WO2005016925A1 - Derives d'azaquinazoline - Google Patents

Derives d'azaquinazoline Download PDF

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Publication number
WO2005016925A1
WO2005016925A1 PCT/IB2004/002558 IB2004002558W WO2005016925A1 WO 2005016925 A1 WO2005016925 A1 WO 2005016925A1 IB 2004002558 W IB2004002558 W IB 2004002558W WO 2005016925 A1 WO2005016925 A1 WO 2005016925A1
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Prior art keywords
cycloalkyl
alkyl
optionally substituted
compound
het
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PCT/IB2004/002558
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English (en)
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Paul John Edwards
Karl Richard Gibson
Simon John Mantell
Graham Nigel Maw
Cedric Poinsard
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Pfizer Limited
Pfizer Inc.
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Priority claimed from GB0319148A external-priority patent/GB0319148D0/en
Priority claimed from GB0405905A external-priority patent/GB0405905D0/en
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Publication of WO2005016925A1 publication Critical patent/WO2005016925A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to azaquinazoline derivatives. More particularly, this invention relates to 6-amino-7-azaquinazoline derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
  • the azaquinazoline derivatives of the present invention are antagonists of the human metabotropic glutamate subtype 1 receptor (mGluRI) and have a number of therapeutic applications, particularly in the treatment of pain.
  • mGluRI human metabotropic glutamate subtype 1 receptor
  • the azaquinazoline derivatives of the invention are selective mGluRI receptor antagonists.
  • they show an affinity for the mGluRI receptor which is greater than their affinity for the mGluR ⁇ receptor.
  • Preferred compounds of the invention show at least a 100-fold selectivity for the mGluRI receptor as compared with the mGluR ⁇ receptor.
  • the compounds of the invention show little or no affinity for the enzyme EGFR kinase.
  • Glutamate is an important neurotransmitter in the central nervous system, activating cation channels via ionotropic glutamate receptors and modulating cell excitability by action at G-protein coupled metabotropic glutamate receptors (mGluRs).
  • mGluRs G-protein coupled metabotropic glutamate receptors
  • Eight metabotropic glutamate receptor subtypes have been identified and further classified into three distinct groups based on their sequence homology, pharmacology and coupling to intracellular effector mechanisms.
  • the group I mGluRs consisting of mGluRI and mGluR ⁇ , are postsynaptic and are primarily coupled to phospholipase C, regulating neuronal excitability via phosphoinositide hydrolysis, release of intracellular
  • mGluR4, mGluR6, mGluR7, mGluR8 are primarily presynaptic auto receptors and inhibit adenylyl cyclase through a pertusis toxin sensitive G-protein, inhibiting cyclic AMP formation and the activation of cAMP dependent protein kinase.
  • Activity at excitatory glutamatergic pathways is associated with a number of neuropathologies including: ischaemic damage, neurodegeneration, pain, depression, drug dependency, epilepsy, Parkinsonism and schizophrenia.
  • Group 1 metabotropic glutamate receptors are localized in brain regions primarily associated with somatosensory processing, including the dorsal root ganglia, superficial and deep spinal dorsal horn, midbrain reticular formation, somatosensory thalamus, amygdala and cortex.
  • Metabotropic glutamate receptors, particularly mGluRI have been shown ⁇ to be involved in processes of nociception and hyperalgesia.
  • Antibodies raised against mGluRI increase tail flick latencies and reduce the responses of dorsal horn neurones to repeated noxious stimuli (Young et al, Journal of Neuroscience, 18, 10180-10188, 1998).
  • Intrathecal group I agonists cause heat hyperalgesia and increase nociceptive behaviours (Fisher and Coderre, Neuroreport, 9, 1169-1172, 1998).
  • group I mGluRs are involved in more persistent pain conditions since administration of specific mGluRI antibodies reduced cold allodynia following nerve damage (Fundytus et al, Neuroreport, 9, 731 - ⁇ , 1998).
  • Antisense oligonucleotides demonstrate that ablation of the mGluRI receptor attenuates the hyperalgesia and allodynia associated with nerve damage (Fundytus et al, British Journal of ⁇ Pharmacology, 132, 3 ⁇ 4-67, 2001) and attenuates the hyperalgesia and allodynia that occurs as a result of chronic inflammation (Fundytus et al, Pharmacology, Biology and Behaviour, 73, 401-10, 2002).
  • Spinal administration of a group I receptor antagonist will reverse the central sensitisation induced by peripheral capsaicin injection (Neugebauer et al, Journal of Neurophysiology, 82, 272-82, 1999).
  • Group I receptor0 agonists enhance behavioural responses and group I receptor antagonists attenuate behavioural responses in the late phase of the formalin test (Fisher and Coderre, Pain, 68, 255-263, 1996).
  • Cerebral ischemia causes an increased release of glutamate and an increase in5 intracellular calcium which can cause cell death and neuronal degeneration.
  • Compounds, which regulate activity at mGluRI are neuroprotective in animal models of cerebral ischemia (De Vry et al, European Journal of Pharmacology, 428, 203-14, 2001).
  • CNS central nervous system
  • mGluRI receptor antagonists have been shown to inhibit seizures in animal models indicating a likely utility in epilepsy (Chapman et al, European Journal of Pharmacology, 368, 17-24, 1999).
  • Group I receptor antagonists are both neuroprotective and also improve learning performance in this model (Renaud et al, Epilepsia, 43, 1306-1317, 2002) indicating a possible application in the treatment of neurodegenerative disease states such as Alzheimers and dementia (including HIV induced dementia).
  • the compounds of the present invention are therefore potentially useful in the treatment of a wide range of disorders, particularly in the treatment of pain, epilepsy and neurodegenerative disorders such as Alzheimer's disease, dementia and stroke.
  • Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
  • the system operates through a specific set of primary sensory neurones and is exclusively activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobio., 57, 1-164 for a review).
  • These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus.
  • nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated).
  • A-delta fibres myelinated
  • C fibres non-myelinated.
  • the activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
  • Pain is a feature of many trauma and disease states. When a substantial injury, via disease or trauma, to body tissue occurs the characteristics of nociceptor activation are altered. There is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. This leads to hypersensitivity at the site of damage and in nearby normal tissue. In acute pain these mechanisms can be useful, allowing for repair processes to take place and the hypersensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is normally due to nervous system injury.
  • pain can be divided into a number of different areas, because of differing pathophysiology, including nociceptive, inflammatory and neuropathic pain. It should be noted that some ⁇ types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components.
  • Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to0 cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and sensitise the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44).
  • the activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for ⁇ sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain.
  • Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to pain from strains/sprains, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, burns, myocardial infarction, acute pancreatitis, renal colic, cancer pain (which may be tumour related0 pain, e.g. bone pain, headache, facial pain and visceral pain, or associated with cancer therapy, e.g. postchemotherapy syndromes, chronic postsurgical pain syndromes, and post radiation syndromes) and back pain (which may be due to hemiated or ruptured intervertabral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament).
  • cancer pain which may be tumour related0 pain, e.g. bone pain, headache, facial pain and visceral pain, or associated with cancer therapy, e.g. postchemotherapy syndromes, chronic postsurgical pain syndromes, and post radiation syndromes
  • back pain which may be due to
  • Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (IASP definition). Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include but are not limited to, diabetic neuropathy, post herpetic neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia and vitamin deficiencies. Neuropathic pain is pathological as it has no protective role.
  • neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1969-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
  • the inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 46-56).
  • Arthritic pain is the most common inflammatory pain.
  • Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability.
  • the exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407).
  • the viscera encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain.
  • Commonly encountered gastrointestinal (Gl) disorders include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, which all regularly produce visceral pain.
  • Other types of visceral pain include the pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis.
  • the compounds of the present invention are potentially useful in the treatment of all kinds of pain, particularly nociceptive pain.
  • Alzheimer's disease amyotrophic lateral sclerosis, anxiety, brain edema, cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischaemia, cognitive disorders, convulsions, dementia (including HIV-induced dementia), depression, drug intoxication, drug-tolerance and withdrawal, emesis, epilepsy, head trauma, Huntington's chorea, hypoglycaemic neuronal damage, inherited ataxias, metabolic derangement, muscular spasms, ocular damage, Parkinson's disease, perinatal hypoxia, psychosis including schizophrenia and bipolar disorder), post-traumatic stress disorder, retinopathy, spasticity, spinal cord lesions due to trauma or infarction/ischaemia or inflamation, stroke, tardive dyskinesia, tremor and urinary incontinence.
  • Alzheimer's disease amyotrophic lateral sclerosis
  • anxiety brain edema
  • cerebral deficits subsequent to cardiac bypass surgery and grafting cerebral ischaemia
  • cognitive disorders convulsions
  • mGluRI receptor antagonists that are better drug candidates.
  • such compounds should bind potently to the mGluRI receptor whilst showing little affinity for other receptors and show functional activity as antagonists. They should be well absorbed from the gastrointestinal tract, be relatively metabolically stable and possess favourable pharmacokinetic properties. When targeted selectively against receptors in the central nervous system they should cross the blood brain barrier freely and when targeted selectively against receptors in the peripheral nervous system they should not cross the blood brain barrier. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.
  • the invention provides a compound of formula (I):
  • X is a bond or C ⁇ -C 3 alkylene
  • R is (a) C 3 -C 8 cycloalkyl optionally substituted with one or more substituents selected from halo, oxo, d-C 6 alkyl, C 3 -C 8 cycloalkyl, Het 1 , CrC 6 alkoxy and cyano, wherein one or two of the methylene (-CH 2 -) groups of said C 3 -C 8 cycloalkyl may optionally be replaced by an -NR 3 -, -O- or -S(O) n - group and wherein said C 3 -C 8 cycloalkyl, whether modified as indicated above or not, may be optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, C ⁇ -Ce alkyl, C 3 -C 8 cycloalkyl, Ci-C ⁇ alkoxy and cyano; or (b) C 3 -C 8 cycloalkyl spiro fuse
  • R 3 is H, C C 6 alkyl or C 3 -C 8 cycloalkyl
  • R 4 is d-Ce alkyl or C 3 -C 8 cycloalkyl, said C ⁇ -C 6 alkyl and C 3 -C 8 cycloalkyl being optionally substituted by one or more R 6 or -(C ⁇ -C 6 alkylene)-R 6 groups and optionally having one methylene group (-CH 2 -) replaced by an -NR 3 -, -O- or -S(O) n - group and said C 3 -C 8 cycloalkyl, whether modified as indicated above or not, being optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, CrC 6 alkyl, C 3 -C 8 cycloalkyl, C C 6 alkoxy and cyano; and
  • R 5 is H, C r C 6 alkyl or C 3 -C 8 cycloalkyl
  • R 2 is -NR 4 R 5 , R 4 and R 5 , taken together, with the nitrogen atom to which they are attached, form a saturated heterocyclic group selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepinyl or diazapinyl, wherein said heterocyclic group is optionally substituted on a ring carbon atom by one or more R 6 or -(CrC 6 alkylene)-R 6 groups, optionally substituted on a ring nitrogen atom by one or more R 9 groups and optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, d- C 6 alkyl, C 3 -C 8 cycloalkyl, d-C 6 alkoxy and cyano;
  • R 6 is Het 1 , Het 2 , -OR 7 , -SR 7 , -SOR 8 , -SO 2 R 8 , -NR 7 R 7 , -COR 7 , -OCOR 7 , -SCOR 7 , -NR 7 COR 7 , -NR 7 SO 2 R 8 , -COOR 7 , -COSR 7 , -CONR 7 R 7 , -OCOOR 8 , -OCOSR 8 , -OCONR 7 R 7 , -NR 7 COOR 7 , -NR 7 COSR 7 , -NR 7 CONR 7 R 7 , oxo, halo, -CN, C C 6 alkyl, C 3 - C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or aryl;
  • each R 7 is independently selected from H, C C 6 alkyl and C 3 -C 8 cycloalkyl; each R 8 is independently selected from CrC 6 alkyl and C 3 -C 8 cycloalkyl;
  • R 9 is C-linked Het 1 , C-linked Het 2 , -SO 2 R 8 , -COR 7 , -COOR 8 , -COSR 8 , -CONR 7 R 7 , d-C 6 ⁇ alkyl, C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or aryl; n is 0, 1 or 2;
  • Het 1 is a 3- to 8-membered, saturated or partially unsaturated heterocyclic group0 comprising one or two ring members selected from -NR 10 -, -O- and -S(O) n -, said heterocyclic group being optionally substituted on a ring carbon atom by one or more substituents selected from oxo, halo, -R 8 or -OR 8 and optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, d-C 6 alkyl, C 3 -C 8 cycloalkyl, CrC 6 alkoxy and cyano; ⁇ R 10 is H, d-C 6 alkyl or C 3 -C 8 cycloalkyl, -COR 8 , -SO 2 R 8 or a bond to the group which is substituted with Het 1 ;
  • Het 2 is a 6-membered aromatic heterocyclic group comprising either (a) 1 to 4 nitrogen0 atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms or a 6-membered aromatic heterocyclic group comprising 1 or 2 nitrogen atoms, said ⁇ - or 6-membered heterocyclic group being optionally substituted by one or more substituents selected from halo, -NR 7 R 7 , d-C 6 alkyl, C 3 -C 8 cycloalkyl, d-C 6 alkoxy and cyano and optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, -NR 7 R 7 , d-C 6 alkyl, C 3 -C 8 cycloalkyl, d-C 6 alkoxy and cyano; and
  • aryl is phenyl or naphthyl optionally substituted by one or more substituents selected from halo, -NR 7 R 7 , d-C 6 alkyl, C 3 -C 8 cycloalkyl, d-C 6 alkoxy and cyano.
  • halo means fluoro, chloro, bromo or iodo and alkyl, alkenyl, alkynyl, alkylene, and alkoxy groups containing the requisite number of carbon atoms can be unbranched or branched chain.
  • alkyl include methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
  • alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.
  • alkylene examples include methylene, 1 ,1-ethylene, 1 ,2-ethylene, 1 ,1 -propylene, 1 ,2-propylene, 1 ,3-propylene and 2,2-propylene.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • 'C-linked' used in the definition of R 9 , means that the Het 1 or Het 2 group is joined via a ring carbon atom.
  • R 1 'spiro' fusion of a C 3 -C 8 cycloalkyl group to a C 3 -C 8 cycloalkyl or Het 1 group means that the two C 3 -C 8 cycloalkyl groups or the C 3 -C 8 cycloalkyl and Het 1 group share a carbon atom in common.
  • R 1 is cyclopentyl spiro fused to cyclobutyl
  • the R 1 group as a whole is spiro[3.4]octanyl.
  • Het 1 are oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepinyl, oxapinyl, 1 ,4-oxazepinyl and 1 ,4-diazepinyl (optionally substituted and benzo-fused as specified above).
  • Het 2 are thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl (optionally substituted and benzo-fused as specified above).
  • Het 1 is a 3- to 6-membered, saturated heterocyclic group comprising one or two ring members selected from -NR 8 - and -O-, said heterocyclic group being optionally substituted on a ring carbon atom by one or more substituents selected from oxo, halo, -R 8 or -OR 8 and optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, d-C 6 alkyl, C 3 - C 8 cycloalkyl, d-C 6 alkoxy and cyano.
  • Het 1 is a 3- to 6-membered, saturated heterocyclic group comprising one or two ring members selected from -NR 8 - and -O-, said heterocyclic group being optionally substituted on a ring carbon atom by one or more oxo groups.
  • Het 1 is aziridinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl, each optionally substituted on a ring carbon atom by one or more oxo groups and optionally substituted on a ring nitrogen atom by d-C 6 alkyl.
  • Het 2 is a ⁇ -membered aromatic heterocyclic group comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms or a 6-membered aromatic heterocyclic group comprising 1 or 2 nitrogen atoms, said ⁇ - or 6-membered heterocyclic group being optionally substituted by one or more substituents selected from halo, -NR 7 R 7 , d-C 6 alkyl, d-C 6 alkoxy and cyano and optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, -NR 7 R 7 , C ⁇ -C 6 alkyl, C 3 -C 8 cycloalkyl, d-C 6 alkoxy and cyano.
  • Het 2 is a ⁇ -membered aromatic heterocyclic group comprising (a) 2 to 4 nitrogen atoms or (b) one oxygen atom and 1 or 2 nitrogen atoms or a 6-membered aromatic heterocyclic group comprising 1 or 2 nitrogen atoms, said 5- or 6-membered heterocyclic group being optionally substituted by one or more substituents selected from halo, d-C 6 alkyl, C 3 -C 8 cycloalkyl, C ⁇ -C 6 alkoxy and cyano and optionally benzo- fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, -NR 7 R 7 , C r C 6 alkyl, C 3 -C 8 cycloalkyl, d-C 6 alkoxy and cyano.;
  • Het 2 is a ⁇ -membered aromatic heterocyclic group comprising (a) 2 to 4 nitrogen atoms or (b) one oxygen atom and 1 or 2 nitrogen atoms or a 6-membered aromatic heterocyclic group comprising 1 or 2 nitrogen atoms, said 5- or 6-membered heterocyclic group being optionally substituted by one or more substituents selected from halo, -NR 7 R 7 , d-C 6 alkyl, C 3 -C 8 cycloalkyl, d-C 6 alkoxy and cyano.
  • Het 2 is a heterocyclic group selected from imidazolyl, pyrazolyl, triazolyl, oxazolyl, pyridyl and pyrimidinyl, said heterocyclic group being optionally substituted by one or more substituents selected from halo, -NR 7 R 7 , C C 6 alkyl, C 3 -C 8 cycloalkyl, d-C 6 alkoxy and cyano.
  • Het 2 is imidazolyl or pyridyl said imidazolyl and pyridyl being optionally substituted by C C 6 alkyl.
  • R 6 is Het 1 , Het 2 , -OR 7 , -NR 7 R 7 , -COR 7 , -NR 7 COR 7 , -NR 7 SO 2 R 8 , -COOR 7 , - - CONR 7 R 7 , oxo, halo, C C 6 alkyl, C 3 -C 8 cycloalkyl or aryl; Most preferably, R 6 is -NR 7 SO 2 R 8 , Het 1 , Het 2 , halo, -NR 7 R 7 or -OR 7 .
  • R 9 is -COR 7 .
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are as defined above, and X is (a) methylene or a bond; or (b) methylene; or (c) a bond.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is as defined above, X is as defined above, either in its broadest aspect or in a preferred aspect under (A)(a)-
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is as defined above and -X-R 1 is:
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is as defined above, either in its broadest aspect or in a preferred aspect under (A)(a)-(c) and R 1 is as defined above, either in its broadest aspect or in a preferred aspect under (B)(a)-(d), or -X-R 1 is as defined above under (C)(a)-(b) and R 2 is -OR 4 or -NR 4 R 5 wherein:
  • R 4 is C C 5 alkyl or C 5 -C 6 cycloalkyl, said C 1 -C5 alkyl and C 5 -C 6 cycloalkyl being optionally substituted by one or more R 6 or -(d-C 6 alkylene)-R 6 groups and optionally having one methylene (-CH 2 -) group replaced by an -NR 3 -, -O- or - S(O) n - group and said C 5 -C 6 cycloalkyl, whether modified as indicated above or not, being optionally benzo-fused, said benzo-fused portion being optionally substituted by one or more substituents selected from halo, d-C 6 alkyl, C 3 -C 8 cycloalkyl, CrC 6 alkoxy and cyano and R 5 is H; or in the case where R 2 is - NR 4 R 5 , R 4 and R 5 when taken together with the nitrogen atom to which they are attached, form a saturated heteroc
  • R 4 is C C 5 alkyl or C 5 -C 6 cycloalkyl, said d-C 5 alkyl and C 5 -C 6 cycloalkyl being optionally substituted by one or more groups selected from Het 1 , Het 2 , -OR 7 - NR 7 R 7 and -NR 7 SO 2 R 7 and optionally having one methylene (-CH 2 -) group replaced by an -O- group and said C 5 -C 6 cycloalkyl, whether modified as indicated above or not, being optionally benzo-fused and R 5 is H; or in the case where R 2 is -NR 4 R 5 , R 4 and R 5 when taken together with the nitrogen atom to which they are attached, form a saturated heterocylic group selected from azetidinyl, piperdinyl and piperazinyl, wherein said heterocyclic group is optionally substituted on a ring carbon atom by one ore more groups selected from -OR 7 -(C C C C
  • R 4 is tetrahydrofuranylmethyl, methylsulphonamidoethyl, methoxyethyl, (N- methylpyrrolidinyl)ethyl, morpholinylethyl, hydroxypropyl, N,N- dimethylaminopropyl, pyrrolidinylpropyl, morpholinylpropyl, imidazolylpropyl, (N,N-dimethylamino)butyl, (hydroxyethyloxy)ethyl, indanyl, cyclohexyl, pyrrolidinonylmethyl, N-methylpiperidinylmethyl, azetidinylethyl, pyrrolidinonyiethyl, (1 -methylpiperazinyl)ethyl, (1 -methylpiperazinyl)propyl or hydroxycyclohexyl and R 5 is H; or in the case where R 2 is -NR 4 R
  • R 4 is tetrahydrofuran-2-ylmethyl, 2-(methylsulphonamido)ethyl, 2-methoxyethyl, 2-(N-methylpyrrolidin-2-yl)ethyI, 2-(morpholin-4-yl)ethyl, 3-hydroxypropyl, 3- 16 (N,N-dimethylamino)propyl, 3-(pyrrolidin-1-yl)propyl, 3-(morpholin-4-yl)propyl, 3- (imidazol-1 -yl)propyl, 4-(N,N-dimethylamino)butyl, 2-((2-hydroxyethyl)oxy)ethyl, indan-2-yl, cyclohexyl, tetrahydrofuran-3-ylmethyl, (pyrrolidin-2-on- ⁇ -yl)methyl, (N-methylpiperidin-4-yl)methyl, 2-azetidinylethyl, 2-(pyrroli
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is as defined above, either in its broadest aspect or in a preferred aspect under (A)(a)-(c) and R 1 is as defined above, either in its broadest aspect or in a preferred aspect under (B)(a)-(d), or -X-R 1 is as defined above under (C)(a)-(b) and R 2 is:
  • compositions of a compound of formula (I) include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisyiate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and triflu
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties. Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • a compound of formula (I) may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of formula (I) and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non-ionised.
  • references to a compound of formula (I) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • a compound of formula (I), as hereinbefore defined, may exist in one or more crystalline (polymorphic) or isomeric forms (including optical, geometric and tautomeric isomers), in an isotopically labelled form or as a prodrug. All such forms and prodrugs are within the scope of the present invention and are further described below. All references to a compound of formula (I) should be interpreted accordingly.
  • 'pro-drugs' of the compounds of formula (I) are also within the scope of the invention.
  • certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design. Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • prodrugs in accordance with the invention include
  • metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug are also included within the scope of the invention.
  • Some examples of metabolites in accordance with the invention include
  • Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1- phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1- phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 60% by volume of isopropanol, typically from 2% to 20%, and from 0 to 6% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 60% by volume of isopropanol, typically from 2% to 20%, and from 0 to 6% by volume of an alkylamine, typically 0.1 % diethylamine.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).
  • the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 1 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 1 3 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes such as 1 C, 8 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, de- acetone, d 6 -DMSO.
  • All of the compounds of formula (I) can be prepared by conventional routes such as by the procedures described in the general methods presented below or by the specific methods described in the Examples section and the Preparations section, or by similar methods thereto.
  • the present invention also encompasses any one or more of these processes for preparing the compounds of formula (I), in addition to any novel intermediates used therein.
  • R 1 , R 2 , R 4 , R 5 and X are as previously defined for a compound of formula (I) unless otherwise stated.
  • a compound of formula (I) may be prepared by the reaction of a compound of the formula (II)
  • L 1 is a suitable leaving group, with a compound of the formula R 4 OH (III) or a compound of the formula
  • L 1 is preferably halo, most preferably fluoro.
  • the reaction is optionally carried out in a suitable solvent, such as dichloromethane or dimethylsulphoxide.
  • the temperature of the reaction may optionally be elevated, preferably to from 80°C to 130°C, where no solvent or a sufficiently high-boiling solvent such as dimethylsulphoxide is used.
  • the use of microwave radiation is particularly effective.
  • a compound of the formula (II) may be prepared by the reaction of a compound of the formula (V)
  • L 2 is preferably halo, most preferably chloro.
  • a base is added to the reaction mixture.
  • an amine base such as N-ethyl-N,N-diisopropylamine, triethylamine, N-methylmorpholine or aminopyridine
  • the reaction is preferably carried out in a suitable solvent, such as dichloromethane, N,N- dimethylformamide or dimethylsulphoxide, at a temperature at or above room temperature.
  • the reaction is preferably carried out in a suitable solvent, such as tetrahydrofuran or dioxan, at a temperature below room temperature. Most preferably, the reaction is carried out in the presence of a tertiary amine base, as a solution in dichloromethane, at room temperature.
  • a suitable solvent such as tetrahydrofuran or dioxan
  • Compounds of formula (I) can also be prepared by using the reactions described above to construct a compound wherein R 1 or R 2 are partially formed and then completing the synthesis by functional group manipulation. For instance, where R 1 or R 2 bears a hydroxy or amino group, this group may optionally be carried through the synthesis in a protected form and deprotected in a final step. Suitable protecting groups are described in 'Protective Groups in Organic Synthesis' by Theorora Greene and Peter Wuts (third edition, 1999, John Wiley and Sons).
  • R 1 or R 2 includes an oxygen, nitrogen or other nucleophilic atom
  • the final step in the synthesis may consist of functionalising a hydroxy or amino group, for instance by the formation of a sulphonamide (see Example 10). Suitable functional group transformations are described in 'Comprehensive Organic Transformations' by Richard Larock (1999, VCH Publishers Inc.).
  • Compounds of formula (I) may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • excipients may be administered alone or in combination with one or more other compounds of formula (I) or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient' is used herein to describe any ingredient other than a compound of formula (I). The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of formula (I) and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences. 19th Edition (Mack Publishing Company, 1996).
  • a compound of formula (I) may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, powders, lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, solid solutions, liposomes, films, ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • a compound of formula (I) may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986, by Liang and Chen (2001).
  • a compound of formula (I) may make up from 1 weight % to 80 weight % of the dosage form, more typically from 6 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (as, for example, the monohydrate, spray-dried monohydrate or anhydrous form), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose as, for example, the monohydrate, spray-dried monohydrate or anhydrous form
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 6 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% of a compound of formula (I), from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 86 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • a compound of formula (I) from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 86 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent.
  • Some components of the formulation may perform more than one function.
  • a compound of formula (I) for use in a film may be water-soluble or insoluble.
  • a water- soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes.
  • a compound of formula (I) may be used in the form of multiparticulate beads.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • ingredients in such a film include anti-oxidants, colorants, flavourings, flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co- solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line. 26(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/36298.
  • a compound of formula (I) may also be administered directly into the blood stream, into muscle, or into an internal organ.- Suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous delivery. Suitable means for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non- aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of a compound of formula (I) used in the preparation of a parenteral formulation may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.
  • a compound of formula (I) may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and poly(d7- lactic-coglycolic)acid (PGLA) microspheres.
  • a compound of formula (I) may also be administered topically to the skin or mucosa, i.e. dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J. Pharm. Sci., 88 (10), 956-968, by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.
  • a compound of the formula (I) can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1 ,1,2-tetrafluoroethane or 1 ,1 ,1,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of a compound of formula (I) comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a compound of formula (I) comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a drug product Prior to use in a dry powder or suspension formulation, a drug product is micronised to a size suitable for delivery by inhalation (typically less than ⁇ microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of a- compound of formula (I), a suitable powder base such as lactose or starch and a performance modifier such as Meucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of a compound of formula (I) per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
  • a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
  • Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff.
  • the overall daily dose will be administered in a single dose or, more usually, as divided doses throughout the day.
  • a compound of formula (I) may be administered rectally or vaginally, e.g. in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations.
  • a compound of formula (I) may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non- biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed, sustained, pulsed, controlled, targeted, or programmed release formulations.
  • a compound of formula (I) may be combined with a soluble macromolecular entitiy, such as a cyclodextrin or a suitable derivative thereof or a polyethylene glycol- containing polymer, in order to improve its solubility, dissolution rate, taste-masking, bioavailability and/or stability in any of the aforementioned modes of administration.
  • a soluble macromolecular entitiy such as a cyclodextrin or a suitable derivative thereof or a polyethylene glycol- containing polymer
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO-A- 91/11172, WO-A-94/02518 and WO-A-98/55148.
  • the total daily dose of a compound of formula (I) is typically in the range of from 1 mg to 1000 mg depending, of course, on the mode of administration and the potency of the selected compound.
  • the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
  • These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • CHO-1a Chinese Hamster Ovary cells stably-transfected with the rat mGluRI a receptor
  • CHO-1a cells were seeded onto shallow 96 well plates and assayed at a confluency of 80-90%.
  • Cells were loaded with Fiuo-3-AM dye (8.8 ⁇ M final concentration; excitation 488nm, emission 530nm) in the presence of probenecid (2.5mM), for 45-90 minutes at 37°C, after which time excess dye was removed by washing.
  • the cell plate was then loaded onto a fluorometric imaging plate reader (FLIPr, Molecular Devices). Baseline readings were measured for 30 seconds.
  • FLIPr fluorometric imaging plate reader
  • Test compounds were added by the FLIPr and allowed to equilibrate for 5 minutes before the addition of a 40 ⁇ M glutamate challenge (this was the approximate ED 90 for glutamate against the receptor expressed in these cells). Readings were taken for a further 2 minutes. Measurements were made of the area of peak obtained in response to the glutamate addition and inhibition curves were constructed. Glutamate dose- response curves were included on each experimental day to allow IC 50 values to be converted to modified Kj values. All the Examples described below were tested in this mGluRI assay and were found to have an IC 50 of 10 ⁇ M or less. For instance, Examples 1 and 3 had binding affinities of 3 and 2 nM respectively.
  • an mGluRI antagonist may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain.
  • an mGluRI antagonist particularly a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:
  • an opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, ***e, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine; (ii) a nonsteroidal antiinflammatory drug (NSAID), e.g.
  • NSAID nonsteroidal antiinflammatory drug
  • a benzodiazepine having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam
  • an H ! antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine
  • a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N- methylmorphinan), ketamine, memantine, pyrroloquinoline quinone or cis-4- (phosphonomethyl)-2-piperidinecarboxylic acid
  • an alpha-adrenergic e.g.
  • a tricyciic antidepressant e.g. desipramine, imipramine, amytriptiline or nortriptiline
  • an anticonvulsant e.g. carbamazepine or valproate
  • a tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK-1 antagonist, e.g. ( ⁇ R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5- (4-methylphenyl)-7H-[1 ,4]diazocino[2,1 -g][1 ,7]naphthridine-6-13-dione (TAK- 637), 5-[[(2R,3S)-2-[(1 R)-1 -[3,5-bis(trif luoromethyl)phenyl]ethoxy-3-(4- fluorophenyl)-4-morpholinyl]methyl]-1 ,2-dihydro-3H-1 ,2,4-triazol-3-one (MK- 869), lanepitant, dapitant or 3-[[2-methoxy-5- (trifluoromethoxy)phenyl
  • a muscarinic antagonist e.g oxybutin, tolterodine, propiverine, tropsium chloride or darifenacin
  • a selective COX-2 inhibitor e.g. celecoxib, rofecoxib or valdecoxib
  • a non-selective COX inhibitor preferably with Gl protection, e.g. nitroflurbiprofen (HCT-1026);
  • a vanilloid receptor agonist e.g. resinferatoxin
  • antagonist e.g. capsazepine
  • a beta-adrenergic such as propranolol
  • a corticosteriod such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HT 1B/ID agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan
  • a cholinergic nicotinic
  • Tramadol (trade mark)
  • a PDEV inhibitor such as sildenafil, vardenafil, taladafil, 5-[2-ethoxy-5-(4- ethylpiperazin-1-ylsulphonyl
  • an alpha-2-delta ligand such as gabapentin, pregabalin, (1 ⁇ ,3 ⁇ ,5 ⁇ )(3-amino- methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-Aminomethyl-5-methyl- heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-Amino- 5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline or (2S,4S)-4-(3- fluorobenzyl)proline;
  • a noradrenaline reuptake inhibitor especially a selective noradrenaline reuptake inhibitor such as (S,S)-reboxetine;
  • an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1- iminoethyl)amino]ethyl]-2-methyl-L-cysteine or (2S,5Z)-2-amino-2-methyl-7-[(1 - iminoethyl)amino]-5-heptenoic acid;
  • iNOS inducible nitric oxide synthase
  • an prostaglandin E 2 subtype 4 (EP4) antagonist such as ⁇ /-[( ⁇ 2-[4-(2-ethyl-4,6- dimethyl-1 H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl ⁇ amino)carbonyl]-4- methylbenzenesulfonamide or 4-[(1 S)-1 -( ⁇ [5-chloro-2-(3-fluorophenoxy)pyridin- 3-yl]carbonyl ⁇ amino)ethyl]benzoic acid;
  • two or more pharmaceutical compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • Such a kit comprises two or more separate pharmaceutical compositions, at least one of which contains an mGluRI antagonist, particularly a compound of formula (I), and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • an mGluRI antagonist particularly a compound of formula (I)
  • means for separately retaining said compositions such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • kit is particularly suitable for administering different dosage forms, for example, oral and parenteral formulations, for administering separate compositions at different dosage intervals, or for titrating separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • CD 3 OD deuteromethanol
  • THF tetrahydrofuran.
  • Ammonia' refers to a concentrated solution of ammonia in water possessing a specific gravity of 0.88.
  • thin layer chromatography TLC
  • R f is the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate.
  • Microwave radiation was performed using machines with a power range of 15 to 300W at 2.45GHz, the actual power supplied varying during the course of the reaction to maintain a constant temperature.
  • the title compound was prepared by a method similar to that described for Example 1 using 3-morpholin-4-yl-propylamine and the fluoro compound of Preparation 1 as starting materials. The title compound was isolated as a yellow oil.
  • the fluoro compound of Preparation 2 (150mg, 0.61 mmol) was treated with N-(2- aminoethyl)-mo ⁇ holine (2ml, 15.2mmol) and the solution was heated at 110°C for 7 hours.
  • the cooled reaction mixture was partitioned between dichloromethane (25ml) and water (25ml) and the phases were separated.
  • the organic phase was dried by filtration through a hydrophobic frit and then concentrated in vacuo.
  • the crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol:ammonia 100:0:0 to 94:6:0.6 (by volume) to yield the title compound (29.9mg) as a bright yellow oil.
  • the title compound was prepared by a method similar to that described for Example 4 using N-(3-aminopropyl)imidazole and the fluoro compound of Preparation 2 as starting materials.
  • the title compound was prepared by a method similar to that described for Example 4 using cyclohexane-1 ,4-diol as the reagent.
  • the amine of Preparation 5 (50mg, 0.175mmol) was added to a solution of triethylamine (29 ⁇ L, 0.21 mmol) in dichloromethane (0.5ml), at 0°C, under an atmosphere of nitrogen. To this mixture was added a solution of methanesulphonyl chloride (14 ⁇ L, 0.175mmol) in dichloromethane (0.5ml). The reaction mixture was left at 0°C for 10 minutes, stirred at room temperature for 40 minutes and then concentrated in vacuo.
  • the crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol:ammonia 100:0:0 to 90:10:1 (by volume) to yield the title product as an oil (28.7mg, 45% yield).
  • the title compound was prepared by a method similar to that described for Example 13 using 2-(2-amino-ethoxy)-ethanol as the relevant starting material.
  • This compound was prepared by a method similar to that described for Example 16 using 2-(4-morpholino)-ethylamine as the appropriate starting material.
  • the title compound was prepared as a yellow solid (28%).
  • the fluoro compound of Preparation 2 (200mg, 0.81 mmol) was dissolved in N- methylpyrrolidinone (5ml) and the resulting solution was treated with N- ethyldiisopropylamine (0.2ml, 1.22mmol) and N-acetylpiperazine (230mg, 1.78mmol) and heated at 120°C for 5 days. The reaction was allowed to cool and poured into water (75ml). The aqueous mixture was extracted with ethylacetate (2 x 50ml) and the combined organic extracts were dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:0 to 90:10 (by volume) to afford the product as an oil.
  • the product was dissolved in hot ethanol (2ml) and a solution of hydrogen chloride in diethylether (1M) was added until a precipitate appeared.
  • the yellow solid was collected by filtration to afford the product as the hydrochloride salt (77mg, 24% yield).
  • the crude product was purified by column chromatography on silica gel eluting with dichloromethane: methanol 100:0 to 90:10 (by volume) to afford the product as an oil.
  • the product was dissolved in hot ethanol (10ml) and a solution of hydrogen chloride in diethylether (2ml of a 1M solution, 2mmol) was added. The resulting solution was evaporated and a solid was obtained following trituration with diethylether. The pale solid was collected by filtration to afford the product as the hydrochloride salt hemihydrate (375mg, 58%).
  • the fluoro compound of Preparation 8 (0.2g, 0.74mmol) was added to a mixture of 4- methoxypiperidine (0.5ml, 4mmol), N,N-diisopropylethylamine (0.5ml, 2.8mmol) and N- methylpyrrolidinone (1.5 ml) and the reaction was heated to 90°C for 60 hours. The mixture was allowed to cool and poured into water (35 ml). The resulting yellow solid was collected by filtration and dried in vacuo to yield the title product (175mg, 65%).
  • the fluoro compound of Preparation 7 (0.2g, 0.74mmol) was added to a mixture of 4- methoxypiperidine (0.5ml, 4mmol), N,N-diisopropylethylamine (0.5ml, 2.8mmol) and N- methylpyrrolidinone (1.5 ml) and the reaction was heated to 90°C for 60 hours. The mixture was allowed to cool and poured into water (35 ml). The resulting yellow solid was collected by filtration and dried in vacuo to yield the title product (150 mg, 58%).
  • the fluoro compound of Preparation 7 (0.2g, 0.74mmol) was added to a mixture of 4,4- difluoropiperidine hydrochloride (0.4g, 2.5mmol), N,N-diisopropylethylamine (1ml, 5.6mmol), tetraethylammonium fluoride hydrate (0.2g, 1. mmol) and dimethylsulfoxide (5ml) and the reaction was heated to 130°C for 60 hours. The mixture was allowed to cool and poured into water (50ml) and the aqueous phase was extracted with ethyl acetate (2 x 50ml). The combined organic phases were dried (Na 2 SO ) and evaporated.
  • the fluoro compound of Preparation 1 (0.5 g, 1.9 mmol) was added to a solution of N.N-dimethylaminopropylamine (0.75 ml, 5.96 mmol) and triethylamine (0.5 ml, 3.8 mmol) in M-methylpyrrolidinone (1.55 ml) in a microwave reaction vial.
  • the mixture was heated under microwave irradiation to 180 °C for 800 seconds.
  • the mixture was allowed to cool and poured into water (30 ml) and the aqueous phase was extracted with ethyl acetate (3 x 50 ml).
  • the combined organic phases were washed with brine (50 ml), dried (Na 2 SO 4 ) and evaporated.
  • This compound was prepared by a method similar to that described for Example 35 using the fluoro compound of Preparation 1 and 1-(2-hydroxyethyl)-4-methylpiperazine as starting materials.
  • the title product was obtained as a white solid in 19% yield.
  • This compound was prepared by a method similar to that described for Example 24 using the fluoro compound of Preparation 11 and N,N-dimethylaminopropylamine as starting materials.
  • the title product was obtained as a yellow solid in 37% yield.
  • the title compound was prepared by a method similar to that described for Preparation 1 using cyclohexylamine as the relevant starting material. The title compound was isolated as an off white solid in 88% yield.
  • the fluoro compound of Preparation 2 (600mg, 2.44mmol) was added to ethane-1 ,2- diamine (4.13ml, 60.9mmol) and the reaction mixture was heated to 130°C for 3 hours.
  • the reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol:ammonia 100:0:0 to 85:15:2 (by volume) to yield the title product as a yellow oil (653mg, 93% yield).
  • Tetrahydrofurfurylamine (1.35ml, 13.1mmol) was added to a stirred solution of 4- chloro-6-fluoro-pyrido[3,4-d]pyrimidine (2g, 10.9mmol) and diisopropylethylamine (2.8ml, 16.3mmol) in dichloromethane (10ml). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and dichloromethane. The organic layer was concentrated in vacuo to yield an off white solid which was recrystallised from acetonitrile to yield the title product as a white solid (2.3g, 85%).
  • the solid was purified by silica gel chromatography (eluting with dichloromethane and then 1 :2 ethyl acetate:dichloromethane) and the resulting solid was recrystallised from toluene to afford the title compound as a white crystalline solid (2.35g, 26%). Melting point 169-171 °C.
  • Cyclooctylamine (692mg, 5.4mmol) was added to a stirred solution of 4-chloro-6- fluoro-pyrido[3,4-d]pyrimidine (0.5g, 2.7mmol) and diisopropylethylamine (0.95ml, 5.4mmol) in dichloromethane (13ml) at 5°C. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was partitioned between water and dichloromethane. The organic layer was concentrated in vacuo to yield an off white solid which was recrystallised in acetonitrile to yield the title compound as a tan solid (0.2g, 27%).

Abstract

L'invention concerne certains dérivés nouveaux de 6-amino-7-azaquinazoline, leurs procédés de préparation, des produits intermédiaires utilisés dans leur préparation, des compositions qui contiennent ces dérivés et l'utilisation de ces dérivés. Une importante utilisation de ces dérivés est le traitement de la douleur.
PCT/IB2004/002558 2003-08-14 2004-08-04 Derives d'azaquinazoline WO2005016925A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0319148.3 2003-08-14
GB0319148A GB0319148D0 (en) 2003-08-14 2003-08-14 Azaquinazoline derivatives
GB0405905.1 2004-03-16
GB0405905A GB0405905D0 (en) 2004-03-16 2004-03-16 Azaquinazoline derivatives

Publications (1)

Publication Number Publication Date
WO2005016925A1 true WO2005016925A1 (fr) 2005-02-24

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NL (1) NL1026828C2 (fr)
PA (1) PA8609001A1 (fr)
PE (1) PE20050340A1 (fr)
TW (1) TW200505918A (fr)
UY (1) UY28467A1 (fr)
WO (1) WO2005016925A1 (fr)

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Publication number Priority date Publication date Assignee Title
JP2006236420A (ja) * 2005-02-22 2006-09-07 Toshiba Corp 記憶媒体、再生方法及び記録方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001032632A2 (fr) * 1999-11-01 2001-05-10 Eli Lilly And Company Composes pharmaceutiques
JP2003012653A (ja) * 2001-06-28 2003-01-15 Yamanouchi Pharmaceut Co Ltd キナゾリン誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001032632A2 (fr) * 1999-11-01 2001-05-10 Eli Lilly And Company Composes pharmaceutiques
JP2003012653A (ja) * 2001-06-28 2003-01-15 Yamanouchi Pharmaceut Co Ltd キナゾリン誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 2003, no. 05 12 May 2003 (2003-05-12) *

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AR045259A1 (es) 2005-10-19
UY28467A1 (es) 2005-03-31
TW200505918A (en) 2005-02-16
NL1026828A1 (nl) 2005-03-09
NL1026828C2 (nl) 2005-10-05
PA8609001A1 (es) 2005-03-03

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