Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
• • 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
• • 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
  • A61P11/02—Nasal agents, e.g. decongestants
• • 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
  • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
• • 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
  • A61P37/08—Antiallergic agents

Definitions

• the present invention relates to adenine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
• the immune system is comprised of innate and acquired immunity, both of which work cooperatively to protect the host from microbial infections. It has been shown that innate immunity can recognize conserved pathogen-associated molecular patterns through toll- like receptors (TLRs) expressed on the cell surface of immune cells. Recognition of invading pathogens then triggers cytokine production (including interferon alpha(IFN ⁇ )) and upregulation of co-stimulatory molecules on phagocytes, leading to modulation of T cell function.
• TLRs toll- like receptors
• TLRs are a family of type I transmembrane receptors characterized by an NH2-terminal extracellular leucine-rich repeat domain (LRR) and a COOH-terminal intracellular tail containing a conserved region called the Toll/IL-1 receptor (TIR) homology domain.
• LRR extracellular leucine-rich repeat domain
• TIR Toll/IL-1 receptor
• TLRs also known as immune response modifiers (IRMS)
• IRMS immune response modifiers
• International Patent Application No. PCT/JP2005/005401 describes a class of 9- substituted-8-oxoadenine compounds having immuno-modulating properties which act via TLR7 that are useful in the treatment of viral or allergic diseases and cancers. It has now surprisingly been found that a subset of the compounds generically disclosed in International Patent Application No. PCT/JP2005/005401 possess properties such as increased aqueous solubility which makes them particularly suitable for use in inhalation therapy. Without being bound to any particular theory, it is believed that the increased solubility of the compounds (in the lung) results in increased potency, leading to a reduction in the dose required for efficacy. This in turn improves the safety margins of the compounds.
• R represents a Cj-Cg alkyl group
• Z represents a C 2 -Cg alkylene group
• Y represents a C1-C3 alkylene group
• R represents a Cj-Cg alkyl group
• n is an integer from 0 to 2
• each group R independently represents halogen, C1-C3 alkyl, C1-C3 alkoxy or
• R 3 represents -(CH 2 ) m -NR 4 R 5 ; m is an integer from 2 to 6; 4 5 4 either R and R each independently represent hydrogen or Cj-Cg alkyl, or R and
• R represents hydrogen or Cj-Cg alkyl; or a pharmaceutically acceptable salt thereof.
• an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched.
• Q-Cg alkyl groups/moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl.
• an alkylene group may be linear or branched.
• Examples of Ci-Cg alkylene groups include methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, 1-methylethylene, 2-methylethylene, 1,2-dimethylethylene, 1-ethylethylene, 2-ethylethylene, X-, 2- or 3-methylpropylene and 1-, 2- or 3- ethylpropylene.
• a C1-C3 haloalkyl substituent group will comprise at least one halogen atom, e.g. one, two, three, four or five halogen atoms, examples of which include
• R and R together represent a 3- to 8- membered saturated heterocyclic ring, it should be understood that the ring will contain no
• R represents a Ci-Cg, or C1-C5, or C1-C4, or C1-C3, or C1-C2 alkyl group.
• R represents a C1-C4 alkyl group, for example, an n-butyl group.
• Z represents a C2-C6 alkylene group, for example, a C2-C4 or C3-C4 alkylene group.
• Z represents a linear C2-C4 or C3-C4 alkylene group such as ethylene, n-propylene or n-butylene.
• Y represents a C1-C3 alkylene group such as methylene, ethylene or n-propylene.
• R represents a Ci-Cg, or C1-C5, or C1-C4, or C1-C3, or C1-C2 alkyl group.
• R represents a C1-C2 alkyl group, for example, a methyl group.
• n is an integer 0, 1 or 2.
• n 0.
• Each group R independently represents halogen (such as fluorine, chlorine, bromine or iodine), C1-C3 alkyl (such as methyl, ethyl or n-propyl), C1-C3 alkoxy (such as methoxy, ethoxy or n-propoxy), or C1-C3 haloalkyl (such as dibromomethyl, dichloromethyl, bromochloromethyl, trifluoromethyl or pentafluoroethyl).
• halogen such as fluorine, chlorine, bromine or iodine
• C1-C3 alkyl such as methyl, ethyl or n-propyl
• C1-C3 alkoxy such as methoxy, ethoxy or n-propoxy
• C1-C3 haloalkyl such as dibromomethyl, dichloromethyl, bromochloromethyl, trifluoromethyl or pentafluoroethyl
• n is 1 or 2 and each group R represents a halogen atom, e.g. fluorine.
• R represents -(CH2) m -NR R where m is an integer 2, 3, 4, 5 or 6.
• m is 2 or 3.
• R and R each independently represent hydrogen or
• Ci-Ce or Ci-C 5 , or C1-C4, or C1-C3, or Ci-C 2 alkyl.
• R and R each independently represent hydrogen or methyl.
• R and R together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6-, 7- or 8-membered, e.g. 5- to 6-membered, saturated heterocyclic ring optionally comprising a further ring hetero group NR where R represents hydrogen or Ci-C ⁇ , or C1-C5, or C1-C4, or C1-C3, or C1-C2 alkyl.
• heterocyclic rings include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and 4-methylpiperazin- 1 -yl.
• R represents n-butyl
• Z represents n-propylene (CH ⁇ ) or n-butylene ((CE ⁇ );
• Y represents methylene
• R represents -(CH 2 ) m -NR R ; m is 2 or 3;
• R and R each independently represent hydrogen or methyl, or R and R together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated heterocyclic ring optionally comprising a further ring hetero group NR ;
• R represents methyl
• Examples of compounds of the invention include:
• Methyl (3- ⁇ [[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3- pyrrolidin-l-ylpropyl)amino]methyl ⁇ phenyl)acetate, Methyl [3-( ⁇ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H- ⁇ urin-9-yl) ⁇ ropyl][3-(4- methylpiperazin- 1 -yl)propyl] amino ⁇ methyl)phenyl] acetate,
• the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises,
• L represents a leaving group (e.g. halogen, mesylate or triflate) and n, Y, R and
• L represents a leaving group (e.g. halogen, mesylate or triflate) and m, n, Y, Z, R,
• R and R are as defined in formula (I), with a compound of formula (VI), HNR R ,
• L represents a leaving group (e.g. halogen, mesylate or triflate) and m, R and R are as defined in formula (I); or
• the reaction may conveniently be carried out in an organic solvent such as l-methyl-2-pyrrolidinone, 1,2-dichloroethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 15O 0 C.
• the reaction may conveniently be carried out in an organic solvent such as acetonitrile, l-methyl-2-pyrrolidinone or N,N-dimethylformamide at a temperature, for example, in the range from 0 to 15O 0 C.
• reaction may conveniently be carried out in an organic solvent such as acetonitrile, l-methyl-2-pyrrolidinone or N,N-dimethylformamide at a temperature, for example, in the range from 0 to 15O 0 C.
• organic solvent such as acetonitrile, l-methyl-2-pyrrolidinone or N,N-dimethylformamide
• reaction may conveniently be carried out in an organic solvent such as l-methyl-2-pyrrolidinone or N,N-dimethylformamide at a temperature, for example, in the range from O to 150 0 C.
• organic solvent such as l-methyl-2-pyrrolidinone or N,N-dimethylformamide
• reaction may conveniently be carried out in an organic solvent such as l-methyl-2-pyrrolidinone, 1,2-dichloroethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 150 0 C.
• organic solvent such as l-methyl-2-pyrrolidinone, 1,2-dichloroethane or tetrahydrofuran
• the compound of formula (B) is prepared by reacting the compound of formula (A) with ammonia in an organic solvent such as methanol, ethanol, propanol, butanol, tetrahydrofuran, 1,4-dioxane, diglyme, acetonitrile or an aqueous mixture of any one of the preceding solvents.
• the reaction may be carried out in an autoclave, and at a temperature, for example, in the range from 20 to 200°C.
• Compounds of formula (C) may be prepared by reacting the compound of formula (B) with a Cj-Cg alkanol in the presence of a base such as sodium hydride and in an organic solvent such as tetrahydrofuran, 1,4-dioxane, diglyme, N,N-dimethylformamide or dimethylsulfoxide, preferably at elevated temperature, e.g. at a temperature in the range from 20 to 15O 0 C.
• a base such as sodium hydride
• an organic solvent such as tetrahydrofuran, 1,4-dioxane, diglyme, N,N-dimethylformamide or dimethylsulfoxide
• an alkali metal such as sodium may be dissolved in the Ci-C ⁇ alkanol and then reacted with the compound of formula (B), preferably at elevated temperature, e.g. at a temperature in the range from 20 to 150 0 C.
• Compounds of formula (D) are prepared by brominating a compound of formula (C).
• the reaction may be carried out using a brominating agent such as bromine, hydroperbromic acid or N-bromosuccinimide, in an organic solvent such as carbon tetrachloride, methylene chloride, dichloroethane, diethyl ether, acetic acid or carbon disulfide.
• a brominating agent such as bromine, hydroperbromic acid or N-bromosuccinimide
• organic solvent such as carbon tetrachloride, methylene chloride, dichloroethane, diethyl ether, acetic acid or carbon disulfide.
• the reaction temperature will generally be in the range from 0°C to the boiling point of the solvent.
• Compounds of formula (E) are prepared by reacting a compound of formula (D) with sodium methoxide in an organic solvent such as methanol and at a temperature, for example, in the range from 20 to 15O 0 C.
• Compounds of formula (F) may be obtained by treating a compound of formula (E) with an acid such as trifluoroacetic acid in an organic solvent such as methanol.
• Compounds of formula (G) are prepared by reacting a compound of formula (F) with a compound of formula LG-Z-LG wherein LG represents a leaving group such as a halogen, mesylate or triflate and Z represents a C2-C6 alkylene group as defined in formula (II).
• the reaction may be carried out in an organic solvent such as N,N-dimethylformamide, dimethylsulfoxide or acetonitrile with a base present, preferably at room temperature (20 0 C).
• a base such as an alkali metal carbonate, e.g. sodium carbonate or potassium carbonate; an alkaline earth metal carbonate, e.g. calcium carbonate; a metal hydroxide, e.g. sodium hydroxide or potassium hydroxide; a metal hydrogenate, e.g. sodium hydride; or a metal alkoxide, e.g. potassium t-butoxide, may be used.
• Compounds of formula (H) may be obtained by treatment of a compound of formula (G) with an acid.
• the reaction may be carried out in an organic solvent such as methanol using either an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as trifluoroacetic acid.
• Compounds of formula (II) are prepared by reacting a compound of formula (H) with an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as trifluoroacetic acid.
• reaction may be carried out in an organic solvent such as acetonitrile or N,N-dimethylformamide using an excess of the amine, preferably at elevated temperature, e.g. at a temperature in the range from 0 to l50°C.
• organic solvent such as acetonitrile or N,N-dimethylformamide
• compounds of formula (V) in which L represents halogen, e.g. chlorine may be prepared by reaction with a halogenating reagent such as thionyl chloride in an organic solvent such as dichloromethane at room temperature (2O 0 C).
• a halogenating reagent such as thionyl chloride in an organic solvent such as dichloromethane at room temperature (2O 0 C).
• Compounds of formula (XI) may be prepared by reacting a compound of formula (H) as defined above with a C2-C6 aminoalcohol in an organic solvent such as acetonitrile or N 1 N- dimethylformamide using an excess of the aminoalcohol, preferably at elevated temperature, e.g. at a temperature in the range from 20 to 150 0 C.
• an organic solvent such as acetonitrile or N 1 N- dimethylformamide
• L represents a leaving group (e.g. halogen, mesylate or triflate)
• P represents a nitrogen-protecting group (e.g. butoxycarbonyl)
• Z is as defined in formula (XII), followed by removal of the nitrogen-protecting group, P, and removal of the oxygen-protecting group in the substituent-OCH3.
• the reaction between the compounds of formula (F) and (XIII) may be carried out in an organic solvent such as N,7V-dimethylformamide, dimethylsulfoxide or acetonitrile with a base present, at a temperature, for example, in the range from 0 to 150°C.
• the base used may be an alkali metal carbonate, e.g. sodium carbonate or potassium carbonate; an alkaline earth metal carbonate, e.g. calcium carbonate; a metal hydroxide, e.g. sodium hydroxide or potassium hydroxide; a metal hydrogenate, e.g. sodium hydride; or a metal alkoxide, e.g. potassium tert-butoxide.
• the removal of the protecting groups may be carried out according to methods known in the art.
• the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or j ⁇ -toluenesulphonate.
• an acid addition salt such as a hydrochloride, hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or j ⁇ -toluenesulphonate.
• the compounds of formula (J) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as modulators of toll-like receptor (especially TLR7) activity, and thus may be used in the treatment of:
• respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature
• skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber- Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma
• eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial; 4.
• nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);
• allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
• oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
• infectious diseases virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para- influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
• virus diseases such as genital warts, common warts, plantar warts,
• the present invention provides a compound of formula (I) or a pharmaceutically- acceptable salt thereof as hereinbefore defined for use in therapy.
• the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
• the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
• the terms “therapeutic” and “therapeutically” should be construed accordingly.
• Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
• Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
• the compounds of the invention may be used in the treatment of asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, bacterial infections and dermatosis.
• the invention still further provides a method of treating, or reducing the risk of, an obstructive airways disease or condition (e.g. asthma or COPD) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
• an obstructive airways disease or condition e.g. asthma or COPD
• the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ( ⁇ g/kg) to 100 micrograms per kilogram body weight ( ⁇ g/kg).
• the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
• the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
• a pharmaceutically acceptable adjuvant diluent or carrier.
• Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
• the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
• the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
• compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafiuoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler ® ; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
• HFA heptafiuoroalkane
• Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
• the compound is desirably finely divided.
• the finely divided compound preferably has a mass median diameter of less than 10 micrometres ( ⁇ m), and may be suspended in a propellant mixture with the assistance of a dispersant, such as a Cg-
• C20 fatty acid or salt thereof (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
• the compounds of the invention may also be administered by means of a dry powder inhaler.
• the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
• a carrier substance for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol.
• Suitable carriers are sugars, for example, lactose, glucose, raff ⁇ nose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch.
• the finely divided compound may be coated by another substance.
• the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
• This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
• a multidose inhaler for example, that known as the Turbuhaler ® in which a dosing unit meters the desired dose which is then inhaled by the patient.
• the active ingredient with or without a carrier substance, is delivered to the patient.
• the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
• an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
• a starch for example, potato starch, corn starch or amylopectin
• a cellulose derivative for example, gelatine or polyvinylpyrrolidone
• a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
• the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
• a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
• the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
• the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
• Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
• liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
• Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
• Such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
• the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
• the invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
• tumour necrosis factor alpha (TNF-alpha) inhibitors such as anti-TNF monoclonal antibodies (for example Remicade, CDP-870 and adalimumab) and TNF receptor immunoglobulin molecules (such as Enbrel); non-selective cyclo-oxygenase COX-l/COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin), COX-2 inhibitors (such as meloxicam, celecoxicam, celecoxicam, celecoxicam, celecoxicam, celecoxicam, celecoxicam, celecoxicam, cele
• the present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5- lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2- alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
• the present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LT B4, LTC4, LTD4, and LTE4) selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zaf ⁇ rlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
• a receptor antagonist for leukotrienes selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxal
• the present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
• PDE phosphodiesterase
• the present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
• a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
• the present invention still further relates to the combination of a compound of the invention and a gastroprotective histamine type 2 receptor antagonist.
• the present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.
• the present invention still further relates to the combination of a compound of the invention and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
• an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochlor
• the present invention further relates to the combination of a compound of the invention and an anticholinergic agent including muscarinic receptor (Ml, M2, and M3) antagonists such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
• Ml, M2, and M3 antagonists such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
• the present invention still further relates to the combination of a compound of the invention together with a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol.
• a beta-adrenoceptor agonist including beta receptor subtypes 1-4
• beta receptor subtypes 1-4 such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol.
• the present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.
• a chromone such as sodium cromoglycate or nedocromil sodium.
• the present invention still further relates to the combination of a compound of the invention together with an insulin-like growth factor type I (IGF-I) mimetic.
• IGF-I insulin-like growth factor type I
• the present invention still further relates to the combination of a compound of the invention and a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
• a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
• the present invention still further relates to the combination of a compound of the invention together with an inhibitor of matrix metalloproteases (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-Il) and MMP-9 and MMP-12.
• MMPs matrix metalloproteases
• the present invention still further relates to the combination of a compound of the invention together with modulators of chemokine receptor function such as antagonists of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRIl (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for the C-X3-C family.
• modulators of chemokine receptor function such as antagonists of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRIl (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for the C-X
• the present invention still further relates to the combination of a compound of the invention together with a cytokine or modulator of cytokine function, including alpha-, beta-, and gamma-interferon; interleukins (IL) including ILl to 15, and interleukin antagonists or inhibitors, including agents which act on cytokine signalling pathways.
• a cytokine or modulator of cytokine function including alpha-, beta-, and gamma-interferon
• interleukins (IL) including ILl to 15
• interleukin antagonists or inhibitors including agents which act on cytokine signalling pathways.
• the present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (omalizumab).
• the present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
• the present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfmavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine
• a compound of the invention can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
• an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincri
• a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5 ⁇ -reductase such as finasteride;
• an antioestrogen for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene
• an agent which inhibits cancer cell invasion for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function
• an inhibitor of growth factor function for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fiuorophenyl)-7-methoxy-6-(3- mo ⁇ holinopropoxy)quinazolin-4-amine (gefitinib, AZDl 839), N-(3-ethynylphenyl)-6
• RPHPLC Reversed Phase preparative High Performance Liquid Chromatography using Waters Symmetry C8, Xterra or Phenomenex Gemini columns using acetonitrile and either aqueous ammonium acetate, ammonia, formic acid or trifluoroacetic acid as buffer where appropriate.
• Column chromatography was carried out on silica gel.
• SCX denotes solid phase extraction with a sulfonic acid sorbent whereby a mixture was absorbed on a sulfonic acid sorbent and eluted with an appropriate solvent such as methanol or acetonitrile and then the free base product was eluted with aqueous ammonia/methanol or acetonitrile.
• step (ii) 2-Butoxy-9-(tetrahydro-2H-pyran-2-yl)-9J ⁇ -puriii-6-amine
• the product from step (i) (4Og) was dissolved in 19%(w/w)-sodium butoxide in butanol (250ml). The reaction mixture was stirred under reflux for 6 hours. The resultant suspension was cooled to room temperature, diluted with water (250ml) and extracted with diethyl ether (200ml x 3). The combined organic phase was washed with water (200ml x 3), dried and concentrated in vacuo.
• the subtitle compound was crystallised from diethyl ether/isohexane (1/1, 300ml) and obtained by filtration. Yield 19g.
• step (ii) (30g) was dissolved in dry dichloromethane (200ml). The solution was stirred at room temperature whilst N-bromosuccinamide (27g) was added portionwise. The mixture was stirred at ambient temperature overnight. 20%(w/v)-Sodium sulfate (200ml) was added and the separated aqueous phase extracted with dichloromethane (200ml x 3). The combined organic phase was washed with saturated sodium hydrogen carbonate solution (200ml x 2) and brine (200ml). After concentration in vacuo, the residue was dissolved in ethyl acetate (300ml), washed with water (200ml), brine (200ml) and dried.
• step (iv) 24g was dissolved in absolute methanol (300ml) and 30ml of trifluoroacetic acid was added. The reaction mixture was stirred at ambient temperature for 3 days and concentrated in vacuo. The subtitle compound was obtained as a white crystalline solid after trituration with methanol/ethyl acetate. Yield 2 Ig.
• step (v) (2Og) was added in portions over 10 minutes to a rapidly stirred mixture of potassium carbonate (4Og) and 1,3-dibromopropane (34ml) in N,N- dimethylformamide (250ml) at ambient temperature and the mixture stirred for 1.5 hours.
• the mixture was diluted with water (800ml) and extracted with ethyl acetate (300ml x 3). The combined extracts were washed with brine (200ml) and dried.
• the mixture was purified by column chromatography (ethyl acetate), to afford the subtitle compound as a white solid. Yield 16g.
• step (vi) 35.8g was dissolved in methanol (400ml) and treated with 4M hydrogen chloride in dioxane (100ml). The mixture was stirred at ambient temperature for 6 hours and concentrated in vacuo. Dichloromethane (500ml) was added and concentrated in vacuo, which afforded a foam that was taken onto the next step without further purification. Yield 38g.
• step (vii) The product of step (vii) (6g) was suspended in acetonitrile (100ml) and 3-aminopropan-l- ol (20ml) was added. The mixture was stirred under reflux overnight. After cooling to room temperature, the mixture was concentrated in vacuo and 20%(w/v)-aqueous sodium hydrogen carbonate was added (100ml). The suspension was stirred at ambient temperature overnight, the solid collected via filtration, stored under high vacuum for 16 hours and dried to give the subtitle compound as a white solid. Yield 4.75g.
• step (viii) (4.75g) was dissolved in N,N-dimethylformamide (40ml). Potassium carbonate (2.0Og) and methyl [3 -(bromomethyl)phenyl] acetate (3.56g) were added. The mixture was stirred at ambient temperature overnight. 20%(w/v) aqueous sodium hydrogen carbonate was added (20ml) and the suspension stirred at ambient temperature overnight. The solid was collected via filtration, dried under high vacuum for 16 hours to give the subtitle compound as a white solid. Yield 4.9 Ig.
• step (ix) The product of step (ix) (200mg) was suspended in dichloromethane (3ml) and thionyl chloride (0.06ml) added. The solution was stirred at ambient temperature for 5 hours and o concentrated in vacuo azeotropically with toluene (100ml). Sodium iodide (200mg) and 2M solution of N,N-dimethylamme (4ml) in tetrahydrofuran were added. The mixture was heated at 5O 0 C for 72 hours in a sealed tube. After cooling to ambient temperature, the mixture was treated with SCX and purified by RPHPLC, to afford the title compound as a white solid. Yield 96mg. 5
• step (i) 500mg was dissolved in a mixture of 1,2-dichloroethane (12ml) and l-methyl-2-pyrrolidinone (3ml). (3-Formyl-phenyl)-acetic acid methyl ester (300mg) o and sodium triacetoxyborohydride (425mg) were added and the mixture stirred at ambient temperature for 4 hours. After removing the solvent, the residue was partitioned between dichloromethane (100ml) and saturated aqueous sodium hydrogen carbonate (100ml), the organic layer dried and concentrated in vacuo. The residue was purified by RPHPLC to afford the title compound. Yield 260mg. 5
• the subtitle compound was prepared by a method analogous to that of Example 1 step (ix) using the product of step (i).
• the subtitle compound obtained (200mg) was taken onto the next step without further purification.
• step (ii) 200mg was dissolved in methanol (5ml) and 4M hydrogen chloride in dioxane (5ml) added. The mixture was stirred at room temperature for 72 hours and concentrated in vacuo. The mixture was purified by RPHPLC, to afford the title compound as a white solid. Yield 35mg.
• the subtitle compound was prepared by a method analogous to that of Example 1 step (vi) using 1,4-dibromobutane. Yield 16g.
• the subtitle compound was prepared by a method analogous to that of Example 1 step (ix) using the product of step (ii). Yield 6g.
• Spleens were removed from male Sprague-Dawley rats (approximately 8-10 weeks old) and a splenocyte suspension was prepared in serum-free MEM medium (modified Eagle's medium). Test compounds were dissolved in dimethylsulfoxide (DMSO), and incubated with splenocytes (5x10 6 cells/ml) keeping the final DMSO concentration at 0.1%.
• DMSO dimethylsulfoxide
• IFN ⁇ interferon alpha
• Recombinant human TLR7 was stably expressed in a HEK293 cell line already stably
• TLR7-specific activation was assessed by determining the level of SEAP produced following overnight incubation of the cells at 37 0 C with the standard compound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO). Concentration dependent induction of SEAP production by compounds was expressed as the minimal effective concentration of compound to induce SEAP release (pMEC).
• Solubility Testing Saturated solutions for determining the solubility were prepared by placing about 0.3 - 3.0 ml of 0.1 M phosphare buffer in glass screw-top sample tubes along with some of the test compound. The tubes were then shaken overnight at constant temperature (20°C). After shaking, undissolved material should be present in the solution, and more test compound should be added and shaking continued if this is not the case. The samples were then transferred to a centrifuge tube and centrifuged using a Heraeus Biofuge Fresco centrifuge at 13000 rpm for 30 minutes. The supernatant was then removed, placed in a new centrifuge tube and centrifuged again for 30 minutes at 13000 rpm.
• the undissolved material formed a pellet at the bottom of the tube and the liquid above the pellet was removed and was ready for assaying.
• the solution was then analysed using HPLC with UV quantification.
• a standard was also prepared by accurately weighing a sample of the test compound and dissolving it in a suitable volume of a solvent that will dissolve it completely (typically, DMSO, ethanol or methanol). This sample was then analysed by HPLC/UV.

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