WO2005085170A1 - Ester derivatives of rhein and their therapeutic use - Google Patents
Ester derivatives of rhein and their therapeutic use Download PDFInfo
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- WO2005085170A1 WO2005085170A1 PCT/GB2005/000832 GB2005000832W WO2005085170A1 WO 2005085170 A1 WO2005085170 A1 WO 2005085170A1 GB 2005000832 W GB2005000832 W GB 2005000832W WO 2005085170 A1 WO2005085170 A1 WO 2005085170A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C66/00—Quinone carboxylic acids
- C07C66/02—Anthraquinone carboxylic acids
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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
-
- 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
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- 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
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- 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]
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- 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
- A61P37/02—Immunomodulators
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- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
- C07D309/10—Oxygen atoms
Definitions
- T-lymphocytes are known to play a central role in the pathogenesis of many inflammatory and autoimmune diseases, including rheumatoid arthritis.
- the activation of T-cells by antigen-presenting cells is the primary event in the initiation of the inflammatory process, which subsequently leads to the activation of other inflammatory cells and in turn the release of pro-inflammatory cytokines, chemotactic agents and matrix-degrading enzymes.
- Multiple sclerosis is a chronic demyelinating inflammatory disease of the central nervous system.
- T-cell proliferation leads to release of the pro-inflammatory cytokines (primarily IL-2 and IFN- ⁇ ) and the recruitment of leucocytes (including macrophages) which orchestrate the inflammatory response.
- cytokines primarily IL-2 and IFN- ⁇
- leucocytes including macrophages
- COPD chronic obstructive pulmonary disease
- COPD chronic obstructive pulmonary disease
- activation of neutrophils and macrophages by proliferating CD8+ T-cells leads to the release of pro- inflammatory cytokines and elastin-degrading enzymes, which causes a chronic and progressive degradation of lung tissues and ultimately reduction in respiratory function.
- Crohn's disease and ulcerative colitis are chronic inflammatory diseases of the intestines collectively known as inflammatory bowel disease (IBD).
- T-cells are central to the progression of this collection of diseases, leading to the activation of immune, mesenchymal and epithelial cells, recruitment of circulating effector cells and ultimately gastrointestinal tissue damage.
- the presentation of antigen by Langerhan's cells to CD4+ T- cells leads to the synthesis of cytokines which stimulate keratinocyte proliferation and the expression of adhesion molecules by endothelial cells and keratinocytes.
- Keratinocytes in turn are stimulated to produce their own cytokines which can act in an autocrine and/or paracrine manner to maintain the psohatic process.
- T-cells There is a similarly strong rationale for the central involvement of T-cells in many other inflammatory diseases, including systemic lupus erythematosus (SLE), asthma, lupus nephritis, glomerulonephritis, IgA nephropathy, gingivitis, periodontal disease, atopic dermatitis, scleroderma and graft vs host disease (GVHD).
- SLE systemic lupus erythematosus
- asthma lupus nephritis
- glomerulonephritis IgA nephropathy
- gingivitis gingivitis
- periodontal disease atopic dermatitis
- scleroderma and graft vs host disease graft
- Rhein (1,8-dihydroxyanthraquinone-3-carboxylic acid) is a well-characterised anti-inflammatory agent, with recognised utility in a range of inflammatory diseases. While this agent has not been demonstrated to inhibit T-cell proliferation, it is known to inhibit the production of pro-inflammatory cytokines (IL-1 ⁇ and TNF ⁇ ) in human osteoarthritic synovium and chondrocytes (J. Martel-Pelletier et al, Journal of Rheumatology, 1998, 25 (4), 753-762) and to inhibit cytokine gene expression in a model of lupus nephritis (S. Lemay et al, Kidney International, 1996, 50 (1), 85-93).
- IL-1 ⁇ and TNF ⁇ pro-inflammatory cytokines
- pro-matrix metalloproteinases pro-matrix metalloproteinases
- Rhein is disclosed as having utility in arthritis and multiple sclerosis (US4346103) and in diabetic nephropathy (EP0990441A1), diseases where overproduction of IL-1 ⁇ is particularly implicated.
- novel compounds which may inhibit cytokine production and T-cell proliferation, and are therefore of utility in the treatment of T-cell mediated diseases including those described above.
- novel compounds are of general formula (I):
- Ri and R 2 are the same or different and are each C ⁇ . 4 alkyl substituted with R 3 , or a four to seven-membered ring which can be optionally substituted with R 8 and can contain one or more additional heteroatoms selected from O, S(O)neig and NR 9 ;
- R 3 is F, CF 3 , OR 4 , NR 5 R 6 or S(O) n R 7 ;
- R 4 , R 5 and R 6 are the same or different and are each H or C ⁇ . 4 alkyl optionally substituted with R 3 , or NR 5 R 6 is a C 4 .
- compositions comprising the compounds of formula I, their use in therapy and, more particularly, their use in the treatment of inflammatory conditions.
- the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms.
- the presence of one or more of these asymmetric centres in a compound of formula (1), (2) and (3) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
- C- alkyl refers to a straight or branched chain alkyl moiety having from one to four carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tetf-butyl and the like.
- C 4 . 6 heterocycloalkyl refers to a saturated heterocyclic moiety having from three to six carbon atoms and one or more heteroatom from the group N, O, S and includes for example azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl and the like.
- salts of compounds of formula (1), (2) and (3) include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, p-toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates and benzoates. Salts may also be formed with bases.
- Such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
- alkali metal salts such as magnesium or calcium salts
- organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
- a carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or terf-butyl ester.
- Compounds of the formulae (1), (2) and (3) may be prepared by any suitable method known in the art and/or by the following processes.
- the synthetic processes described herein may be used with the appropriate homochiral starting material and/or isomers maybe resolved from mixtures using conventional separation techniques (e.g. HPLC).
- the compounds according to the invention may be prepared by the following process.
- the groups Ri, R 2 , R 3 , R 4 , R 5 , R 6 R , R 8 and R 9 are as defined above, except where otherwise indicated.
- functional groups such as amino, hydroxyl or carboxyl groups, present in the various compounds described below, and which it is desired to retain, may need to be in protected form before any reaction is initiated.
- a process for preparing compounds of formula (1) comprises conversion of the activated ester in the presence of base (such as diacerein to rhein), followed by reaction with the required activated acid such as acid chloride or anhydride.
- the carboxylic acid can be reduced to give the alcohol and the hydroxyl group further substituted, or desired amides can be formed by reacting the carboxylic acid or activated acid with suitable amines.
- Diacerein and the corresponding activated acids are either commercially available or readily obtained from commercially available materials by those skilled in the art of synthetic organic chemistry.
- a process for preparing compounds of general formulae (2) and (3) will be similar to that described for (1), but will necessitate the additional steps of selectively protecting one hydroxyl group prior to the reaction with the acid chloride, and this will have to be followed by a deprotection step to reveal the target compound.
- Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances.
- Compounds of the invention exhibit in vitro inhibiting activities with respect to
- T-cell proliferation Compounds according to the invention also exhibit in vitro inhibition of pro-inflammatory cytokine release.
- the activity of the compounds may be determined by use of the appropriate cellular assay, for example as described below.
- This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat or fur industries or as pets) suffering from disorders or diseases which can be attributed to T-cell proliferation as previously described, and more specifically, a method of treatment involving the administration of the T-cell proliferation inhibitors of formula (1), (2) or (3) as the active constituents.
- compounds of formula (1), (2) and (3) are useful in human or veterinary medicine, since they are active as inhibitors of T-cell proliferation.
- this invention concerns: a method of management (by which is meant treatment or prophylaxis) of disease or conditions mediated by T-cells in mammals, in particular in humans, which method comprises administering to the mammal an effective amount of a compound of formula (1), (2) or (3) above, or a pharmaceutically acceptable salt thereof; and a compound of formula (1), (2) or (3) for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by T-cells; and the use of a compound of formula (1), (2) or (3) in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by T-cells.
- the disease or conditions referred to above include inflammatory and autoimmune diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, inflammatory bowel disease including ulcerative colitis and Crohn's disease, ulcerative colitis, multiple sclerosis, periodontitis, gingivitis, graft versus host reactions, psoriasis, scleroderma, atopic dermatitis, asthma, systemic lupus erythematosus (SLE), nephropathy and chronic obstructive pulmonary disease (COPD).
- Dermal conditions that may be treated include those given above, and also psoriatic arthritis, epider olysis bullosa, atopic dermatitis and vasculitis.
- Anti- angiogenic activity may allow the treatment of conditions such as age-related macular degeneration and cancer.
- the compounds of formula (1), (2) or (3) may be administered orally, topically, parenterally, by inhalation or nasal spray or rectally in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
- compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyeryl distearate may be employed. They may also be coated by the techniques described in US4256108,
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate polyvinyl- pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
- dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate
- the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation.
- compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring agents, may also be present.
- Pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example gycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the compounds of formulae (1), (2) and (3) may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are cocoa butter and polyethylene glycols.
- topical use creams, ointments, jellies, solutions or suspensions, etc containing the compounds of formulae (1), (2) and (3) are employed.
- topical application includes mouth washes and gargles.
- Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above- indicated conditions (about 2.5 mg to about 7 g per patient per day).
- inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 g per patient per day).
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a formulation intended for the oral administration of humans may vary from about 5 to about 95 percent of the total composition.
- Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
- the following Examples illustrate the invention.
- Example 1 4,5-Bis(tetrahydropyran-4-carbonyloxy)-9,10-dioxo- dihydroanthracene-2-carboxylic acid 1.
- Diacerein 150 g, 0.41 mol was stirred in 10% (w/w) Na 2 CO 3 solution (4 L) resulting in a red mixture. After stirring overnight the mixture was acidified to pH2 with 5M HCI solution to give a yellow precipitate. This was filtered and dried in a vac-oven at 50 °C (168 g, >100%).
- Example 2 4.5-Bisbutyryloxy-9,10-dioxo-9,10-dihydroanthracene-2- carboxylic acid 4,5-Dihydroxy-9,10-dioxoanthracene-2-carboxylic acid (3.0 g) was suspended in pyridine (100 ml) and stirred at RT for 30 mins. Butyryl chloride was added (3.6 g, 5 equiv.) to give a clear reaction mixture which was stirred at RT over the weekend. The reaction mixture was reduced to a smaller volume and quenched with 2M HCI (200 ml), adjusting the pH to pH 2.
- reaction Upon complete addition, the reaction was allowed to warm to RT and stirred overnight. Reaction mixture was evaporated to dryness to give the product which was used immediately.
- reaction mixture was reduced to a smaller volume (approx 20 ml), and 2M HCI (100 ml) added.
- the reaction mixture was then filtered to give a yellow solid which was slurried in ethyl acetate (25 ml) followed by water (50 ml). The solid was isolated by filtration to give (16) as a yellow solid (2.1 g, 60%).
- the compound of Example 1 has been shown to have efficacy in the LPS mouse and rat EAE models.
- Example 1 0.1 ml of an emulsion containing equal parts of guinea-pig spinal cord, phosphate buffered saline and incomplete Freund's adjuvant with 8 mg/ml Mycobacterium tuberculosis H37Ra.
- the compound of Example 1 150 mg/kg was dosed orally in a 10% acacia gum vehicle (1 ml/kg) twice a day from the day of inoculation. Body weights and neurological scores were observed daily from day 7 post- inoculation. The total daily score was calculated for each group and plotted over time. Non-parametric statistical analyses (Kruskal-Wallis) one-way analysis, followed by a Dunn's test, were employed.
- the compound of Example 1 showed significant efficacy in the treatment of clinical signs induced in the EAE model.
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Abstract
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXPA06010058A MXPA06010058A (en) | 2004-03-04 | 2005-03-04 | Ester derivatives of rhein and their therapeutic use. |
CA002558082A CA2558082A1 (en) | 2004-03-04 | 2005-03-04 | Ester derivatives of rhein and their therapeutic use |
AU2005219642A AU2005219642B2 (en) | 2004-03-04 | 2005-03-04 | Ester derivatives of rhein and their therapeutic use |
EP05726943A EP1723097A1 (en) | 2004-03-04 | 2005-03-04 | Ester derivatives of rhein and their therapeutic use |
US10/591,157 US7728035B2 (en) | 2004-03-04 | 2005-03-04 | Ester derivatives of rhein and their therapeutic use |
JP2007501352A JP4478713B2 (en) | 2004-03-04 | 2005-03-04 | Rain's ester derivatives and their therapeutic use |
BRPI0508352-4A BRPI0508352A (en) | 2004-03-04 | 2005-03-04 | reine derived esters and their therapeutic uses |
IL177752A IL177752A0 (en) | 2004-03-04 | 2006-08-29 | Ester derivatives of rhein and their therapeutic use |
NO20064031A NO20064031L (en) | 2004-03-04 | 2006-09-07 | Ester derivatives of thein and their therapeutic use |
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Application Number | Priority Date | Filing Date | Title |
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GB0404953.2 | 2004-03-04 | ||
GBGB0404953.2A GB0404953D0 (en) | 2004-03-04 | 2004-03-04 | Pro-drugs |
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WO2005085170A1 true WO2005085170A1 (en) | 2005-09-15 |
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PCT/GB2005/000832 WO2005085170A1 (en) | 2004-03-04 | 2005-03-04 | Ester derivatives of rhein and their therapeutic use |
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US (1) | US7728035B2 (en) |
EP (1) | EP1723097A1 (en) |
JP (1) | JP4478713B2 (en) |
KR (1) | KR20070010142A (en) |
CN (1) | CN1938258A (en) |
AU (1) | AU2005219642B2 (en) |
BR (1) | BRPI0508352A (en) |
CA (1) | CA2558082A1 (en) |
GB (1) | GB0404953D0 (en) |
IL (1) | IL177752A0 (en) |
MX (1) | MXPA06010058A (en) |
NO (1) | NO20064031L (en) |
WO (1) | WO2005085170A1 (en) |
ZA (1) | ZA200607386B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008056156A1 (en) * | 2006-11-10 | 2008-05-15 | Sosei R & D Ltd. | Salts of dihydroxyanthraquinone carboxylic acids and their therapeutic use |
CN102552430A (en) * | 2011-12-03 | 2012-07-11 | 彭旦明 | Effective fractions for inhibiting scars and preparation method thereof |
CN102603575A (en) * | 2012-01-04 | 2012-07-25 | 丛晓东 | Rhein-arginine eutectic compound, and preparation method, purification method and application thereof in preparation of medicines for treating diabetic complications |
CN104547207A (en) * | 2015-01-29 | 2015-04-29 | 陈文斌 | Externally applied traditional Chinese medicinal preparation for eliminating old scar and preparation method thereof |
CN106619503A (en) * | 2016-09-23 | 2017-05-10 | 辽宁大学 | RH (rhein) amide derivative nanosuspension as well as preparation method and application thereof |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101735271A (en) * | 2008-11-05 | 2010-06-16 | 上海慈瑞医药科技有限公司 | Bong-seeking bisphosphonate rhein ester derivates and preparation method thereof |
CN102225896B (en) * | 2011-04-07 | 2013-10-30 | 栗进才 | Ether derivatives of rhein and their therapeutic use |
JP2015527322A (en) * | 2012-07-10 | 2015-09-17 | ジョージア ステイト ユニバーシティ リサーチ ファンデーション, インコーポレイテッド | Anthraquinone analogs and methods for making and using the same |
TWI743047B (en) * | 2015-08-17 | 2021-10-21 | 安成生物科技股份有限公司 | Methods for inhibiting expression of asc, expression of nlrp3, and/or formation of nlrp3 inflammasome complex using diacerein or its analogs |
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EP0822177A1 (en) * | 1996-07-31 | 1998-02-04 | Laboratoire Medidom S.A. | Process for producing rhein and diacerhein |
US6124358A (en) * | 1996-12-23 | 2000-09-26 | Mazal Pharmaceutique (Sarl) | Pharmaceutical composition containing rhein or diacerhein with improved bioavailability |
-
2004
- 2004-03-04 GB GBGB0404953.2A patent/GB0404953D0/en not_active Ceased
-
2005
- 2005-03-04 AU AU2005219642A patent/AU2005219642B2/en not_active Ceased
- 2005-03-04 CN CNA2005800099641A patent/CN1938258A/en active Pending
- 2005-03-04 CA CA002558082A patent/CA2558082A1/en not_active Abandoned
- 2005-03-04 JP JP2007501352A patent/JP4478713B2/en active Active
- 2005-03-04 BR BRPI0508352-4A patent/BRPI0508352A/en not_active IP Right Cessation
- 2005-03-04 EP EP05726943A patent/EP1723097A1/en not_active Withdrawn
- 2005-03-04 ZA ZA200607386A patent/ZA200607386B/en unknown
- 2005-03-04 MX MXPA06010058A patent/MXPA06010058A/en not_active Application Discontinuation
- 2005-03-04 WO PCT/GB2005/000832 patent/WO2005085170A1/en active Application Filing
- 2005-03-04 KR KR1020067020192A patent/KR20070010142A/en not_active Application Discontinuation
- 2005-03-04 US US10/591,157 patent/US7728035B2/en not_active Expired - Fee Related
-
2006
- 2006-08-29 IL IL177752A patent/IL177752A0/en unknown
- 2006-09-07 NO NO20064031A patent/NO20064031L/en not_active Application Discontinuation
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US4244968A (en) * | 1976-03-16 | 1981-01-13 | Proter S.P.A. | Treatment of arthritis and substances for use in such treatment |
JPS58225015A (en) * | 1983-02-25 | 1983-12-27 | プロツタ−・エス・ピ−・エ− | Antisclerotic |
EP0822177A1 (en) * | 1996-07-31 | 1998-02-04 | Laboratoire Medidom S.A. | Process for producing rhein and diacerhein |
US6124358A (en) * | 1996-12-23 | 2000-09-26 | Mazal Pharmaceutique (Sarl) | Pharmaceutical composition containing rhein or diacerhein with improved bioavailability |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008056156A1 (en) * | 2006-11-10 | 2008-05-15 | Sosei R & D Ltd. | Salts of dihydroxyanthraquinone carboxylic acids and their therapeutic use |
CN102552430A (en) * | 2011-12-03 | 2012-07-11 | 彭旦明 | Effective fractions for inhibiting scars and preparation method thereof |
CN102603575A (en) * | 2012-01-04 | 2012-07-25 | 丛晓东 | Rhein-arginine eutectic compound, and preparation method, purification method and application thereof in preparation of medicines for treating diabetic complications |
CN102603575B (en) * | 2012-01-04 | 2014-08-13 | 丛晓东 | Rhein-arginine eutectic compound, and preparation method, purification method and application thereof in preparation of medicines for treating diabetic complications |
CN104547207A (en) * | 2015-01-29 | 2015-04-29 | 陈文斌 | Externally applied traditional Chinese medicinal preparation for eliminating old scar and preparation method thereof |
CN106619503A (en) * | 2016-09-23 | 2017-05-10 | 辽宁大学 | RH (rhein) amide derivative nanosuspension as well as preparation method and application thereof |
CN106619503B (en) * | 2016-09-23 | 2019-09-13 | 辽宁大学 | A kind of Rhein amide derivatives nano suspension and its preparation method and application |
Also Published As
Publication number | Publication date |
---|---|
MXPA06010058A (en) | 2007-05-10 |
BRPI0508352A (en) | 2007-07-31 |
US7728035B2 (en) | 2010-06-01 |
JP4478713B2 (en) | 2010-06-09 |
CA2558082A1 (en) | 2005-09-15 |
JP2007526293A (en) | 2007-09-13 |
GB0404953D0 (en) | 2004-04-07 |
IL177752A0 (en) | 2006-12-31 |
EP1723097A1 (en) | 2006-11-22 |
ZA200607386B (en) | 2008-05-28 |
AU2005219642B2 (en) | 2009-04-23 |
KR20070010142A (en) | 2007-01-22 |
NO20064031L (en) | 2006-09-15 |
CN1938258A (en) | 2007-03-28 |
US20070185036A1 (en) | 2007-08-09 |
AU2005219642A1 (en) | 2005-09-15 |
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