WO2009019473A1 - Treatments for inflammatory arthritis - Google Patents

Treatments for inflammatory arthritis Download PDF

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Publication number
WO2009019473A1
WO2009019473A1 PCT/GB2008/002671 GB2008002671W WO2009019473A1 WO 2009019473 A1 WO2009019473 A1 WO 2009019473A1 GB 2008002671 W GB2008002671 W GB 2008002671W WO 2009019473 A1 WO2009019473 A1 WO 2009019473A1
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WIPO (PCT)
Prior art keywords
imiquimod
derivative
pharmaceutically acceptable
acceptable salt
agent
Prior art date
Application number
PCT/GB2008/002671
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French (fr)
Inventor
Brian M. Foxwell
Sandra Sacre
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Imperial Innovations Limited
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Publication of WO2009019473A1 publication Critical patent/WO2009019473A1/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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

Definitions

  • the present invention relates to imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for use in treating inflammatory arthritis and related conditions.
  • the present invention also relates to the use of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating inflammatory arthritis and related conditions.
  • the present invention also relates to a kit comprising a pharmaceutical composition comprising imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof and instructions indicating that the composition is for use in treating inflammatory arthritis and related conditions.
  • the present invention relates to a method of treating inflammatory arthritis and related conditions comprising administration of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof. The method is preferably carried out on a subject in need of treatment.
  • the inflammatory arthritis is preferably rheumatoid arthritis.
  • Rheumatoid arthritis is a chronic inflammatory disease occurring in 0.5%-l% of the population. This disease affects the joints and is characterized by thickening of the synovial membrane. This disease leads to progressive debilitation in joint function which results in pain, disability, loss of man power and shorter life expectancy. In addition there are a number of similar related conditions; psoriatic arthritis, juvenile arthritis, ankylosing spondelytis, Crohn's disease and psoriasis.
  • steroids such as dexamethasone and methyl-prednisolone
  • steroids are widely used in the treatment of rheumatoid arthritis. While treatment with steroids can be effective, there are a number of serious side effects.
  • anti-TNF therapy also prevents joint destruction and thus is considered to have disease modifying anti-arthritic drug (DMARD) activity.
  • DMARD disease modifying anti-arthritic drug
  • it is extremely expensive and this places a heavy financial burden either on the patient or the healthcare system or both and this seriously limits availability.
  • Many patients in the developed world and the majority in the developing world are not able to afford this treatment.
  • possible side effects of anti-TNF therapy include anaphylaxis and cytopenia.
  • systemic neutralisation of TNF leads to increased susceptibility to infection and the long-term effects are still unknown.
  • anti- TNF drugs orally which is a disadvantage.
  • those patients that do respond approximately 50% will become refractory to treatment in 2 years due to the development of immunity to the biological treatment.
  • DARDS disease modifying anti-rheumatic drugs
  • methotrexate an anti-metabolite drug, which is widely used for the treatment of rheumatoid arthritis, psoriatic arthritis and psoriasis.
  • Methotrexate has been successful in the treatment of these diseases, but can cause substantial side effects, such as severe skin reaction, infections such as pneumonia, severe damage to liver, kidneys, lungs and gastrointestinal tract. Again a significant number of patients do not respond or become refractory with time.
  • a number of DMARD pharmaceutical agents containing gold are also used in the treatment of rheumatoid arthritis.
  • examples of such agents include gold sodium thiomalate and auranofin.
  • Potential side effects from being treated with antiinflammatory gold agents are oral ulcers, altered taste, serious skin rashes, renal problems, inflammation of the intestines (enterocolitis), liver injury and lung disease. Furthermore, resistance to gold has been known to develop in patients.
  • a further class of drugs are the non-steroidal anti-inflammatory drugs (NSAID's). These are used to alleviate symptoms but not modify disease progression and includes the Cox 2 inhibitors "VIOXX” ® , (a registered trademark of Merck & Co., Inc) and "CELEBREX” ® , (a registered trademark of G.D. Searle & Co). However there is major concern about the safety of these drugs with evidence of increased cardiovascular risk.
  • NSAID's non-steroidal anti-inflammatory drugs
  • the first aspect of the present invention provides imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for use in treating inflammatory arthritis and related conditions.
  • ALDARA Imiquimod
  • derivatives of imiquimod have the following structure:
  • R 1 is -R 2 , -OR 2, -NR 2 R 3 , -R 2 C(O)OR 2 or -R 2 OC(O)R 2 ;
  • R 2 is a) alkyl, alkenyl or alkynyl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, aryl, heteroaryl, carbocycle or heterocycle, wherein the aryl, heteroaryl, carbocycle or heterocycle is optionally substituted by one or more groups independently selected from C]. 6 alkyl, C 1-6 alkoxy and halogen; or b) 5 to 7 membered aryl, heteroaryl, carbocycle or heterocycle, optionally substituted by one or more groups independently selected from C 1-6 alkyl, C 1-6 alkoxy and halogen; and
  • R 3 is hydrogen or R 2 .
  • Imiquimod comprises the formula set out above wherein R 1 is isobutyl.
  • alkyl as used herein means a straight or branched chain saturated hydrocarbon group, preferably with 1 to 10 carbons, more preferably 1 to 6 carbons, most preferably iso-butyl.
  • alkene as used herein means a straight or branched chain unsaturated hydrocarbon group containing at least one carbon-carbon double bond. An alkene preferably has 2 to 10 carbons, more preferably 2 to 6 carbons.
  • alkyne as used herein means a straight or branched chain unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, preferably with 2 to 10 carbons, more preferably 2 to 6 carbons.
  • carbocycle as used herein means a cyclic hydrocarbon group which may be saturated or may contain one or more units of un-saturation, but which is not aromatic.
  • a carbocycle is preferably 5-7 membered.
  • heterocycle means a cyclic group containing one or more species of heteroatom selected from the group consisting of a nitrogen atom, a sulphur atom and an oxygen atom.
  • a heterocyclic group may be unsaturated or may contain one or more units of un-saturation, but is not aromatic.
  • a heterocycle is preferably 5-7 membered.
  • aryl group used herein means an aryl group constituted by 5 to 10 carbon atoms, which may be monocyclic or bicyclic. Preferably, an aryl is 5-7 membered.
  • heteroaryl as used herein means an aromatic cyclic group containing one or more species of heteroatom selected from the group consisting of a nitrogen atom, a sulphur atom and an oxygen atom.
  • a heteroaryl is 5-7 membered.
  • halogen as used herein means preferably fluorine, chlorine, bromine or iodine.
  • Imiquimod or a derivative thereof may be provided as a pharmaceutically acceptable salt.
  • the inflammatory arthritis includes rheumatoid arthritis and the related conditions psoriatic arthritis, juvenile arthritis, ankylosing spondelytis but drugs are envisaged to be useful for other chronic diseases driven by TNF such as, Crohn's disease and psoriasis.
  • the inflammatory arthritis is rheumatoid arthritis and the related conditions are psoriatic arthritis, juvenile arthritis, ankylosing spondelytis, Crohn's disease and psoriasis.
  • Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof according to the present invention inhibit TNF production.
  • Imiquimod and/or a derivative thereof and/or a pharmaceutically acceptable salt thereof and/or another agent may be used in combination, which may be for simultaneous, separate or sequential use.
  • imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof can be for topical administration.
  • imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof can be for oral administration.
  • the oral administration of imiquimod can be in combination with an agent that reduces the gastrotoxicity associated with imiquimod.
  • the agent can be a prodrug of TLR7 agonists, such as ANA-975.
  • Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof and an agent that reduces gastrotoxicity may be for simultaneous, separate or sequential use.
  • Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof may be used in combination with a further anti-inflammatory agent.
  • Administration of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof and other anti-inflammatory agent can be simultaneous, separate and/or sequential.
  • Imiquimod, derivatives and/or salts thereof, in combination with another pharmaceutical agent can act additively or synergistically.
  • the other anti-inflammatory agent may be termed a 5-HT receptor antagonist including promazine hydrochloride, ketanserine tartrate or mianserine hydrochloride, a serotonin reuptake inhibitor including fluoxetine hydrochloride, citalopram or sertraline, an interferon inhibitor, a non-steroidal anti-inflammatory agent (NSAID), a disease modifying anti-rheumatic drug (DMARD), a biological agent (biologicals), a steroid, an immunosuppressive agent, a salicylate and/or a microbicidal agent.
  • NSAID non-steroidal anti-inflammatory agent
  • DMARD disease modifying anti-rheumatic drug
  • biological agent biological agent
  • steroid an immunosuppressive agent
  • a salicylate and/or a microbicidal agent.
  • Nonsteroidal anti-inflammatory agents include anti-metabolite agents (including methotrexate) and anti-inflammatory gold agents (including gold sodium thiomalate, aurothiomalate or gold salts, such as auranofin).
  • Biologicals include anti-TNF agents (including adalimumab, etanercept, infliximab, anti-EL-1 reagents, anti-IL-6 reagents, anti-B cell reagents (retoximab), anti-T cell reagents (anti-CD4 antibodies), anti-IL-15 reagents, anti-CLTA4 reagents, anti-RAGE reagents), antibodies, soluble receptors, receptor binding proteins, cytokine binding proteins, mutant proteins with altered or attenuated functions, RNAi, polynucleotide aptamers, antisense oligonucleotides or omega 3 fatty acids.
  • Steroids include cortisone, prednisolone or dexamethasone.
  • Immunosuppressive agents include cylcosporin, FK506, rapamycin, mycophenolic acid.
  • Salicylates include aspirin, sodium salicylate, choline salicylate and magnesium salicylate.
  • Microbicidal agents include quinine and hydroxychloroquine.
  • imiquimod and derivatives may be administered in combination with one or more of a 5-HT receptor antagonist, a serotonin reuptake inhibitor, an NSAID, DMARD or immunosuppressant.
  • the further anti-inflammatory agent is administered orally (including buccally or sublingually) or parenterally (including subcutaneously, intramuscularly, intravenously or intradermally).
  • the invention provides the use of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating inflammatory arthritis and related conditions.
  • the second aspect is a kit comprising a pharmaceutical composition comprising imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof and instructions indicating that the composition is for use in treating inflammatory arthritis and related conditions.
  • Compositions in accordance with the invention may be supplied as part of a sterile, pharmaceutical composition which will normally include a pharmaceutically acceptable carrier.
  • This pharmaceutical composition may be in any suitable form. It may be provided in unit dosage form and will generally be provided in a sealed container.
  • the kit of the invention may comprise a plurality of said unit dosage forms.
  • the oral pharmaceutical compositions may be presented as discrete units such as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids; or as edible foams or whips; or as emulsions).
  • Suitable excipients for tablets or hard gelatine capsules include lactose, maize starch or derivatives thereof, stearic acid or salts thereof.
  • Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid, or liquid polyols etc.
  • excipients which may be used include for example water, polyols and sugars.
  • suspensions oils e.g. vegetable oils
  • oil-in-water or water in oil suspensions may be used.
  • compositions may contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colourants, odourants, salts, buffers, coating agents or antioxidants. They may also contain further therapeutically active agents.
  • Route of administration may include; parenterally (including subcutaneous, intramuscular, intravenous, by means of, for example a drip patch), some further suitable routes of administration include (but are not limited to) oral (including buccal and sublingual), rectal, nasal, topical, infusion, vaginal, intradermal, intraperitoneally, intracranially, intrathecal and epidural administration or administration via oral or nasal inhalation, by means of, for example a nebuliser or inhaler, or by an implant.
  • the oral or nasal inhalation routes may be delivered using a mechanical form including, but not restricted to, an inhaler or nebuliser device.
  • administration is by a SPAG (small particulate aerosol generator) may be used.
  • SPAG small particulate aerosol generator
  • Dosages of the substances of the present invention can vary between wide limits, depending upon the condition to be treated, the health of the individual to be treated, etc. and a physician may determine appropriate dosages to be used. The dosage may be repeated as often as appropriate.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the imiquimod or derivative which produces a therapeutic effect
  • compositions and uses described in this application are envisaged to have human, animal and veterinary applications. They are preferably applicable to mammals, in particular humans but are also applicable for use in production animals, in particular sheep, cows, pigs, chickens and goats, as well as companion animals, in particular cats and dogs and sporting animals, such as horses.
  • the third aspect of the invention is a method of treating inflammatory arthritis and related conditions comprising administering imiquimod, a derivative or a salt thereof.
  • the derivative is defined according to the first aspect of the invention.
  • the method is preferably carried out on a subject in need of treatment.
  • the term "treatment” includes prophylactic treatment (i.e. prevention). In most circumstances, prevention of inflammatory arthritis or a related condition is unlikely to be carried out. Usually, it is only when the presence of inflammatory arthritis or a related condition is diagnosed in a subject that prevention means are applied. However, prophylactic treatment may be appropriate if there is a known family history of significant inflammatory arthritis or a related condition or if tests (e.g. genetic tests) identify that an individual has a predisposition to inflammatory arthritis or a related condition.
  • the fourth aspect of the invention is imiquimod, a derivative or a salt thereof for treating inflammatory arthritis or a related condition.
  • Figure 1 illustrates that imiquimod inhibits, R-848 increases and CpG has no effect on spontaneous TNF production from rheumatoid synovial cultures. Levels of TNF production are shown in ng/ml ⁇ SEM from 7 - 12 unrelated RA patients.
  • FIG. 2 illustrates that gardiquimod enhances spontaneous TNF production in rheumatoid synovial cultures.
  • RA synovial membrane cells were incubated for 24 hours in the presence of media alone or media containing 1 or 5 ⁇ g/ml gardiquimod (gard).
  • Figure 3 illustrates that imiquimod selectively inhibits activation of TLR8 signaling -
  • (a) Primary human M-CSF macrophages were incubated with 10 ⁇ g/ml imiquimod alone or in combination with 10 ng/ml Flagellin, 10 ng/ml Pam3, 1 ⁇ g/ml R-848 or 10 ng/ml LPS for 6 hours. Data was pooled from triplicate wells from 3 separate donors and shown as a percentage of the appropriate maximal responses (100%).
  • M-CSF macrophages were incubated with media alone or 1 ⁇ g/ml R-848 in the presence of 0, 2.5, 5 or 10 ⁇ g/ml imiquimod for 6 hours.
  • TNF was measured from triplicate cultures ⁇ SD and is representative of 3 separate donors, (c) Rheumatoid arthritis synovial fibroblasts were incubated with media alone or media containing 20 ⁇ g/ml Polyriboinosinic-polyribocytidylic acid (Poly IC) in the presence or 0 or 10 ⁇ g/ml imiquimod for 6 hours. Data shows triplicate cultures ⁇ SD and is representative of 3 separate donors.
  • Poly IC Polyriboinosinic-polyribocytidylic acid
  • Figure 4 illustrates that guanosine activates whereas cGMP and hypoxanthine do not activate macrophages to induce TNF production.
  • Primary human M-CSF macrophages were incubated with media alone, 1 ⁇ g/ml R-848, 0.1-30 ⁇ g/ml guanosine or 10-30 ⁇ g/ml cGMP for 6 hours
  • Human M-CSF macrophages were incubated with 0.1-20 ⁇ g/ml hypoxanthine for 6 hours.
  • Figure 5 illustrates that loxoribine (figure 5a) and gardiquimod (figure 5b) have no effect on TNF production by primary human macrophages stimulated with lOng/ml LPS or 1 ⁇ g/ml R-848.
  • Figure 6 illustrates the structure of loxoribine.
  • Figure 7 illustrates the structure of gardiquimod.
  • Figure 8 illustrates that loxoribine has no effect on spontaneous release of TNF from RA synovial membrane cultures from 6 donors.
  • FIG. 9 illustrates that CL075 and CL097 increase TNF production in human M- CSF macrophages.
  • FIG. 10 illustrates the structure of CL075.
  • Figure 11 illustrates the structure of CL097.
  • Figure 12 illustrates the structure of R-848.
  • Cell culture reagents used were Penicillin-Streptomycin, RPMI 1640 and DMEM obtained from Cambrex (Belgium), Indomethacin from Sigma (USA) and FBS from PAA (Austria).
  • the TLR ligands used were chloroform extracted Escherichia coli (E.coli) LPS and resiquimod (R-848), CpG (ODN 2006) and imiquimod from Invivogen (USA).
  • Flagellin (purified), Pam 3 cys-ser(lys) 4 .3HCl (Pam3) and gardiquimod were from Alexis (UK). All reagents other than LPS were free from LPS contamination as assessed using the limulus amebocyte lysate (LAL) assay from Cambrex (USA).
  • Sandwich ELISAs were employed to measure TNF and IL-6 (Pharmingen, UK).
  • Absorbance was read on a spectrophotometric ELISA plate reader (Labsystems Multiscan Biochromic) and analyzed using Ascent software V2.6 (Thermo
  • RA synovial membrane cells were isolated from patients undergoing joint replacement surgery as previously described (Foxwell et al., Proc. Natl. Acad. Sci. USA 95,8211-8215, 1998). All patients gave written informed consent and the study was approved by the local ethics committee. Immediately after isolation, cells were cultured at IxIO 5 cells/well in 96-well tissue culture plates (Falcon, UK) in RPMI 1640 containing 10% (v/v) FBS and 100 U/ml penicillin/streptomycin. Primary human synovial fibroblasts were cultured as described previously (Butler et al. Eur. Cytokine Netw. 5:441-8, 1994).
  • Peripheral blood monocytes were isolated and cultured as previously described (Foxwell et al., Proc. Natl. Acad. Sci. USA 95, 8211- 8215, 1998). Macrophages were derived from monocytes after differentiation for 4 days with 100 ng/ml M-CSF (PeproTech, UK).
  • Rheumatoid arthritis synovial membrane cells were also cultured in the presence of media alone or media containing l ⁇ g/ml and 5 ⁇ g/ml gardiquimod (see Figure 2). Gardiquimod enhances spontaneous TNF production.
  • Example 2 The inhibitory effect of imiquimod being unexpected was investigated further. Although imiquimod is a TLR7 agonist it is structurally similar to R-848, a ligand for both TLRs 7 and 8. We therefore investigated if imiquimod could actually act as an inhibitor of TLR8 activity in human macrophages.
  • M-CSF macrophages were also incubated with media alone or 1 ⁇ g/ml R-848 in the presence of 0, 2.5, 5 or 10 ⁇ g/ml imiquimod for 6 hours. TNF was measured from triplicate cultures ⁇ SD and is representative of 3 separate donors (see figure 3(b)).
  • Rheumatoid arthritis synovial fibroblasts were incubated with media alone or media containing 20 ⁇ g/ml Poly IC in the presence or 0 or 10 ⁇ g/ml imiquimod for 6 hours. Data shows triplicate cultures ⁇ SD and is representative of 3 separate donors (see figure 3(c)).
  • Imiquimod did inhibit TNF production induced by R848 (figure 3a) an effect that was dose dependent (Figure 3b). In contrast the drug had no effect on TNF production induced from macrophages by LPS (TLR4), Pam3Cys (TLR1,2) or flagellin (TLR5). Activation of TLR3 (Poly IC) induces no TNF or IL-6 production from human macrophages but does induce EL-6 from RA-synovial fibroblasts (data not shown). This also was not inhibited by imiquimod (Figure 3c). These results indicate that imiquimod inhibits TNF production in synovial membranes by blocking TLR8.
  • Loxoribine and gardiquimod were no effect on TNF production (see figures 5a and 5b).
  • Loxoribine and gardiquimod are structurally similar to imiquimod and, like imiquimod, they are also TLR7 ligands (see figures 6 and 7). However, the structural difference renders these molecules unable to inhibit TLR4 (LPS) and TLR8 (R-848) induced TNF.
  • Loxoribine had no effect on spontaneous release of TNF (see figure 8).
  • Loxoribine is structurally similar to imiquimod and like imiquimod it is also a TLR7 ligand.
  • the lack of any inhibitory effect of loxoribine on the spontaneous production of TNF by rheumatoid arthritis synovial membrane cultures indicates that loxoribine would not be a useful treatment for rheumatoid arthritis.

Abstract

The present invention relates to imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for use in treating inflammatory arthritis and related conditions. The present invention relates to the use of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating inflammatory arthritis and related conditions. The present invention also relates to a kit comprising a pharmaceutical composition comprising imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof and instructions indicating that the composition is for use in treating inflammatory arthritis and related conditions. In addition, the present invention relates to a method of treating inflammatory arthritis and related conditions comprising administration of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof. The method is preferably carried out on a subject in need of treatment. The inflammatory arthritis is preferably rheumatoid arthritis.

Description

Treatments for inflammatory arthritis
The present invention relates to imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for use in treating inflammatory arthritis and related conditions. The present invention also relates to the use of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating inflammatory arthritis and related conditions. The present invention also relates to a kit comprising a pharmaceutical composition comprising imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof and instructions indicating that the composition is for use in treating inflammatory arthritis and related conditions. In addition, the present invention relates to a method of treating inflammatory arthritis and related conditions comprising administration of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof. The method is preferably carried out on a subject in need of treatment. The inflammatory arthritis is preferably rheumatoid arthritis.
Rheumatoid arthritis is a chronic inflammatory disease occurring in 0.5%-l% of the population. This disease affects the joints and is characterized by thickening of the synovial membrane. This disease leads to progressive debilitation in joint function which results in pain, disability, loss of man power and shorter life expectancy. In addition there are a number of similar related conditions; psoriatic arthritis, juvenile arthritis, ankylosing spondelytis, Crohn's disease and psoriasis.
Current treatments for rheumatoid arthritis have a number of disadvantages, including expense and/or severe side effects. At present, steroids such as dexamethasone and methyl-prednisolone, are widely used in the treatment of rheumatoid arthritis. While treatment with steroids can be effective, there are a number of serious side effects.
These side effects include hypertension, growth deficiencies in younger patients, osteoporosis, cataracts, psychosis, elevated blood sugar, glaucoma, etc. In addition, some patients are resistant to long-term use of steroids or become so with time. New and alternative treatments currently used for rheumatoid arthritis are based on biologicals such as antibodies and soluble receptors. The most widely used of these is based on blocking TNF function with neutralizing antibodies or soluble receptors and has defined TNF as a key pathway in the inflammatory processes in rheumatoid arthritis. This type of anti-TNF therapy has been successful in the treatment of a number of diseases, with a substantial proportion of patients (approximately 60%) showing significant clinical benefit. Besides treating the inflammation, anti-TNF therapy also prevents joint destruction and thus is considered to have disease modifying anti-arthritic drug (DMARD) activity. However, it is extremely expensive and this places a heavy financial burden either on the patient or the healthcare system or both and this seriously limits availability. Many patients in the developed world and the majority in the developing world are not able to afford this treatment. In addition, possible side effects of anti-TNF therapy include anaphylaxis and cytopenia. Moreover systemic neutralisation of TNF leads to increased susceptibility to infection and the long-term effects are still unknown. Currently it is not possible to take anti- TNF drugs orally, which is a disadvantage. Moreover of those patients that do respond approximately 50% will become refractory to treatment in 2 years due to the development of immunity to the biological treatment.
Another class of drugs are the disease modifying anti-rheumatic drugs (DMARDS). An example of these is methotrexate, an anti-metabolite drug, which is widely used for the treatment of rheumatoid arthritis, psoriatic arthritis and psoriasis. Methotrexate has been successful in the treatment of these diseases, but can cause substantial side effects, such as severe skin reaction, infections such as pneumonia, severe damage to liver, kidneys, lungs and gastrointestinal tract. Again a significant number of patients do not respond or become refractory with time.
A number of DMARD pharmaceutical agents containing gold are also used in the treatment of rheumatoid arthritis. Examples of such agents include gold sodium thiomalate and auranofin. Potential side effects from being treated with antiinflammatory gold agents are oral ulcers, altered taste, serious skin rashes, renal problems, inflammation of the intestines (enterocolitis), liver injury and lung disease. Furthermore, resistance to gold has been known to develop in patients.
A further class of drugs are the non-steroidal anti-inflammatory drugs (NSAID's). These are used to alleviate symptoms but not modify disease progression and includes the Cox 2 inhibitors "VIOXX"®, (a registered trademark of Merck & Co., Inc) and "CELEBREX" ®, (a registered trademark of G.D. Searle & Co). However there is major concern about the safety of these drugs with evidence of increased cardiovascular risk.
As a result of lack of efficacy, development of resistance, unacceptable side-effects and expense of existing treatments and route of administration, it is hugely desirable to find alternative treatments for rheumatoid arthritis. Thus there is a huge unmet medical need for an orally-available, well tolerated, inexpensive drug that could selectively block the production of TNF associated with pathological inflammation found in rheumatoid arthritis and related conditions.
The first aspect of the present invention provides imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for use in treating inflammatory arthritis and related conditions.
Imiquimod ("ALDARA") has previously been known for treating certain diseases of the skin including genital herpes simplex virus, papilloma virus and skin cancer.
According to the present invention derivatives of imiquimod have the following structure:
Figure imgf000005_0001
wherein
R1 is -R2, -OR2, -NR2R3, -R2C(O)OR2 or -R2OC(O)R2;
R2 is a) alkyl, alkenyl or alkynyl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, aryl, heteroaryl, carbocycle or heterocycle, wherein the aryl, heteroaryl, carbocycle or heterocycle is optionally substituted by one or more groups independently selected from C].6 alkyl, C1-6 alkoxy and halogen; or b) 5 to 7 membered aryl, heteroaryl, carbocycle or heterocycle, optionally substituted by one or more groups independently selected from C1-6 alkyl, C1-6 alkoxy and halogen; and
R3 is hydrogen or R2.
Imiquimod comprises the formula set out above wherein R1 is isobutyl.
The term "alkyl" as used herein means a straight or branched chain saturated hydrocarbon group, preferably with 1 to 10 carbons, more preferably 1 to 6 carbons, most preferably iso-butyl. The term "alkene" as used herein means a straight or branched chain unsaturated hydrocarbon group containing at least one carbon-carbon double bond. An alkene preferably has 2 to 10 carbons, more preferably 2 to 6 carbons. The term "alkyne" as used herein means a straight or branched chain unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, preferably with 2 to 10 carbons, more preferably 2 to 6 carbons.
The term "carbocycle" as used herein means a cyclic hydrocarbon group which may be saturated or may contain one or more units of un-saturation, but which is not aromatic. A carbocycle is preferably 5-7 membered.
The term "heterocycle" as used herein means a cyclic group containing one or more species of heteroatom selected from the group consisting of a nitrogen atom, a sulphur atom and an oxygen atom. A heterocyclic group may be unsaturated or may contain one or more units of un-saturation, but is not aromatic. A heterocycle is preferably 5-7 membered.
The term "aryl group" used herein means an aryl group constituted by 5 to 10 carbon atoms, which may be monocyclic or bicyclic. Preferably, an aryl is 5-7 membered.
The term "heteroaryl" as used herein means an aromatic cyclic group containing one or more species of heteroatom selected from the group consisting of a nitrogen atom, a sulphur atom and an oxygen atom. Preferably, a heteroaryl is 5-7 membered.
The term "halogen" as used herein means preferably fluorine, chlorine, bromine or iodine.
Imiquimod or a derivative thereof may be provided as a pharmaceutically acceptable salt.
The inflammatory arthritis includes rheumatoid arthritis and the related conditions psoriatic arthritis, juvenile arthritis, ankylosing spondelytis but drugs are envisaged to be useful for other chronic diseases driven by TNF such as, Crohn's disease and psoriasis. In a preferred embodiment the inflammatory arthritis is rheumatoid arthritis and the related conditions are psoriatic arthritis, juvenile arthritis, ankylosing spondelytis, Crohn's disease and psoriasis.
Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof according to the present invention inhibit TNF production.
Imiquimod and/or a derivative thereof and/or a pharmaceutically acceptable salt thereof and/or another agent may be used in combination, which may be for simultaneous, separate or sequential use.
In a further embodiment of the invention, imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof can be for topical administration.
In a yet further embodiment, imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof can be for oral administration. Where/if gastrointestinal toxicity occurs, the oral administration of imiquimod can be in combination with an agent that reduces the gastrotoxicity associated with imiquimod. The agent can be a prodrug of TLR7 agonists, such as ANA-975. Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof and an agent that reduces gastrotoxicity may be for simultaneous, separate or sequential use.
Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof may be used in combination with a further anti-inflammatory agent. Administration of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof and other anti-inflammatory agent can be simultaneous, separate and/or sequential. Imiquimod, derivatives and/or salts thereof, in combination with another pharmaceutical agent, can act additively or synergistically.
The other anti-inflammatory agent may be termed a 5-HT receptor antagonist including promazine hydrochloride, ketanserine tartrate or mianserine hydrochloride, a serotonin reuptake inhibitor including fluoxetine hydrochloride, citalopram or sertraline, an interferon inhibitor, a non-steroidal anti-inflammatory agent (NSAID), a disease modifying anti-rheumatic drug (DMARD), a biological agent (biologicals), a steroid, an immunosuppressive agent, a salicylate and/or a microbicidal agent. Nonsteroidal anti-inflammatory agents include anti-metabolite agents (including methotrexate) and anti-inflammatory gold agents (including gold sodium thiomalate, aurothiomalate or gold salts, such as auranofin). Biologicals include anti-TNF agents (including adalimumab, etanercept, infliximab, anti-EL-1 reagents, anti-IL-6 reagents, anti-B cell reagents (retoximab), anti-T cell reagents (anti-CD4 antibodies), anti-IL-15 reagents, anti-CLTA4 reagents, anti-RAGE reagents), antibodies, soluble receptors, receptor binding proteins, cytokine binding proteins, mutant proteins with altered or attenuated functions, RNAi, polynucleotide aptamers, antisense oligonucleotides or omega 3 fatty acids. Steroids include cortisone, prednisolone or dexamethasone. Immunosuppressive agents include cylcosporin, FK506, rapamycin, mycophenolic acid. Salicylates include aspirin, sodium salicylate, choline salicylate and magnesium salicylate. Microbicidal agents include quinine and hydroxychloroquine. For example, imiquimod and derivatives may be administered in combination with one or more of a 5-HT receptor antagonist, a serotonin reuptake inhibitor, an NSAID, DMARD or immunosuppressant.
In one embodiment, the further anti-inflammatory agent is administered orally (including buccally or sublingually) or parenterally (including subcutaneously, intramuscularly, intravenously or intradermally).
In a further embodiment, the invention provides the use of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating inflammatory arthritis and related conditions.
The second aspect is a kit comprising a pharmaceutical composition comprising imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof and instructions indicating that the composition is for use in treating inflammatory arthritis and related conditions. Compositions in accordance with the invention may be supplied as part of a sterile, pharmaceutical composition which will normally include a pharmaceutically acceptable carrier. This pharmaceutical composition may be in any suitable form. It may be provided in unit dosage form and will generally be provided in a sealed container. The kit of the invention may comprise a plurality of said unit dosage forms.
The oral pharmaceutical compositions may be presented as discrete units such as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids; or as edible foams or whips; or as emulsions). Suitable excipients for tablets or hard gelatine capsules include lactose, maize starch or derivatives thereof, stearic acid or salts thereof. Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid, or liquid polyols etc.
For the preparation of solutions and syrups, excipients which may be used include for example water, polyols and sugars. For the preparation of suspensions oils (e.g. vegetable oils) may be used to provide oil-in-water or water in oil suspensions.
The pharmaceutical compositions may contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colourants, odourants, salts, buffers, coating agents or antioxidants. They may also contain further therapeutically active agents.
Route of administration may include; parenterally (including subcutaneous, intramuscular, intravenous, by means of, for example a drip patch), some further suitable routes of administration include (but are not limited to) oral (including buccal and sublingual), rectal, nasal, topical, infusion, vaginal, intradermal, intraperitoneally, intracranially, intrathecal and epidural administration or administration via oral or nasal inhalation, by means of, for example a nebuliser or inhaler, or by an implant. For administration via the oral or nasal inhalation routes the may be delivered using a mechanical form including, but not restricted to, an inhaler or nebuliser device.
Further, where the oral or nasal inhalation routes are used, administration is by a SPAG (small particulate aerosol generator) may be used.
Dosages of the substances of the present invention can vary between wide limits, depending upon the condition to be treated, the health of the individual to be treated, etc. and a physician may determine appropriate dosages to be used. The dosage may be repeated as often as appropriate. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the imiquimod or derivative which produces a therapeutic effect
The compositions and uses described in this application are envisaged to have human, animal and veterinary applications. They are preferably applicable to mammals, in particular humans but are also applicable for use in production animals, in particular sheep, cows, pigs, chickens and goats, as well as companion animals, in particular cats and dogs and sporting animals, such as horses.
The third aspect of the invention is a method of treating inflammatory arthritis and related conditions comprising administering imiquimod, a derivative or a salt thereof. The derivative is defined according to the first aspect of the invention. In the third aspect of the invention, the method is preferably carried out on a subject in need of treatment.
In the present invention, the term "treatment" includes prophylactic treatment (i.e. prevention). In most circumstances, prevention of inflammatory arthritis or a related condition is unlikely to be carried out. Usually, it is only when the presence of inflammatory arthritis or a related condition is diagnosed in a subject that prevention means are applied. However, prophylactic treatment may be appropriate if there is a known family history of significant inflammatory arthritis or a related condition or if tests (e.g. genetic tests) identify that an individual has a predisposition to inflammatory arthritis or a related condition.
The fourth aspect of the invention is imiquimod, a derivative or a salt thereof for treating inflammatory arthritis or a related condition.
Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by a person who is skilled in the art in the field of the present invention.
The preferred embodiments, as described for the first aspect of the invention, are the same for other aspects of the invention mutatis mutandis.
The present invention is described with reference to the figures, in which:
Figure 1 illustrates that imiquimod inhibits, R-848 increases and CpG has no effect on spontaneous TNF production from rheumatoid synovial cultures. Levels of TNF production are shown in ng/ml ± SEM from 7 - 12 unrelated RA patients.
Figure 2 illustrates that gardiquimod enhances spontaneous TNF production in rheumatoid synovial cultures. RA synovial membrane cells were incubated for 24 hours in the presence of media alone or media containing 1 or 5μg/ml gardiquimod (gard).
Figure 3 illustrates that imiquimod selectively inhibits activation of TLR8 signaling - (a) Primary human M-CSF macrophages were incubated with 10 μg/ml imiquimod alone or in combination with 10 ng/ml Flagellin, 10 ng/ml Pam3, 1 μg/ml R-848 or 10 ng/ml LPS for 6 hours. Data was pooled from triplicate wells from 3 separate donors and shown as a percentage of the appropriate maximal responses (100%). (b) M-CSF macrophages were incubated with media alone or 1 μg/ml R-848 in the presence of 0, 2.5, 5 or 10 μg/ml imiquimod for 6 hours. TNF was measured from triplicate cultures ±SD and is representative of 3 separate donors, (c) Rheumatoid arthritis synovial fibroblasts were incubated with media alone or media containing 20 μg/ml Polyriboinosinic-polyribocytidylic acid (Poly IC) in the presence or 0 or 10 μg/ml imiquimod for 6 hours. Data shows triplicate cultures ±SD and is representative of 3 separate donors.
Figure 4 illustrates that guanosine activates whereas cGMP and hypoxanthine do not activate macrophages to induce TNF production. - (a) Primary human M-CSF macrophages were incubated with media alone, 1 μg/ml R-848, 0.1-30μg/ml guanosine or 10-30μg/ml cGMP for 6 hours, (b) Human M-CSF macrophages were incubated with 0.1-20μg/ml hypoxanthine for 6 hours.
Figure 5 illustrates that loxoribine (figure 5a) and gardiquimod (figure 5b) have no effect on TNF production by primary human macrophages stimulated with lOng/ml LPS or 1 μg/ml R-848.
Figure 6 illustrates the structure of loxoribine.
Figure 7 illustrates the structure of gardiquimod.
Figure 8 illustrates that loxoribine has no effect on spontaneous release of TNF from RA synovial membrane cultures from 6 donors.
Figure 9 illustrates that CL075 and CL097 increase TNF production in human M- CSF macrophages.
Figure 10 illustrates the structure of CL075.
Figure 11 illustrates the structure of CL097. Figure 12 illustrates the structure of R-848.
The present invention is described with reference to the following non-limiting examples:
Examples
General Materials and Methods
Reagents
Cell culture reagents used were Penicillin-Streptomycin, RPMI 1640 and DMEM obtained from Cambrex (Belgium), Indomethacin from Sigma (USA) and FBS from PAA (Austria). The TLR ligands used were chloroform extracted Escherichia coli (E.coli) LPS and resiquimod (R-848), CpG (ODN 2006) and imiquimod from Invivogen (USA). Flagellin (purified), Pam3cys-ser(lys)4.3HCl (Pam3) and gardiquimod were from Alexis (UK). All reagents other than LPS were free from LPS contamination as assessed using the limulus amebocyte lysate (LAL) assay from Cambrex (USA).
ELISA (enzyme-linked immunosorbent assay).
Sandwich ELISAs were employed to measure TNF and IL-6 (Pharmingen, UK).. Absorbance was read on a spectrophotometric ELISA plate reader (Labsystems Multiscan Biochromic) and analyzed using Ascent software V2.6 (Thermo
Labsystems, Cambridge, United Kingdom). Cell viability was not significantly affected over this time period when examined by the 3-[4,5 dimethylthiazol-2-yl]-2,5- diphenyl-tetrazolium bromide (MTT) assay (Sigma).
Statistical methods
Mean, standard deviation (SD) and standard error of the mean (SEM) were calculated using GraphPad version 3 (GraphPad Software Inc., USA). For statistical analysis, a one tailed student's t-test of paired data was used with a 95% confidence interval. SEM was used for pooled experimental data whilst SD was used in graphs showing representative experiments.
Cell culture
RA synovial membrane cells were isolated from patients undergoing joint replacement surgery as previously described (Foxwell et al., Proc. Natl. Acad. Sci. USA 95,8211-8215, 1998). All patients gave written informed consent and the study was approved by the local ethics committee. Immediately after isolation, cells were cultured at IxIO5 cells/well in 96-well tissue culture plates (Falcon, UK) in RPMI 1640 containing 10% (v/v) FBS and 100 U/ml penicillin/streptomycin. Primary human synovial fibroblasts were cultured as described previously (Butler et al. Eur. Cytokine Netw. 5:441-8, 1994). Peripheral blood monocytes were isolated and cultured as previously described (Foxwell et al., Proc. Natl. Acad. Sci. USA 95, 8211- 8215, 1998). Macrophages were derived from monocytes after differentiation for 4 days with 100 ng/ml M-CSF (PeproTech, UK).
Example 1
Rheumatoid arthritis synovial membrane cells were cultured for 24 hours in the presence of media alone or media containing lOμg/ml imiquimod, lμg/ml R-848 (resiquimod) or 2μM CpG. Supernatants were harvested and the level of TNF (n=16) was measured by ELISA. Addition of imiquimod led to a significant inhibition of TNF production by 47.3% ± 27 (p = 0.0101) (Figure 1). R-848 increases spontaneous TNF production and CpG has no effect. A student's paired t-test was used to analyse the data.
Rheumatoid arthritis synovial membrane cells were also cultured in the presence of media alone or media containing lμg/ml and 5μg/ml gardiquimod (see Figure 2). Gardiquimod enhances spontaneous TNF production.
Example 2 The inhibitory effect of imiquimod being unexpected was investigated further. Although imiquimod is a TLR7 agonist it is structurally similar to R-848, a ligand for both TLRs 7 and 8. We therefore investigated if imiquimod could actually act as an inhibitor of TLR8 activity in human macrophages.
Primary human M-CSF macrophages were incubated with 10 μg/ml imiquimod alone or in combination with 10 ng/ml Flagellin, 10 ng/ml Pam3, 1 μg/ml R-848 or 10 ng/ml LPS for 6 hours. Data was pooled from triplicate wells from 3 separate donors and shown as a percentage of the appropriate maximal responses (100%) (see figure 3(a)).
M-CSF macrophages were also incubated with media alone or 1 μg/ml R-848 in the presence of 0, 2.5, 5 or 10 μg/ml imiquimod for 6 hours. TNF was measured from triplicate cultures ±SD and is representative of 3 separate donors (see figure 3(b)).
Rheumatoid arthritis synovial fibroblasts (RASFs) were incubated with media alone or media containing 20 μg/ml Poly IC in the presence or 0 or 10 μg/ml imiquimod for 6 hours. Data shows triplicate cultures ±SD and is representative of 3 separate donors (see figure 3(c)).
Primary human M-CSF macrophages were also incubated with media alone, 1 μg/ml R-848, 0.1-30 μg/ml guanosine, 10-30μg/ml cGMP or 0.1-20 μg/ml hypoxanthine for 6 hours (see figure 4). TNF was measured from triplicate cultures ±SD.
Imiquimod did inhibit TNF production induced by R848 (figure 3a) an effect that was dose dependent (Figure 3b). In contrast the drug had no effect on TNF production induced from macrophages by LPS (TLR4), Pam3Cys (TLR1,2) or flagellin (TLR5). Activation of TLR3 (Poly IC) induces no TNF or IL-6 production from human macrophages but does induce EL-6 from RA-synovial fibroblasts (data not shown). This also was not inhibited by imiquimod (Figure 3c). These results indicate that imiquimod inhibits TNF production in synovial membranes by blocking TLR8. Example 3
Primary human macrophages were stimulated with lOng/ml LPS or lμg/ml R-848 in the presence of loxoribine (purchased from Alexis (UK)) or gardiquimod (purchased from Invivogen (USA)).
Both loxoribine and gardiquimod had no effect on TNF production (see figures 5a and 5b). Loxoribine and gardiquimod are structurally similar to imiquimod and, like imiquimod, they are also TLR7 ligands (see figures 6 and 7). However, the structural difference renders these molecules unable to inhibit TLR4 (LPS) and TLR8 (R-848) induced TNF.
Example 4
The effect of loxoribine on rheumatoid arthritis synovial membrane cultures from 6 donors was tested.
Loxoribine had no effect on spontaneous release of TNF (see figure 8).
Loxoribine is structurally similar to imiquimod and like imiquimod it is also a TLR7 ligand. The lack of any inhibitory effect of loxoribine on the spontaneous production of TNF by rheumatoid arthritis synovial membrane cultures indicates that loxoribine would not be a useful treatment for rheumatoid arthritis.
Example 5
TLR7/8 ligands CL075 and CL097 were tested in primary human M-CSF macrophages. CL075 and CL097 both increased TNF production (see figure 9), suggesting that it is unlikely that they would be useful for treating rheumatoid arthritis. The structures of CL075 and CL097 are illustrated in figures 10 and 11.

Claims

Claims
1. Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for use in treating inflammatory arthritis or a related condition.
2. Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for the use according to claim 1 , wherein the derivative has the following formula:
Figure imgf000018_0001
wherein
R1 is -R2, -OR2, -NR2R3, -R2C(O)OR2 or R2OC(O)R2;
R2 is a) alkyl, alkenyl or alkynyl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, aryl, heteroaryl, carbocycle or heterocycle, wherein the aryl, heteroaryl, carbocycle or heterocycle is optionally substituted by one or more groups independently selected from Ci-6 alkyl, Ci-6 alkoxy and halogen; or b) 5 to 7 membered aryl, heteroaryl, carbocycle or heterocycle, optionally substituted by one or more groups independently selected from Ci -6 alkyl, Ci-6 alkoxy and halogen; and
R3 is hydrogen or R2. I o
3. Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for the use according to claim 1 or claim 2, wherein the inflammatory arthritis is rheumatoid arthritis.
4. Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for the use according to any one of claims 1 to 3, wherein imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof is for topical administration.
5. Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for the use according to any one of claims 1 to 4, wherein imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof is administered in combination with a further anti-inflammatory agent.
6. Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for the use according to claim 5, wherein the further anti-inflammatory agent is a 5-
HT receptor antagonist including promazine hydrochloride, ketanserine tartrate or mianserine hydrochloride, a serotonin reuptake inhibitor including fluoxetine hydrochloride, citalopram or sertraline, an interferon inhibitor, a non-steroidal anti-inflammatory agent (NSAED), a disease modifying anti-rheumatic drug (DMARD), a biological agent, a steroid, RNAi, aptamers, an immunosuppressive agent, a salicylate and/or a microbicidal agent.
7. Imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof for the use according to claims 5 or 6, wherein the further anti-inflammatory agent is for oral and/or parenteral administration.
8. The use of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating inflammatory arthritis or a related condition.
9. A kit comprising a pharmaceutical composition comprising imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof and instructions indicating that the composition is for use in treating inflammatory arthritis or a related condition.
10. The kit of claim 9, wherein the derivative has the following formula:
Figure imgf000020_0001
wherein
R1 is -R2, -OR2, -NR2R3, -R2C(O)OR2 or R2OC(O)R2;
R2 is a) alkyl, alkenyl or alkynyl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, aryl, heteroaryl, carbocycle or heterocycle, wherein the aryl, heteroaryl, carbocycle or heterocycle is optionally substituted by one or more groups independently selected from C i-6 alkyl, Ci-6 alkoxy and halogen; or b) 5 to 7 membered aryl, heteroaryl, carbocycle or heterocycle, optionally substituted by one or more groups independently selected from Ci-6 alkyl, Ci-6 alkoxy and halogen; and
R3 is hydrogen or R2.
11. This kit according to claim 9 or claim 10, wherein the inflammatory arthritis is rheumatoid arthritis.
12. The kit according to any one of claims 9 to 11, wherein imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof is for topical administration.
13. The kit according to any one of claims 9 to 12, wherein imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof is administered in combination with a further anti-inflammatory agent.
14. The kit according to claim 13, wherein the further anti-inflammatory agent is a 5-HT receptor antagonist including promazine hydrochloride, ketanserine tartrate or mianserine hydrochloride, a serotonin reuptake inhibitor including fluoxetine hydrochloride, citalopram or sertraline, an interferon inhibitor, a non-steroidal anti-inflammatory agent (NSAID), a disease modifying anti-rheumatic drug (DMARD), a biological agent, a steroid, RNAi, aptamers, an immunosuppressive agent, a salicylate and/or a microbicidal agent.
15. The kit of claims 13 or 14, wherein the further anti-inflammatory agent is for oral and/or parenteral administration.
16. A method of treating inflammatory arthritis or a related condition in a subject, comprising administration of imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof to the subject.
17. The method of claim 16, wherein the derivative has the following formula:
Figure imgf000021_0001
H wherein
R1 is -R2, -OR2, -NR2R3, -R2C(O)OR2 or R2OC(O)R2;
R2 is a) alkyl, alkenyl or alkynyl, optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, aryl, heteroaryl, carbocycle or heterocycle, wherein the aryl, heteroaryl, carbocycle or heterocycle is optionally substituted by one or more groups independently selected from C1-6 alkyl, Ci-6 alkoxy and halogen; or b) 5 to 7 membered aryl, heteroaryl, carbocycle or heterocycle, optionally substituted by one or more groups independently selected from Ci-6 alkyl, Ci-6 alkoxy and halogen; and
R3 is hydrogen or R2.
18. The method of claim 16 or claim 17 wherein the subject is a mammal.
19. The method of claim 18, wherein the mammal is a human.
20. The method of any one of claims 16 to 19, wherein the inflammatory arthritis is rheumatoid arthritis.
21. The method according to any one of claims 16 to 20, wherein imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof is for topical administration.
22. The method according to any one of claims 16 to 21, wherein imiquimod, a derivative thereof or a pharmaceutically acceptable salt thereof is administered in combination with a further anti-inflammatory agent.
23. The method according to claim 22, wherein the further anti-inflammatory agent is a 5HT receptor antagonist including promazine hydrochloride, ketanserine tartrate or mianserine hydrochloride, a serotonin reuptake inhibitor including fluoxetine hydrochloride, citalopram or sertraline, an interferon inhibitor, a non- steroidal anti-inflammatory agent (NSAID), a disease modifying anti-rheumatic drug (DMARD), a biological agent, a steroid, RNAi, aptamers, an immunosuppressive agent, a salicylate and/or a microbicidal agent.
24. The method of claims 22 or 23, wherein the further anti-inflammatory agent is for oral and/or parenteral administration.
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