GB2398780A - 1,8-dihydroxyanthraquinone-6-carboxamide derivatives as inhibitors of T-cell proliferation for treatment of autoimmune or inflammatory conditions - Google Patents

Abstract

A compound of general formula (<B>1</B>): <EMI ID=1.1 HE=41 WI=77 LX=908 LY=81 TI=CF> <PC>wherein: ```R1 and R2 are the same or different and are each H, C1-4 alkyl or COR5; ```R3 is H or C1-4 alkyl; and ```R4 is C1-4 alkyl substituted with R6, C2-4 alkyl substituted with R7, aryl substituted with R7 or heteroaryl optionally substituted with R7, C3-6cycloalkyl optionally substituted with R7 or C4-6 heterocycloalkyl optionally substituted with R7; or ```NR3R4 is a four to seven-membered ring which is optionally substituted with R7 and can contain one or more additional heteroatoms taken from O, S(O)n and NR1 wherein n is 0-2; ```R5 is C1-4 alkyl, aryl or heteroaryl; ```R6 is aryl substituted with R7, heteroaryl optionally substituted with R7, C3-6cycloalkyl optionally substituted with R7 or C4-6 heterocycloalkyl optionally substituted with R7; ```R7 is OR3, CO2R3, N(R3)2 where each R3 is the same or different or form a four to seven-membered ring which may contain one or more additional heteroatoms taken from O, S(O)n and NR1 wherein n is 0-2, or N(R3)2 is a five or six-membered ring such as a lactam, succinimide or hydantoin of the formula: <EMI ID=1.2 HE=36 WI=89 LX=921 LY=1717 TI=CF> <PC>```or a salt, solvate or hydrate thereof, may have utility in the treatment of an autoimmune or inflammatory condition. Such conditions include a chronic degenerative disease (such as rheumatoid arthritis, osteoarthritis or osteoporosis), a chronic demyelinating disease (such as multiple sclerosis), a respiratory disease (such as asthma or allergic rhinitis or chronic obstructive pulmonary disease [COPD]), an inflammatory bowel disease [IBD](such as ulcerative colitis or Chron's disease), a dermatological condition (such as psoriasis, scleroderma or atopic dermatitis) a dental disease (such as periodontal disease or gingivitis), diabetic nephropathy, lupus nephritis, IgA nephropathy, glomerulonephritis, systemic lupus erythematosus (SLE) or graft vs host disease. These carboxamide derivatives are capable of inhibiting T-cell proliferation in assays. In addition, the physiochemical properties of the template can be greatly enhanced by utilising the amide substituent to introduce solubility-enhancing groups.

Description

NOVEL AMIDES AS INHIBITORS OF T-CELL PROLIFERATION

Field of the Invention

The present invention relates to novel dihydroxyanthraquinone carboxamide derivatives with improved physicochemical properties and that inhibit Tcell proliferation, processes for their preparation and their utility in the treatment of disease.

Background to the Invention

T-lymphocytes are known to play a central role in the pathogenesis of many inflammatory and autoimmune diseases. 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. In rheumatoid arthritis, the recruitment and activation of synovial macrophages by CD4+ T-cells leads to the secretion of high levels of TNFa, IL-1 b and other proinflammatory cytokines.

T-cell proliferation may be involved in multiple sclerosis, a chronic demyelinating inflammatory disease of the central nervous system. Further, in chronic obstructive pulmonary disease (CORD), neutrophils and macrophages are activated by proliferating CD8+ T-cells.

Crohn's disease and ulcerative colitis are chronic inflammatory diseases of the intestines collectively known as inflammatory bowel disease (IBD). Once again, T-cells are central to the progression of this collection of diseases.

In psoriasis, 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.

There is a similarly strong rationale for the central involvement of Tcells 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).

Rhein (1,8-dihydroxyanthraquinone-3-carboxylic acid) is an anti inflammatory agent with recognised utility in a range of inflammatory diseases This agent inhibits the production of pro-inflammatory cytokines (IL-1b and TNFa) in human ostecarthrtic synovium and chondrocytes (J. Martel-Pelletier et al, Journal of Rheumatology, 1998, 25 (4), 753-762) and inhibits cytokine gene expression in a model of lupus nephritis (S. Lemay et a/, Kidney International, 1996, 50 (1), 85-93).

US-A-4346103 discloses the use of rhein in arthritis and multiple sclerosis. EP-A-0990441 discloses its use in diabetic nephropathy. The use of rhein has been limited by its rather poor physicochemical properties. This issue is not addressed completely with the well characterized pro-drug diacerein where utility in the clinical setting is again limited by poor physicochemical properties (P. Nicolas et al, Clin. Pharmacokinet., 1998, 35 (5), 347-359).

Derivatives of resin, Including some carboxamides are disclosed in EP-A 0822178 and WO-A-02053146.

Summary of the Invention

The present invention is related to the observation that simple carboxamide derivatives of rhein are capable of inhibiting T-cell proliferation in assays where rhein itself and other simple derivatives fail to produce a response.

In addition, the physicochemical properties of the template can be greatly enhanced by utilsing the amide substituent to introduce solubility-enhancing groups. It is likely that these agents will be of clinical utility in a wide range of inflammatory and autoimmune diseases, including those described above.

Compounds according to the present invention are of formula (1):

O O

IN

OR2 0 OR1 wherein: R. and R2 are the same or different and are each H. C, 4 alkyl or COR5; R3 is H or C'4 alkyl; and R4 is C,4 alkyl substituted with R6, C24 alkyl substituted with R7, aryl substituted with R7, heteroaryl optionally substituted with R7, c3-6cycloalkyl optionally substituted with R7 or C4 6 heterocycloalkyl optionally substituted with R7; or R3 and R4 form a four to seven-membered ring which can be optionally substituted with R7 and can contain one or more additional heteroatoms taken from O. S( )n and NR, wherein n is 0-2; R5 is C,4 alkyl, aryl or heteroaryl; R6 is aryl substituted with R7, heteroaryl optionally substituted with R7, C36cycloalkyl optionally substituted with R7 or C46 heterocycloalkyl optionally R7is OR3, CO2R3, N(R3)2 where each R3 may be the same or different or form a four to seven-membered ring which may contain one or more additional heteroatoms taken from O. S( )n and NR, wherein n is 0-2; in addition N(R3)2 may form a five or six- membered ring such as a lactam, succinimide or hydantoin such as the following

O O O N R3 R3

and the salts, solvates and hydrates thereof.

Description of Preferred Embodiments

It will be appreciated that 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) 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.

The term ''C, 4 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, tert-butyl and the like.

The term "C2 4 alkyl" refers to a straight or branched chain alkyl moiety having from two to four carbon atoms, including for example, ethyl, propyl, isopropyl, butyl, tert-butyl and the like.

The term "C3 6cycloalkyl" refers to a saturated alicyclic moiety having from three to six carbon atoms and Includes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "C4 6heterocycloalkyl" 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.

The term "aryl" means an optionally substituted phenyl or naphthyl group with the substituent(s) being selected, for example, from halogen, trifluoromethyl, C, 4 alkyl, alkoxy, phenyl and the like.

The term "heteroaryl" refers to aromatic ring systems of five to ten atoms or which at least one atom is selected from the group, O. N. or S and includes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like.

The term "halogen" means fluorine, chlorine, bromine or iodine.

Salts of compounds of formula (1) 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.

The terms "protected amino" and "protected carboxy" mean amino and carboxy groups which are protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert- butoxycarbonyl, acetyl or like groups, or in the form of a phthalimido or like group. A carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester.

Compounds of the general formula (1) may be prepared by any suitable method known in the art and/or by the following processes.

It will be appreciated that where a particular stereoisomer of formula (1) is required, 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).

Further, it will be appreciated that 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. In such instances, removal of the protecting group may be the final step In a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details see "Protective Groups in Organic Synthesis", Wiley Interscience, T W Greene, PGM Wuts.

A process for preparing compounds of general formula (1) comprisesconversion of diacerein to its corresponding acid chloride or activated ester followed by quenching with the corresponding amine. Diacerein and the corresponding amines are either commercially available or readily obtained from commercially available materials by people who are skilled in the art of synthetic organic chemistry.

Any mixtures offinal products or intermediates obtained can be separated on the basis of the physico-chemcal 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.

The compounds of formula (1) according to the invention exhibit in vitro inhibiting activities with respect to T-cell proliferation. Compounds according to the invention also exhibit in vitro inhibition of proinflammatory cytokine release.

The activity of the compounds may be determined by use of the appropriate cellular assay.

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 Tcell proliferation inhibitors of formula (1) as the active constituents.

Accordingly, the compounds of formula (1) can be used among other things in the treatment of osteoarthritis and rheumatoid arthritis, psoriasis, systemic lupus erythromatoss (SLE), multiple sclerosis, chronic obstructive pulmonary disease (CORD) and inflammatory bowel disease including ulcerative colitis and Crohn's disease.

As mentioned above, compounds of formula (1) are useful in human or veterinary medicine since they are active as inhibitors of T-cell proliferation.

Accordingly in another aspect, this invention concerns: a method of management (by which is meant treatment of prophylaxis) of disease or conditions mediated T-cells in mammals, in particular in humans, which method comprises administering to the mammal an effective, amount of a compound of formula (1) above, or a pharmaceutically acceptable salt thereof; and a compound of formula (1) 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) 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 diseases or conditions referred to above Include inflammatory and autoimmune diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, 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 (CORD).

For the treatment of rheumatoid arthritis, multiple sclerosis, and in other diseases and indications resulting from the over-activity of Tcells such as those highlighted above, the compounds of formula (1) 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 The term parenteral as used herein includes subcutaneous Injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats etc. the compounds of the invention are effective in the treatment of humans.

The pharmaceutical composition containing the active ingredient may be In a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. 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 nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These 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 corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, steanc 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. For example, a time delay material such as glyceryl monostearate or glyeryl distearate may be employed. They may also be coated by the techniques described in the US-A 4256108, US-A-4166452 and US-A4265874, toform osmotictherapeutictablets for control release.

Formulations for oral use may also be presented as hard gelatin capsules where in the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such 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 occuring 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 dervied from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. 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 actve ingredent in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraff'n The oily suspensions may contain a thckening 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. These 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 orwetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring agents, may also be present.

The 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 Creches oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occuring gums, for example gum acacia or gum tragacanth, naturally-occuring 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, sorbtol 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- butane dial. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of formula (1) 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. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc containing the compounds of Formula (1) are employed. (For purposes of this application, topical application shall include 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 gms per patient per day). For example, 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 gms 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. For example, a formulation intended for the oral administration of humans may vary from about 5 to about 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 Example illustrates the invention.

Acetic acid 8-acetoxy-6-(morpholine-4-carbonyl)-9,10-dioxo-9,10dihydro-anthracen-1-yl ester 0 0 \:O 0 O>/

O O

Thionyl chloride (81 HI, 1.1 mmol) was added to a suspension of 4,5 diacetoxy-9,10-dioxo-anthracene-2-carboxylic acid (diacerein, 200 mg, 0. 55 mmol) in a mixture of pyridine (80 pI, 1 mmol) and dimethoxyethane (10 ml). The mixture was reflexed for 1 hour, then cooled to 5 C. After 1 h a dioxane solution of morpholine (97 I, 1.1 mmol) was added and the mixture was stirred at room temperature for 2h. The solvent was evaporated under reduced pressure and the residue was triturated in distilled water, filtered then was successively with water, ethanol and diisopropyl ether. The obtained yellow solid was dried at 80 C (162 mg).

MP = 208 C.

AH NMR (DMSO-d6): 8.11 (2H, m), 7.94 (1 H. t), 7.66 (2H, m), 3.66 (4H, m), 3.35 (4H, m), 2.40 (OH, s).

Compounds related in structure to those of the present invention are described in another British Patent Application filed on the same day and also in the name of Arakis Ltd.

Claims (13)

1. A compound of general formula (1):

O O

of, /R3 OR2 0 OR wherein: R. and R2 are the same or different and are each H. C, 4 alkyl or COR5; R3 is H or C,4 alkyl, and R4 Is C'4 alkyl substituted with R6, C2 4 alkyl substituted with R7, aryl substituted with R7 or heteroaryl optionally substituted with R7, c3-6cycloalk optionally substituted with R7 or C4 6 heterocycloalkyl optionally substituted with R7; or NR3R4 is a four to seven-membered ring which is optionally substituted with R7 and can contain one or more additional heteroatoms taken from O. S( )n and NR, wherein n is 0-2; R5is C,4 alkyl, aryl or heteroaryl; t R6 is aryl substituted with R7, heteroaryl optionally substituted with R7, C36cycloalkyl optionally substituted with R7 or C46 heterocycloalkyl optionally R7is OR3, CO2R3, N(R3)2 where each R3is the same or different or form a four to seven-membered ring which may contain one or more additional heteroatoms taken from O. S( )n and NR, wherein n is 0-2, or N(R3)2 is a five or sx-membered ring such as a lactam, succinimide or hydantoin of the formula:

O O O

NO -R3 R3 or a salt, solvate or hydrate thereof.

2 A compound of claim 1, which is acetic acid 8-acetoxy-6-(morpholine-4 carbonyl)-9, 1 0-d ioxo-9, 1 0-d i hydro-anthracen-1 -yl ester.

3. A pharmaceutical composition for use in therapy, comprising a compound of claim 1 or claim 2 and a pharmaceutically acceptable diluent or carrier.

4. Use of a compound of any of claims 1 to 3, for the manufacture of a human or veterinary medicament for the treatment of an autoimmune or inflammatory condition.

5. Use according to claim 4, wherein the condition is a chronic degenerative disease such as rheumatoid arthritis, osteoarthritis or osteoporosis.

6. Use according to claim 4, wherein the condition is a chronic demyelnating disease such as multiple sclerosis.

7. Use according to claim 4, wherein the condition Is a respiratory disease such as asthma or chronic obstructive pulmonary disease (CORD).

8. Use according to claim 4, wherein the condition is an inflammatory bowel disease (IBD) such as ulcerative colitis or Crohn's disease.

9. Use according to claim 4, wherein the condition is a dermatological condition such as psoriasis, scleroderma or atopic dermatitis.

10. Use according to claim 4, wherein the condition is a dental disease such as periodontal disease or gingivitis.

11. Use according to claim 4, wherein the condition is diabetic nephropathy, lupus nephritis, IgA nephropathy or glomerulonephritis.

12. Use according to claim 4, wherein the condition is systemic lupus erythematosus (SLE).

13. Use according to claim 4, wherein the condition is graft vs host disease.