EP2734497A1 - Dimères d'indane pouvant être utilisés dans le traitement des maladies inflammatoires auto-immunes - Google Patents

Dimères d'indane pouvant être utilisés dans le traitement des maladies inflammatoires auto-immunes

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Publication number
EP2734497A1
EP2734497A1 EP12740703.9A EP12740703A EP2734497A1 EP 2734497 A1 EP2734497 A1 EP 2734497A1 EP 12740703 A EP12740703 A EP 12740703A EP 2734497 A1 EP2734497 A1 EP 2734497A1
Authority
EP
European Patent Office
Prior art keywords
compound
quat
tert
mmol
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP12740703.9A
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German (de)
English (en)
Inventor
Helen Sheridan
Neil Frankish
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Venantius Ltd
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Venantius Ltd
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Publication date
Application filed by Venantius Ltd filed Critical Venantius Ltd
Publication of EP2734497A1 publication Critical patent/EP2734497A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • This invention relates to compounds particularly for use in the autoimmune inflammatory disease and specifically the treatment of inflammatory bowel disease.
  • Cytokines can be produced by various cell populations and have been shown to augment or limit immune responses to pathogens and influence the autoimmune response.
  • One family of cytokines which uses the common receptor gamma chain (cc), a component of receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21, has been classically defined as growth and survival factors.
  • IL-2 production can induce an immune response by promoting the proliferation and generation of CD4+ Thl, CD4+ Th2 and CD8+ CTL effector cells.
  • Many of the immunosuppressive drugs used in the treatment of autoimmune diseases and organ transplant rejection such as corticosteroids and immune suppressive drugs (ciclosporin, tacrolimus) work by inhibiting the production of IL-2 by antigen -activated T cells.
  • Others (sirolimus) block IL-2R signalling, thereby preventing the clonal expansion and function of antigen-selected T cells [ref: Opposing functions of IL-2 and IL-7 in the regulation of immune responses Shoshana D. Katzman, Katrina . Hoyer, Hans Dooms, Iris K. Gratz, Michael D. Rosenblum, Jonathan S. Paw, Sara H. Isakson, Abul K. Abbas. Cytokine 56 (201 1) 1 16-121]
  • IL-2 can inhibit the immune response by promoting the survival and functionality of natural (thymic) regulatory T-cells (Tregs), promoting the generation of induced (peripheral) Tregs and inhibiting the generation of CD4+ Thl 7 effector cells [ref: IL-2 and autoimmune disease.
  • Teregs natural regulatory T-cells
  • Tregs promoting the generation of induced (peripheral) Tregs and inhibiting the generation of CD4+ Thl 7 effector cells
  • IL-2 and autoimmune disease IL-2 and autoimmune disease.
  • Interleukin-2/IL-2R deficiency with time leads to multiorgan inflammation and the formation of autoantibodies of various specificities.
  • IL-2 signalling has been shown to be important in both the initiation and regulation of immune responses. In these dual and opposing roles, IL-2 acts to balance immune response, both driving immune cell activation and subsequent reduction.
  • the potential clinical applicability of either augmenting or inhibiting signals mediated by IL-2 is significant and includes cancer, autoimmune inflammatory diseases, organ transplantation and HIV.
  • IBD Inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • IBD inducing and maintaining remission.
  • IBD patients may be maintained on remission by use of a 5-aminosalycilate.
  • aminosalycilates in UC provides considerable benefit, both in inducing remission in mild to moderate disease and in preventing relapse, the usefulness of these drugs to maintain remission in CD is questionable and is no longer recommended.
  • the mainstay of treatment of active disease is a corticosteroid, commonly used for limited periods to return both UC and CD patients to remission, though budesonide, designed for topical administration with limited systemic absorption, has no benefit in maintaining remission.
  • Alternatives such as the immunosuppressive drugs azathioprine and mercaptopurine, together with methotrexate and cyclosporine have limited efficacy and the capability of inducing grave adverse effects.
  • Anti- TNFa antibodies such as infliximab and adalimubab, may be used in those patients unresponsive to standard immunosuppressive therapy. However, many patients fail to respond to anti-TNFa therapy, either due to their particular phenotype or by the production of autoantibodies.
  • the invention provides a compound of the relative stereochemistry and formula:
  • R is selected from one or more of the same or different of
  • Ri is selected from one or more of the same or different of
  • the compounds herein include pharmacologically acceptable salts, esters, amides, solvates, and prodrugs thereof.
  • the invention also provides a compound of the absolute stereochemistry and formula:
  • R is selected from one or more of the same or different of hydrogen
  • Ri is selected from one or more of the same or different of
  • aryl optionally substituted aryl, and an amino acid selected from leucine, valine, isoleucine, and glycine.
  • alkyl contains from 1 to 10 carbon atoms in a straight or branched chain and may be saturated or unsaturated, or cycloalkyl groups containing 3 to 8 carbon atoms which may be saturated or unsaturated.
  • alkyl is substituted with one or more of the same or different from alkyl, alkoxy, alkylamino, amido, amino, aryl, aralkyl, aryloxy, carboxy, halo, hydroxy, nitrile, nitro or oxo groups.
  • aryl is substituted with one or more of the same or different from alkyl, alkoxy, alkylamino, amido, amino, anhydride, aryl, aralkyl, aryloxy, carboxy, halo, hydroxy, nitrile, nitro, or oxo groups.
  • amino is substituted with one or more of the same of different from alkyl, hydroxyalkyl, aryl, and substituted aryl. In some cases amino is substituted with aryl substituted by one or more of OH, NH 2 , and COOH. In one embodiment R is OH.
  • Ri is H.
  • the invention also provides compounds of the following formula with the absolute stereochemistry and formula
  • R is selected from: OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , NH 2 , NHCH 2 CH 2 OH, NHCH 3 , N(CH 3 ) 2 , NH(4-OH-3-benzoic acid)
  • R 1 is H or leucine and R is selected from: OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , NH 2 , NHCH 2 CH 2 OH, NHCH 3 , N(CH 3 ) 2 , NH(4-OH-3-benzoic acid).
  • R may be selected from one or more of the same or different of: H, hydroxy, alkoxy, alkyl carbonyl, aryloxy, anhydride, substituted anhydride,amino, substituted amino, amide, alkylamino, nitro, nitrite, nitrile, mono and polybenzoid aryl groups, substituted aryl groups, thiol, thioureyl, phenylthiol groups, sulphonic acid groups, sulphoxide groups, sulphone groups, alkyl containing 1 to 10 carbon atoms or cycloalkyl groups containing 3 to 8 carbon atoms which may be saturated or unsaturated, and substituted alkyl or cycloalkyl which may be saturated or unsaturated.
  • Ri may be selected from one or more of the same or different of: H, alkoxy, alkyl carbonyl, aryl, acetoxy, alkyl containing 1 to 10 carbon atoms or cycloalkyl groups containing 3 to 8 carbon atoms which may be saturated or unsaturated, substituted akyl, and an amino acid selected from leucine, valine, isoleucine, and glycine. Also provided are pharmacologically acceptable salts, esters, amides and solvates thereof.
  • alkyl or cycloalkyl are substituted with one or more of the same of different of halo, oxo, hydroxy, alkoxy, aryloxy, carboxy, amino, amide, alkylamino, nitro, nitrate, nitrite, nitroso groups, nitrile, heterocyclic groups, aryl, aralkyl groups, alkyl substituted by OH, COOH, and/or NH 2 .
  • amino is substituted with one or more of the same of different of hydroxyl, alkylhydroxyl, aryl, and aryl substituted by one or more of OH, N3 ⁇ 4, and COOH.
  • anhydride is substituted with aryl or aryl substituted by one or more of OH, NH 2 , and
  • R is OH and Ri is H.
  • R is not OH. In this instance, in some cases salts thereof are excluded.
  • Ri is not H. In this instance, in some cases salts thereof are excluded.
  • R is not OH and Ri is not H. In this instance, in some cases salts thereof are excluded.
  • the invention also provides compounds of the structural formula I:
  • the present invention provides compounds of relative stereochemistry as demonstrated in structural formula II:
  • the invention also provides the N-Methyl-(D)-Glucamine salt of the compound of formula III:
  • the invention further provides a pharmaceutical composition comprising an effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • the invention also provides a method for the prophylaxis or treatment of inflammatory bowel disease, comprising administering to a subj ect an effective amount of a compound of the inventio.
  • the invention further provides a method for the prophylaxis or treatment of ulcerative colitis, comprising administering to a subject an effective amount of a compound of the invention.
  • the compounds of the invention are also potentially useful in either augmenting or inhibiting signals mediated by IL-2.
  • the clinical uses include the treatment of cancer, autoimmune inflammatory disorders, organ transplantation and HIV.
  • the invention provides a compound as exemplified below
  • the invention also provides a compound of the formula:
  • the preferred isomer is
  • the invention further provides a pharmaceutical composition comprising any of the compounds described above.
  • the active compound may be present in the medicament for use in man at a suitable dose to achieve the desired effect.
  • the final dose may be between 0.1 and 10 mg/kg.
  • Such formulations may comprise one or more pharmaceutically acceptable excipient, carrier or diluent.
  • the compounds of the invention may be administered in a number of different ways.
  • the compounds may be administered orally.
  • Preferred pharmaceutical formulations for oral administration include tablets, capsules, caplets, solutions, suspensions or syrups.
  • the pharmaceutical formulations may be provided in a form for modified release such as a time release capsule or tablet.
  • the medicament may be administered orally, parenterally, intranasally, transcutaneously or by inhalation.
  • the invention also provides a method for the prophylaxis or treatment of inflammatory bowel disease, comprising administering to a subject an effective amount of a compound of the invention.
  • the invention further provides a method for the prophylaxis or treatment of ulcerative colitis, comprising administering to a subject an effective amount of a compound of the invention.
  • compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituted refers to the replacement of hydrogen atoms in a given structure with a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • alkyl refers to a straight or branched chain hydrocarbon, preferably having from one to ten carbon atoms.
  • exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, isopentyl, n-pentyl, and the like.
  • unsaturated means that a moiety has one or more units of unsaturation.
  • cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring.
  • exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • cycloalkyl includes a fused ring system where, for example, a cycloalkyl ring is fused with an aromatic ring.
  • aryl used alone or as part of a larger moiety refers to monocyclic or polycyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl refers to a benzene ring or to a fused benzene ring system, such as anthracene, phenanthrene, or naphthalene ring systems.
  • Examples of aryl groups include phenyl, 2-naphthyl, 1-naphthyl, and the like.
  • alkoxy refers to a group --OX, where X is alkyl, as herein defined.
  • aryloxy alone or as part of another group includes any of the above aryl groups linked to an oxygen atom.
  • alkoxycarbonyl refers to a group— C(0)OX where X is alkyl as defined herein.
  • amino refers to a nitrogen radical substituted with hydrogen, alkyl, aryl, or combinations thereof.
  • amino groups include— NHMethyl,— NH 2 , ⁇ N(Methyl)2,— NPhenylMethyl, -NHPhenyl, -NEthylMethyl, and the like.
  • An "alkylamino” refers to a nitrogen radical substituted with at least one alkyl group. Examples of alkylamino groups include— NHMethyl, -N(Methyl)2, -NPropylMethyl, -NHButyl, -NEthylMethyl, -NPhenylMethyl, and the like.
  • arylamino refers to a nitrogen atom substituted with at least one aryl group.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • hydroxyl refers to a group—OH.
  • thiol refers to a group— SH.
  • the compounds of the invention may crystallize in more than one form. This characteristic is referred to as polymorphism, and such polymorphic forms (“polymorphs”) are within the scope of the invention.Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x- ray diffraction patterns, solubility, and melting point.
  • Certain of the compounds described herein are capable of existing as stereoisomers.
  • the scope of the present invention includes mixtures of stereoisomers as well as purified or enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds of the invention as well as any wholly or partially equilibrated mixtures thereof.
  • Certain compounds of the invention contain one or more chiral centers. Therefore the present invention includes racemates, purified enantiomers, and enantiomerically enriched mixtures of the compounds of the invention.
  • the compounds of the present invention include racemic and chiral indane dimers. - -
  • salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term pharmaceutically acceptable salts refer to non-toxic salts of the compounds of this invention.
  • Salts of the compounds of the present invention may comprise acid addition salts.
  • Solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of the invention, or a salt or physiologically functional derivative thereof) and a solvent.
  • solvents for the purpose of the invention, should not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Most preferably the solvent used is water.
  • Prodrug refers to any pharmaceutically acceptable derivative of a compound of the present invention that, upon administration to a mammal, is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof.
  • Such derivatives for example, esters and amides, will be clear to those skilled in the art.
  • Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by an oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each with aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders may be prepared by comminuting the compound to a suitable fine size and mixing with an appropriate pharmaceutical carrier such as - - an edible carbohydrate such as starch or mannitol. Flavorings, preservatives, dispersing agents, and coloring agents and the like may also be included.
  • Capsules may made by preparing a powder, liquid, or suspension mixture and encapsulating within gelatin or other suitable shell material.
  • Lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol may be added to the mixture.
  • a disintegrating or solubilizing agent such as calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • Other agents such as binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol and the like.
  • Suitable lubricants for these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Suitabel disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets may be formulated by preparing a powder mixture, granulating the mixture, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture may be prepared by mixing the compound, suitably comminuted, with a diluent or base as described above.
  • Optional ingredients include binders such as carboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone, solution retardants such as paraffin, resorption accelerators such as a quaternary salt, and/or absorption agents such as bentonite, kaolin, or the like.
  • the powder mixture can be wet- granulated with a binder such as syrup, starch paste, or solutions of cellulosic or polymeric materials, and pressing through a screen.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through other steps such as granulating.
  • a clear or opaque protective coating consisting of a sealing coat of a suitable material such as shellac, sugar or polymeric material, and a polish coating for example of wax can be provided. If appropriate colourants be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilisers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives; flavor additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners; and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in suitable polymers, wax, or the like.
  • the compounds of formula (I) and salts, solvates, and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • the compounds of the invention and salts, solvates, and physiologically functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include, for example, polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the compounds may also be coupled to a biodegradable polymer achieve controlled release of a drug.
  • Such polymers include polylactic acid, polycyanoacrylates, and block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the skin/epidermis of a patient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis.
  • Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • the formulations may be applied as a topical ointment or cream.
  • the formulation may include lozenges, pastilles, and mouthwashes.
  • a powder having a particle size for example in the range 20 to 500 microns may be used.
  • the powder may be administered by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of of of metered dose pressurized aerosols, nebulizers, or insufflators and the like.
  • the formulation may be presented as suppositories or as enemas.
  • the formulation may be in the form of pessaries, tampons, creams, gels, sprays or the like.
  • the formulation may be aqueous and non-aqueous sterile injection solutions which may contain various additives such as anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and the like.
  • the compounds of the present invention and their salts, solvates, and physiologically functional derivatives thereof, may be employed alone or in combination with other therapeutic agents.
  • the compound of the invention and the other pharmaceutically active agent(s) may be administered together or separately. If administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compound of the invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the invention salts, solvates, or physiologically functional derivatives thereof with other treatment agents may be in combination by administration concomitantly in either a single pharmaceutical composition including both compound or in separate pharmaceutical compositions each including one of the compounds.
  • the combination of drugs may be administered separately in a sequential manner in which one agent is administered first and a second agent is administered second or the other way around. Such administration may be in a similar time frame or over longer time.
  • Fig. 1 Is the X-ray crystal structure showing the absolute stereochemistry for the enantiomer compound 4 (R)-(+)-methylbenzylamine salt (compound 9);
  • Fig. 2 Is the X-ray crystal structure showing the absolute stereochemistry for the enantiomer compound 2 (S)-(-)-methylbenzylamine salt (compound 8);
  • Fig. 2A Is a view of a molecule of compound 8 from the crystal structure showing the numbering scheme employed. Anisotropic atomic displacement ellipsoids for the non- hydrogen atoms are shown at the 50% probability level. Hydrogen atoms are displayed with an arbitrarily small radius. Only the major disorder component is shown;
  • Fig. 3 Is a graph of the effect of compounds 2, 3, 4 and 5 at 30 mg/kg on disease activity index (DAI) over 7 days in 5% DSS colitis
  • Fig. 4 lis a bar chart of the effect of compounds 2, 3, 4 and 5 at 30 mg/kg on disease activity index (DAI) at day 7 in 5% DSS colitis;
  • Fig. 5 Is a graph of the effect of compounds 5, 7, 2 and 6 at 10 mg/kg on disease activity index (DAI) over 7 days in 5% DSS colitis;
  • Fig. 6 Is a bar chart of the effect of compounds 5, 7, 2 and 6 at 10 mg/kg on disease activity index (DAI) at day 7 in 5% DSS colitis. Asterisks indicate a significant (P ⁇ 0.05) difference (1 way ANOVA) from the vehicle control group;
  • Fig. 7 Is a graph showing the effect of compound 6 on weight loss in 5% DSS-treated mice. Data are Mean ⁇ SEM from 6-7 mice per group;
  • Fig. 8 Is a graph showing the effect of compound 6 on DAI in 5% DSS-treated mice. Data are Mean ⁇ SEM from 6-7 mice per group;
  • Fig. 9 Is a bar chart showing the effect of compound 6 on DAI in 5% DSS-treated mice on day 7. Data are Mean ⁇ SEM. Asterisks indicate a significant (P ⁇ 0.05) difference (1 way ANOVA) from the vehicle control group;
  • Fig. 10 Is a bar chart showing the effect of compound 6 on colon length of 5 % DSS- treated mice on day 7. Asterisks indicate a significant (P ⁇ 0.05) difference (1 way ANOVA) from the vehicle control group;
  • Fig. 11 Shows representative haematoxylin and eosin-stained sections from distal colons of mice. Higher magnifications (X10) are shown;
  • Fig. 12 Is a bar chart showing the effect of compound 6 on histology scores of colons from DSS-treated mice. Data are Mean ⁇ SEM from 5-6 mice. Asterisks indicate a significant (P ⁇ 0.05) difference (1 way ANOVA) from the vehicle control group. Note, maximum score 10;
  • Fig. 13 Is a bar chart showing the effect of compound 6 on myeloperoxidase (MPO) activity in the colons of untreated or vehicle, prednisolone and compound 2 treated mice exposed to 5% DSS. Data are Mean ⁇ SEM from 5-6 mice. Asterisks indicate a significant (P ⁇ 0.05) difference (1 way ANOVA) from the vehicle control group;
  • Fig. 14(A) to (C) are bar charts showing the effect of compound 6 on Levels of cytokines (ILlp (A), TNFa (B) and IL6 (C)) in mice treated with DSS. Data are Mean ⁇ SEM from 5-6 mice. Asterisks indicate a significant (P ⁇ 0.05) difference (1 way ANOVA) from the vehicle control group;
  • Fig. 15 Is a group showing weight loss in ILICT 7"" mice treated with vehicle or compound 6. Mice were administered compound 6 (300 mg/kg/week) or vehicle orally on a Monday/Wednesday/Friday (MWF) dosing schedule. Mice were ⁇ 4 weeks of age at start of experiment and were treated for 9 weeks. Mice were weighed weekly and data are presented as Mean ⁇ SEM from 9-12 mice per group. Mice were monitored for overt disease, rectal prolapse, and moribund animals were humanely killed;
  • Fig. 16 Is a scatter graph representing Serum Amyloid A (SAA) levels of individual mice, and Mean (bar), from surviving animals at week 9 (11 and 9 mice in compound 6 or vehicle-treated groups, respectively). Student's t-test was used to test for statistical differences between groups;
  • SAA Serum Amyloid A
  • Fig. 17 Are representative hematoxylin and eosin-stained sections from distal colons from IL10 " ' " mice treated for 9 weeks with vehicle or compound 6;
  • Fig. 18 Histology scores of distal colons of ILIO " ' "" mice treated with vehicle or compound 6. Scatter graph representing histology score of individual mice, and Mean (bar), from surviving animals at week 9 (1 1 and 9 mice in compound 6 or vehicle-treated groups, respectively). Student's t-test was used to test for statistical differences between groups;
  • Fig. 19 is a scatter graph showing weight loss in 5% DSS-treated mice at day 7. Data are Mean ⁇ SEM from 6-7 mice per group; for compound 31 and 47, in DSS murine colitis (Method 2); Fig. 20 is a scatter graph showing DAI in 5% DSS-treated mice on day 7. Data are Mean ⁇ SEM from 6-7 mice per group; for compound 31 and 47, in DSS murine colitis (Method
  • Fig. 21 is a bar chart illustrating the effect of compounds 10-16 and 18-38 on IL2 release from Jurkat cells.
  • Fig.22 is a bar chart illustrating the effect of compounds 2-5 and 39-47 on IL2 release from Jurkat cells
  • Compound 1 represents a pair of diastereoisomers that result from the reduction and demethylation of the ketone compound A which has a chiral centre at C-2, and is, as a result, a pair of enantiomers.
  • This compound comprises two diastereoisomers:-
  • Diastereoisomer B Diastereoisomer C lysis of Diastereoisomer B gives rise to compounds 2 and 3
  • the diastereoisomers can be resolved chemically or chromatographically into their constituent enantiomers.
  • the absolute stereochemistry of compound 4 has been established by single crystal X-ray of compound 4 (R)-(+)-rnethylbenzylamine salt (compound 9) (Fig. 1).
  • the invention also relates to compounds of the formula:
  • This diastereoisomer is composed of two enantiomers.
  • the absolute stereochemistry of the preferred enantiomer is presented below
  • the reaction was quenched by the addition of sat. NH 4 C1.
  • the layers were separated and the aqueous layer extracted with diethyl ether (2 x 120 mL).
  • the combined organic layers were washed with water, brine, dried over MgS0 4 and evaporated.
  • the solid product precipitated from the crude on removal of most of the solvent. This was filtered off and washed with cold diethyl ether to give 0.98 g (62%) of a cream solid.
  • the reaction was quenched by pouring onto ice and the crude product extracted into ethyl acetate by stirring the aqueous mixture for 10-15 min with ethyl acetate then pouring into a separatory funnel and allowing it to separate.
  • the combined organic layers were washed with water, brine, dried over MgS0 4 and evaporated to give 0.34 g (68%) of a cream-tart solid.
  • the product was isolated as a mixture of two diastereoisomers in an approximately 2: 1 ratio.
  • the ester was placed in a round-bottomed flask and 10% aq. NaOH (1 mL) was added to it followed by sufficient methanol to form a solution (6 mL). The solution was heated at 40 °C and monitored by TLC (80:20, hexane:ethyl acetate). After ca. 4h, no further ester was seen.
  • Diastereoisomer A (2.5 mmol, 1.0 g) and N-BOC D-phenylalanine (3.1 mmol, 0.8 g) were placed in a round bottom flask fitted with a condenser and suspended in CH 3 CN (25 mL) under nitrogen. To this suspension was added pyridine (3.1 mmol, 0.3 mL) followed by a solution of DCC (3.1 mmol, 0.7 g) and DMAP (10% mol, 0.25 mmol, 0.05 g) in CH 3 CN (2 mL). The mixture was stirred for 20 h at 50°C, and then allowed to reach room temperature.
  • the diastereoisomer a2 (2.3 mmol, 1.45 g) was dissolved in methanol (25mL) and NaOH (1 1.5 mmol, 0.45 g) was added and the mixture stirred at reflux temperature and monitored by TLC. After 20h, the starting material was consumed. The reaction was cooled to room temperature and quenched by addition of sat. NH 4 C1. The methanol was removed in vacuo and the aqueous solution acidified to pH 1 with cone. HCl.
  • Salts were prepared by dissolving the free acid of compounds 2, 3, 4 and 5 in aqueous or aqueous organic solvent in the presence of the appropriate base and isolating the salt by evaporation of solvent.
  • Reaction mixture was quenched with ice (25 mL) and extracted with DCM (3 x 25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na 2 S0 4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20 % ethyl acetate in chloroform as an eluent to yield 250 mg (68 %) of the intermediate 1 as an off white solid.
  • reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10 % methanol in chloroform as an eluent to yield 160 mg of the material [38 % product mass (581.5) in UPLC] as a solid.
  • the solid was dissolved in THF: H 2 0 (1 : 1, 10 mL) was added lithium hydroxide dihydrate (6 mg, 0.27 mmol) at 0°C and then stirred at room temperature for 1 h.
  • the reaction mixture was neutralized with 1.5 N HC1 (P H 7.0) and then extracted with ethyl acetate (3 x 10 mL), washed with 10 % aqueous NaHC0 3 (10 mL) followed by brine (10 mL).
  • Cytokines can be produced by various cell populations and have been shown to augment or limit immune responses to pathogens and influence the autoimmune response.
  • One family of cytokines which uses the common receptor gamma chain (cc), a component of receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21, has been classically defined as growth and survival factors.
  • IL-2 production can induce an immune response by promoting the proliferation and generation of CD4+ Thl, CD4+ Th2 and CD8+ CTL effector cells.
  • Many of the immunosuppressive drugs used in the treatment of autoimmune diseases and organ transplant rejection such as corticosteroids and immune suppressive drugs (ciclosporin, tacrolimus) work by inhibiting the production of IL-2 by antigen-activated T cells.
  • Others (sirolimus) block IL-2R signalling, thereby preventing the clonal expansion and function of antigen-selected T cells [ref: Opposing functions of IL-2 and IL-7 in the regulation of immune responses Shoshana D. Katzman, atrina K. Hoyer, Hans Dooms, Iris . Gratz, Michael D. Rosenblum, Jonathan S. Paw, Sara H. Isakson, Abul K. Abbas. Cytokine 56 (201 1) 1 16-121]
  • IL-2 can inhibit the immune response by promoting the survival and functionality of natural (thymic) regulatory T-cells (Tregs), promoting the generation of induced (peripheral) Tregs and inhibiting the generation of CD4+ Thl7 effector cells [ref: IL-2 and autoimmune disease.
  • Teregs natural regulatory T-cells
  • Tregs promoting the generation of induced (peripheral) Tregs and inhibiting the generation of CD4+ Thl7 effector cells
  • IL-2 and autoimmune disease IL-2 and autoimmune disease.
  • Interleukin-2/IL-2R deficiency with time leads to multiorgan inflammation and the formation of autoantibodies of various specificities.
  • IL-2 signalling has been shown to be important in both the initiation and regulation of immune responses. In these dual and opposing roles, IL-2 acts to balance immune response, both driving immune cell activation and subsequent reduction.
  • the potential clinical applicability of either augmenting or inhibiting signals mediated by IL-2 is significant and includes cancer, autoimmune inflammatory diseases, organ transplantation and HIV.
  • the T cell line Jurkat 6.1 (ATCC) was used. Cells were pre-treated for 30min with ⁇ ⁇ or
  • Figs. 21 and 22 The effect of synthetic compounds 2-5, 10-16, 18-38 and 39-47 on release of IL2 from Jurkat cells is demonstrated in Figs. 21 and 22. Compounds were evaluated at 1 and 10 ⁇ concentrations. Most compounds demonstrated an inhibition of release relative to the negative controls. However, compounds 40 (12.71 pg/ml), 43 (12.79 pg/ml), 44 (12.43 pg/ml), 45 (14.29 pg/ml) and 46 (72.07pg/ml) (Fig. 22) were among the most potent significantly reducing 112 release relative to the negative control (326.67 pg/ml) and approaching the efficacy of ciclosporin (101.00 pg/ml) at 1 ⁇ .
  • IL-2 signalling has been shown to be important in both the initiation and regulation of immune responses. In these dual and opposing roles, IL-2 acts to balance immune response, both driving immune cell activation and subsequent reduction.
  • the potential clinical applicability of either augmenting or inhibiting signals mediated by IL-2 is significant and includes cancer, autoimmune inflammatory diseases, organ transplantation and HIV.
  • IBD Inflammatory Bowel Disease
  • IBD Inflammatory Bowel Disease
  • UC ulcerative colitis
  • CD Crohn's Disease
  • IBD inducing and maintaining remission.
  • IBD patients may be maintained on remission by use of a 5-aminosalycilate.
  • aminosalycilates in UC provides considerable benefit, both in inducing remission in mild to moderate disease and in preventing relapse, the usefulness of these drugs to maintain remission in CD is questionable and is no longer recommended.
  • the mainstay of treatment of active disease is a corticosteroid, commonly used for limited periods to return both UC and CD patients to remission, though budesonide, designed for topical administration with limited systemic absorption, has no benefit in maintaining remission.
  • Anti-TNFa antibodies such as infliximab and adalimubab may be used in those patients unresponsive to standard immunosuppressive therapy. However, many patients fail to respond to anti-TNFa therapy, either due to their particular phenotype or by the production of autoantibodies.
  • the dextran sodium sulphate (DSS) colitis model is an experimental mouse model that exhibits many of the symptoms observed in human UC, such as diarrhoea, bloody faeces, mucosal ulceration, shortening of the colon, weight loss and alterations in certain colon cytokines.
  • the study is widely used as a model for studying the pathogenesis of UC and also for screening new therapeutic interventions for the treatment of UC.
  • mice 6-8 weeks of age, were obtained from a commercial supplier (Harlan UK). Mice were fed irradiated diet and housed in individually ventilated cages (Tecniplast UK) under positive pressure.
  • DSS DSS (5%) was dissolved in drinking water.
  • Compounds were administered orally at a dose of 10 mg/kg or 30 mg/kg on days 0-7, and mice were culled on day 8 or day 9, depending on the severity of the disease. The mice were checked each day for morbidity and the weight of individual mice was recorded. Induction of colitis was determined upon autopsy, length of colon and histology. Colons were recovered and stored at -20°C for immunological analysis. All of the compounds and experimental groups are randomly alphabetically labelled. Throughout experiments all data recording was performed in a blind manner. The codes on boxes / groups were not broken until after the data was analysed i.e. boxes labelled A, B, C etc were identified as untreated, DSS-treated, or DSS + compound -treated.
  • DAI disease activity index
  • Compound 5 N-Methyl-(D)-Glucamine salt (compound 7) was determined, surprisingly, to be the most soluble compound from this group of analogous compounds by a considerable margin, with a solubility of >60,000 ⁇ g/mL in Milli-RO water, 0.14 ⁇ g/mL in pH 4 buffer, >60,000 ⁇ g/mL in pH 7.0 and >3,000 ⁇ g/mL in pH 9.0 buffer.
  • N-Methyl-(D)-Glucamine was chosen as the salt candidate for both compound 2 and compound 5. Effect of enantiomers compound 2 and compound 5 and their N-Methyl-(D)-Glucamine salts (compounds 6 and 7) at 10 mg/kg in 5% DSS murine colitis
  • Compound 6 was selected as the most favoured enantiomer.
  • the activity of compound 6 in the 5% DSS murine model of colitis at varying dose levels was tested to acertain if there was a dose/response relationship and to make a comparison with a potent oral steroid, Prednisolone, commonly used to return patients suffering from acute exacerbations of IBD to remission.
  • a potent oral steroid Prednisolone
  • mice were administered compound 6 at dose levels 3, 10 and 30 mg/Kg (equivalent to 6.6-20 mg Kg of the compound 2).
  • a group of DSS-treated mice was also treated with prednisolone, 5 mg/Kg.
  • Prednisolone is a corticosteroid in clinical use in the treatment of human IBD and the quantity used in this study is the optimal dose of prednisolone for this model.
  • compound 6 at three doses (3, 10 and 30 mg/Kg) caused no overt reactions in mice.
  • Compound 6 ameliorated the severity of colitis following acute DSS treatment in multiple parameters of disease examined.
  • the capacity of compound 6 to ameliorate disease in the DSS model was dose-dependent.
  • Compound 6 at 30 mg/Kg was therapeutic in the DSS model at a comparable, or better, efficacy relative to prednisolone at 5 mg/Kg.
  • the severity of these symptoms are progressive; by day 7 the DSS-treated mice have lost up to 15% of their body weight and all mice have perfuse rectal bleeding.
  • the DAI values on the day of autopsy showed that mice treated with compound 6 3-30 mg/kg had at each dose level, a significantly (PO.05 - P ⁇ 0.01) lower DAI than vehicle controls.
  • Prednisolone (5 mg/kg) also significantly (P ⁇ 0.01 ; ANOVA; Dunnett Multiple Comparison Test) reduced DAI scores (Fig. 9).
  • MPO Colonic myeloperoxidase activity
  • Prednisolone (5 mg/kg) also reduced (p ⁇ 0.05) these increases in cytokine levels; for each cytokine there was no significant difference between the effect of prednisolone 5 mg/kg and compound 6 at the higher dose level of 30 mg/kg at day 7
  • compound 6 at three doses (3, 10 and 30 mg/Kg) caused no overt reactions in mice.
  • Compound 6 ameliorated the severity of colitis following acute 5% DSS treatment by multiple parameters of disease examined and the capacity to ameliorate the disease is dose-dependent. Further, compound 6 at 30 mg/ g was therapeutic in the DSS model at a comparable or better efficacy, relative to prednisolone (5 mg/Kg).
  • mice with a deletion in the IL10 ""A" gene spontaneously develop chronic colitis, with the age of onset and the severity of the disease being dependent on background mouse strain and the conditions in which the animals are housed.
  • the onset of colitis in IL10 " _ ⁇ mice housed under the conditions used in this study was also strain dependent, with an earlier onset and greater severity, in terms of mortality, in BALB/c strain mice relative to C57BL/6 strain animals.
  • BDF1 H Pylori-ires, murine norovirus-free mice
  • mice Harlan Laboratories, UK
  • mice were 8-10 weeks old on supply and used at 10-12 weeks of age. All mice were held in individually ventilated cages (IVCs) in an SPF (Specific Pathogen Free) barrier unit. The animals were identified by numbered cages and by ear punches.
  • the animals were fed Rat and Mouse Expanded diet from B & K. Both feed and water (from drinking bottles) were available ad libitum. There was a constant room temperature of 21 ⁇ 2°C and a mean relative humidity of 55 ⁇ 10%. The day-night cycle was constant, with light and dark phases of 12 hours each. Animal health was monitored daily and cages were cleaned at regular intervals.
  • mice were randomised into study groups. All the mice in any one cage received the same treatment and were ear punched for identification purposes. Daily body weight measurements were used to calculate the volume of test item or vehicle administered in the applicable groups.
  • DSS DSS (MP Biomedicals 021601 1090, lot# M2709) was prepared as a 5% (w/v) solution in the drinking water and made fresh daily on days 0 to 6 inclusive. DSS was administered from day 0 to day 7.
  • Test items were stored at -20°C until the initiation of the study. Each test item was formulated as a homogenous suspension in 0.5% carboxymethyl cellulose (CMC, Sigma C4888) in sterile water (Sigma W3500, lot# RNBC 1419), using an Ultraturax homogeniser, on study day -1. Compound 31 was formulated at 2mg/ml and 47 was formulated at 4mg/ml. After formulation the test item and the vehicle stocks anonymised with a letter code. All solutions were stored at 4°C during the study, with 3.8ml of each suspension being dispensed daily. Test items were administered by oral gavage, daily at 09.00hrs, at lOml/kg, from study day 0 to study day 6.
  • 5-ASA (5-Aminosalicylic acid, Sigma A3537, Iot# 05 1M1878V) was aliquoted into preweighed amounts between 71 and 84mg. Like test item suspensions, these aliquots were anonymised by a letter code. Individual aliquots were formulated as a lOmg/ml suspension in 0.5% CMC (Sigma C4888) in sterile water (Sigma W3500, lot# RNBC 1419) on each day of dosing. 5-ASA was administered by oral gavage, daily at 09.00hrs, at lOml/kg to give a dose of lOOmg/kg, from study day 0 to study day 6.
  • Fig. 21 is a bar chart illustrating the effect of compounds on IL2 release from Jurkat cells.
  • Fig. 22 is a bar chart illustrating the effect of compounds on IL2 release from Jurkat cells.
  • Weighting scheme w l / [ ⁇ 2 (F o 2 )+(0.0600P) 2 +0.2200P]
  • the single crystal X-ray data establishes that the structure of compound 8 is monoclinic, space group P2 ⁇ , with one molecule of compound 8 in the asymmetric unit (Table 2).

Abstract

Cette invention concerne des composés pouvant en particulier être utilisés dans une maladie inflammatoire auto-immune et notamment dans le traitement des maladies inflammatoires de l'intestin, lesdits composés répondant à la formule : où R est choisi parmi un ou plusieurs des éléments, identiques ou différents, suivants : hydrogène, hydroxyle, alkyle éventuellement substitué, aryle éventuellement substitué, alcoxy, aryloxy, thiol, et amino éventuellement substitué, et R1 est choisi parmi un ou plusieurs des éléments, identiques ou différents, suivants : hydrogène, acétyle, alkyle éventuellement substitué, aryle éventuellement substitué, et acide aminé choisi parmi leucine, valine, isoleucine, et glycine.
EP12740703.9A 2011-07-22 2012-07-20 Dimères d'indane pouvant être utilisés dans le traitement des maladies inflammatoires auto-immunes Withdrawn EP2734497A1 (fr)

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WO2017012556A1 (fr) * 2015-07-22 2017-01-26 南京海融医药科技股份有限公司 Composé d'acide arylpropionique et son utilisation pharmaceutique

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