRESSED AS THE AVERAGE NUMBER OF POSITIVE CELLS COUNTED.

[0173]Table 7 shows a reduction in the number of necrotic cells for the infected group receiving a diet supplemented with Flavomycin® (example 1) compared to the comparative example 1. This indicates that animals receiving a diet supplemented with Flavomycin® experience less cell necrosis, which can be explained by the suppression of inflammatory responses. For the number of parietal cells, there is a greater number of cells measured in the group receiving a diet supplemented with Flavomycin®. This can be explained by the fact that the reduction in inflammation, due to the administration of Flavomycin®, causes less damage to the parietal cells of the stomach.

EXPERIMENT 6

[0174] Physiological evaluation of animals without H. suis infection using immunohistochemistry experiments, as detailed above. TABLE 8: RESULTS OF IMMUNOHISTOCHEMICAL EXPERIMENTS TO DETERMINE THE EFFECT OF FLAVOMICIN® SUPPLEMENTATION ON THE NUMBER OF NECROTIC AND PARIETAL CELLS IN UNINFECTED ANIMALS, EXPRESSED AS THE AVERAGE NUMBER OF POSITIVE CELLS COUNTED.

[0175]Table 8 shows a reduction in the number of necrotic cells which is a result of reduced inflammation. The number of parietal cells is approximately the same in example 2 and comparative example 2. This indicates that treatment with Flavomycin does not negatively impact the number of parietal cells.

[0176]Taking all the results together, the administration of Flavomycin® shows an anti-inflammatory effect since the infiltration of B cells, T cells and macrophages, as well as the levels of IL-113, IL-8MIP, and IFN-Y were reduced in the groups of animals receiving a diet supplemented with Flavomycin®. Furthermore, it is shown that the anti-inflammatory effects are independent of H. suis infection.

Claims (6)

1. Use of a compound [anti-inflammatory compound (C), hereinafter] CHARACTERIZED by the fact that it is in the manufacture of a medicament for the treatment of an inflammatory disease in a mammal in need thereof, wherein the inflammatory disease is not driven by microbial infection, wherein the inflammatory disease is selected from the group consisting of arthritis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, systemic lupus erythematosus (SLE), pancreatitis, scleroderma, type I diabetes, gastrointestinal inflammatory disorder, allergic conjunctivitis, glomerulonephritis, Sjögren's syndrome, uvetitis, dermatitis, ankylosing spondylitis and fibromyalgia, wherein the gastrointestinal inflammatory disorder is in the absence of a Helicobacter pylori infection, wherein said anti-inflammatory compound (C) acts on inflammatory mechanisms in mammals, and wherein said anti-inflammatory compound (C) is the compound according to general formula (Ib) or the pharmaceutically acceptable salt or mixture thereof, 2. Use, according to claim 1, CHARACTERIZED in that said anti-inflammatory compound (C) acts on inflammatory mechanisms in non-human mammals, in particular, the non-human mammal is a pig; a ruminant such as notably cattle, horses; a camel; a sheep; a goat; a cat; a dog; or a rodent such as notably a mouse, a rabbit or a rat; preferably a pig. 3. Use, according to claim 1 or 2, CHARACTERIZED in that said anti-inflammatory compound (C) acts on the expression of at least one cytokine by suppressing or inhibiting the expression of at least one cytokine, wherein said cytokine is selected from the group consisting of pro-inflammatory cytokines, in particular IL-1α, IL-1β, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23, TNF-α, LT, LIF, Oncostatin, and IFN-α, IFN-β, IFN-ϒ or mixtures thereof; anti-inflammatory cytokines, in particular IL-4, IL-10, IL-11, W-13, TGF β or mixtures thereof; and chemokines, in particular IL-8, Gro-α, MIP-1, MCP-1, ENA-78, RANTES or mixtures thereof. 4. Use, according to any one of claims 1 to 3, CHARACTERIZED in that said inflammatory disease is mediated by at least one cytokine, as defined in claim 3. 5. Use, according to claim 1, CHARACTERIZED in that the inflammatory disease is selected from the group consisting of inflammatory gastrointestinal disorders such as acute gastritis, chronic gastritis, development and recurrence of gastric ulcers, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome and ulcerative colitis. 6. Use, according to any one of claims 1 to 5, CHARACTERIZED in that the medicament is in the form of a pharmaceutical composition comprising a therapeutically effective amount of the anti-inflammatory compound (C), as defined in claim 1, and a pharmaceutically acceptable vehicle.