The present invention relates to imidazo[1,2-a]pyrimidine derivatives, that are useful for treating cellular proliferative diseases, for treating disorders associated with MET activity, and for inhibiting the receptor tyrosine kinase MET. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

Tyrosine kinase inhibitors

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.

Heterocyclic compounds and uses thereof

Neuropathic pain, a form of chronic pain caused by injury to or disease of the peripheral or central nervous system, is a formidable therapeutic challenge to clinicians because it does not respond well to traditional pain therapies. Our knowledge about the pathogenesis of neuropathic pain has grown significantly over last 2 decades. Basic research with animal and human models of neuropathic pain has shown that a number of pathophysiological and biochemical changes take place in the nervous system as a result of an insult. This property of the nervous system to adapt morphologically and functionally to external stimuli is known as neuroplasticity and plays a crucial role in the onset and maintenance of pain symptoms. Many similarities between the pathophysiological phenomena observed in some epilepsy models and in neuropathic pain models justify the rational for use of anticonvulsant drugs in the symptomatic management of neuropathic pain disorders. Carbamazepine, the first anticonvulsant studied in clinical trials, probably alleviates pain by decreasing conductance in Na+ channels and inhibiting ectopic discharges. Results from clinical trials have been positive in the treatment of trigeminal neuralgia, painful diabetic neuropathy and postherpetic neuralgia. The availability of newer anticonvulsants tested in higher quality clinical trials has marked a new era in the treatment of neuropathic pain. Gabapentin has the most clearly demonstrated analgesic effect for the treatment of neuropathic pain, specifically for treatment of painful diabetic neuropathy and postherpetic neuralgia. Based on the positive results of these studies and its favourable adverse effect profile, gabapentin should be considered the first choice of therapy for neuropathic pain. Evidence for the efficacy of phenytoin as an antinociceptive agent is, at best, weak to modest. Lamotrigine has good potential to modulate and control neuropathic pain, as shown in 2 controlled clinical trials, although another randomised trial showed no effect. There is potential for phenobarbital, clonazepam, valproic acid, topiramate, pregabalin and tiagabine to have antihyperalgesic and antinociceptive activities based on result in animal models of neuropathic pain, but the efficacy of these drugs in the treatment of human neuropathic pain has not yet been fully determined in clinical trials. The role of anticonvulsant drugs in the treatment of neuropathic pain is evolving and has been clearly demonstrated with gabapentin and carbamazepine. Further advances in our understanding of the mechanisms underlying neuropathic pain syndromes and well-designed clinical trials should further the opportunities to establish the role of anticonvulsants in the treatment of neuropathic pain.

Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy.

Capsaicin-sensitive, TRPV1 (transient receptor potential vanilloid 1) receptor-expressing primary sensory neurons exert local and systemic efferent effects besides the classical afferent function. The TRPV1 receptor is considered a molecular integrator of various physico-chemical noxious stimuli. In the present study its role was analysed in acute nociceptive tests and chronic neuropathy models by comparison of wild-type (WT) and TRPV1 knockout (KO) mice. The formalin-induced acute nocifensive behaviour, carrageenan-evoked inflammatory mechanical hyperalgesia and partial sciatic nerve lesion-induced neuropathic mechanical hyperalgesia were not different in WT and KO animals. Acute nocifensive behaviour after intraplantar injection of phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), was absent in TRPV1 KO animals showing that PKC activation elicits nociception exclusively through TRPV1 receptor sensitization/activation. Thermal hyperalgesia (drop of noxious heat threshold) and mechanical hyperalgesia induced by a mild heat injury (51 degrees C, 15s) was smaller in KO mice suggesting a pronociceptive role for TRPV1 receptor in burn injury. Chronic mechanical hyperalgesia evoked by streptozotocin-induced diabetic and cisplatin-evoked toxic polyneuropathy occurred earlier and were greater in the TRPV1 KO group. In both polyneuropathy models, at time points when maximal difference in mechanical hyperalgesia between the two groups was measured, plasma somatostatin concentrations determined by radioimmunoassay significantly increased in WT but not in TRPV1 KO mice. It is concluded that sensitization/activation of the TRPV1 receptor plays a pronociceptive role in certain models of acute tissue injury but under chronic polyneuropathic conditions it can initiate antinociceptive counter-regulatory mechanisms possibly mediated by somatostatin released from sensory neurons.

Investigation of the role of TRPV1 receptors in acute and chronic nociceptive processes using gene-deficient mice.

https://link.springer.com/content/pdf/10.1016/j.nurt.2009.07.004.pdf

Diabetic painful and insensate neuropathy: pathogenesis and potential treatments.

A pyrazolo[1,5-a]pyrimidine derivative represented by general formula (1) and having such a potent analgesic effect that it is useful as an analgesic, wherein R1 represents hydrogen, lower alkyl, cycloalkyl, thienyl, furyl, lower alkenyl or phenyl; R2 represents naphthyl, cycloalkyl, furyl, thienyl, pyridyl, phenoxy or phenyl; R3 represents hydrogen, phenyl or lower alkyl; R4 represents hydrogen, lower alkyl, lower alkoxy-carbonyl, phenyl-substituted lower alkyl, phenyl or halogen; R5 represents hydrogen or lower alkyl; R6 represents hydrogen, lower alkyl, phenyl-substituted lower alkyl or benzoyl; Q represents carbonyl or sulfonyl; A represents a single bond, lower alkylene or lower alkenylene; and n represents 0 or 1.

Pyrazolo(1,5-a)pyrimidine derivative

Attenuation of fasting-induced phosphorylation of mitogen-activated protein kinases (ERK/p38) in the mouse hypothalamus in response to refeeding.

Nociceptive responses in an animal model of peripheral nerve injury were studied. The left common sciatic nerve was exposed, tightly ligated at two locations and transected between the ligatures. A bilateral decrease in the nociceptive threshold to mechanical stimulation was observed within 3 h after the operation. The skin of the lateral dorsal part of the injured paw was hypoalgesic, while the medial dorsal paw innervated by the intact saphenous nerve and the contralateral dorsal paw exhibited hyperalgesia. Amitriptyline, an antidepressant, at 25, 50 and 100 mg/kg per day, p.o., and gabapentin, an anticonvulsant, at 30, 100 and 300 mg/kg per day, p.o., significantly inhibited the decrease in the mechanical nociceptive threshold in the injured and uninjured paws. The effects of amitriptyline at 25 and 50 mg/kg were evident at doses that did not cause neurologic deficits as assessed by the inclined screen test. Indomethacin, a cyclooxygenase inhibitor, and morphine (except at the highest dose of 30 mg/kg, s.c.) showed no analgesic effects in this model. The tail-flick latency was also significantly decreased compared with intact rats. Similar bilateral hyperalgesia was observed when axotomy was performed using silk thread instead of chromic gut. When this axotomy model was applied to mice, the nociceptive thresholds in both paws immediately showed a significant decrease in the same manner as in rats. The bilateral and systemic hyperalgesia observed in this axotomy model, which resembles the clinical features of chronic neuropathic pain, suggests the involvement of the central nervous system in the maintenance of the chronic pain state.

Effects of amitriptyline and gabapentin on bilateral hyperalgesia observed in an animal model of unilateral axotomy

The novel analgesic compound OT-7100 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimid ine) attenuates mechanical nociceptive responses in animal models of acute and peripheral neuropathic hyperalgesia.

Tsuneo Yasuda

Papers

Pyrazolo(1,5-a)pyrimidine derivative

Attenuation of fasting-induced phosphorylation of mitogen-activated protein kinases (ERK/p38) in the mouse hypothalamus in response to refeeding.

Effects of amitriptyline and gabapentin on bilateral hyperalgesia observed in an animal model of unilateral axotomy

The novel analgesic compound OT-7100 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimid ine) attenuates mechanical nociceptive responses in animal models of acute and peripheral neuropathic hyperalgesia.

Antinociceptive effect of the novel compound OT-7100 in a diabetic neuropathy model.