EP2313382A1 - Dérivés de 5-(4-méthanesulfonyl-phényl)-thiazole pour le traitement de maladies inflammatoires aiguës et chroniques - Google Patents

Dérivés de 5-(4-méthanesulfonyl-phényl)-thiazole pour le traitement de maladies inflammatoires aiguës et chroniques

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Publication number
EP2313382A1
EP2313382A1 EP09765806A EP09765806A EP2313382A1 EP 2313382 A1 EP2313382 A1 EP 2313382A1 EP 09765806 A EP09765806 A EP 09765806A EP 09765806 A EP09765806 A EP 09765806A EP 2313382 A1 EP2313382 A1 EP 2313382A1
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European Patent Office
Prior art keywords
compound
substituted
unsubstituted
tnf
alpha
Prior art date
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Application number
EP09765806A
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German (de)
English (en)
Inventor
Victor Rubio Royo
Antonio de la Hera Martínez
Melchor Álvarez de Mon Soto
Ana Muñoz Muñoz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Faes Farma SA
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Faes Farma SA
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Priority claimed from EP08380177A external-priority patent/EP2135864A1/fr
Priority claimed from US12/139,661 external-priority patent/US7781594B2/en
Application filed by Faes Farma SA filed Critical Faes Farma SA
Priority to EP09765806A priority Critical patent/EP2313382A1/fr
Publication of EP2313382A1 publication Critical patent/EP2313382A1/fr
Withdrawn legal-status Critical Current

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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms

Definitions

  • the present invention relates to the use of compounds derived from 5-(4- methanesulfonyl-phenyl)-thiazole in the preparation of a medicinal product for the treatment of acute and chronic inflammatory diseases or conditions, such as rheumatoid arthritis.
  • Immunology is the scientific study of the discrimination between self and non-self. The breakdown of tolerance to self is in the origin of auto-immune diseases. Moreover, other conditions such as transplantation, atherosclerosis, septic and nonseptic acute and chronic inflammatory pathologies and many others diseases, up to now not considered as auto-immune, exhibit immune cell-mediated pathogenic mechanisms. Activation of immune inflammatory effector responses is considered by most authors as being based on two signals:
  • TCR-CD3 T-cell receptor complex clonal antigen's receptor
  • MHC Major Histocompatibility Complex
  • extracellular soluble or membrane-bound antigens cross link the Immunoglobulin CD79 (Ig/CD79) clonal receptor complex to deliver the signal 1 to the antibody-secreting lymphocyte lineage.
  • a second signal in addition to antigen-delivered signal 1 , is required to avoid tolerance by anergy or clonal deletion.
  • Signal 2 is delivered by co-stimulators such as CD86 expressed on the surface of professional antigen-presenting cells (APC), like human monocytes and their differentiation lineage progeny.
  • APC professional antigen-presenting cells
  • PRR signalling pathways such as TLR4 (the receptor for the Gram- negative wall bacteria lipo-polysaccharide or LPS) deliver the expression of high levels of co-stimulatory surface molecules (i.e., CD80 or CD86).
  • co-stimulatory ligands CD80 - CD86 cross link CD28 on the surface of helper T-cells.
  • signal 1 i.e., anti-CD3 antibody cross linking
  • signal 2 i.e., CD28 cross linking by specific antibodies
  • approved immune suppressor drugs have some troubles to inhibit the activation of pro-inflammatory cytokine cascades under conditions of high levels of co-stimulation. The latter occur in auto-immune diseases and many other severe acute and chronic inflammatory conditions.
  • APCs are not only crucial for the acquired immune system to decide the class of immune response since they deeply influence whether there is an effector (i.e. T-cell help, Th, cellular cytoxicity, Th, antibody production, B-cell) responses or a tolerant response (by anergy or apoptosis) mediated by the challenged clon.
  • APCs can also deliver themselves effector immediate immune responses.
  • TNF- alpha Tumour Necrosis Factor Alpha
  • TNF-alpha promotes an augmented response and activation of the vascular endothelium, accompanied with secretion of Interleukin 8 (IL-8) and other pro -inflammatory cytokines as well as pro- coagulant activities.
  • IL-8 Interleukin 8
  • TNF-alpha promotes thrombosis and ischaemia with cancer necrosis, which led to the original definition as cachectin or TNF-alpha.
  • TNF-alpha is a pleiotropic cytokine involved in many other disease conditions.
  • LPS may trigger the secretion of massive amounts of TNF-alpha which strongly contribute to the development of septic shock.
  • TNF-alpha is considered as a therapeutic target in auto- immune inflammatory diseases, such as rheumatoid arthritis, spondiloarthropathies, Crohn's disease, uveitis and psoriasis.
  • auto- immune inflammatory diseases such as rheumatoid arthritis, spondiloarthropathies, Crohn's disease, uveitis and psoriasis.
  • anti-TNF-alpha has currently been broadly considered as a state of the art strategy to deal with those diseases in which the reduction of available levels of bioactive TNF-alpha might contribute to ameliorate the patient's condition.
  • TNF-alpha antagonists is growing rapidly and includes atherosclerosis, metabolic syndrome, encephalitis, viral hepatitis, glomerulonephritis, inadequate inflammatory response to tumours and septic shock as among several others.
  • TNF-alpha production monocytes and T-lymphocytes.
  • APCs In the course of an acquired immune response, exposition of APCs to danger signals under pro -inflammatory instructive scenarios, triggers the secretion of IL-12 p70 (an heterodimer of p35 and p40), being the latter a co-stimulatory molecule that polarizes the cytokine secretion profile of the activated Th-cells towards Th-I type.
  • ThI -cells exhibit a characteristic cytokine profile in which interferon gamma (IFN-gamma) secretion is a bonafide footprint. These cells do secrete high amounts of TNF-alpha too.
  • IFN-gamma interferon gamma
  • IFN-gamma produced by ThI promotes many effects that may be relevant in the understanding of inflammatory diseases. On one hand, it further activates monocytes and increases the level of TNF-alpha secretion by a given stimuli. On the other hand, it promotes a stronger signalling pathway downstream TNF-alpha receptors.
  • IFN-gamma in addition to its own direct effects such as anti- viral activity, increases expression in MHC-II and contributes to inflammation and lesions by increasing the still strong effects of TNF-alpha.
  • IL-8 pro -inflammatory cytokine pathways
  • IL-8 in spite of its original name, was described as a chemokine produced by macrophages and other cell types such as epithelial cells, and it is also synthesized by endothelial cells, and accordingly is also termed CXCL8. While neutrophil granulocytes are the primary target cells of IL-8 there is a relative wide range of cells (endothelial cells, macrophages, mast cells, Keratinocytes) responding to this chemokine, too.
  • IL-8 Primary function of IL-8 is the induction of chemotaxis in its target cells (e.g. neutrophil granulocytes). In neutrophils series of cell-physiological responses required for migration and its target function phagocytosis are also induced like increase of intracellular Ca2+, exocytosis (e.g. histamine release), respiratory burst. IL-8 can be secreted by any cells with TLRs which are involved in the innate immune response. IL-8's primary function is to recruit neutrophils to phagocytose the antigen which trigger the antigen pattern TLRs. By conveying IL-8 target cells to the endothelium and other target tissues IL-8 is thus implicated in the amplification and execution of many of the TNF-alpha pathogenic roles, in addition to its role in the body defence.
  • TLRs which are involved in the innate immune response.
  • IL-8's primary function is to recruit neutrophils to phagocytose the antigen which trigger the antigen pattern T
  • Leucocyte migration and homing are not only regulated by chemokines and their receptors but also by a number of adhesion molecules.
  • the selectin CD62L is acknowledged as a therapeutic target to prevent leucocytes migration to the lymph nodes and thus is evaluated as a parameter to rank the in vitro effects of nonsteroid anti- inflammatory drugs (NSAIDs).
  • NSAIDs nonsteroid anti- inflammatory drugs
  • immune suppressor and anti-TNF-alpha molecules affect the normal immune defence mechanisms because they promote cytotoxic effects upon immune cells or inhibit the proliferative mechanism that underlie under the clonal expansion preceding the successful effector immune responses.
  • TNF-alpha cytoplasmic membrane-inserted or secreted soluble forms
  • many efforts have been displayed to design therapeutic agents that block the interaction of extracellular TNF- alpha with both TNF-receptor I and/or TNF-receptor II.
  • the most relevant approaches have been the use of soluble decoy TNF-receptor that captures TNF-alpha and thanks to the long time of dissociation prevents the pro -inflammatory ligand interaction with the cellular receptors.
  • a second strategy has been to produce humanised anti-human TNF-alpha antibodies either conventional or created as bis-specific single chain molecules that target as well other molecules relevant in a given disease (i.e., anti-VEGF/anti-TNF- alpha in rheumatoid arthritis).
  • the molecules described above are TNF-alpha antagonists, they restrict their mechanism of action to the blockade of extracellular secreted TNF-alpha.
  • a comprehensive and not exhaustive list of targets that drive to TNF-alpha production and secretion might be: a) molecules driving transcriptional expression of TNF-alpha; b) molecules driving TNF-alpha-RNA transport from the nucleus to the cytoplasm and RNA splicing; c) molecules directing TNF-alpha translation; d) molecules regulating TNF-alpha-mRNA stability; e) molecules directing Golgi vesicles to the membrane where the pro-TNF-alpha surface form is anchored; f) molecules such as TNF-alpha-converting enzyme (TACE) implicated in the secretory shedding of TNF- alpha and g) molecules regulating the internalization of the surface form of pro-TNF- alpha and its signaling. All of these refer to cellular targets of TNF-alpha production and secretion.
  • TACE TNF-alpha-converting enzyme
  • compounds of formula (I) have shown a number of highly interesting immune modulating effects potentially useful for the control of the pathogenic mechanisms of acute and chronic inflammatory diseases and therefore, with potential clinical applications.
  • the compounds used in the invention have been able to inhibit TNF-alpha production by peripheral blood mononuclear cells (PBMC) from patients suffering from a chronic inflammatory disease, such as rheumatoid arthritis, as well as to inhibit IFN-gamma secretion by those cells after T-cells stimulation.
  • PBMC peripheral blood mononuclear cells
  • the immune cells are sessile, and enter organs to patrol the body tissues that infiltrate in the inflamed conditions where they concentrate in the lesions distributed according to the disease activity, target organs and extension of damage. Since the compounds used in the invention are expected to modulate some aspect of the patho-physiological process, then imaging studies can be used to characterize the number of receptors, binding efficiency, receptor occupancy and medicament probe concentration. Given the homing properties of leukocytes, the detection of the therapeutic target brings together information about the location of the target cells and the lesion sites.
  • the compounds of formula (I) also exhibit a potential use as imaging biomarkers in drug development, clinical trials and individualized medicine, which allows to provide information not only on pharmacokinetics, distribution and dosing but also relevant data on the individualized response patterns in preclinical and clinical trials.
  • the latter may lead to the definition of validated, reliable, individualized surrogate biomarkers of clinical endpoints administering to a patient who needs such prognostic and individualized evaluation of effective amount of a compound of formula (I) or a pharmaceutical composition thereof optimized for the distinct bio-imaging technology known by persons skilled in the art.
  • the present invention relates to the use of a compound of formula (I):
  • Ri is selected from hydrogen, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
  • R 2 is selected from hydrogen, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, and N(R'R") wherein R' and R" are independently hydrogen or Ci-C 6 alkyl; and
  • R3 is a Ci-C 6 alkyl radical, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in the preparation of a medicament for the treatment of an acute or chronic inflammatory disease, by inhibiting the production of at least one pro-inflammatory cytokine selected from TNF- alpha and IFN-gamma, or by inmunomodulating the IL-8 chemokine and/or the IL-IO regulatory cytokine.
  • the acute or chronic inflammatory disease is selected from acute and chronic seropositive or seronegative olygo arthritis and polyarthritis, spondiloarthropathies, glomerulonephritis, colagenopathies, tubulo- interstitial nephritis, metabolic syndrome, atherosclerosis, osteoarthritis, asthma, chronic obstructive pulmonary disease, interstitial lung disease, multiple sclerosis, demyelinating diseases, meningitis, encephalitis, meningoencephalitis, inflammatory radiculopathies and peripheral neuropathies, inflammatory bowel disease, cirrhosis, hepatitis, heart failure, ischemic disease, renal failure, inflammatory cystitis, benign prostatic hyperplasia, prostatitis, myocarditis, pericarditis, uveitis, atopic dermatitis, eccema, urticaria, psoriasis, rosacea, allergic rhin
  • These therapeutic indications are the consequence of at least an abnormal immune-response, an immune-disregulation, an immune-disturbance, an immune- pathogenesis, an immune-therapy, an immune-suppression or an immune-modulating biological response.
  • Ri is selected from hydrogen, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
  • R3 is a Ci-C 6 alkyl radical, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the invention is aimed at a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (F) as defined above, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and at least one pharmaceutically acceptable carrier, adjuvant and/or vehicle.
  • Another aspect of the present invention relates to a compound of formula (F) as defined above, for its use as a medicament.
  • Another aspect of the invention refers to the use of a compound of formula (I) as defined above as an imaging biomarker in imaging and pharmaco- imaging technologies, for finding immunological lesions, target cells and target molecules.
  • FIG. 1 Different fluorescent features of selected microparticles for the development of Cytometric Bead Array (CBA).
  • Figure 12 Effect of compound 12 on the shedding of CD62L in lymphocytes (a) and monocytes (b) of PBMC from healthy volunteers.
  • Ci_6 alkyl refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no insaturation, having one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc.
  • Ci_6 alkyl radicals may be optionally substituted by one or more substituents such as cycloalkyl, aryl, heterocyclyl, halo, hydroxy, alkoxy, cyano, amino, nitro or alkylthio.
  • cycloalkyl refers to a stable 3-to 8-membered ring radical which is saturated or partially saturated, and which consists solely of carbon and hydrogen atoms, such as cyclohexyl or cyclopentyl. Unless otherwise stated specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals which are optionally substituted by at least one substituent independently selected from the group consisting of hydrogen, Ci_6 alkyl radical, halo, hydroxyl, -N(Rs)(R 4 ), wherein R3 and R 4 are independently selected from hydrogen and linear or branched Ci_ 6 alkyl radical.
  • aryl refers to a stable 5- to 8-membered aromatic ring radical, and which consists solely of carbon and hydrogen atoms, such as phenyl or cyclooctatetraene. Unless otherwise stated specifically in the specification, the term
  • aryl is meant to include aryl radicals which are optionally substituted by at least one substituent independently selected from the group consisting of hydrogen, Ci_ 6 alkyl radical, halo, hydroxyl, -N(R 3 )(R 4 ), wherein R 3 and R 4 are independently selected from hydrogen and linear or branched Ci_6 alkyl radical.
  • Heterocyclyl refers to a stable 3-to 8 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur.
  • the heterocycle may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to pyrrolidine, pyridine, thiophene, furan, etc.
  • heterocyclyl is meant to include heterocyclyl radicals which are optionally substituted by at least one substituent independently selected from the group consisting of hydrogen, Ci_6 alkyl radical, halo, hydroxyl, - N(R 3 )(R 4 ), wherein R 3 and R 4 are independently selected from hydrogen and linear or branched Ci_6 alkyl radical.
  • halo refers to bromo, chloro, iodo or fluoro.
  • acute and chronic seropositive or seronegative olygo arthritis and polyarthritis refers to diseases with synovitis involving one or several dyarthrodial joints, with either positive or negative rheumatoid factor, including rheumatoid arthritis and both primary and secondary Sjogren syndrome.
  • pondiloarthropahies refers to immune pathogenically HLA-B27- associated inflammatory diseases with involvement of sacro-ileal joints and/or spinal and/or peripheral joints, also including uveitis.
  • glomerulonephritis refers to inflammatory lesions of the renal glomerulus.
  • tubulo-interstitial nephritis refers to inflammatory diseases involving tubules and renal interstitium.
  • colagenopathies refers to systemic inflammatory diseases with pathogenic immune mechanism including systemic lupus erythematosus (SLE), dermatomyositis and sclerodermia.
  • inflammatory bowel disease refers to inflammatory diseases of the gastrointestinal tract with pathogenic immune mechanism, either with or without systemic features, including Crohn's disease and ulcerative colitis.
  • obstructive pulmonary disease refers to bronchial diseases with either reversible or irreversible decrease of the flow expiratory volume (FEV), including asthma and chronic obstructive pulmonary disease.
  • FEV flow expiratory volume
  • interstitial lung disease refers to inflammatory diseases involving lung interstitium.
  • demyelinating diseases refers to inflammatory diseases of the central nervous system with an immune pathogenic mechanism provoking myelin lysis, including multiple sclerosis and optical neuritis.
  • meningitis, encephalitis and meningoencephalitis refers to inflammatory diseases of the meninges and/or other structures of the central nervous system.
  • inflammatory radiculopathies and peripheral neuropathies refers to inflammatory diseases of the peripheral nervous system.
  • inflammatory cystitis refers to inflammatory diseases of the bladder.
  • benign prostatic hyperplasia refers to non-malignant hyperthrophy and/or hyperplasia of the prostate.
  • atopic dermatitis, eccema and urticaria refers to allergic skin diseases with immune pathogenic mechanism with or without involvement of IgE.
  • psoriasis refers to hyperkeratosic and erythematous skin reaction with an immune system pathogenic mechanism.
  • rosacea refers to common inflammatory condition of the skin characterised by erythema (flushing and redness) on the central face and across the cheeks, nose or forehead also can also less commonly affect the neck and chest.
  • allergic rhinitis refers to intermittent (also called seasonal) or persistent (also called perennial) inflammatory nose mucosa diseases of immune hipersenivity pathogenic mechanism.
  • spontaneous shock refers to systemic inflammatory diseases mediated by an abnormal immune response to microbial agents and other ethio logical factors.
  • sarcoidosis and amyloidosis refers to idiopathic immunological diseases with organ and/or systemic involvement and no well defined ethiology in which an abnormal immune response can be observed.
  • organ specific auto-immune diseases refers to immune system- mediated lesion of organs with no defined ethio logical factors, including myastenia gravis, tyroiditis, hypophysitis, adrenalitis and others.
  • organ transplantation refers to prevention and treatment of rejection of transplanted cells, tissues and organs.
  • infection and tumour-induced inflammation refers to abnormal immune responses secondary to microbial agents or cancer stimuli.
  • TNF-alpha dependent cellular degeneration, apoptosis or necrosis refers to tissue degeneration or death induced by TNF-alpha.
  • graft versus host disease refers to inflammatory immune responses induced by graft cells.
  • caquexia refers to systemic anorexia or malnutrition and weight loss induced by inflammatory or neoplasic diseases.
  • atherosclerosis refers to any hardening of arteries secondary to atheroma or accumulation in the arthery walls that is made up of inflammatory cells (mostly macrophage cells) and cell debris, that contain lipids.
  • ischemic diseases refers to lesion of organs secondary to reduced tissue oxigenation and/or blood flow including heart and cerebrovascular ischaemia.
  • autocrine and paracrine pathological cell growth refers to malignant or benign diseases with cell use of TNF-alpha as a cytokine regulating activation and proliferation factor for the cells.
  • the compounds used in the invention are intended to include compounds that only differ in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the substitution of an hydrogen with deuterium or tritium, or the substitution of a carbon with a 13 C- or
  • salts, prodrugs and derivatives can be prepared by means of methods known in the state of the art.
  • “Pharmaceutically acceptable” preferably relates to molecular entities and compositions which are physiologically tolerable and do not typically cause an allergic reaction or a similar unfavorable reaction, such as gastric disorders, dizziness and the like, when administered to a human or animal.
  • pharmaceutically acceptable means that it is approved by a regulatory agency of a federal or state government or is included in the US pharmacopoeia or another generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • the pharmaceutically acceptable salts of the compounds described previously herein are synthesized from the previously described compound containing a basic or acidic unit by means of conventional chemical methods.
  • Such salts are generally prepared, for example, by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of both.
  • Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, are generally preferred.
  • acid addition salts include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, for example, and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate, for example.
  • alkaline addition salts include inorganic salts such as sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium, for example, and organic alkaline salts such as ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, glucamine and basic amino acid salts for example.
  • prodrug is defined herein as a chemical compound which has undergone a chemical derivation such as a substitution or addition of an additional chemical group in order to change (for pharmaceutical use) some of its physical chemistry properties, such as solubility or bioavailability, for example an ester or ether derived from an active compound giving an active compound per se after the administration to a subject.
  • chemical derivation such as a substitution or addition of an additional chemical group in order to change (for pharmaceutical use) some of its physical chemistry properties, such as solubility or bioavailability, for example an ester or ether derived from an active compound giving an active compound per se after the administration to a subject.
  • solubility or bioavailability for example an ester or ether derived from an active compound giving an active compound per se after the administration to a subject.
  • solvate is understood to mean any form of a compound of the invention having another molecule (most likely a polar solvent) bound to it through a non-covalent bond.
  • solvates include hydrates and alcoholates, for example methanolate.
  • Particularly preferred prodrugs are those increasing the bioavailability of the compounds of this invention when such compounds are administered to a patient (allowing an orally administered compound to be more quickly absorbed into the blood, for example) or those increasing the distribution of the original compound to a biological compartment (the brain or the lymphatic system, for example) with respect to the original species.
  • the compounds used in the invention may be in crystalline form, i.e. as polymorphs, either as free compounds or as solvates (hydrates, for example) and it is understood that both forms are within the scope of the present invention.
  • Solvation methods are generally known in the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment, the solvate is a hydrate.
  • Salts, solvates and prodrugs can be prepared by means of methods known in the state of the art. It will be observed that pharmaceutically unacceptable salts, solvates or prodrugs are also included within the scope of the invention because they can be useful in the preparation of pharmaceutically acceptable salts, solvates or prodrugs.
  • the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable form or in substantially pure form.
  • a pharmaceutically acceptable form is understood, inter alia, as having a pharmaceutically acceptable purity level, excluding normal pharmaceutical additives such as diluents and excipients, and without including any material considered to be toxic at normal dosage levels.
  • the purity levels for the drug are preferably above 50%, more preferably above 70%, and still more preferably above 90%. In a preferred embodiment, it is above 95% of the compound of formula (I), or of its salts, solvates or prodrugs.
  • the compounds used in the invention shown by the formula (I) described above can include enantiomers depending on the presence of chiral centers or isomers depending on the presence of multiple bonds (for example, Z, E).
  • the individual isomers, enantiomers, diastereoisomers and mixtures thereof are within the scope of the present invention.
  • the compound of formula (I) may be labeled with fluorescent or luminiscent tags or flags, introducing the markers by any method known by a skilled person in the art.
  • Ri is a substituted or unsubstituted Ci-C 6 alkyl.
  • Ri is methyl.
  • R 2 is hydrogen, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl.
  • R 2 is a substituted or unsubstituted cycloalkyl. More preferably, R 2 is cyclopentyl.
  • R 3 is methyl.
  • the compound of formula (I) used in the present invention is selected from the following compounds:
  • the compounds of formula (I) used in the present invention can be obtained by available synthetic procedures. For example, they can be prepared by a process which is summarised in the following scheme:
  • This process firstly comprises an esterification reaction of the compound 4-R 3 - thiophenylacetic acid to render the methyl ester derivative.
  • Said reaction can be carried out using a methylating agent, such as MeI, in the presence of a salt, such as NaHCO 3 , or using MeOH as methylating agent in the presence of an acidic medium.
  • the methyl ester derivative is oxidized at the sulphur atom using an oxidizing agent, for instance, oxone, thus obtaining the sulfone compound from the thioether group.
  • an oxidizing agent for instance, oxone
  • Said thioamides include compounds wherein Ri is selected from hydrogen, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl as defined above.
  • R 2 radical through the hydro xyl group
  • the hydroxyl group is reacted with an halide of formula R 2 -HaI, preferably R 2 -Br, to provide the compound of formula (I).
  • the present invention provides a compound of formula (F):
  • Ri is selected from hydrogen, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic and R 3 is a Ci-C 6 alkyl radical, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • Ri is a substituted or unsubstituted Ci-C 6 alkyl.
  • Ri is methyl
  • R 3 is methyl.
  • the compound of formula (F) of the invention is selected from the following: or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the present invention further provides pharmaceutical compositions comprising the novel compound of formula (F) of the present invention, or pharmaceutically acceptable salts, solvates or prodrugs thereof and at least one pharmaceutically acceptable carrier, adjuvant and/or vehicle, for the administration to a patient.
  • the compounds of formula (I), their pharmaceutically acceptable salts, prodrugs and/or solvates will be formulated in a suitable pharmaceutical composition, in the therapeutically effective amount, together with one or more pharmaceutically acceptable carriers, adjuvants, and/or vehicles.
  • carrier, adjuvant and/or vehicle relates to molecular entities or substances with which the active ingredient is administered.
  • Such pharmaceutical carriers, adjuvants or vehicles can be sterile liquids, such as waters and oils, including those of petroleum or with an animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, excipients, disintegrants, wetting agents or diluents.
  • Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • compositions can be administered by any suitable method of administration, for example, oral, parenteral (for example, subcutaneous, intraperitoneal, intravenous, intramuscular, etc.), rectal administration, etc., typically orally due to the chronic nature of the disease to be treated.
  • parenteral for example, subcutaneous, intraperitoneal, intravenous, intramuscular, etc.
  • rectal administration etc., typically orally due to the chronic nature of the disease to be treated.
  • said pharmaceutical compositions can be in an oral administration pharmaceutical form, either in solid or liquid form.
  • oral administration pharmaceutical forms include tablets, capsules, granulates, solutions, suspensions, etc., and can contain conventional excipients such as binders, diluents, disintegrants, lubricating agents, wetting agents, etc., and can be prepared by conventional methods.
  • the pharmaceutical compositions can also be adapted for their parenteral administration, in the form of, for example, sterile, lyophilized products, suspensions or solutions in the suitable dosage form; in this case, said pharmaceutical compositions will include suitable excipients, such as buffers, surfactants, etc. In any case, the excipients will be chosen according to the selected administration pharmaceutical form.
  • the compound of formula (I) will preferably be found in a pharmaceutically acceptable or substantially pure pharmaceutical form, i.e. the compound of formula (I) has a pharmaceutically acceptable purity level excluding pharmaceutically acceptable excipients and does not include material considered to be toxic at normal dosage levels.
  • the purity levels for a compound of formula (I) are preferably greater than 50%, more preferably greater than 70%, more preferably greater than 90%. In a preferred embodiment, they are greater than 95%.
  • the therapeutically effective amount of the compound of formula (I) to be administered will generally depend, among other factors, on the individual to be treated, on the severity of the disease suffered by said individual, on the chosen method of administration, etc. For this reason, the doses mentioned in this invention must only be considered as guidelines for the person skilled in the art, and the latter must adjust the doses according to the aforementioned variables. Nevertheless, a compound of formula (I) can be administered once or more times a day, for example, 1, 2, 3 or 4 times a day, in a typical total daily amount comprised between 0.1 and 1000 mg/kg of body mass/day, preferably 10 mg/kg of body mass/day.
  • the compound of formula (I), its pharmaceutically acceptable salts, prodrugs and/or solvates, as well as the pharmaceutical compositions containing them can be used together with other additional drugs useful for treating acute and chronic inflammatory diseases.
  • Said additional drugs can form part of the same pharmaceutical composition or alternatively, can be provided in the form of a separate composition for its simultaneous or non-simultaneous administration with the pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • the expression "acute and chronic inflammatory disease” relates to any disease, disorder or condition which results from the activation and pathogenic involvement of inflammatory/immune cells and inflammatory cytokine cascade under condition in which abnormal co-stimulation is a pathogenic mechanism.
  • the predominant cells involved are inflammatory/immune cells such as monocytes, macrophages, APC, T, B and Natural Killer (NK) cells, plasma cells, granulocytes and mast cells, or combinations of the above cell subpopulations implicated in the diseases proposed for treatment.
  • cytokine refers to a secreted protein that affects the functions of other cells, particularly as it relates to the modulation of interactions between cells of the immune system or cells involved in the inflammatory response.
  • cytokines are TNF-alpha (tumor necrosis factor- ⁇ ), IFN-gamma (inter feron- ⁇ ), the IL-8 (interleukin- 8) chemokine, and the regulatory cytokine IL-IO (interleukin-10).
  • IL-IO production is induced by high TNF-alpha levels and promotes a negative feed-back upon TNF-alpha production, upon blockade of pro-inflammatory cytokine transcription.
  • the acute or chronic inflammatory disease is selected from acute and chronic seropositive or seronegative olygo arthritis and polyarthritis, spondiloarthropathies, glomerulonephritis, colagenopathies, tubulo- interstitial nephritis, metabolic syndrome, atherosclerosis, osteoarthritis, asthma, chronic obstructive pulmonary disease, interstitial lung disease, multiple sclerosis, demyelinating diseases, meningitis, encephalitis, meningoencephalitis, inflammatory radiculopathies and peripheral neuropathies, inflammatory bowel disease, cirrhosis, hepatitis, heart failure, ischemic disease, renal failure, inflammatory cystitis, benign prostatic hyperplasia, prostatitis, myocarditis, pericarditis, uveitis, atopic dermatitis, eccema, urticaria, psoriasis, rosacea, allergic rhin
  • the acute or chronic inflammatory disease is seropositive or seronegative chronic polyarthritis, more preferably is rheumatoid arthritis.
  • Another aspect of the present invention is a method for treating an acute or chronic inflammatory disease, which comprises administering to a patient who needs such treatment a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutical composition thereof.
  • treatment means the administration of a compound with a formulation according to the invention for preventing, alleviating or eliminating the disease or one or more symptoms associated to said disease.
  • Treatment also includes preventing, alleviating or eliminating the physiological sequel of the disease.
  • Another aspect of the invention refers to the use of a compound of formula (I) as defined above as an imaging biomarker in imaging and pharmaco -imaging technologies, for finding immunological lesions, target cells and target molecules.
  • the pharmaco-imaging technology extends the scope of biomarkers obtained by the rapidly growing combination of adequate preclinical (molecular, cellular, organ and whole animal tracking and study of proof of concept and mechanisms, efficacy assessment, etc) and clinical (human medical) in vivo imaging technologies, to those valuable information data generated by compounds described herein and used as medicines.
  • NMR 1 H (CDCl 3 ), ⁇ : 7.9 (d, 2 H), 7.75 (d, 2H), 5.4 (s, IH), 3.8 (s, 3H), 3,1 (s, 3H).
  • the degree of disease activity was defined as follows: a) DAS28 > 3,2 and/or b) 6 or more swollen articulations and 6 or more painful articulations.
  • exclusion criteria were considered the following: a) to suffer from active infectious diseases in the inclusion visit; b) to suffer from oncological diseases prior the inclusion; 3) to suffer from another systemic or organ specific auto-immune disease which had not entered into a complete remission at least one year prior the inclusion visit; d) to suffer from a severe renal, cardiac or hepatic condition not related with the changes at those levels induced by the rheumatoid arthritis as main disease; e) to suffer a severe deterioration of the general status due to a condition not related with the main disease; f) to have received treatment with corticosteroids, immunosuppresors, cytostatic or any other drugs with known activity on the immune system during the year prior the inclusion visit with the exception of the indicated doses of Methrotexate; 7) to be pregnant or within the puerperium in the inclusion visit.
  • Herasafe HS 12 Heraeus, Germany.
  • FCS Phoetal bovine serum
  • PHA Phytohaemaglutinin M
  • - Antibiotic mixture A mixture of Sodium Ampycilline 10 mg/ml (Britapen, Beecham A., Toledo, Spain), Gentamycin sulphate 1.6 mg/ml (Tamadit Lab., Dr. Esteve SA., Madrid, Spain) and Amphotherycine B 0.5 ⁇ g/ml (Fungizona, Squibb, Esplugues, Barcelona, Spain) was added to the culture medium.
  • - Anti-CD3 monoclonal antibody Orthoclone OKT3, Orthopharmaceutical Corporation, Raritan, NJ, USA).
  • Venous blood Mononuclear cells were obtained from venous blood as collected by antecubital venous punction. Fifty ml of blood were extracted and stored in lithium heparin tubes (Venojet), further diluted with saline 1/1 (vol/vol) being all performed under sterile conditions. b) Human Cell subsets harvesting. For isolating PBMC, the remaining blood components were separated by a density gradient on Ficoll. This method is based on the differences on density of blood cells. In a 50 ml centrifuge tube containing the diluted and heparinized blood, 15 ml Ficoll-Hipaque (density 1.077 g/ml) was carefully placed on.
  • PBMC erythrocytes, Ficoll and plasma
  • PBMC erythrocytes, Ficoll and plasma
  • the extracted blood was stored in tubes both with and without anti-coagulant (collected by antecubital venopunction and arterial catheter, respectively). Blood was allowed to coagulate at room temperature in the laboratory, further separating the serum by centrifugation (600xg during 20 minutes). Supernatant were collected, filtered, divided in aliquotes and stored at -7O 0 C. Concentration assays for different cytokines were performed by using the commercial kits described in Table 2.
  • PE phycoerythrin-labeled
  • FACSCalibur flow cytometer equipped with argon laser tuned at 488 nm was used in order to induce phycoerythrin fluorescence.
  • study cells with no labelling and other irrelevant labelled with monoclonal antibodies of equal isotypes than the ones used in the study (IgGl-FITC, PE y TC, IgG2a FITC, PE, TC), were used.
  • lymphocytes Faced against a mitogen stimulation, lymphocytes suffer a blastogenesis and cellular differentiation process.
  • the method used to quantify the cellular proliferation was the assay of the incorporation of 3 [H] -Thymidine to the DNA de novo synthesized, and the emission of betha-radiation from the cellular cultures dried extracts (to which the tritiated base was added) was detected before its ending and harvesting.
  • the purified cellular preparations were incubated in 96 microwells plain bottom plates at concentrations of 5 x 10 4 cells/well (200 ⁇ l final volume), in the presence of different concentrations of various mitogens with triplicate repetitions and along 4 days of culture. The response to a specific stimuli depended on the density and cell type studied, as well as of the culture time and of the mitogenic agent concentration.
  • DNA synthesis was expressed in counts per minute (c.p.m.). Each assay was performed in triplicate, rejecting those data with a variability higher than 10 % in the mean of the triplicate as they might indicate a technical error or a contamination of the culture. Cultures were performed with a constant amount of cells per well as well as with a constant volume of 200 ⁇ l. All mitogens and cytokines were first tested by carrying out dose-response curves and time-response.
  • the experimental protocol consisted of a plate pre-washing out with Wash Buffer. After decantation, the mixture of capture microparticles was re-suspended in the vortex. Standards and samples were added in the adequate dilution. After permanent stirring incubation during 1 h, the PE detection reagent was added and incubated again during 2h at room temperature. After a washing-out, the acquisition was performed in the flow cytometer. Table 3. -Kit CBA Human Soluble Protein Multiplex Flex Set System.
  • PBMC peripheral blood mononuclear cells
  • PBMC TNF-alpha production by PBMC of healthy volunteers in the presence or in the absence of LPS were first investigated.
  • PBMC PBMC (5 x 10 4 cells/well, 200 ⁇ l) from 10 healthy volunteers were cultured in parallel in duplicate in tissue culture plates, 96 well, flat-bottom with low evaporation lid (353072 Falcon, Becton Dickinson labware, Franklin Lakes, USA, 07417-1886 NJ) in complete medium (RPMI-1640 with glutamine Cat BE-12-70F, Cambrex Biosciences, B4880 Verviers, Belgium), supplemented with phoetal bovine serum (origin USA, Gibco ref.
  • Immune modulator effects of compound 12 were further characterised on the production of a cytokine panel by PBMC either after monocyte stimulation with either LPS or lymphocyte activation with a combination of monoclonal antibodies anti-CD3 and anti-CD28. This study was performed in the presence or absence of titrated doses of compound 12 in cultures of PBMC obtained from healthy volunteers and patients with rheumatoid arthritis.
  • PBMC peripheral blood mononuclear cells
  • CBA Flex Multiplex Set (BDTM Cytometric Bead Array, CBA: IL-8, IL-IO, TNF-alpha and IFN-gamma Becton Dickinson Biosciences Pharmingen, San Diego CA 92121).
  • PBMC peripheral blood mononuclear cells
  • Example 7 Effects of compound 12 on the production of IFN-gamma.
  • PBMC peripheral blood mononuclear cells
  • Compound 12 at a concentration of 10 "6 M significantly inhibited the production of IFN-gamma by PBMC from healthy volunteers either LPS-stimulated or stimulated with monoclonal antibodies anti-CD3 and anti-CD28 (p ⁇ 0.05) (Figure 5).
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • Example 8 Effects of compound 12 on Interleukin 8 (IL-8) production.
  • the effect of compound 12 on the IL-8 production by the PBMC from healthy volunteers was further investigated, both in the presence and absence of LPS stimuli and monoclonal antibodies anti-CD3 and anti-CD28.
  • PBMC (5 x 10 4 cells/well) from 13 healthy volunteers were cultured in duplicate in 200 ⁇ l of complete medium supplemented with the highest solvent concentration (10 ⁇ 6 M), and 10 "6 M, 10 "7 M and 10 "8 M of compound 12, in the presence and absence of either LPS (10 ⁇ g/ml) or anti- CD3 (12.5 ng/ml) + anti-CD28 (l/3xl ⁇ 5 ), during 24 hours.
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • 10 "6 M, 10 "7 M and 10 "8 M of compound 12 were cultured in duplicate in 200 ⁇ l of complete medium supplemented with the highest solvent concentration (10 ⁇ 6 M), and 10 "6 M, 10 "7 M and 10 "8 M of compound 12, in the presence and in the absence of either LPS (10 ⁇ g/ml) or anti-CD3 (12.5 ng/ml) + anti-CD28 (l/3xl ⁇ 5 ), during 24 hours.
  • Culture supernatants were frozen at -2O 0 C and IL-8 concentration was quantified by BD FACS Array Bioanalyser by using CBA Flex
  • Example 9 Effects of compound 12 on Interleukin 10 (IL-IO) production.
  • PBMC (5 x 10 4 cells per well) from 13 healthy volunteers were cultured in duplicate 200 ⁇ l of complete medium supplemented with the highest solvent concentration (10 ⁇ 6 M), and 10 "6 M, 10 "7 M and 10 "8 M of compound 12, in the presence and absence of either LPS (10 ⁇ g/ml) or anti-CD3 (12.5 ng/ml), + anti-CD28 (l/3xl ⁇ 5 ), during 24 hours.
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • 10 "6 M, 10 "7 M and 10 "8 M of compound 12 in the presence and absence of either LPS (10 ⁇ g/ml) or anti-CD3 (12.5 ng/ml), + anti-CD28 (l/3xl ⁇ 5 ), during 24 hours.
  • Culture supernatants were frozen at -2O 0 C and IL-10 concentration was assayed by BD FACS Array Bioanalyser by using CBA Flex Set, specific to determine IL-10 concentration, following the manufacturer instructions.
  • Compound 12 showed no effects on the IL-10 production by PBMC from healthy volunteers in the presence and in the absence of both studied stimuli ( Figures 9). However, the presence of compound 12 in the culture, at a concentration of 10 "8 , significantly upmodulated IL-10 production after stimulation of PBMC from patients with rheumatoid arthritis with LPS (p ⁇ 0.05). Compound 12 induced no significant effects neither on the spontaneous production of IL-10 nor after the stimulation with monoclonal antibodies anti-CD3 and anti-CD28 by PBMC from patients with rheumatoid arthritis ( Figure 10).
  • Example 10 Effect of compound 12 on the proliferative response of PBMC.
  • PBMC peripheral blood mononuclear cells
  • Culture stimulation conditions were the absence or presence or phytohaemaglutinin (PHA Sigma Ref #L-8902, Madrid, Spain), 10 ⁇ g/ml; PHA 2 ⁇ g/ml with exogenous IL-2 supplementation (25 IU/ml, Human recombinant IL-2, Macrolin, Chiron Iberica, batch #SA753228/4, Madrid, Spain) and monoclonal antibodies anti-CD3 (12.5 ng/ml) + anti-CD28 (1 :320.000).
  • Methyl- 3 H- Thymidine was added (American Radiochemical 60 Ci/mmol methyl- 3 H-Thymidine, ITISA, Madrid, Spain) during the last 8 hours of culture.
  • Example 11 Effect of compound 12 on the shedding of CD62L by PBMC
  • CD62L shedding CD62L -Phycoerithryn (PE), clon BD SKI l Cat No. 341012, BD Biosciences
  • MFI geometric mean fluorescence intensity

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Abstract

L'invention porte sur l'utilisation d'un composé de formule (I) ou d’un sel, d’un promédicament et/ou d’un solvate pharmaceutiquement acceptables correspondants, dans la préparation d'un médicament pour le traitement d'une maladie inflammatoire aiguë ou chronique, par l'inhibition de la production d'au moins une cytokine pro-inflammatoire choisie parmi TNF-alpha et IFN-gamma, ou par immunomodulation de la chimiokine IL-8 et/ou de la cytokine régulatrice IL-10. L'invention porte également sur de nouveaux composés de formule (I') ou sur un sel, un promédicament et/ou un solvate pharmaceutiquement acceptables correspondants, ainsi que sur une composition pharmaceutique renfermant lesdits composés.
EP09765806A 2008-06-16 2009-06-15 Dérivés de 5-(4-méthanesulfonyl-phényl)-thiazole pour le traitement de maladies inflammatoires aiguës et chroniques Withdrawn EP2313382A1 (fr)

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EP09765806A EP2313382A1 (fr) 2008-06-16 2009-06-15 Dérivés de 5-(4-méthanesulfonyl-phényl)-thiazole pour le traitement de maladies inflammatoires aiguës et chroniques

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EP08380177A EP2135864A1 (fr) 2008-06-16 2008-06-16 Dérivés de 5-(4-methanesulfonyl-phenyl)-thiazole pour le traitement de maladies inflammatoires aiguës et chroniques
US12/139,661 US7781594B2 (en) 2008-06-16 2008-06-16 5-(4-methanesulfonyl-phenyl)-thiazole derivatives for the treatment of acute and chronic inflammatory diseases
PCT/EP2009/057324 WO2009153226A1 (fr) 2008-06-16 2009-06-15 Dérivés de 5-(4-méthanesulfonyl-phényl)-thiazole pour le traitement de maladies inflammatoires aiguës et chroniques
EP09765806A EP2313382A1 (fr) 2008-06-16 2009-06-15 Dérivés de 5-(4-méthanesulfonyl-phényl)-thiazole pour le traitement de maladies inflammatoires aiguës et chroniques

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RU2502513C2 (ru) * 2012-01-11 2013-12-27 Государственное бюджетное учреждение здравоохранения Свердловской области "Свердловский областной клинический психоневрологический госпиталь для ветеранов войн" (ГБУЗ СО "СОКП Госпиталь для ветеранов войн") Способ лечения больных с полиорганной патологией озонотерапией
CN111343975A (zh) * 2017-11-23 2020-06-26 埃慕尼克股份公司 用于预防或治疗慢性炎性疾病和/或自身免疫疾病的维多地莫的剂量方案
KR102076936B1 (ko) * 2019-08-12 2020-02-13 연세대학교 산학협력단 티아졸 또는 이의 염을 유효성분으로 포함하는 알러지성 질환 또는 아토피 피부염 예방 또는 치료용 조성물

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AU2009259451A1 (en) 2009-12-23
WO2009153226A1 (fr) 2009-12-23
TW201010988A (en) 2010-03-16
NZ589894A (en) 2011-08-26
CO6331429A2 (es) 2011-10-20
TWI403506B (zh) 2013-08-01
RU2011101439A (ru) 2012-07-27
UY31896A (es) 2010-01-29
RU2495031C2 (ru) 2013-10-10
JP2011524352A (ja) 2011-09-01
CA2728139A1 (fr) 2009-12-23
AR072113A1 (es) 2010-08-04
KR20110022679A (ko) 2011-03-07
IL209801A0 (en) 2011-02-28
MX2010013978A (es) 2011-03-29
CN102083806A (zh) 2011-06-01
AU2009259451B2 (en) 2013-03-14
ZA201008877B (en) 2012-02-29
BRPI0915325A2 (pt) 2015-10-27
SA109300384B1 (ar) 2013-04-20
MA32473B1 (fr) 2011-07-03

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