WO2013014659A1 - Indene derivatives for use in the treatment of inflammatory bowel disease - Google Patents
Indene derivatives for use in the treatment of inflammatory bowel disease Download PDFInfo
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- WO2013014659A1 WO2013014659A1 PCT/IE2012/000037 IE2012000037W WO2013014659A1 WO 2013014659 A1 WO2013014659 A1 WO 2013014659A1 IE 2012000037 W IE2012000037 W IE 2012000037W WO 2013014659 A1 WO2013014659 A1 WO 2013014659A1
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- COXZEKKBJOWBAG-UHFFFAOYSA-N OC1c2ccccc2CC1(Cc(cc1)ccc1C(O)=O)C1=Cc2ccccc2C1 Chemical compound OC1c2ccccc2CC1(Cc(cc1)ccc1C(O)=O)C1=Cc2ccccc2C1 COXZEKKBJOWBAG-UHFFFAOYSA-N 0.000 description 1
- COXZEKKBJOWBAG-AHWVRZQESA-N O[C@H]1c2ccccc2C[C@@]1(Cc(cc1)ccc1C(O)=O)C1=Cc2ccccc2C1 Chemical compound O[C@H]1c2ccccc2C[C@@]1(Cc(cc1)ccc1C(O)=O)C1=Cc2ccccc2C1 COXZEKKBJOWBAG-AHWVRZQESA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- 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]
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- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
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- 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
- C07C65/17—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 containing rings other than six-membered aromatic rings
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- 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 new compounds for use in the treatment of 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.
- 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-TNFoc 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 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:
- polymorphism polymorphic forms
- 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 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.
- the invention includes a solvate of any of the compounds of the invention.
- 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.
- the invention includes a prodrug of any of the compounds of the invention.
- 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.
- 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, intra-nasally, trans-cutaneously or by inhalation.
- compositions 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 described herein 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.
- compositions 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.
- Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means 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;
- DAI disease activity index
- Fig. 4 is 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 (PO.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 (XI 0) 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 myeloperoxidase (MPO) activity in the colons of untreated or vehicle, prednisolone and compound 6 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 (ILl p, TNF and IL6) 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 grph showing weight loss in IL10 " " 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 (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. 17 are representative hematoxylin and eosin-stained sections from distal colons from ILlO ' ⁇ mice treated for 9 weeks with vehicle or compound 6;
- Fig. 18 Is a scatter graph showing histology scores of distal colons of IL10 " ' " 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.
- 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:-
- 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)-(+)-methylbenzylamine salt (compound 9) (Fig. 1).
- the absolute stereochemistry of compound 2 was confirmed by single crystal X-ray of compound 2 (S)-(-)-methylbenzylamine salt (compound 8) (Fig. 2 and 2A).
- 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 then 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-tan 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 CI. The methanol was removed in vacuo and the aqueous solution acidified to pH 1 with cone. HC1.
- 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.
- IBP 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
- Diarrhea no stool formation, fur stained around the anus.
- 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.
- the partition coefficient of compound 5 and related analogous compounds was investigated using the HPLC method (reverse phase CI 8 HPLC column) at neutral, acidic and alkaline pH.
- 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 2 (and its N-Methyl-(D)-Glucamine salt, compound 6) is the most potent of the four enantiomers by a considerable margin, and the only enantiomer to retain activity at the lower dose level of 10 mg/kg.
- 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 ascertain 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.
- 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.
- 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.
- 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.
- compound 6 at 30 mg/Kg was therapeutic in the DSS model at a comparable or better efficacy, relative to prednisolone (5 mg/Kg).
- mice with a deletion in the IL 10 "" _" 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.
- Serum was recovered from mice and Serum Amyloid A (SAA) and was analysed as a marker for severity of colitis. There were significantly (P ⁇ 0.05; Student's t-test) reduced SAA levels in compound 6 treated mice relative to vehicle treated IL10 "7"" mice (Fig. 16). Histology sections of colons from IL10 " _ mice treated with vehicle or compound 6 are shown in Fig. 17. Histology sections of colons from IL10 mice treated with vehicle or compound 6 were scored. The extent of colon pathology was significantly reduced (P ⁇ 0.05; Student's t-test) in IL10 " ' " mice receiving compound relative to mice treated with vehicle (Fig. 18).
- Weighting scheme w l / [ ⁇ 2 (F o 2 )+(0.0600P) 2 +0.2200P]
Abstract
Description
Claims
Priority Applications (10)
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JP2014520787A JP5898768B2 (en) | 2011-07-22 | 2012-07-20 | Indene derivatives for use in the treatment of inflammatory bowel disease |
BR112014001551A BR112014001551A2 (en) | 2011-07-22 | 2012-07-20 | Indene derivatives for use in the treatment of inflammatory bowel disease |
CA2839606A CA2839606A1 (en) | 2011-07-22 | 2012-07-20 | Indene derivatives for use in the treatment of inflammatory bowel disease |
EP12740702.1A EP2734496A1 (en) | 2011-07-22 | 2012-07-20 | Indene derivatives for use in the treatment of inflammatory bowel disease |
CN201280035083.7A CN103764608B (en) | 2011-07-22 | 2012-07-20 | Be used for the treatment of the indene derivative of inflammatory bowel |
RU2013155270/04A RU2601307C2 (en) | 2011-07-22 | 2012-07-20 | Indene derivatives applicable in treatment of inflammatory bowel disease |
AU2012288404A AU2012288404A1 (en) | 2011-07-22 | 2012-07-20 | Indene derivatives for use in the treatment of inflammatory bowel disease |
US14/124,937 US9586885B2 (en) | 2011-07-22 | 2012-07-20 | Compounds for use in the treatment of inflammatory bowel disease |
NZ618936A NZ618936A (en) | 2011-07-22 | 2012-07-20 | Indene derivatives for use in the treatment of inflammatory bowel disease |
HK14110028.9A HK1196597A1 (en) | 2011-07-22 | 2014-10-08 | Indene derivatives for use in the treatment of inflammatory bowel disease |
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US201161510628P | 2011-07-22 | 2011-07-22 | |
US61/510,628 | 2011-07-22 |
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US (1) | US9586885B2 (en) |
EP (1) | EP2734496A1 (en) |
JP (1) | JP5898768B2 (en) |
CN (1) | CN103764608B (en) |
AU (1) | AU2012288404A1 (en) |
BR (1) | BR112014001551A2 (en) |
CA (1) | CA2839606A1 (en) |
HK (1) | HK1196597A1 (en) |
NZ (1) | NZ618936A (en) |
RU (1) | RU2601307C2 (en) |
TW (1) | TWI537246B (en) |
WO (1) | WO2013014659A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2734497A1 (en) * | 2011-07-22 | 2014-05-28 | Venantius Limited | Indane dimers for use in the treatment of autoimmune inflammatory disease |
CN110426464A (en) * | 2019-07-08 | 2019-11-08 | 苏州天马药业有限公司 | The HPLC detection method of isomers in a kind of meglumine |
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WO1997020806A1 (en) | 1995-12-06 | 1997-06-12 | Venantius Limited | Indane compounds with smooth muscle relaxing and/or mast cell stabilising and/or anti-inflammatory activity |
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DE19619036A1 (en) | 1996-04-30 | 1997-11-13 | Schering Ag | New vitamin D derivatives with carbo- or heterocyclic substituents at C-25, process for their preparation and their use in the manufacture of medicinal products |
AU3899097A (en) * | 1996-08-05 | 1998-02-25 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Substituted aromatic compounds |
IL136208A0 (en) * | 1997-11-20 | 2001-05-20 | Childrens Medical Center | Use of substituted diphenyl indanone, indane and indole compounds for the treatment or prevention of sickle cell disease, inflammatory diseases characterized by abnormal cell proliferation, diarrhea and scours |
CN1332961C (en) * | 1999-10-20 | 2007-08-22 | 田边制药株式会社 | Inhibitors of alpha L beta 2 mediated cell adhesion |
BRPI0409376A (en) | 2003-04-15 | 2006-04-25 | Inflazyme Pharm Ltd | indene derivatives as pharmaceutical agents |
US7592461B2 (en) * | 2005-12-21 | 2009-09-22 | Bristol-Myers Squibb Company | Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
WO2013014660A1 (en) | 2011-07-22 | 2013-01-31 | Venantius Limited | Indane dimers for use in the treatment of autoimmune inflammatory disease |
EP2855416A1 (en) | 2012-05-24 | 2015-04-08 | Venantius Limited | Indane dimers for use in the treatment of autoimmune inflammatory disease |
WO2013174917A1 (en) | 2012-05-24 | 2013-11-28 | Venantius Limited | Compounds for use in the treatment of autoimmune inflammatory disease |
-
2012
- 2012-07-20 CA CA2839606A patent/CA2839606A1/en not_active Abandoned
- 2012-07-20 AU AU2012288404A patent/AU2012288404A1/en not_active Abandoned
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- 2012-07-20 US US14/124,937 patent/US9586885B2/en not_active Expired - Fee Related
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- 2012-07-20 EP EP12740702.1A patent/EP2734496A1/en not_active Withdrawn
- 2012-07-20 WO PCT/IE2012/000037 patent/WO2013014659A1/en active Application Filing
- 2012-07-20 JP JP2014520787A patent/JP5898768B2/en not_active Expired - Fee Related
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WO1997020806A1 (en) | 1995-12-06 | 1997-06-12 | Venantius Limited | Indane compounds with smooth muscle relaxing and/or mast cell stabilising and/or anti-inflammatory activity |
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CN110426464A (en) * | 2019-07-08 | 2019-11-08 | 苏州天马药业有限公司 | The HPLC detection method of isomers in a kind of meglumine |
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BR112014001551A2 (en) | 2017-06-13 |
AU2012288404A1 (en) | 2014-01-09 |
TWI537246B (en) | 2016-06-11 |
CN103764608A (en) | 2014-04-30 |
JP2014524921A (en) | 2014-09-25 |
RU2601307C2 (en) | 2016-11-10 |
CN103764608B (en) | 2016-02-03 |
US20140128466A1 (en) | 2014-05-08 |
NZ618936A (en) | 2015-07-31 |
CA2839606A1 (en) | 2013-01-31 |
JP5898768B2 (en) | 2016-04-06 |
RU2013155270A (en) | 2015-08-27 |
HK1196597A1 (en) | 2014-12-19 |
TW201311637A (en) | 2013-03-16 |
US9586885B2 (en) | 2017-03-07 |
EP2734496A1 (en) | 2014-05-28 |
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