WO2005080349A1 - Pyrimidine derivatives - Google Patents

Abstract

The present invention relates to novel pyrimidine derivatives, pharmaceutical compositions containing these compounds and their use in the treatment of diseases, particularly pain, which diseases are caused directly or indirectly by an increase or decrease in activity of the cannabinoid receptor.

Description

PYRIMIDINE DERIVATIVES

The present invention relates to novel pyrimidine derivatives, pharmaceutical compositions containing these compounds and their use in the treatment of diseases, particularly pain, which diseases are caused directly or indirectly by an increase or decrease in activity of the cannabinoid receptor. Cannabinoids are a specific class of psychoactive compounds present in Indian cannabis (Cannabis sativa), including about sixty different molecules, the most representative being cannabinol, cannabidiol and several isomers of tetrahydrocannabinol. Knowledge of the therapeutic activity of cannabis dates back to the ancient dynasties of China, where, 5,000 years ago, cannabis was used for the treatment of asthma, migraine and some gynaecological disorders. These uses later became so established that, around 1850, cannabis extracts were included in the US Pharmacopoeia and remained there until 1947. Cannabinoids are known to cause different effects on various systems and/or organs, the most important being on the central nervous system and on the cardiovascular system. These effects include alterations in memory and cognition, euphoria, and sedation. Cannabinoids also increase heart rate and vary systemic arterial pressure. Peripheral effects related to bronchial constriction, immunomodulation, and inflammation have also been observed. The capability of cannabinoids to reduce intraocular pressure and to affect respiratory and endocrine systems is also well documented. See e.g. L.E. Hollister, Health Aspects of Cannabis, Pharmacological Reviews. Vol. 38, pp. 1-20, (1986). More recently, it was found that cannabinoids suppress the cellular and humoral immune responses and exhibit anti-inflammatory properties. Wirth et al., Anti- inflammatory Properties of Cannabichrome, Life Science, Vol. 26, pp. 1991 - 1995, (1980). In spite of the foregoing benefits, the therapeutic use of cannabis is controversial, both due to its relevant psychoactive effects (causing dependence and addiction), and due to manifold side effects that have not yet been completely clarified. Although work in this field has been ongoing since the 1940's, evidence indicating that the peripheral effects of cannabinoids are directly mediated, and not secondary to a CNS effect, has been limited by the lack of receptor characterisation, the lack of information concerning an endogenous cannabinoid ligand and, until recently, the lack of receptor subtype selective compounds. The first cannabinoid receptor was found to be mainly located in the brain, in neural cell lines, and, only to a lesser extent, at the peripheral level. In view of its location, it was called the central receptor ("CB1 "). See Matsuda et al., "Structure of a Cannabinoid Receptor and Functional Expression of the Cloned cDNA," Nature, Vol. 346, pp. 561-564 (1990). The second cannabinoid receptor ("CB2") was identified in the spleen, and was assumed to modulate the non psychoactive effects of the cannabinoids. See Munro et el., "Molecular Characterisation of a Peripheral Receptor for Cannabinoids," Nature, Vol. 365, pp. 61-65 (1993). Recently, some compounds have been prepared which are capable of acting as agonists on both the cannabinoid receptors. For example, use of derivatives of dihydroxypyrrole-(l,2,3-d,e)-l,4-benzoxazine in the treatment of glaucoma and the use of derivatives of 1,5-diphenyl-pyrazole as immunomodulators or psychotropic agents in the treatment of various neuropathologies, migraine, epilepsy, glaucoma, etc are known. See U.S. Patent No. 5,112,820 and European Patent No. EP 0 576 357, respectively. However, because these compounds are active on both the CB1 and CB2 receptor, they can lead to serious psychoactive effects. The foregoing indications and the preferential localisation of the CB2 receptor in the immune system confirms a specific role of CB2 in modulating the immune and anti- inflammatory response to stimuli of different sources. The total size of the patient population suffering from pain is vast (almost 300 million), dominated by those suffering from back pain, osteo-arthritic pain and postoperative pain. Neuropathic pain (associated with neuronal lesions such as those induced by diabetes, HIV, herpes infection, or stroke) occurs with lower, but still substantial prevalence, as does cancer pain. The pathogenic mechanisms that give rise to pain symptoms can be grouped into two main categories: - those that are components of inflammatory tissue responses (Inflammatory Pain): - those that result from a neuronal lesion of some form (Neuropathic Pain). Chronic inflammatory pain consists predominantly of osteoarthritis, chronic low back pain and rheumatoid arthritis. The pain results from acute and on-going injury and/or inflammation. There may be both spontaneous and provoked pain. There is an underlying pathological hypersensitivity as a result of physiological hyperexcitability and the release of inflammatory mediators which further potentiate this hyperexcitability. CB2 receptors are expressed on inflammatory cells (T cells, B cells, macrophages, mast cells) and mediate immune suppression through inhibition of cellular interaction/ inflammatory mediator release. CB2 receptors may also be expressed on sensory nerve terminals and therefore directly inhibit hyperalgesia. The role of CB2 in immunomodulation, inflammation, osteoporosis, cardiovascular, renal and other disease conditions is now being examined. In light of the fact that cannabinoids act on receptors capable of modulating different functional effects, and in view of the low homology between CB2 and CB1, the importance of developing a class of drugs selective for the specific receptor sub-type is evident. Based on the foregoing, there is a need for compounds which are capable of selectively modulating the receptor for cannabinoids and, therefore, the pathologies associated with such receptors. Thus, CB2 modulators offer a unique approach toward the pharmacotherapy of immune disorders, inflammation, osteoporosis, renal ischemia and other pathophysiological conditions. International Patent Application Number PCT/EP03/09221 (WO 04/018434) (Glaxo Group Limited,) discloses compounds of formula (B):

in which: Y is phenyl, substituted with one, two or three substituents; R¹ is selected from hydrogen, C_1-6 alkyl, C_3-7 cycloalkyl, and halosubstitutedCι_-6 alkyl;

R³ is an optionally substituted 5- to 6- membered aromatic heterocyclyl group, or group A:

⁽A⁾ R⁴ is selected from hydrogen, Cι_-6 alkyl, C₃_₇ cycloalkyl, and halosubstitutedCi-β alkyl, COCH_3, or SO₂Me; R⁶ is methyl, chloro or CHxFn wherein n is 1, 2, or 3, x is 0, 1 or 2 and n and x add up to 3; Ra can be independently selected from hydrogen, fluoro, chloro or trifluoromethyl; Rb can be independently be selected from hydrogen, Cι_-6 alkyl, Cι_-6 alkoxy, haloCι-₆ alkoxy, hydroxy, cyano, halo, sulfonyl, CONH₂, COOH or NHCOOC_1-6alkyl; R⁷ can be independently hydrogen or C].-₆ alkyl; and pharmaceutically acceptable derivatives thereof, and discloses that these compounds are capable of selectively modulating the CB2 receptor. The compound 4-isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide is disclosed in J Comb. Chem. 2004, 6, 105-111 (Porcheddu et al) as one of a number of 2,4,5-trisubstituted pyrimidines generated in a resin capture and release strategy for making a combinatorial array. A pharmaceutical utility for these compounds is not disclosed. The present invention provides novel pyrimidine derivatives of formula (I) below (excluding 4-isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide) and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions containing compounds of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5- carboxylic acid diethylamide) or derivatives, and-.th.eir use as CB2 receptor modulators, which are useful in the treatment of a variety of disorders. The present invention further comprises a method for treating disease mediated by CB2 receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of formula (I) (including 4- isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof. The invention provides compounds of formula (I):

wherein: Y is phenyl, substituted with one, two or three substituents; R¹ is selected from hydrogen, Cι-₆ alkyl, C₃-₇ cycloalkyl, and lialosubstituted -g alkyl; R² is C(R⁷)₂R³; R³ is an optionally substituted 5- to 6- membered aromatic heterocyclyl group, or group A:

(A) R⁴ is selected from hydrogen, Cι_₆ alkyl, C₃. cycloalkyl, and halosubstitutedCι-₆ alkyl, COCH_3, or SO₂Me; R⁶ is a substituted or unsubstituted C_1-10 alkyl or C₃.₇cycloalkyl excluding unsubstituted methyl or CHxFn wherein n is 1, 2, or 3, x is 0, 1 or 2 and n and x add up to

3; Ra can be independently selected from hydrogen, fluoro, chloro or trifluoromethyl; Rb can be independently be selected from hydrogen, Cι_-6 alkyl, Cι-₆ alkoxy, haloCι-₆ alkoxy, hydroxy, cyano, halo, sulfonyl, CONH₂, COOH or NHCOOCι_-6alkyl; R⁷ can be independently hydrogen or Cι-₆ alkyl; and pharmaceutically acceptable derivatives thereof, with the proviso that the compound is not 4-isopropyl-2-phenylamino-pyrimidine-5 -carboxylic acid diethylamide. In one particular embodiment Y is substituted by 1 or 2 substituents. Substituents for Y are selected from: Cι-6 alkyl, halosubstitutedC_1-6 alkyl, C_1-6 alkoxy, hydroxy group, cyano group, halo, Cι_-6alkyl sulfonyl group, COOH, halosubstituted C^ alkoxy, CONH₂, -NHCOd-galkyl, CH₂COOH, SCι-₆alkyl or SO₂NR^8aR^8b wherein R^8a and R^8b are independently selected from H or C.-₆alkyl. In one particular embodiment Y is substituted by halo, cyano or methoxy. In one particular embodiment R¹ is hydrogen or Cι-₆alkyl, for example hydrogen. In one particular embodiment R is Cι-₆ alkyl or hydrogen, for example methyl or hydrogen. In particular, R⁴ may be hydrogen. In one particular embodiment R² is CH₂R³. In one particular embodiment R is group A, pyridinyl, or pyrimidinyl, any of which can be optionally substituted. When R³ is a substituted 5- to 6- membered aromatic heterocyclyl group, the substituent or substituents may be selected from: Cι_₆ alkyl, Cι-₆ alkoxy, haloCι_-6 alkoxy, hydroxy, cyano, halo, sulfonyl, CONH₂, COOH, methylsulfonyl, NHCOCH₃, (=O), CONHCHs or NR^8aR^8b wherein R^8a and R^8b are independently selected from H or Ci. ₆alkyl. In one particular embodiment the halo is fluoro. In one particular embodiment substituents when R³ is an 5- to 6- membered aromatic heterocyclyl group are halo, methoxy, and cyano. In one particular embodiment Rb is selected from hydrogen, halo, methoxy, and cyano. When R⁶ is a substituted Cuo alkyl or C_3- cycloalkyl in one embodiment there may be 1, 2, or 3 substituents independently selected from hydroxy, halo, cyano, Cι_-6 alkoxy, NR^8aR^8b wherein R^8a and R^8b are independently selected from H or -₆alkyl, NHCOR⁹, and SO_qR⁹ wherein R⁹ is C_1-6alkyl and q is 0, 1 or 2. In one particular embodiment R⁶ is C_2-ι₀ alkyl, for example t-butyl. In a further embodiment, any or all of R¹ , R², R⁴, R⁶ and Y is selected from the group consisting of the values ascribed to it in the Examples hereinbelow. In one particular embodiment the compounds are selective for CB2 over CB1. Most suitably the compounds are 100 fold selective i.e. compounds of formula (I) have an EC50 value at the cloned human cannabinoid CB2 receptor of at least 100 times the EC50 values at the cloned human cannabinoid CB1 receptor or have less than 10% efficacy at the CB1 receptor. The invention is described using the following definitions unless otherwise indicated. References herein to "compound(s) of formula (I)" include 4-isopropyl-2- phenylamino-pyrimidine-5 -carboxylic acid diethylamide unless explicitly mentioned otherwise. The term "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, ester, salt of such ester or solvate of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof. It will be appreciated by those skilled in the art that compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds, and that the compounds of formula (I) may be derivatised at more than one position. It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiological acceptable salts thereof. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse , J. Pharm. Sci., 1977, 66, 1-19. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzyle ylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropyl amine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from, pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particular examples of pharmaceutically acceptable salts include the ammonium, calcium, magnesium, potassium, and sodium salts, and those formed from maleic, fumaric, benzoic, ascorbic, pamoic, succinic, hydrochloric, sulfuric, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric acids. The terms 'halogen or halo' are used to represent fluorine, chlorine, bromine or iodine. The term 'alkyl' as a group or part of a group means a straight or branched chain alkyl group or combinations thereof. Examples include methyl, ethyl, n-propyl, i-propyl, n- butyl, s-butyl, t-butyl, pentyl, hexyl, 1,1-dimethylethyl, or combinations thereof. The term 'alkoxy' as a group or as part of a group means a straight, branched or cyclic chain alkyl group having an oxygen atom attached to the chain, for example a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy group, pentoxy, hexyloxy group, cyclopentoxy or cyclohexyloxy group. The term 'cycloalkyl' means a closed 3- to 7- membered non-aromatic ring, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl The term 'aryl' means a 5- or 6- membered aromatic ring, for example phenyl, or a 7- to 12- membered bicyclic ring system where at least one of the rings is aromatic, for example naphthyl. When R³ is an optionally substituted aromatic heterocyclyl group, the ring may contain 1, 2, 3, or 4 hetero atoms. The hetero atoms may for example be selected from oxygen, nitrogen or sulphur. Examples of 5- membered heterocyclyl groups in this instance include furanyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thienyl, pyrazolyl or tetrazolyl. Examples of 6-membered heterocyclyl groups are pyridinyl, pyrizinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl. Examples of compounds of the present invention are 4-tert -butyl-2-(3-chloro- phenylamino)-pyrimidine-5 -carboxylic acid 4-fluoro-benzylamide and pharmaceutically acceptable derivatives thereof. Compounds of formula (I) can be prepared as set forth in the following scheme:

wherein L is a leaving group, for example halo, PG is a protecting group for example methyl, ethyl or benzyl, X is a leaving group, for example halo, OCι-₆ alkyl e.g. O-methyl or O-ethyl or NR^cR^d wherein R^c and R^d are independently selected from Cι-₆ alkyl e.g. methyl and R¹ , R², R⁴, R⁶ and Y are as defined for compounds of formula (I). It is to be understood that the present invention encompasses all isomers of compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).

Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formulas I and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as ³H, ^πC, ¹⁴C, ¹⁸F, ¹²³I and ¹²⁵I. Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³H, ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ^I4C, isotopes are particularly useful because of their ease of preparation and detectability. ^πC and ⁸F isotopes are particularly useful in PET (positron emission tomography), and I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half- life or reduced dosage requirements and, hence, may be particularly useful in some circumstances. Isotopically labeled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent. The compounds of formula (I) bind selectively to the CB2 receptor, and are therefore useful in treating CB2 receptor mediated diseases. In view of their ability to bind to the CB2 receptor, the compounds of formula (I) may be useful in the treatment of the disorders that follow. Thus, the compounds of formula (I) may be useful as analgesics. For example they may be useful in the treatment of chronic inflammatory pain (e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) including the property of disease modification and joint structure preservation; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea. The compounds of formula (I) may also be useful disease modification or joint structure preservation in multiple sclerosis, rheumatoid arthritis, osteo-arthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis. The compounds of formula (I) may be particularly useful in the treatment of neuropathic pain. Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia). The compounds of formula (I) may also be useful in the treatment of fever. The compounds of formula (I) may also be useful in the treatment of inflammation, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD); gastrointestinal tract disorders (e.g. aphthous ulcer, Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastrointestinal reflux disease); organ transplantation; other conditions with an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin's disease, sclerodoma, myaesthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, myocardial ischemia, pyrexia, systemic lupus erythematosus, tendinitis, bursitis, and Sjogren's syndrome. The compounds of formula (I) may also be useful in the treatment of bladder hyperrelexia following bladder inflammation. The compounds of formula (I) may also be useful in the treatment of immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation. The compounds of formula (I) may also be effective in increasing the latency of HIV infection. The compounds of formula (I) may also be useful in the treatment of diseases of abnormal platelet function (e.g. occlusive vascular diseases). The compounds of formula (I) may also be useful in the treatment of neuritis, heart burn, dysphagia, pelvic hypersensitivity, urinary incontinence, cystitis or incontinence. The compounds of formula (I) may also be useful for the preparation of a drug with diuretic action. The compounds of formula (I) may also be useful in the treatment of impotence or erectile dysfunction. The compounds of formula (I) may also be useful for attenuating the hemodynamic side effects of non-steroidal anti-inflammatory drugs (NSAID's) and cyclooxygenase-2 (COX-2) inhibitors. The compounds of formula (I) may also be useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt- Jakob disease, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease, metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment. The compounds may also be useful for the treatment of amyotrophic lateral sclerosis (ALS) and neuroinflamation. The compounds of formula (I) may also be -useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like. The compounds of formula (I) may also be useful in the treatment of tinnitus. The compounds of formula (I) may also be useful in the treatment of psychiatric disease for example schizophrenia, depression (which term is used herein to include bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, depression accompanying dementia for example of the Alzheimer's type, schizoaffective disorder or the depressed type, and depressive disorders resulting from general medical conditions including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc), anxiety disorders (including generalised anxiety disorder and social anxiety disorder), panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder, memory disorders, including dementia, amnesic disorders and age-associated memory impairment, disorders of eating behaviours, including anorexia nervosa and bulimia nervosa, sexual dysfunction, sleep disorders (including disturbances of circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawal from abuse of drugs such as of cocaine, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine (phencyclidine-like compounds), opiates (e.g. cannabis, heroin, morphine), amphetamine or amphetamine-related drugs (e.g. dextroamphetamine, methylamphetamine) or a combination thereof. The compounds of formula (I) may also be useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependence- inducing agent. Examples of dependence-inducing agents include opioids (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine. The compounds of formula (I) may also be useful in the treatment of kidney dysfunction (nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome), liver dysfunction (hepatitis, cirrhosis), gastrointestinal dysfunction (diarrhoea) and colon cancer. It is to be understood that references to treatment includes both treatment of established symptoms and prophylactic treatment unless explicitly stated otherwise. According to a further aspect of the invention, we provide a compound of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5 -carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine. According to another aspect of the invention, we provide a compound of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5 -carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by the activity of cannabinoid 2 receptors. According to a further aspect of the invention, we provide a method of treating a mammal including a human suffering from a condition which is mediated by the activity of cannabinoid 2 receptors which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) (including 4-isopropyl-2- phenylamino-ρyrimidine-5-carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof. According to a further aspect of the invention, we provide a method of treating a mammal including a human suffering from an immune disorder, an inflammatory disorder, pain, rheumatoid arthritis, multiple sclerosis, osteoarthritis or osteoporosis which method comprises administering to said subject an effective amount of a compound of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5 -carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof. The pain may for example be selected from inflammatory pain, visceral pain, cancer pain, neuropathic pain, lower back pain, muscular skeletal, post operative pain, acute pain and migraine. More particularly the inflammatory pain may be pain associated with rheumatoid arthritis or osteoarthritis. According to one aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable derivative thereof, for use as a medicament in the treatment of pain. According to another aspect of the invention, we provide the use of a compound of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof in the manufacture of a therapeutic agent for the treatment or prevention of a condition such an immune disorder, an inflammatory disorder, pain, rheumatoid arthritis, multiple sclerosis, osteoarthritis or osteoporosis. In order to use a compound of formula (I) (including 4-isopropyl-2-phenylamino- pyrimidine-5-carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect of the invention is provided a pharmaceutical composition comprising a compound of formula (I) (including 4-isopropyl-2-phenylamino- pyrimidine-5 -carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. As used herein, "modulator" means both antagonist, partial agonist and a full agonist, and inverse agonist. In a particular embodiment the present modulators are agonists. Compounds of formula (I) and their pharmaceutically acceptable derivatives may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, dermally, intranasally, transdermally, rectally, via inhalation or via buccal administration. Compositions of formula (I) and their pharmaceutically acceptable derivatives which are active when given orally can be formulated as liquids, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, olive oil, glycerine, glucose (syrup) or water with a flavouring, suspending or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, hydroxypropylmethyl cellulose (HPMC), microcrystalline cellulose (MCC), acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a soft shell capsule, semisolid capsule shell or hard capsule shell. Where the composition is in the form of a soft shell capsule e.g. gelatin any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums or oils, and are incorporated in a soft capsule shell. An example of a hard capsule shell is a gelatin capsule shell. Examples of semisolid capsule shells are MDC (mono and diglyceride capric acid), Gelucire and Labrasol capsule shells. Typical parenteral compositions consist of a solution or suspension of a compound or derivative in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil. Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane. A typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable derivative thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs. Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane. Suitably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose. Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, for example from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg/Kg, of a compound of formula (I) or a pharmaceutically acceptable derivative thereof calculated as the free acid. Each dosage unit for intranasal administration contains suitably 1-400 mg and even more suitably 10 to 200 mg per person. A topical formulation contains suitably 0.01 to 5.0% of a compound of formula (I). The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to

40 mg/Kg, of a compound of formula (I) or a pharmaceutically acceptable derivative thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of formula (I) or a pharmaceutically acceptable derivative thereof calculated as the free acid. The daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity. It may be advantageous to prepare the compounds of the present invention as nanoparticles. This may improve the oral bioavailability of the compounds. For the purposes of the present invention "nanoparticulate" is defined as solid particles with 50% of the particles having a particle size of less than lμm, more particularly less than 0.75μm The particle size of the solid particles of compound (I) may be determined by laser diffraction. A suitable machine for determining particle size by laser diffraction is a Lecotrac laser particle size analyser, using an HELOS optical bench fitted with a QUIXEL dispersion unit. Numerous processes for the synthesis of solid particles in nanoparticulate form are known. Typically these processes involve a milling process, such as a. wet milling process in the presence of a surface modifying agent that inhibits aggregation and/or crystal growth of the nanoparticles once created. Alternatively these processes may involve a precipitation process, such as a process of precipitation in an aqueous medium from a solution of the drug in a non-aqueous solvent. Accordingly, in a further aspect, the present invention provides a process for preparing compound (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide) in nanoparticulate form as hereinbefore defined, which process comprises milling or precipitation. Representative processes for the preparation of solid particles in nanoparticulate form are described in the patents and publications listed below.

U.S. Patent No. 4,826,689 to Violanto & Fischer, U. S. Patent No. 5,145,684 to

Liversidge et al

U.S Patent No. 5,298,262 to Na & Rajagopalan, U.S. Patent No. 5,302,401 Liversidge et al U.S. Patent No. 5,336,507 to Na & Rajagopalan, U.S. Patent No. 5,340,564 to Illig & Sarpotdar

U.S. Patent No. 5,346,702 to Na Rajagopalan, U.S. Patent No. 5,352,459 to Hollister et al U.S. Patent No. 5,354,560 to Lovrecich, U.S. Patent No. 5,384,124 to Courteille et al, U.S. Patent No. 5,429,824 to June, U.S. Patent No. 5,503,723 to Ruddy et al, U.S. Patent No. 5,510 118 to Bosch et al, U.S. Patent No. 5,518 to Bruno et al, U.S. Patent No. 5,518,738 to Eickhoff et al, U.S. Patent No. 5,534,270 to De Castro, U.S. Patent No. 5,536,508 to Canal et al, U.S. Patent No. 5,552,160 to Liversidge et al, U.S. Patent No. 5,560,931 to Eickhoff et al, U.S. Patent No. 5,560,932 to Bagchi et al, U.S. Patent No. 5,565,188 to Wong et al, U.S. Patent No. 5,571,536 to Eickhoff et al, U.S. Patent No. 5,573,783 to Desieno & Stetsko, U.S Patent No. 5,580,579 to Ruddy et al, U.S. Patent No 5,585,108 to Ruddy et al, U.S. Patent No. 5,587,143 to Wong, U.S. Patent No. 5,591456 to Franson et al, U.S. Patent No. 5,622,938 to Wong, U.S. Patent No 5,662,883 to Bagchi et al, U.S. Patent No. 5,665,331 to Bagchi et al, U.S Patent No. 5,718,919 to Ruddy et al, U.S. Patent No. 5,747,001 to Wiedmann et al, WO93/25190, WO96/24336, WO 97/14407, WO 98/35666, WO 99/65469, WO 00/18374, WO 00/27369, WO 00/30615 and WO 01/41760. Such processes may be readily adapted for the preparation of compound (I) in nanoparticulate form. Such processes form a further aspect of the invention. In a particular embodiment the process -of the present invention uses a wet milling step carried out in a mill such as a dispersion mill in order to produce a nanoparticulate form of the compound. The present invention may be put into practice using a conventional wet milling technique, such as that described in Lachman et al, The Theory and Practice of Industrial Pharmacy, Chapter 2, "Milling" p.45 (1986). In a further refinement, WO 02/00196 (PCT/EP01/07085) (SmithKline Beecham pic) describes a wet milling procedure using a mill in which at least some of the surfaces are made of nylon (polyamide) comprising one or more internal lubricants, for use in the preparation of solid particles of a drug substance in nanoparticulate form. In another aspect the present invention provides a process for preparing compounds of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5- carboxylic acid diethylamide) in nanoparticulate form comprising wet milling a suspension of compound in a mill having at least one chamber and agitation means, said chamber(s) and/or said agitation means comprising a lubricated nylon, as described in WO 02/00196 (PCT/EP01/07085). The suspension of a compound of the invention for use in the wet milling is typically a liquid suspension of the coarse compound in a liquid medium. By "suspension" is meant that the compound is essentially insoluble in the liquid medium. Representative liquid media include an aqueous medium. Using the process of the present invention the average particle size of coarse compound of the invention may be up to 1mm in diameter. This advantageously avoids the need to pre-process the compound. In. a further aspect of the invention the aqueous medium to be subjected to the milling comprises compound (I) present in from about 1% to about 40% w/w, for example from about 10% to_. about 30% w/w, more particularly about 20% w/w. The aqueous medium may further comprise one or more pharmaceutically acceptable water-soluble carriers which are suitable for steric stabilisation and the subsequent processing of compound (I) after milling to a pharmaceutical composition, e.g. by spray drying. Pharmaceutically acceptable excipients most suitable for steric stabilisation and spray-drying are surfactants such as poloxamers, sodium lauryl sulphate and polysorbates etc; stabilisers such as celluloses e.g. hydroxypropylmethyl cellulose; and carriers such as carbohydrates e.g. mannitol. In a further aspect of the invention the aqueous medium to be subjected to the milling may further comprise hydroxypropylmethyl cellulose (HPMC) present in from about 0.1 to about 10% w/w. The process of the present invention may comprise the subsequent step of drying compound of the invention to yield a powder. Accordingly, in a further aspect, the present invention provides a process for preparing a pharmaceutical composition containing a compound of the present invention which process comprises producing compound of formula (I) (including 4-isopropyl-2- phenylamino-pyrimidine-5-carboxylic acid diethylamide) in nanoparticulate form optionally followed by drying to yield a powder.

A further aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide)or a pharmaceutically acceptable derivative thereof in which the compound of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof is present in solid particles in nanoparticulate form, in admixture with one or more pharmaceutically acceptable carriers or excipients. By "drying" is meant the removal of any water or other liquid vehicle used during the process to keep compound of formula (I) in liquid suspension or solution. This drying step may be any process for drying known in the art, including freeze drying, spray granulation or spray drying. Of these methods spray drying is particularly advantageous. All of these techniques are well known in the art. Spray drying/fluid bed granulation of milled compositions is carried out most suitably using a spray dryer such as a Mobile Minor Spray Dryer [Niro, Denmark], or a fluid bed drier, such as those manufactured by Glatt, Germany. In a further aspect the invention provides a pharmaceutical composition as hereinbefore defined, in the form of a dried powder, obtainable by wet milling solid particles of compound of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine- 5 -carboxylic acid diethylamide) followed by spray-drying the resultant suspension. In a particular embodiment, the pharmaceutical composition as hereinbefore defined, further comprises HPMC present in less than 15% w/w, for example in the range 0.1 to 10% w/w. The CB2 receptor compounds for use in the instant invention may be used in combination with other therapeutic agents, for example COX-2 inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib or COX- 189; 5-lipoxygenase inhibitors; NSAID's, such as aspirin, diclofenac, indomethacin, nabumetone or ibuprofen; leukotriene receptor antagonists; DMARD's such as methotrexate; adenosine Al receptor agonists; sodium channel blockers, such as lamotrigine; NMDA receptor modulators, such as glycine receptor antagonists; gabapentin and related compounds; tricyclic antidepressants such as amitriptyline; neurone stabilising antiepileptic drugs; mono- aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; 5HTι agonists, such as triptans, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, frovatriptan, almotriptan or rizatriptan; EPi receptor ligands, EP receptor ligands; EP₂ receptor ligands; EP₃ receptor ligands; EP₄ antagonists; EP₂ antagonists and EP₃ antagonists; bradykinin receptor ligands and vanilloid receptor ligand, antirheumatoid arthritis drugs, for example anti TNF drugs e.g. enbrel, remicade, anti-IL- 1 drugs, or DMARDS e.g. leflunamide. When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. Additional COX-2 inhibitors are disclosed in US Patent Nos. 5,474,995 US5,633,272; US5,466,823, US6,310,099 and US6,291,523; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691, WO99/12930, WO00/26216, WO00/52008, WOOO/38311, WO01/58881 and WO02/18374. The invention thus provides, in a further aspect, a combination comprising one or more compounds of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5- ^• carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents. Suitable 5HT3 antagonists which may be used in combination with the compounds of the invention include for example ondansetron, granisetron, metoclopramide. Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide. Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine. Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine. Suitable tricyclic antidepressants which may be used in combination with the compounds of the invention include imipramine, amitriptiline, chlomipramine and nortriptiline. Suitable dopaminergic antidepressants which may be used in combination with the compounds of the invention include bupropion and amineptine. Compounds of the present invention (including 4-isopropyl-2-phenylamino- pyrimidine-5-carboxylic acid diethylamide) may used in combination with PDE4 inhibitors. The PDE4 inhibitor useful in this invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act in as PDE4 inhibitor, and which is only or essentially only a PDE4 inhibitor, not compounds which inhibit to a degree of exhibiting a therapeutic effect other members of the PDE family as well as PDE4. It turns out that there are at least two binding forms on human monocyte recombinant PDE 4 (hPDE 4) at which inhibitors bind. One explanation for these observations is that hPDE 4 exists in two distinct forms. One binds the likes of rolipram and denbufylline with a high affinity while the other binds these compounds with a low affinity. The most suitable PDE4 inhibitors of for use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. Generally it is most advantageous to use a PDE4 antagonists which has an IC₅₀ ratio of about 0.1 or greater as regards the IC₅₀ for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC₅₀ for the form which binds rolipram with a low affinity. Most suitable are those PDE4 inhibitors which have an IC₅₀ ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0. Reference is made to U.S. patent 5,998,428, which describes these methods in more detail. It is incorporated herein in full as though set forth herein. Compounds of the present invention or combinations with PDE4 can be used in treating inflammation, lung disorders and as bronchodilators.. A further aspect of the invention is one or more compounds of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide) or a pharmaceutical derivative thereof in combination with one or more PDE4 inhibitors or a pharmaceutical derivative thereof and pharmaceutical compositions comprising said combination. A further aspect of the invention is a method of treating inflammation, lung disorders for example asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD) and cough or a disorder which can be treated with a broncodilator which comprises administering to a mammal including man, an effective amount of one or more compounds of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5- carboxylic acid diethylamide) or a pharmaceutical derivative thereof and an effective amount of one or more PDE4 inhibitors or a pharmaceutical derivative thereof. An additional aspect of the invention is the use of an effective amount of one or more compounds of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5- carboxylic acid diethylamide) or a pharmaceutical derivative thereof and an effective amount of one or more PDE4 inhibitors or a pharmaceutical derivative thereof in the manufacture of a medicament in the treatment of inflammation or lung disorders for example asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease, (COPD) and cough, or for the manufacture of a bronchodilator. When used herein cough can have a number of forms and includes productive, non-productive, hyper-reactive, asthma and COPD associated. A suitable patient pack may comprise an effective amount of one or more compounds of formula (I) (including 4-isopropyl-2-phenylamino-pyrimidine-5- carboxylic acid diethylamide) or a pharmaceutical derivative thereof and an effective amount of one or more PDE4 inhibitors or a pharmaceutical derivative thereof. Suitable PDE4 compounds are cis [cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-l-carboxylate] also known as cilomilast or Ariflo , 2- carbomethoxy-4~cyano-4-(3 -cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan- 1-one, and cis [4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan- l-ol]. They can be made by the processed described in US patents 5,449,686 and 5,552,438. Other PDE4 inhibitors, specific inhibitors, which can be used in this invention are AWD- 12-281 from ASTA MEDIC A (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787; Parke-Davis/Warner- Lambert); a benzodioxole derivative Kyowa Hakko disclosed in WO 9916766; V- 11294 A from Napp (Landells, L.J. et al Eur Resp J [Annu Cong Eur Resp Soc (Sept 19- 23, Geneva) 1998] 1998, 12(Suppl. 28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and a pthalazinone (WO 99/47505) from Byk-Gulden (now Altana); or a compound identified as T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 162). Additional PDE4 inhibitors are disclosed oπ pages 2 to 15 of WO01/13953.

Specifically selected are arofylline, atizoram, BAY-19-8004, benafentrine, BYK-33043,

CC-3052, CDP-840, cipamfylline, CP-220629, CP-293121, D-22888, D-4396, denbufylline, filaminast, GW-3600, ibudilast, KF-17625, KS-506-G, laprafylline, NA- 0226A, NA-23063A, ORG-20241, ORG-30029, PDB-093, pentoxifylline, piclamilast, rolipram, RPR-117658, RPR-122818, RPR-132294, RPR-132703, RS-17597, RS-25344-

000, SB-207499, SB210667, SB211572, SB-211600, SB212066, SB212179, SDZ-ISQ-

844, SDZ-MNS-949, SKF-107806, SQ-20006, T-2585, tibenelast, tolafentrine, UCB-

29646, V-l 1294A, YM-58997, YM-976 and zardaverine. Suitably the PDE4 inhibitor is selected from cilomilast, AWD-12-281, NCS-613, D-4418,

CI-1018, V-l 1294A, roflumilast or T-440. The combinations referred to above may contain one or more compounds of formula

(I) (or pharmaceutical derivative thereof) in combination with one or more additional therapeutic agents (or pharmaceutical derivative thereof). ' It will be appreciated that the compounds of any of the above combinations or compositions may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone.

Appropriate doses will be readily appreciated by those skilled in the art.

Determination of cannabinoid CB1 Receptor Agonist Activity The cannabinoid CB 1 receptor agonist activity of the compounds of formula (I) was determined in accordance with the following experimental method.

Experimental Method Yeast (Saccharomyces cerevisiae) cells expressing the human cannabinoid CB1 receptor were generated by integration of an expression cassette into the ura3 chromosomal locus of yeast strain MMY23. This cassette consisted of DNA sequence encoding the human CB1 receptor flanked by the yeast GPD promoter to the 5' end of CB1 and a yeast transcriptional terminator sequence to the 3' end of CB1. MMY23 expresses a yeast/mammalian chimeric G-protein alpha subunit in which the C-terminal 5 amino acids of Gpal are replaced with the C-terminal 5 amino acids of human G i3 (as described in Brown et al. (2000), Yeast 16:11-22). Cells were grown at 30°C in liquid Synthetic Complete (SC) yeast media (Guthrie and Fink (199.1), Methods in Enzymology, Vol. 194) lacking uracil, tryptophan, adenine and Teucine to late logarithmic phase (approximately 6 OD₆₀o/ml). Agonists were prepared as 10 mM stocks in DMSO. EC₅₀ values (the concentration required to produce 50% maximal response) were estimated using dilutions of between 3- and 5-fold (BiomekFX, Beckman) into DMSO. Agonist solutions in DMSO (1% final assay volume) were transferred into black, clear bottom, microtitre plates fromNUNC (96- or 384-well). Cells were suspended at a density of 0.2 OD₆₀₀/ml in SC media lacking histidine, uracil, tryptophan, adenine and leucine and supplemented with lOmM 3-aminotriazole, 0.1M sodium phosphate pH 7.0, and 20μM fluorescein di-β- D-glucopyranoside (FDGlu). This mixture (50ul per well for 384-well plates, 200ul per well for 96-well plates) was added to agonist in the assay plates (Multidrop 384, Labsystems). After incubation at 30°C for 24 hours, fluorescence resulting from degradation of FDGlu to fluorescein due to exoglucanase, an endogenous yeast enzyme produced during agonist-stimulated cell growth, was determined using a Spectrofluor microtitre plate reader (Tecan; excitation wavelength: 485nm; emission wavelength:

535nm). Fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter fit to generate a concentration effect value. Efficacy (E_max) was calculated from the equation Emax = MaX[_Compound X] " Min[_compound X] / MaX[_HU210] " Min[HU210] x 100%» where MaX[_COmpound X] and Min[_compound X] are the fitted maximum and minimum respectively from the concentration effect curve for compound X, and Max[_HU2iQ] and Min_[HU2io_] are the fitted maximum and minimum respectively from the concentration effect curve for (6aR,10aR)-3-(l,r-Dimethylheptyl)-6a,7,10,10a-tetrahydro-l-hydroxy- 6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol (HU210; available from Tocris). Equieffective molar ratio (EMR) values were calculated from the equation EMR = EC₅₀ [compound X] / EC50 [HU210] Where EC₅₀ [c_ompound x] is the EC₅₀ of compound X and EC₅₀ [HU210] is the EC₅₀ of HU210. The compound of Example 1 tested according to this method had an EC₅₀ value >30,000nM and/or efficacy value of <50% at the cloned human cannabinoid CB1 receptor.

Determination of cannabinoid CB2 Receptor Agonist Activity The cannabinoid CB2 receptor agonist activity of the compounds of formula (I) was determined in accordance with the following experimental method.

Experimental Method Yeast (Saccharomyces cerevisiae) cells expressing the human cannabinoid CB2 receptor were generated by integration of an expression cassette into the ura3 chromosomal locus of yeast strain MMY23. This cassette consisted of DNA sequence encoding the human CB2 receptor flanked by the yeast GPD promoter to the 5' end of CB2 and a yeast transcriptional terminator sequence to the 3' end of CB2. MMY23 expresses a yeast/mammalian chimeric G-protein alpha subunit in which the C-terminal 5 amino acids of Gpal are replaced with the C-terminal 5 amino acids of human G i3 (as described in Brown et al. (2000), Yeast 16:11-22). Cells were grown at 30°C in liquid Synthetic Complete (SC) yeast media (Guthrie and Fink (1991), Methods in Enzymology, Vol. 194) lacking uracil, tryptophan, adenine and leucine to late logarithmic phase (approximately 6 OD₆oo/ml). Agonists were prepared as 10 mM stocks in DMSO. EC₅₀ values (the concentration required to produce 50% maximal response) were estimated using dilutions of between 3- and 5 -fold (BiomekFX, Beckman) into DMSO. Agonist solutions in DMSO (1% final assay volume) were transferred into black, clear bottom, microtitre plates from NUNC (96- or 384-well). Cells were suspended at a density of 0.2 OD₆₀₀/ml in SC media lacking histidine, uracil, tryptophan, adenine and leucine and supplemented with lOmM 3-aminotriazole, 0.1M sodium phosphate pH 7.0, and 20M fluorescein di-β- D-glucopyranoside (FDGlu). This mixture (50ul per well for 384-well plates, 200ul per well for 96-well plates) was added to agonist in the assay plates (Multidrop 384, Labsystems). After incubation at 30°C for 24 hours, fluorescence resulting from degradation of FDGlu to fluorescein due to exoglucanase, an endogenous yeast enzyme produced during agonist-stimulated cell growth, was determined using a Spectrofluor microtitre plate reader (Tecan; excitation wavelength: 485nm; emission wavelength: 535nm). Fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter fit to generate a concentration effect value. Efficacy (E_maχ) was calculated from the equation . E_max = MaX[_Compound XJ " Min[_compound X] / aX[HU210] - MinjHU210] 100%> where MaX[_COmpound X] and Min[_Compo_Und x] are the fitted maximum and minimum respectively from the concentration effect curve for compound X, and Max[HU2io] and Min_[HU2io_] are the fitted maximum and minimum respectively from the concentration effect curve for (6aR,10aR)-3 -(1,1 '-Dimethylheptyl)-6a,7, 10,1 Oa-tetrahydro-1 -hydroxy- 6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol (HU210; available from Tocris). Equieffective molar ratio (EMR) values were calculated from the equation EMR = EC₅o [compound X\ I EC₅₀ [HU210] Where EC₅₀ [compound x] is the EC₅₀ of compound X and EC₅₀ [_Hu2io] is the EC₅₀ of

HU210. The compound of Example 1 tested according to this method had an EC₅₀ value of <300 nM and an efficacy values of >50% at the cloned human cannabinoid CB2 receptor. The following. examples are illustrative, but not limiting of the embodiments of the present invention.

Conditions, Hardware, and Software used for LC/MS

Hardware Agilent 1100 gradient pump Agilent 1100 Autosampler Agilent 1100 PDA Dectector Agilent 1100 Degasser Micromass ZQ mass spectrometer PL-ELS 1000

Software Micromass Masslynx versions 3.5/4.0

Column

The column used is a Supelcosil™ ABZ+PLUS, the dimensions of which are 4.6mm x 33mm. The stationary phase particle size is 3μm.

Solvents

A : Aqueous solvent = lOmMol Ammonium Acetate + 0.1% Formic Acid

B : Organic solvent = 95 %Acetonitrile + 0.05% Formic Acid

Method

The generic method used has 5.5 minute runtime, which comprises of a 4.7-minute gradient (0-100% B) followed by a 0.6 minute column flush and 0.2 minute re- equilibration step.

Flow rate

The above method has a flow rate of 3ml/mins

Conditions, Hardware, and Software used for NMR

All NMR spectra were recorded at 400MHz

Hardware

Bruker 400MHz Ultrashield™ Bruker B-ACS60 Autosampler Bruker Advance 400 Console

Software

User interface - NMR Kiosk Controlling software - XWin NMR version 3.0

Abbreviations

The following abbreviations are used herein and are represented by:

DMF is N,N-dimethylforamide

Example 1: 4-tert -Butyl-2-(3-chloro-phenylamino)-pyrimidine-5-carboxylic acid 4-fluoro-benzylamide (a) 4-tert-Butyl-2-hydroxy-pyrimidine-5-carboxylic acid ethyl ester

AcOH, reflux

A stirred solution of 2-dimethylaminomethylene-4,4-dimethyl-3-oxo-pentanoic acid ethyl ester (21.4g) (prepared as in G Menozzi, J Het Chem, 1987, 24, 1669) and urea (6.1g) in glacial acetic acid (100 ml) was heated at reflux for 16h. The solution was evaporated and then co-evaporated twice from toluene. A solution of the residue in ethyl acetate (400 ml) was washed twice with water, dried (MgSO ), and evaporated in vacuo to give the title compound as an off-white solid (5.9g, 28%). NMR (DMSO-d6) δ 1.23-1.35 (12H, m), 4.22 (2H, q), 8.2 (1H, s), 12.22 (1H, s). LC/MS t = 2.2 min. Molecular ion observed [MH⁺] = 225 consistent with the molecular formula CπHι₆N₂O₃

(b) 4-tert-Butyl-2-Ghloro-pyrimidine-5-carboxylic acid ethyl ester

A mixture of 4-tert-butyl-2-hydroxy-pyrimidine-5-carboxylic acid ethyl ester (14.2g) in phenyl dichlorophosphate (60ml) was stirred and heated at 180° for 30 min. Ice was cautiously added to the cooled mixture and stirring continued for 15 min. Aqueous saturated sodium bicarbonate was carefully added, and the mixture extracted with ethyl acetate (2x200ml). The combined, dried (MgSO4) organic extracts were evaporated in vacuo to give the title compound as a yellow oil (15.3g).

NMR (DMSO-d6) δ 1.24-1.38 (12H, m), 4.36 (2H, q), 8.82 (1H, s).

LC/MS t = 3.4 min. Molecular ion observed [MH⁺] = 243 consistent with the molecular formula C_πH₁₅ClN₂O₂.

(c) 4-tert -Butyl-2-(3-chloro-phenylamino)-pyrimidine-5-carboxylic acid ethyl ester

3-Chloroaniline (4 ml) was added to a solution of 4-tert-butyl-2-chloro-pyrimidine-5- carboxylic acid ethyl ester (3.0 g) in 1,4-dioxan (10 ml), and the solution stirred at 100° for 3h. The solvent was evaporated in vacuo, and the residue partitioned between ethyl acetate and 2M hydrochloric acid. The organic layer was washed twice with 2M hydrochloric acid, twice with brine, and the dried (MgSO4) organic layer was evaporated in vacuo, and the resultant brown oil solidified on standing to give the title compound

(3.99g).

NMR (DMSO-d6) δ 1.32 (3H, t), 1.40 (9H, s), 4.31, (2H, q), 7.05 (IH, d), 7.34 (IH, t),

7.60 (IH, d), 8.1 (IH, s), 8.59 (IH, s), 10.2 (IH, s).

LC/MS t = 4.2 min. Molecular ion observed [MH⁺] = 334 consistent with the molecular formula C₁₇H₂₀C1N₃O_2.

(d) 4-tert-Butyl-2-(3-chloro-phenylamino)-pyrimidine-5-carboxylic acid

A solution of potassium hydroxide (1.91g) in ethanol (20ml) was added to a solution of 4-tert -butyl-2-(3-chloro-phenylamino)-pyrimidine-5-carboxylic acid ethyl ester (3.79g) in ethanol (10ml) and the stirred solution heated at reflux for 6.5h. The cooled solution was evaporated in vacuo and the residue in water (50ml) was washed with ether (2x30ml), then acidified to pHl with concentrated hydrochloric acid. The resultant off- white precipitate was filtered off, washed with water, and dried in vacuo at 60° to constant weight, to give the title compound (3.02g, 87%).

NMR (DMSO-d6) δ 1.45 (9H, s), 7.01 (IH, d), 7.30 (IH, t), 7.61 (IH, d), 8.10 (IH, s), 8.60 (IH, s), 10.1 (IH, s), 13.2 (IH, br s).

LC/MS t = 4.1 min. Molecular ion observed [MH⁺] = 306 consistent with the molecular formula C₁₅H₁₆ClN₃O₂.

(e) 4-tert -Butyl-2-(3-chloro-phenylamino)-pyrimidine-5-carboxylic acid 4-fluoro- benzylamide

N-Ethylmorpholine (110 μl) was added to a solution of 4-tert-butyl-2-(3-chloro- phenylamino)-pyrimidine-5 -carboxylic acid (lOOmg) in DMF (2 ml) at 23° with stirring, followed by 4-fluorobenzylamine (45 μl), 1-hydroxy-benzotriazole (69 mg), and l-[(3- dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (75 mg). After stirring overnight, the solvent was evaporated in vacuo, and the residue partitioned between ethyl acetate and aqueous 5% sodium bicarbonate solution. The organic layer was separated, washed with aqueous 5% sodium bicarbonate, water, aqueous 5% citric acid , water, and brine. The dried organic layer was evaporated in vacuo to give the title compound as a very pale yellow solid (81mg). NMR (DMSO-d6) δ 1.32 (9H, s), 4.40 (2H, d), 6.99 (IH, d), 7.20 (2H, t), 7.30 (IH, t), 7.45 (2H, dd), 7.64 (IH, d), 8.12 (IH, s), 8.37 (IH, s), 9.0 (IH, t), 9.95 (IH, s).

LC/MS t = 3.9 min. Molecular ion observed [MET^1"] = 413 consistent with the molecular formula C₂₂H₂₂ClFN₄O.

Nanoparticle preparations and formulations for pharmaceutical use incorporating compounds of the present invention either pre or post nanomilling can be prepared in various forms and with numerous excipients. Examples of such preparations and formulations are given below.

Example 2: Preparation of Nanomilled Compound

2.5 g of compound of Example 1 is weighed into a 10 ml centrifuge tube. 25 ml of 0.3mm yttrium zirconium (YTZ) ceramic milling beads (Manufacturer: Tosoh, Japan; Supplier: Glen Creston Ltd., batch no. 5280130030)") is weighed into a 50 ml milling pot. 22.5 ml of aqueous 1.5% HPMC is measured with a measuring cylinder into a 100 ml beaker. This solution is homogenised for 3 seconds with an Ultra Turrax T25 homogeniser. Approximately 200 mg of the 2.5 g of the compound is added to the HPMC solution and homogenised at the lowest speed setting until the powder is wetted. This is repeated until all the compound has been added. The speed of the homogeniser is then increased to maximum and the suspension is homogenised for a further 3 minutes. This suspension is allowed to stand for 30 minutes in order to allow some of the foam to disperse. The suspension is then poured into the 50 ml pot containing the YTZ milling beads, stirring to release any trapped air. The lid to the pot is then fitted and the pot sealed with some Nesco film. This procedure is repeated for a second 50 ml nanomilling pot and both pots are placed on a Retsch mill and milled for a total of 8 hours.

The milling pots are removed from the Retsch mill and left to cool and for the foam to disperse overnight. In the morning the suspension and bead mixture is passed through a 200μ, 40 mm diameter screen. The contents from each 50 ml pot are washed with aqueous 1.5% HPMC: 10% of the original suspension volume (i.e. 2.5 ml). The suspension from the 2 pots is combined to make 1 batch. The suspension obtained from the method above is named the concentrate.

A sample of the. concentrate is diluted 1 in 4 with aqueous 1.5% HPMC to give a nominal concentration of 25 mg/ml. This first dilution is assayed by HPLC. The concentration of the concentrate is calculated (mg/ml).

HPLC conditions:

Column: Symmetry Cι g 5μ 3.9 150 mm column; flow rate 1.0 ml/min; column temp 40°C; UV detection at 280nm. Mobile phase gradient: A: water + 0.1% trifluoro acetic acid (TFA) B: acetonitrile + 0.1% TFA A particle size analysis is carried out on the Lecotrac laser particle size analyser.

Example 3: Inhalant Formulation

A compound of formula (I) or a pharmaceutically acceptable derivative thereof, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount ofdrug per use.

Example 4: Tablet Formulation

Tablets/Ingredients Per Tablet

1. Active ingredient 40 mg (Compound of formula (I) or pharmaceutically acceptable derivative) 2. Corn Starch 20 mg

3. Alginic acid 20 mg

4. Sodium Alginate 20 mg

5. Mg stearate 1.3 mg

Procedure for tablet formulation:

Ingredients 1, 2, 3 and 4 are blended in a suitable mixer/blender. Sufficient water is added portion-wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules. The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. The wet granules are then dried in an oven at 140°F (60°C) until dry. The dry granules are lubricated with ingredient No. 5, and the lubricated granules are compressed on a suitable tablet press.

Example 5: Parenteral Formulation

A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula (I) in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

Claims

1. A compound of formula (I) :

wherein: Y is phenyl, substituted with one, two or three substituents; R¹ is selected from hydrogen, Cι_₆ alkyl, C₃.₇ cycloalkyl, and halosubstitutedC_1-6 alkyl; R^z is C(R')₂R ; R³ is an optionally substituted 5- to 6- membered aromatic heterocyclyl group, or group A:

(A) R⁴ is selected from hydrogen, Cι_-6 alkyl, C_3-7 cycloalkyl, and halosubstitutedCι_-6 alkyl, COCH_3, or SO₂Me; R⁶ is a substituted or unsubstituted Cι;-₁₀ alkyl or C₃-₇cycloalkyl excluding unsubstituted methyl or CHxFn wherein n is 1, 2, or 3, x is 0, 1 or 2 and n and x add up to

3; Ra can be independently selected from hydrogen, fluoro, chloro or trifluoromethyl; Rb can be independently be selected from hydrogen, Cι-₆ alkyl, Cι_-6 alkoxy, haloC_1-6 alkoxy, hydroxy, cyano, halo, sulfonyl, CONH₂, COOH or NHCOOCι_-6alkyl; R⁷ can be independently hydrogen or Cι_-6 alkyl; or a pharmaceutically acceptable derivative thereof, with the proviso that the compound is not 4-isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide.

2. A compound as claimed in claim 1 selected from 4-tert -butyl-2-(3-chloro- phenylamino)-pyrimidine-5-carboxylic acid 4-fluoro-benzylamide or a pharmaceutically acceptable derivative thereof.

3. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 or claim 2 (including 4-isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide) or a pharmaceutically acceptable derivative threreof.

4. A pharmaceutical composition as claimed in claim 3 further comprising a pharmaceutical carrier or diluent.

5. A method of treating a human or animal subject suffering from a condition which is mediated by the activity of CB2 receptors which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) as claimed in claim 1 or claim 2 (including 4-isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof.

6. Use of a compound of formula (I) as claimed in claim 1 or claim 2 (including 4- isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof as a pharmaceutical.

7. Use of a compound of formula (I) as claimed in claim 1 or claim 2 (including 4- isopropyl-2-phenylamino-pyrimidine-5-carboxylic acid diethylamide) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for treating a condition which is mediated by the activity of CB2 receptors.

8. A pharmaceutical composition, method of treatment, or use as claimed in any one of claims 3 to 7 comprising one or more further therapeutic agents.

9. A pharmaceutical composition as claimed in claim 8 wherein the further therapeutic agent is a PDE4 inhibitor.

10. A compound of formula (I) as claimed in claims 1 or 2, or a pharmaceutically acceptable derivative thereof, for use as a medicament in the treatment of pain.