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WO2010073011A2 - Composés utiles comme médicaments - Google Patents

Composés utiles comme médicaments Download PDF

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Publication number
WO2010073011A2
WO2010073011A2 PCT/GB2009/002945 GB2009002945W WO2010073011A2 WO 2010073011 A2 WO2010073011 A2 WO 2010073011A2 GB 2009002945 W GB2009002945 W GB 2009002945W WO 2010073011 A2 WO2010073011 A2 WO 2010073011A2
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WO
WIPO (PCT)
Prior art keywords
thiadiazol
compound
formula
benzenesulfonamide
dichloro
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PCT/GB2009/002945
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English (en)
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WO2010073011A3 (fr
Inventor
Jacob Westman
Original Assignee
Betagenon Ab
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Publication of WO2010073011A2 publication Critical patent/WO2010073011A2/fr
Publication of WO2010073011A3 publication Critical patent/WO2010073011A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to pharmaceutically-useful compounds.
  • the invention also relates to the use of such compounds in the treatment of conditions ameliorated by the activation of AMPK, such as skin diseases, lung disease, obesity, dry-type age-related macular degeneration, cardioprotection or, preferably, hyperinsulinemia, diabetes, cancer, fibrosis, neurodegenerative diseases, sexual dysfunction, heart failure, inflammation and osteoporosis.
  • AMPK AMPK
  • AMPK represents a new target for the treatment of several diseases, including metabolic syndrome.
  • Hyperinsulinemia hypersecretion of insulin
  • Metabolic syndrome has become increasingly common, and affects an estimated 47 million adults in the US alone.
  • the syndrome is characterized by a combination of metabolic risk factors such as central obesity, atherogenic dyslipidemia, hypertension, insulin resistance or glucose intolerance.
  • the syndrome is also characterised by hyperinsulinemia, a prothrombotic state in the blood, and a proinflammatory state.
  • Underlying causes of metabolic syndrome include obesity, physical inactivity and genetic factors. Sufferers are at an increased risk of coronary heart disease and other diseases related to the build up of plaques in artery walls, for example stroke, peripheral vascular disease and type 2 diabetes.
  • Type 2 diabetes is the most common metabolic disease with a high incidence in western countries, with more than 170 million people currently affected by type 2 diabetes.
  • Type 2 diabetes is a chronic, presently incurable disease and sufferers have a high risk of developing life threatening complications as the disease progresses.
  • the overall cost to society of diabetes and its complications is huge.
  • Insulin is both a potent hormone and growth factor. In addition to obesity, hyperinsulinemia is apparent in conditions such as impaired glucose tolerance, early or mild type 2 diabetes, polycystic ovary syndrome and Alzheimer's disease. Evidence is accumulating that hyperinsulinemia plays a major role in the development of these diseases.
  • a medicament that reduces insulin resistance and/or hyperinsulinemia may therefore represent an efficient therapeutic strategy to treat or prevent disorders caused by, linked to, or contributed to by insulin resistance and/or hyperinsulinemia or associated conditions.
  • insulin secretagogues such as sulphonylureas stimulate only the insulin secretion step
  • metformin mainly acts on glucose production from the liver
  • peroxisome proliferator-activated receptor- ⁇ (PPAR- ⁇ ) agonists such as the thiazolidinediones, enhance insulin action
  • exenatide needs to be administered by subcutaneous injection, has storage stability shortcomings, is reported to cause nausea and vomiting and, more recently, has been shown to be coupled to several severe cases of acute pancreatitis.
  • insulin secretagogues and insulin injections may cause hypoglycaemia and weight gain and patients may also become unresponsive to insulin secretagogues over time.
  • Metformin an indirect AMPK activator
  • ⁇ -glucosidase inhibitors often lead to gastrointestinal problems and PPAR-agonists tend to cause increased weight gain and oedema.
  • Dipeptidyl peptidase-IV (DPP-IV) inhibitors belong to a new class of oral antidiabetic agents for the treatment of patients with type 2 diabetes. Inhibition of the enzyme DPP- IV results in prolonged activity of glucagon-like peptide-1 (GLP-1) and glucose- dependent insulinotropic peptide (GIP), the incretin hormones. Sitagliptin was the first DPP-IV inhibitor to be approved by FDA for treatment of type 2 diabetes and several other DPP-IV inhibitors are in late clinical phases.
  • Several side-effects for DPP-IV inhibitors as a class may be expected, such as inflammation, allergic reactions and hypertension since many peptides, neuropeptides, and cytokines are cleaved by DPP-IV. Some of the reported side effects of certain DPP-IV inhibitors include anemia, thrombocytopenia, and splenomegaly.
  • AMP-activated protein kinase is a protein kinase enzyme that consists of three protein sub-units and is activated by hormones, cytokines, exercise, and stresses that diminish cellular energy state (e.g. glucose deprivation). Activation of AMPK increases processes that generate adenosine 5'-triphosphate (ATP) (e.g. fatty-acid oxidation) and restrains others such as fatty acid-, glycerolipid- and protein-synthesis that consume ATP, but are not acutely necessary for survival. Conversely, when cells are presented with a sustained excess of glucose, AMPK activity diminishes and fatty acid-, glycerolipid- and protein-synthesis are enhanced.
  • ATP adenosine 5'-triphosphate
  • AMPK activity diminishes and fatty acid-, glycerolipid- and protein-synthesis are enhanced.
  • AMPK thus is a protein kinase enzyme that plays an important role in cellular energy homeostasis. Therefore, the activation of AMPK is coupled to glucose lowering effects and triggers several other biological effects, including the inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, and the reduction of hyperinsulinemia.
  • AMPK is a preferred a preferred target for the treatment of the metabolic syndrome and especially type 2 diabetes.
  • AMPK is also involved in a number of pathways that are important for many different diseases (e.g. AMPK is also involved in a number of pathways that are important in cancer, CNS disorders, fibrosis, osteoporosis, heart failure and sexual dysfunction).
  • Current anti-diabetic drugs e.g. metformin, glitazones
  • AMPK activators due to the biological effects of AMPK activation at the cell level, compounds that are AMPK activators, and preferably direct activators of AMPK 1 may find utility as anti-diabetic drugs, as well as for the treatment of many other diseases (some of which are listed below)
  • ALS amyotrophic lateral sclerosis
  • a medicament such as an AMPK activator may be effective in the treatment of neurodegenerative diseases due to stimulation of autophagy. Traumatic brain injury studies in mice using rapamycin, a known mTOR signaling inhibitor were able to show an increased the number of surviving neurons at the site of injury (Erlich et al, Neurobiol. of Disease,2007, 26(1), 86-93). Since AMPK activator inhibits mTOR signalling it may therefore be neuroprotective following traumatic brain injury. AMPK activation may have neuroprotective properties during ischemia/hypoxia (Spasi et al, The Neuroscientist, 2009,15 (4), 309-316).
  • an AMPK activator may be useful in the treatment of brain injury caused by brain ischemia and stroke.
  • AD Alzheimer's disease 1 longitudinal studies have established a strong association with hyperinsulinemia. Hyperinsulinemia is also related to a significant decline in memory-related cognitive scores, but not to decline in other cognitive domains. Thus, hyperinsulinemia is associated with a higher risk of AD and decline in memory.
  • Insulin-degrading enzyme also appears to constitute a mechanistic link between hyperinsulinemia and AD (Wei and Folstein (2006), Neurobiology of Aging, 27, 190-198). This enzyme degrades both insulin and amyloid- ⁇ (A ⁇ ) peptide, a short peptide found in excess in the AD brain. Evidence suggests that hyperinsulinemia may elevate A ⁇ through insulin's competition with the latter for insulin-degrading enzyme. Formation of neurofibrillary tangles, which contain hyperphosphorylated tau, represents a key step in the pathogenesis of neurodegenerative diseases.
  • peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction, revealing an additional link between hyperinsulinemia and neurodegeneration.
  • Transforming growth factor b1 present in keratinocytes, has shown to in transgenic mice expressing wild-type TGFbI in the epidermis to develope inflammatory skin lesions, with gross appearance of psoriasis like plaques, generalized scaly erythema, and Koebner's phenomenon.
  • the TGFbI wt skin exhibited multiple molecular changes that typically occur in human Th1 inflammatory skin disorders, such as psoriasis (EMBO Journal (2004) 23, 1770-1781). This observation suggests that certain pathological condition-induced TGFbI overexpression in the skin may synergize with or induce molecules required for the development of Th1 inflammatory skin disorders such as psoriasis and other skin disorders.
  • an AMPK activator able to affect TGFbI signaling may be of therapeutic value in skin disorders such as, but not limited to, psoriasis. Fibrosis
  • fibrosis is involved in many pathological states in the body (T. A. Wynn (2008) J. Pathology 214, 199-210. It has been shown that AMPK negatively regulates TGF ⁇ -stimulated myofibroblast transdifferentiation and may therefore play a role in disorders where fibrosis develops (Mishra et al (2008), J. Biol. Chem. 283, 10461- 10469).
  • the resulting reduction of collagen may be of therapeutic value in any disease state or condition where fibrosis play a role for example, but not limited to, scar healing, keloids, scleroderma, cystic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis, interstitial lung disease (RBILD), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP) and lymphoid interstitial pneumonia (LIP), organ transplant fibrosis, systemic sclerosis, liver cirrhosis, macular eye degeneration, retinal and vitreal retinopathy, Crohn ' s/inflammatory bowel disease, nephrogenic systemic fibrosis, ulcerative colitis post surgical scar tissue formation, radiation and chemotherapeutic-drug induced fibrosis, and cardiovascular fibrosis including endomyocardial fibrosis.
  • NIP nonspecific
  • Metformin an indirect AMPK activator, has recently been investigated on the differentiation and mineralization of osteoblastic MC3T3-E1 cells as well as intracellular signal transduction. Metformin can increase collagen-l and osteocalcin mRNA expression, stimulate alkaline phosphatase activity, and enhance cell mineralization (Kanazawa et al. Biochem. Biophys. Res. Commun. 2008, 375(3), 414-419). Metformin can also, when activating AMPK, induce endothelial nitric oxide synthase (eNOS) and bone morphogenetic protein-2 (BMP-2) expressions. Thus, it may be that an AMPK activator can induce the differentiation and mineralization of osteoblasts via activation of the AMPK signaling pathway, and that an AMPK activator may find utility in the treatment of osteoporosis by promoting bone formation.
  • eNOS endothelial nitric oxide synthase
  • BMP-2 bone morphogenetic protein-2
  • Insulin per se can promote the proliferation of mesangial cells and the production of matrix proteins, and also stimulates the expression of growth factors such as IGF-1 and TGF- ⁇ , that are involved in mitogenic and fibrotic processes in nephropathy. Insulin also interferes with the systemic RAS and specifically increases the effect of angiotensin Il on mesangial cells. Hyperinsulinemia also increases levels of endothelin-1 and is associated with increased oxidative stress, in conclusion, reduction of hyperinsulinemic levels may be of therapeutic value for patients with progressive renal disease (e.g. chronic renal failure; Sarafidis and Ruilope Am. J.
  • progressive renal disease e.g. chronic renal failure; Sarafidis and Ruilope Am. J.
  • adiponectin an adipose-derived hormone
  • AMPK adipose-derived hormone
  • Obesity is associated with resistance to the effects of leptin and leptin stimulates fatty acid oxidation via the phosphorylation and activation of AMPK and Acetyl-CoA carboxylase (ACC).
  • AMPK Acetyl-CoA carboxylase
  • Studies in obese Wistar rats have shown a lower level of AMPK activation in diet-induced obesity.
  • an AMPK activator may be of therapeutic value in obesity (Janovska A et al, MoI. Cell. Endocrinology. 2008, 284(1-2), 1-10.
  • Central obesity is a typical sign of Cushing's syndrome. In a patient study the patients exhibited a 70% lower AMPK activity in visceral adipose tissue as compared to control patients.
  • glucocorticoids inhibit AMPK activity in adipose tissue (Kola et al, J. Clin.Endocrinol. Metab. 2008, 93(12), 4969-4973). Therefore an AMPK activator may also be beneficial as a therapeutic in Cushing's syndrome.
  • AMPK activity increases during ischemia and functions to sustain ATP, cardiac function and myocardial viability.
  • the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease and cardioprotection (Wong et al, Clin. ScL, 2009, 116, 607-620).
  • Erectile dysfunction is associated with reduced penile nitric oxide synthase (NOS) expression.
  • NOS penile nitric oxide synthase
  • Studies in obese rats show that treatment with the indirect AMPK activator metformin increase nNOS and eNOS expression in penile tissue.
  • the levels of AMPK and phosphorylated AMPK were also decreased but were subsequently elevated by metformin treatment.
  • Oxidative stress causes retinal pigment epithelium (RPE) cell dysfunction and is a major risk factor leading to the development of dry-type age-related macular degeneration.
  • Sublethal oxidative stress dose-dependently inhibits RPE cell phagocytosis of photoreceptor outer segments (POS) and activates AMPK.
  • POS photoreceptor outer segments
  • Aicar a pharmacological activator of AMPK has also been shown to inhibit RPE cell phagocytosis of POS in a dose-dependent manner (Qin and De Vries, J. Biol. Chem. 2008, 283(11), 6744-6751).
  • an AMPK activator could have therapeutic potential in treating dry macular degeneration.
  • cancer cells require high rates of fatty acid and protein synthesis for their invasive growth and survival.
  • inhibition of cancer cell proliferation is possibly using AMPK activators.
  • the effects are associated with down-regulation of mTOR and eEF2.
  • AMPK activators also suppress lipid synthesis in tumour cells. It has also been shown that it is a link between AMPK and other anti-cancer targets such as LKB1 and caspase-3 activation.
  • PCOS Polycystic ovary syndrome
  • AICAR ⁇ -aminoimidazole ⁇ -carboxamide
  • AICAR ⁇ -aminoimidazole ⁇ -carboxamide
  • Metformin an indirect AMPK activator, could be shown to reduce several inflammatory parameters in animal models of multiple sclerosis and thus an AMPK activator could have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases (Nath et al J. Immunology, 2009, 182, 8005-8014).
  • AMPK plays a role in modulating neutrophil function and neutrophil-dependent inflammatory events, such as acute lung injury (Zhao et al, Am. J. Physiol. Lung Cell MoI. Physiol., 2008. 295. L497-L504. This may also apply to reduction of the inflammatory response present in asthmatic patients. Studies in mice that develop lupus-like disease similar to human systemic lupus erythematosus has shown that AMPK activation inhibits a inflammatory cascade. This observation suggests that an AMPK activator may be of therapeutic value for systemic lupus erythematosus (Radjavi et al, FASEB J.2008, 22:942.12).
  • COPD chronic obstructive pulmonary disease
  • TGF- ⁇ has emerged as an important contributor to small airway disease (SAD), also called obstructive bronchiolitis.
  • SAD small airway disease
  • Several studies have reported an increased expression of TGF- ⁇ 1 in the airway epithelium of smokers. TGF- ⁇ 1 expression in epithelial cells from patients with chronic bronchitis has been correlated with basal membrane thickness and the number of peribronchiolar fibroblasts.
  • an AMPK activator that targets TGF- ⁇ signalling may represent a suitable therapeutic option in SAD.
  • WO 2005/002673 and WO 2004/004720 disclose a single thiadiazole for use in the treatment of diseases that may be ameliorated by the inhibition of raf kinase (e.g. Alzheimer's disease). There is no suggestion or disclosure of 1 ,3,4-thiadiazoles substituted in the 5-position by a substituted phenyl group attached via an alkyl linker.
  • thiadiazole compounds containing a naphthalene substituent attached via and amido linker for use in the treatment of human cytomegalovirus.
  • thiadiazoles that are substituted in the 2-position with a single-ringed heteroaromatic or, particularly, aryl group.
  • Bovet el al discloses that a thiadiazole bearing an unsubstituted benzyl substituent in the 5-position does not have hypoglycemic activity and there is no disclosure or suggestion of substituted benzyl substituents in the 5-position.
  • WO 2004/103980 discloses inter alia thiadiazoles that may be useful in the treatment of diabetes.
  • JP 03258771 discloses inter alia 1 ,2,4-oxadiazoles that may be useful as herbicides. However, there is no mention of the use of the compounds disclosed therein in the treatment of diabetes.
  • X represents -Q-[CR x R y ] n -Z- or -C(O)-;
  • T represents N 1 or more preferably S or O;
  • G represents O, or more preferably, N; provided that when T is O or S, then G is N, and provided that when T is N, then G is O; when G is N, the dotted line between the point of attachment of X to the ring and G is a double bond and the dotted line between the point of attachment of X to the ring and T is a single bond; when T is N, the dotted line between the point of attachment of X to the ring and T is a double bond and the dotted line between the point of attachment of X to the ring and G is a single bond;
  • Ai to A 5 respectively represent C(R 1 ), C(R 2 ), C(R 3 ), C(R 4 ) and C(R 5 ), or, alternatively, up to two of A 1 to A 5 may independently represent N;
  • Di to D 5 each respectively represent C(R 6a ), C(R 6b ), C(R 6c ), C(R 6d ) and C(R 6e ), or, alternatively, up to two of D 1 to D 5 may independently represent N;
  • Q and Z independently represent S(O) 2 , or more preferably, a bond, S, or O;
  • B represents S(O) 2 , or more preferably, a bond, S, or O; one of R x and R y is Cy 1 or Het 1 (which latter two groups are optionally substituted by one or more R 6f substituents) and the other is H or, more preferably, R x and R y are independently selected from H, halo, C 1-6 alkyl (optionally substituted by one or more halo atoms), or R x and R y are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms);
  • Cy 1 represents a 5- to 8-membered aromatic, fully saturated or partially unsaturated carbocyclic ring;
  • Het 1 represents a 5- to 8-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N;
  • R 6a to R 6e independently represents, on each occasion when used herein, H, cyano, -NO 2 , halo, -R 8 , -OR 8 , -N(R 8 )C(O)R 8 , -NR 9 R 10 , -SR 11 , -Si(R 12 J 3 , -OC(O)R 13 , -C(O)OR 13 , -C(O)R 14 , -C(O)NR 15a R 15b , -S(O) 2 NR 15c R 15d , aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R 16 ), or any two R 6a to R 6e groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I 1 an aromatic or non-aromatic 3- to 8-membered ring, optionally
  • R 7 on each occasion when used herein, is selected from H or C r C 6 alkyl, Ci-C 6 cycloalkyl, aryl and heteroaryl (wherein the latter four groups are optionally substituted by one or more halo atoms);
  • salts that may be mentioned include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Examples of pharmaceutically acceptable addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids
  • organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids
  • metals such as sodium, magnesium, or preferably, potassium and calcium.
  • “Pharmaceutically functional derivatives” of compounds of formula I as defined herein includes ester derivatives and/or derivatives that have, or provide for, the same biological function and/or activity as any relevant compound. Thus, for the purposes of this invention, the term also includes prodrugs of compounds of formula I.
  • prodrug of a relevant compound of formula I includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
  • parenteral administration includes all forms of administration other than oral administration.
  • Prodrugs of compounds of formula I may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent.
  • Prodrugs include compounds of formula I wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N- Mannich bases.
  • General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” p. I-92, Elesevier, New York-Oxford (1985).
  • Compounds of formula I may contain double bonds and may thus exist as E (entadel) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • Compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • a 'chiral pool' method by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by •conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • alkyl refers to an unbranched or branched, cyclic, saturated or unsaturated (so forming, for example, an alkenyl or alkynyl) hydrocarbyl radical, which may be substituted or unsubstituted (with, for example, one or more halo atoms).
  • alkyl refers to an acyclic group, it is preferably C M0 alkyl and, more preferably, Ci -6 alkyl (such as ethyl, propyl, (e.g. n-propyl or isopropyl), butyl (e.g. branched or unbranched butyl), pentyl or, more preferably, methyl).
  • alkyl is a cyclic group (which may be where the group “cycloalkyl” is specified), it is preferably C 3- I 2 cycloalkyl and, more preferably, C5. 1 0 (e.g. C 5-7 ) cycloalkyl.
  • alkylene refers to d.i 0 (e.g. Ci -6 ) alkylene and, preferably Ci -3 alkylene, such as pentylene, butylene (branched or unbranched), preferably, propylene ( ⁇ -propylene or isopropylene), ethylene or, more preferably, methylene (i.e. -CH 2 -).
  • halogen when used herein, includes fluorine, chlorine, bromine and iodine.
  • aryl when used herein includes C 6-I4 (such as C 6-I3 (e.g. C 6- I 0 )) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
  • C 6- I 4 aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. Most preferred aryl groups include phenyl.
  • carbocyclic when used herein in connection with the Cy 1 group includes references to carbocyclic groups (e.g. Cs -6 carbocyclic groups) that are monocyclic and which may be may be fully saturated, partly unsaturated or wholly aromatic in character.
  • Cy 1 groups may be selected from the group comprising of cyclobutyl, cyclobutenyl, cyclopropyl, cyclopropenyl, preferably cyclopentenyl, more preferably, cyclohexenyl, yet more particularly, cyclopentyl, cyclohexyl, and phenyl.
  • the point of attachment of carbocyclic groups may be via any atom of the ring system.
  • heterocyclic when used herein in connection with the Het 1 group includes references to heterocyclic groups that are monocyclic and which may be fully saturated, partly unsaturated or wholly aromatic in character.
  • Het 1 represents a 5- to 8-membered heterocyclic group, that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N.
  • the Het 1 group may contain up to 3 heteroatom ring members selected from O, N and S.
  • the heterocyclic group may contain 1 , 2 or 3 heteratom ring members.
  • Het 1 may be selected from the group comprising of azepinyl, diazepinyl, dihydrofuranyl (e.g. 2,3-dihydrofuranyl, 2,5-dyhdrofuranyl), 4,5-dihydro-1/-/-maleimido, dioxolanyl, furanyl, furazanyl, hydantoinyl, imidazolyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, 1 ,2- or 1 ,3-oxazinanyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, pyrrolyl, sulfolanyl, a
  • Het 1 groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • a heteroatom such as a nitrogen atom
  • heteroaryl when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group).
  • Heteroaryl groups include those which have between 5 and 14 (e.g. 10) members and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic. However, when heteroaryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
  • Heterocyclic groups that may be mentioned include benzothiadiazolyl (including 2,1 ,3-benzothiadiazolyl), isothiochromanyl and, more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1 ,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro- 2H-1 ,4-benzoxazinyl), benzoxazolyl, benzomo ⁇ holinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, fur
  • heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heteroaryl groups may also be in the N- or S- oxidised form.
  • heteroaryl groups include pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenetyl, pyranyl, carbazolyl, acridinyl, quinolinyl, benzoimidazolyl, benzthiazolyl, purinyl, cinnolinyl and pterdinyl.
  • Particularly preferred heteroaryl groups include monocylic heteroaryl groups.
  • R 16 groups may be the same or different.
  • a term such as "Ai to A 5 " this will be understood by the skilled person to mean any of (i.e. some or all, as applicable) A 1 , A 2 , A 3 , A 4 and A 5 inclusively.
  • T when T represents S, X represents -Q-[CR x R y ] n -Z-, Z represents a bond, Q represents O or S, R x and R y are independently selected from H, halo or Ci -6 alkyl
  • C(R 1 ) to C(R 4 ) are all H, C(R 5 ) represents H, OCH 3 or Cl and when:
  • C(R 6a ) represents C(CH 3 ), C(R 6b ) represents C(CI) and C(R 6c ) to C(R 6e ) represent C(H);
  • C(R 1 ) to C(R 4 ) are all C(H), C(R 5 ) represents C(OCH 3 ), C(R b ) and C(R d ) represent H and C(R a ), C(R 0 ) and C(R e ) represent C(CH 3 );
  • C(R 4 ) represents C(OCH 3 ) while the other represents C(H) and C(R C ) represents C(CI) or C(OCH 3 ); or (d) one of C(R 1 ) or C(R 3 ) represents C(OCH 3 ), while the other represents
  • C(H), C(R 2 ), C(R 4 ) and C(R 5 ) represent H
  • C(R a ) to C(R d ) represent
  • T when T represents S, X represents -Q-[CR x R y ] n -Z-, Z represents a bond, Q represents a bond, R x and R y are independently selected from H, d-6 alkyl (optionally substituted by one or more halo atoms), C(R 6a ) represents C(CH 3 ), C(R 6b ) represents C(CI) and C(R 6c ) to C(R 6e ) represent C(H) or C(R 6e ) represents C(CH 3 ), C(R 6d ) represents C(CI) and C(R 6a ) to C(R 6c ) represent C(H) and when:
  • C(R 5 ) represents C(CI), C(F) or C(NO 2 ) and C(R 1 ) to C(R 4 ) are all H;
  • one of C(R 1 ) or C(R 3 ) represents C(F) or C(OCH 3 ), while the other represents C(H) and C(R 2 ), C(R 4 ) and C(R 5 ) represent C(H); or
  • T represents O
  • X represents -Q-[CR*R y ] n -Z- and R x and R y are independently selected from H, halo or Ci -6 alkyl (optionally substituted by one or more halo atoms)
  • T represents S
  • X represents -Q-[CR x R y ] n -Z-
  • Z represents S
  • Q represents a bond and R x and R y are independently selected from H 1 halo or Ci -6 alkyl (optionally substituted by one or more halo atoms), and Y represents -C(O)-,
  • T represents S
  • X represents -Q-[CR x R y ] n -Z- and R* and R y are independently selected from H, halo or Ci -6 alkyl (optionally substituted by one or more halo atoms)
  • T represents S
  • X represents -Q-[CR ⁇ n -Z-
  • Z represents a bond
  • Q represents
  • R x and R y are independently selected from H, halo or Ci -6 alkyl (optionally substituted by one or more halo atoms), C(R 1 ) to C(R 4 ) are all H, C(R 5 ) represents H,
  • C(R a ) to C(R b ) are selected from:
  • C(R 6a ) represents C(CH 3 ), C(R 6b ) represents C(CI) and C(R 6c ) to C(R 6e ) represent C(H);
  • C C(R 6e ) represents C(CH 3 )
  • C(R 6d ) represents C(CI)
  • C(R 6a ) to C(R 6c ) represent C(H)
  • T represents S 1 X represents -Q-[CR x R y ] n -Z-, Z represents a bond, Q represents a bond, R x and R y are independently selected from H, halo or C 1-6 alkyl (optionally substituted by one or more halo atoms), C(R 1 ) to C(R 5 ) and C(R a ) to C(R e ) are selected from:
  • C(R 1 ) to C(R 4 ) are all C(H), C(R 5 ) represents C(H), C(OCH 3 ) or C(CI) 1 C(R a ), C(R b ), C(R d ) and C(R e ) represent C(H) and C(R C ) represents C(H), C(CI), C(Br), C(F), C(CH 3 ), C(OCH 3 ), C(NHC(O)CH 3 ); (b) C(R 1 ) to C(R 4 ) are all C(H), C(R 5 ) represents C(OCH 3 ), C(R b ) and C(R d ) represent H and C(R a ), C(R C ) and C(R e ) represent C(CH 3 );
  • C(R 1 ) and C(R 3 ) are C(H), C(R 5 ) represents C(OCH 3 ), one of C(R 2 ) and C(R 4 ) represents C(OCH 3 ) while the other represents C(H) and C(R C ) represents C(CI) or C(OCH 3 ); or
  • one of C(R 1 ) or C(R 3 ) represents C(OCH 3 ), while the other represents C(H), C(R 2 ), C(R 4 ) and C(R 5 ) represent H, and C(R a ) to C(R d ) represent H, and
  • T represents S
  • X represents -Q-[CR x R y ] n -Z-
  • Z represents a bond
  • Q represents a bond
  • R x and R y are independently selected from H
  • C(R 6a ) represents C(CH 3 )
  • C(R 6b ) represents C(CI) and C(R 6c ) to C(R 66 ) represent C(H) or C(R 6e ) represents C(CH 3 )
  • C(R 6d ) represents C(CI) and C(R 6a ) to C(R 60 ) represent C(H) and C(R 1 ) to C(R 5 ) are selected from:
  • C(R 5 ) represents C(CI), C(F) or C(NO 2 ) and C(R 1 ) to C(R 4 ) are all H;
  • one of C(R 1 ) or C(R 3 ) represents C(F) or C(OCH 3 ), while the other represents C(H) and C(R 2 ), C(R 4 ) and C(R 5 ) represent C(H); or
  • one of A 2 or A 4 represents N, the other represents C(H) and C(R 1 ), C(R 3 ) and C(R 5 ) represent C(H), and
  • each of the preferred embodiments (i) to (vi) may be applied separately (i.e. individually) as a preferred definition of the compounds of formula I, or may be taken together in any combination thereof in defining more preferred compounds of formula I.
  • R 6c represents Cl or F
  • one of R 6b or R 6d represents Cl and the other represents H
  • R 6c represents Cl
  • X represents -CH 2 -
  • one of R 6b or R 6d represents Cl and the other represents H
  • Y represents -NHS(O) 2 -[CH 2 Jq-, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof).
  • Q represents S(O) 2 and Z represents S, O or, more preferably, a bond.
  • Q and Z represent a bond
  • n represents 1
  • one of R x and R y is is Cy 1 or Het 1 (which latter two groups are optionally substituted by one or more R 6f substituents), and the other is H; and
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms).
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a cyclobutyl, cyclopentyl, cyclohexyl or, more preferably, cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms, or more preferably unsubstituted).
  • each -[CR x R y ]- unit may be independently selected from:
  • R x and R y are independently selected from H, halo, Ci -6 alkyl (optionally substituted by one or more halo atoms);
  • each -[CR 1 ⁇ - unit may be independently selected from:
  • R x and R y are independently selected from H, halo, Ci -3 alkyl (optionally substituted by one or more halo atoms);
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a non-aromatic ring selected from cyclobutyl, cyclopentyl, cyclohexyl or, more particularly, cyclopropyl, which ring is itself optionally substituted by one or more substituents selected from halo or Ci-6 alkyl (optionally substituted by one or more halo atoms); and
  • (c) a unit wherein -[CFW]- may represent -[CH(phenyl)]- or -[CH(pyridyl)]-, which groups are optionally substituted by one or more R 5 substituents), provided that no more than one unit (e.g. no units) is selected from (b) or (c)).
  • one -[CR x R y ]- unit forms a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms) and, if other -[CR x R y ]- units are present, then the additional R x and R y groups are independently selected from H, halo, Ci -6 alkyl (optionally substituted by one or more halo atoms).
  • R x and R y are independently substituted by one or more R 6f substituents
  • the other is H or, more preferably,
  • R x and R y are independently selected from H, halo, C 1-6 alkyl (substituted by one or more halo atoms).
  • R x and R y are independently selected from halo, Ci -6 alkyl (substituted by one or more halo atoms).
  • Compounds of formula I that may be mentioned include those in which: at least one of R x and R y is unsubstituted Ci -6 alkyl.
  • R x and R y are independently selected from H, halo, C 1-6 alkyl (substituted by one or more halo atoms), or R x and R y are linked to form, along with the carbon atom to which they are attached, a non-aromatic 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms).
  • Het 1 represents pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl or morpholinyl.
  • X represents -[CH(Ph)Ji-, -C(O)-, preferably -Q-[CR ⁇ VZ-, °r yet more preferably,
  • X represents -C(O)-, preferably -Q-[CR ⁇ n -Z-, or more preferably, -[CH 2 I n --
  • Compounds of formula I that may be mentioned include those in which:
  • Y represents -NHS(O) 2 -[CH 2 Iq-, -NHNHS(O) 2 -, -NHS(O) 2 NH-, -S(O) 2 - Or -S(O) 2 NH-.
  • Y represents -NHC(O)O- or, more preferably, -NHNHS(O) 2 -, -NHS(O) 2 NH-, -S(O) 2 - or - S(O) 2 NH-.
  • T represents N or, more preferably, O.
  • R 1 to R 5 when present, represents R 7 or, more preferably, -OR 7 , halo,
  • R 1 to R 5 which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, an aromatic or non-aromatic 3- to 8-membered ring selected from 2,3-dihydrobenzo[1 ,4]dioxinyl or tetrahydroquinolinyl, which may optionally be substituted by one or more halo atoms.
  • R 1 to R 5 when present, represents R 7 or, more preferably, -OR 7 , halo,
  • R 1 to R 5 when present, represents R 7 (e.g. -CH 3 ), preferably -OR 7 (e.g.
  • -OCH 3 or more preferably, -OCHF 2 or -OCF 3 ), or, more preferably, halo, -CF 3 , -CN or
  • R 1 to R 4 when present, represents R 7 (e.g. -CH 3 ), preferably -OR 7 (e.g.
  • -OCH 3 or more preferably, -OCHF 2 or -OCF 3 ), or, more preferably, halo, -CF 3 , -CN or
  • R 5 when present, represents -CH 3 , preferably Cl, or, more preferably, H, Br, I, F, -CF 3 ,
  • R 5 when present, represents -CH 3 or, more preferably. H, -CF 3 , -CN, -C(O)R 7 ,
  • R 6a to R 6e independently represent -C(O)NR 15a R 15b or, more preferably, H, cyano, -NO 2 , - Br, -Cl, -F, -R 8 , -OR 8 , -NR 9 R 10 , -SR 11 , -C(O)OR 13 , -C(O)R 14 , -S(O) 2 NR 15c R 15d , aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R 16 ), or any two R 6 groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, quinoline, tetrahydroquinoline, isoquinoline or tetrahydroisoquinoline, wherein the additional ring system of the quinoline, tetra
  • R e a to R e e j nc j e p enc j en tiy represent -C(O)NR 15a R 15b or, more preferably, -R 8 or yet more preferably, H, cyano, -NO 2 , -Br, -Cl, -F, -OR 8 , -NR 9 R 10 , -SR 11 , -C(O)OR 13 , -C(O)R 14 ,
  • aryl or heteroaryl which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and
  • R 6a to R 6e independently represents -C(O)NR 15a R 15b , -R 8 , or, more preferably, H, cyano, -
  • y represents -R 8 or, more preferably, H, cyano, -NO 2 , -Br, -Cl,
  • R ⁇ a tQ R 6 ⁇ independently represents H, -Br, -F or, most preferably -Cl.
  • R 6t independently represents H, halo, -R 7 , -CF 3 , -CN, -NO 2 , -C(O)R 7 , -C(O)OR 7 ,
  • n is 2, or more preferably, 1.
  • Compounds of formula I that may be mentioned include those in which: q is 1 , or more preferably, O.
  • Compounds of formula I that may be mentioned include those in which: B represents a bond; r represents 0 or 1.
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or C 1 ⁇ alkyl (optionally substituted by one or more halo atoms);
  • Q represents a bond or O
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or C 1-6 alkyl (optionally substituted by one or more halo atoms);
  • a 5 represents C(CF 3 ) or, more preferably, C(CI).
  • a 1 and A 3 independently represent C(halo), e.g. C(CI) or C(F), preferably N or, more preferably, C(H).
  • a 2 and A 4 represents C(R 2 );
  • a 1 , A 3 and A 5 independently represent C(H) or N.
  • a 2 represents C(R 2 );
  • a 1 and A 3 to A 5 independently represent C(H) or N.
  • a 1 and A 3 to A 5 independently represent C(H).
  • a 5 represents C(R 5 );
  • R 5 represents -CF 3 ;
  • Ai to A 4 independently represent C(H).
  • T S
  • G represents N
  • R x and R y are linked to form, along with the carbon atom to which they are attached, a cyclopropyl ring which ring is itself optionally substituted by one or more substituents selected from halo or C ⁇ alkyl (optionally substituted by one or more halo atoms);
  • Q represents a bond or O
  • T S
  • G represents N
  • a 5 represents N or, more preferably, C(H).
  • Y represents -NHC(O)NH-.
  • G represents N
  • a 2 and A 4 represent C(R 2 );
  • a 1 , A 3 and A 5 independently represent C(H) or N.
  • Y is -NHC(O)NH- or, more preferably, -NHS(O) 2 -[CH 2 Jq-; and/or q is 0.
  • Y is not -NHC(O)NH- or, more preferably, -NHS(O) 2 -[CH 2 ] q -; and/or q is 0.
  • X represents -[CH 2 ] n -; G represents N or O; R 1 to R 4 independently represent H, halo, -CF 3 , -CN, -NO 2 , -C(O)R 7 , -C(O)OR 7 ,
  • R 5 represents H, Br, I, F, -CF 3 , -CN, -C(O)R 7 , -C(O)OR 7 , -N(R 7 J 3 + Or -SO 3 R 7 ; provided that at least one of R 1 to R 5 is not H; and
  • R 6a to R 66 independently represent, H, cyano, -NO 2 , halo, -R 8 , -OR 8 , -NR 9 R 10 , -SR 11 ,
  • Y represents -NHS(O) 2 .
  • Q and Z independently represent a bond, S, or O;
  • R x and R y are independently selected from H, halo, C 1-6 alkyl (optionally substituted or, more preferably, substituted by one or more halo atoms), or R x and R y are linked to form, along with the carbon atom to which they are attached, an aromatic or non-aromatic 3- to
  • 8-membered ring optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or C 1-6 alkyl (optionally substituted by one or more halo atoms);
  • R 1 to R 5 are as defined above or, preferably, at least one of R 1 to R 5 represents -CF 3 or, more preferably, at least one of R 1 to R 4 represents -CF 3 and R s represents H.
  • Q and Z independently represent a bond, S, or O;
  • R x and R y are independently selected from H, halo, Ci -6 alkyl (optionally substituted by one or more halo atoms), or R x and R y are linked to form, along with the carbon atom to which they are attached, an aromatic or, more preferably, non-aromatic 3- to 8- membered ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted by one or more substituents selected from halo or Ci -6 alkyl (optionally substituted by one or more halo atoms). More preferred compounds of formula I include those of the examples described hereinafter.
  • Preferred compounds of formula I include:
  • Preferred compounds of formula I include compounds (i), (H), (Ix) to (Ixv), (Ixix), (Ixxi), (Ixxvi), (xc) to (cxxv) and (clxx) to (clxxii) as described above.
  • Yet further preferred compounds of formula I include compounds (xv), (xxxvi) to (xl), (iii), (iv), (xi), (xii), (xiv), (xvi) to (xxii), (xxiv) to (xxxv), (xli) to (liii), (Ixxviii) and (Ixxix).
  • Yet further preferred compounds of formula I include compounds (i) to (iv), (vi) to (liv), (xcvi), (xcvii), (cxx) to (cxxiii), (cxxvi) to (cxli), (cxliii) to (cil), (cli), (cliii) to (clix) and (clxxiii).
  • Yet further preferred compounds of formula I include compounds (xv), (xxxvi) to (xl) and (Ixvi).
  • Compounds of formula I may be known and/or may be commercially available. Compounds of formula I that are not commercially available may be prepared in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
  • a process for the preparation of a compound of formula I which process comprises: (i) for compounds of formula I wherein Y represents -NHC(O)-[CH 2 ] r -B- or, more preferably, -NHC(O)NH-, -NHC(O)O-, -NHS(O) 2 NH- or -NHS(O) 2 -[CH 2 Jq-, reaction of a compound of formula II,
  • Y x represents -C(O)-[CH 2 JrB- or, more preferably, -C(O)NH-, -C(O)O-, -S(O) 2 NH-, or -S(O) 2 -[CH 2 ]q-
  • L 2 represents a suitable leaving group such as halo (e.g. chloro)
  • Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, NaOH, triethylamine, pyridine, another suitable base, e.g. one of those mentioned at process step (xii) below or mixtures thereof) and an appropriate solvent (e.g.
  • a suitable base e.g. NaH, NaOH, triethylamine, pyridine, another suitable base, e.g. one of those mentioned at process step (xii) below or mixtures thereof
  • an appropriate solvent e.g.
  • pyridine which may serve as the base and solvent
  • DMF or dichloromethane e.g. further in the presence of water and, optionally, a phase transfer catalyst
  • room temperature e.g. as described in Hurst, D. T.; Stacey, A. D., Nethercleft, M., Rahim, A., Harnden, M. R. Aust J. Chem. 1998, 41, 1221 ;
  • Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example, in the presence of a suitable solvent (e.g. a polar aprotic solvent such as toluene) and at elevated temperature (e.g. reflux), for example as described in the journal article mentioned in respect of process (i) above;
  • a suitable solvent e.g. a polar aprotic solvent such as toluene
  • elevated temperature e.g. reflux
  • dotted lines, Ai to A 5 , X, T, G and Di to D 5 are as hereinbefore defined or, more preferably, T is S or O and G is N, for example under standard oxidation conditions, e.g. in the presence of a suitable oxidising reagent (e.g. Dess-Martin periodinane, pyridinium chlorochromate, sodium dichromate, Jones' reagent, KMnO 4 , or Na 2 Cr 2 O 7 ) in an appropriate solvent (e.g. dichloromethane, tetrahydrofuran, aqueous sulfuric acid or aqueous acetic acid) and optionally at reduced to elevated temperature (e.g. from 0 0 C to 100 0 C), or e.g. as described in Kurkjy et al. (1952) J. Am. Chem. Soc. (74), 6260-6262;
  • a suitable oxidising reagent e.g. Dess-Martin periodinane,
  • L 3 represents a suitable leaving group such as halo (e.g. chloro, bromo and iodo) or methylsulfonyl
  • halo e.g. chloro, bromo and iodo
  • AA represents HO- or HS-
  • q and Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, KH), in a suitable solvent (e.g. tetrahydrofuran) and optionally at reduced to elevated temperature (e.g. from 0 0 C to 100 0 C), or under the reaction conditions discussed in Kidwai et al. (2000), Bioorg. Med. Chem 8, 69-72 or Alemagna et a/. (1968) Tetrahedron, 24, 3209-3217 or Toyooka et ai, (1987) Chem. Pharm. Bull. 35(3), 1030-1035;
  • a suitable base e.g. NaH, KH
  • a suitable solvent e.g. tetrahydrofuran
  • L 5 represents a suitable leaving group such as halo (e.g. chloro)
  • the dotted lines, Ai to A 5 , X, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N 1 with a compound of formula X,
  • D 1 to D 5 are as hereinbefore defined, for example under standard reaction conditions, e.g. such as those described in process (i) above;
  • dotted lines, Ai to As, X, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N, with a compound corresponding to a compound of formula III, but wherein Y x instead represents -C(O)- or -S(O) 2 -, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, NaOH, triethylamine, pyridine, another suitable base mentioned at process step (i) above or mixtures thereof) and solvent (e.g. pyridine (which may serve as the base and solvent) DMF or dichloromethane (e.g.
  • a suitable base e.g. NaH, NaOH, triethylamine, pyridine, another suitable base mentioned at process step (i) above or mixtures thereof
  • solvent e.g. pyridine (which may serve as the base and solvent) DMF or dichloromethane (e.g.
  • Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. toluene or xylenes), in the presence of suitable dehydration means (e.g. Dean-Stark apparatus, 3A molecular sieves, magnesium turnings), optionally in the presence of a suitable Lewis acid (e.g BF 3 OEt 2 ), and at elevated temperature (e.g. from 30 0 C to 150 0 C) using conventional or microwave heating means;
  • a suitable solvent e.g. toluene or xylenes
  • suitable dehydration means e.g. Dean-Stark apparatus, 3A molecular sieves, magnesium turnings
  • a suitable Lewis acid e.g BF 3 OEt 2
  • elevated temperature e.g. from 30 0 C to 150 0 C
  • L 5a represents a halogen atom (e.g. Br, Cl or I) and wherein the dotted lines, Di to D 5 , T 1 G and Y are as hereinbefore defined or, more preferably, T is S or O and G is N 1 with a compound of formula XIV,
  • Z a is O or S and A 1 to A 5 , Q, R x , R y and n are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. MeONa, EtONa, NaH), a suitable solvent (e.g. MeOH, EtOH 1 THF), and at elevated temperature (e.g. from 30 0 C to 150 0 C);
  • a suitable base e.g. MeONa, EtONa, NaH
  • a suitable solvent e.g. MeOH, EtOH 1 THF
  • T' represents S, NH or O and G, X 1 Y, A 1 to A 5 and Di to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example, in an appropriate solvent (e.g. toluene, xylenes, DCM), optionally in the presence of an acid (e.g. methanesulfonic acid) and at reduced to elevated temperatures (e.g. from 0°C to 140 0 C);
  • an appropriate solvent e.g. toluene, xylenes, DCM
  • an acid e.g. methanesulfonic acid
  • elevated temperatures e.g. from 0°C to 140 0 C
  • L 6a represents a suitable leaving group (e.g. a halo, such as chloro, bromo, iodo, a sulfonate group or an acid anhydride) or OH, with a compound of formula XVII,
  • G' represents NH 2 or OH and T, Y and D 1 to D 5 are as hereinbefore defined, when L 6a represents a suitable leaving group, under reaction conditions known to those skilled in the art, for example such as those described in JP3258771 , e.g. in an appropriate solvent (e.g. toluene, xylenes, DCM, chloroform), optionally in the presence of an base (e.g. pyridine, Hunig's base, triethylamine) and at reduced to elevated temperatures (e.g. from O 0 C to 140 0 C) or when L 6a represents OH, under standard coupling reaction conditions, for example, in the presence of a suitable coupling reagent (e.g.
  • L 7a represents a halogen atom (e.g. Br, Cl or I) and the dotted lines, T, G, Y and D 1 to D 5 are as hereinbefore defined, with a compound of formula XIX,
  • L 8 represents a halogen atom (e.g. Br, Cl or I)
  • X aa is -Q-[CR x R y ] n - and A 1 to A 5 , Q, R x , R y and n are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in an appropriate solvent (e.g. THF, MTBE, DMA, NMP), with a suitable catalytic system (such as those described in J. E. Milne, S. L. Buchwald, J. Am. Chem. Soc, 2004, 126, 13028-13032, N. Hadei, E. A. B. Kantchev, C. J. O'Brien, M. G. Organ, Org.
  • an appropriate solvent e.g. THF, MTBE, DMA, NMP
  • a suitable catalytic system such as those described in J. E. Milne, S. L. Buchwald, J. Am. Chem. Soc, 2004,
  • E represents CH 2 or a bond and the dotted lines, T, G, Ai to A 5 and D-i to D 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example with a suitable catalyst (e.g. Pd/C, Raney Nickel, RhCI(PPh 3 ) 3 , Lindlar catalyst), with a suitable source of hydrogen (e.g. hydrogen gas, hydrazine, dihydronaphthalene, dihydroanthracene, isopropanol, formic acid), optionally in an appropriate solvent (e.g. MeOH, EtOH 1 water or mixtures thereof), optionally at elevated pressures (e.g. greater than 1 atmosphere) and at reduced to elevated temperatures (e.g. from O 0 C to 140 0 C);
  • a suitable catalyst e.g. Pd/C, Raney Nickel, RhCI(PPh 3 ) 3 , Lindlar catalyst
  • a suitable source of hydrogen e.g. hydrogen gas, hydrazine, dihydr
  • a 1 to A 5 , and X are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. MeOH, EtOH, THF), and optionally at reduced to elevated temperature (e.g. from O 0 C to 100 0 C), followed by reaction of the resulting intermediate with a suitable oxidant (e.g. FeCI 3 ) in the presence of a suitable solvent (e.g. MeOH, EtOH 1 THF), and optionally at elevated temperature (e.g. from 30 0 C to 100 0 C); and
  • a suitable solvent e.g. MeOH, EtOH, THF
  • a suitable oxidant e.g. FeCI 3
  • R a represents a linear or branched C 1 to C 6 alkyl group, with a compound of formula XXV,
  • Compounds of formula Il may be prepared by: (a) for compounds of formula Il wherein Z is a bond, cyclisation of a compound of formula XXVI,
  • a 1 to A 5 , T and G are as hereinbefore defined or, more preferably, T is S or O and G is N, and X' is -Q-[CFW] n - or -C(O)-, under reaction conditions known to those skilled in the art, for example, in an appropriate solvent (e.g. toluene, xylenes or DCM), optionally in the presence of an acid (e.g. methanesulfonic acid) and at reduced to elevated temperatures (e.g. from O 0 C to 14O 0 C);
  • an appropriate solvent e.g. toluene, xylenes or DCM
  • an acid e.g. methanesulfonic acid
  • elevated temperatures e.g. from O 0 C to 14O 0 C
  • L 6 represents a suitable leaving group (e.g. a halo, such as chloro, bromo, iodo, a sulfonate group or an acid anhydride) or OH
  • X' and A 1 to A 5 are as hereinbefore defined with thiosemicarbazide, under reaction conditions known to those skilled in the art, for example, for example such as those described in JP3258771 , e.g. in an appropriate solvent (e.g. toluene, xylenes, DCM, chloroform), optionally in the presence of an base (e.g. pyridine, Hunig's base, triethylamine) and at reduced to elevated temperatures (e.g.
  • an appropriate solvent e.g. toluene, xylenes, DCM, chloroform
  • an base e.g. pyridine, Hunig's base, triethylamine
  • elevated temperatures e.g.
  • a suitable coupling reagent e.g. 1 ,1 '-carbonyldiimidazole, ⁇ /./V-dicyclohexylcarbodiimide, 1-(3-dimethylamino- propyl)-3-ethylcarbodiimide (or hydrochloride thereof), ⁇ /./V-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, 2-(1 H- benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate, benzotriazol-1 - yloxytris-pyrrolidinophosphonium hexafluorophosphate, bromo-tris- pyrrolidin
  • a suitable coupling reagent e.g. 1 ,1 '-carbonyldiimidazole,
  • L 7 represents a suitable leaving group (e.g. chloro, bromo, iodo) and the dotted lines, T and G are as hereinbefore defined or, more preferably, T is S or O and G is N, with a compound of formula XIX as hereinbefore defined, under reaction conditions known to those skilled in the art, for example those described under process (xiii) above;
  • a suitable leaving group e.g. chloro, bromo, iodo
  • Halo represents a halogen atom (e.g. iodo, bromo or chloro)
  • the dotted lines, A 1 to A 5 , X, T and G, are as hereinbefore defined, or, more preferably, T is S or O and G is N, with a compound of formula XII as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in a suitable solvent (e.g. tetrahydrofuran or diethyl ether) and subsequent reaction at reduced to elevated temperatures (e.g. from -78 0 C to 100 0 C), or e.g. as described in Kurkjy et al. (1952) J. Am. Chem. Soc. (74), 6260-6262.
  • a suitable solvent e.g. tetrahydrofuran or diethyl ether
  • Compounds of formula Vl wherein L 3 represents halo may be prepared by reaction of a compound of formula Il with NaNO 2 and a suitable halogen source (e.g. hydrochloric acid), under reaction conditions known to those skilled in the art, for example such as those described in Foroumadi et al. (1999) Arzneim. Forsch. 49, 1035- 1038 or Foroumadi et al (2005) Arch. Pharm. Chem. Life ScL , 338, 112-116, for example in the presence of a suitable metal (e.g. copper powder).
  • a suitable halogen source e.g. hydrochloric acid
  • dotted lines, Ai to A 5 , X, T and G are as hereinbefore defined, or, more preferably, T is S or O and G is N, with a suitable chlorine source (e.g. chlorine gas), under reaction conditions known to those skilled in the art, for example such as those described in Naganawa et al. (2006) Biorg. Med. Chem. 14, 6628-6639, e.g. in the presence of a suitable solvent (e.g. 33% aqueous acetic acid) and at reduced to room temperatures (e.g. from -20 0 C to 25 0 C).
  • a suitable chlorine source e.g. chlorine gas
  • Compounds of formula Xl may be prepared by reaction of a compound of formula Vl, wherein L 3 is halo (e.g. chloro), with hydrazine, under reaction conditions known to those skilled in the art, for example such as those described in Shafiee et al. (1976), J. Het. Chem. 13, 117-121 , e.g. in the presence of a suitable solvent (e.g. ethanol, methanol), optionally in the presence of a suitable base (e.g. triethylamine, Hunig's base) and at reduced to elevated temperatures (e.g. from -78°C to 110 0 C).
  • a suitable solvent e.g. ethanol, methanol
  • a suitable base e.g. triethylamine, Hunig's base
  • dotted lines, Di to Ds, X, T and G are as hereinbefore defined, or, more preferably, T is S or O and G is N, with a halogen (bromine, chlorine or iodine), under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. acetic acid) and in the presence of a suitable base (e.g. NaOAc) as described in Pippich et al. J. Heterocyclic Chemistry (1997) 34, 823-828.
  • a suitable solvent e.g. acetic acid
  • a suitable base e.g. NaOAc
  • a hydrazine hydrate under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. DMF, MeOH, EtOH, THF), and optionally at reduced to elevated temperatures (e.g. from O 0 C to 100 0 C).
  • a suitable solvent e.g. DMF, MeOH, EtOH, THF
  • elevated temperatures e.g. from O 0 C to 100 0 C.
  • a 1 to A 5 , X and R a are as hereinbefore defined, with Lawesson's reagent, under reaction conditions known to those skilled in the art, for example such as those described in Bradley et al. (2005), Liquid Crystals Today, 14, 15-18, e.g. in the presence of a suitable solvent (e.g. THF).
  • a suitable solvent e.g. THF
  • G' is OH or NH 2 and T is as hereinbefore defined or, more preferably, more preferably, T is S or O and G' is NH 2 , under reaction conditions known to those skilled in the art, for example such as those described in process step (b) above.
  • E and A 1 to A 5 are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example with a suitable metal catalyst (e.g. Pd(OAc) 2 , Pd(dba) 2 , PdCI 2 , Pd(PPh 3 ) 4 , Pd(OCOCF 3 ) 2 (PPh 3 ) 2 ), a suitable base (e.g. NaOAc, K 2 CO 3 , Na 2 CO 3 , K 3 PO 4 , triethylamine, Hunig's base, LiCI), optionally in the presence of a suitable ligand (e.g.
  • a suitable metal catalyst e.g. Pd(OAc) 2 , Pd(dba) 2 , PdCI 2 , Pd(PPh 3 ) 4 , Pd(OCOCF 3 ) 2 (PPh 3 ) 2
  • a suitable base e.g. NaOAc, K 2 CO 3 , Na 2 CO 3 , K 3 PO 4
  • L 9 represents a suitable leaving group (e.g. chloro, bromo or iodo) and Ai to A 5 are as defined hereinbefore, under reaction conditions known to those skilled in the art, for example those described above for the preparation of a compound of formula XXIX.
  • a suitable leaving group e.g. chloro, bromo or iodo
  • compounds of XXIX, XXX and XL may be prepared by synthetic methods analogous to those described in US 2,420,434 and US 2,511 ,371.
  • Compounds of formula XV may be prepared by reaction of a compound of formula XVII as hereinbefore defined, with a compound of formula XXVII as hereinbefore defined, under reaction conditions known to those skilled in the art, for example, in an appropriate solvent (e.g. DCM, Et 2 ⁇ or THF) and optionally in the presence of a base (e.g. Hunig's base, triethylamine, DMAP, pyridine) and at reduced to elevated temperatures (e.g. from 0 0 C to 80 0 C) and the uncyclised intermediate isolated.
  • an appropriate solvent e.g. DCM, Et 2 ⁇ or THF
  • a base e.g. Hunig's base, triethylamine, DMAP, pyridine
  • elevated temperatures e.g. from 0 0 C to 80 0 C
  • J represents Ci -4 alkyl
  • T represents NH
  • D 1 to D 5 are as defined hereinbefore, with hydroxylamine, under reaction conditions known to those skilled in the art, for example, in the presence of a suitable base (e.g. triethylamine, Hunig's base, DMAP), in a suitable solvent (e.g. diethyl ether, ethanol, methanol) and at reduced to elevated temperatures (e.g. from 0 0 C to 120 0 C).
  • a suitable base e.g. triethylamine, Hunig's base, DMAP
  • a suitable solvent e.g. diethyl ether, ethanol, methanol
  • morpholine and sulfur under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (e.g. DMF, MeOH, EtOH, THF), and optionally at reduced to elevated temperatures (e.g. from 0 0 C to 100°C).
  • a suitable solvent e.g. DMF, MeOH, EtOH, THF
  • elevated temperatures e.g. from 0 0 C to 100°C.
  • R a is as hereinbefore defined, under standard reaction conditions, e.g. such as those described in process (viii) above.
  • Substituents such as R 1 , R 2 , R 3 and R 4 in final compounds of formula I (or precursors thereto and other relevant intermediates) may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions (e.g. carbonyl bond reductions in the presence of suitable and, if necessary, chemoselective, reducing agents such as LiBH 4 or NaBH 4 ), oxidations, alkylations, acylations, hydrolyses, esterifications, and etherifications.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I 1 at any time during the reaction sequence.
  • the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • the term "functional groups” means, in the case of unprotected functional groups, hydroxy-, thiolo-, aminofunction, carboxylic acid and, in the case of protected functional groups, lower alkoxy, N-, O-, S- acetyl, carboxylic acid ester.
  • compounds of formula I may be AMPK agonists, i.e. they may activate AMPK.
  • AMPK' we mean that the steady state level of phosphorylation of the Thr-172 moiety of the AMPK- ⁇ subunit is increased compared to the steady state level of phosphorylation in the absence of the agonist.
  • ACC acetyl-CoA carboxylase
  • disorder or condition ameliorated by the activation of AMPK will be understood by those skilled in the art to include lung disease, obesity, dry-type age- related macular degeneration, cardioprotection or, preferably, diabetes, hyperinsulinemia and associated conditions, cancer, a condition/disorder where fibrosis plays a role, sexual dysfunction, osteoporosis, inflammation, heart failure and neurodegenerative diseases.
  • Compounds of formula I may also be indicated for use in the treatment of a disorder or a condition caused by, linked to, or contributed to by, hyperinsulinemia.
  • a compound of formula I or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for the manufacture of a medicament for the treatment of a disorder or condition ameliorated by the activation of AMPK.
  • hyperinsulinemia disorder or condition caused by, linked to, or contributed to by, hyperinsulinemia
  • hyperinsulinemia and associated conditions such as cardiovascular disease or, preferably, type 2 diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinism in childhood, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, atherosclerosis, cerebrovascular conditions such as stroke, systemic lupus erythematosus, neurodegenerative diseases such as Alzheimer's disease, and polycystic ovary syndrome.
  • Other disease states include progressive renal disease such as chronic renal failure.
  • Preferred disorders include hyperinsulinemia and, particularly, type 2 diabetes.
  • Certain compounds of formula I may also have the additional advantage that they exhibit partial agonist activity and may therefore be useful in conditions, such as late type 2 diabetes, in which stimulation of the production of insulin is required.
  • agonist activity we include direct and indirect-acting agonists.
  • a method of treatment of a disorder or condition ameliorated by the activation of AMPK comprises the administration of an effective amount of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, to a patient in need of such treatment.
  • Compounds of formula I may also be of use in the treatment of cancer (primary and metastatic cancers).
  • cancer will be understood by those skilled in the art to include one or more diseases in the class of disorders that is characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion, proliferation or by implantation into distant sites by metastasis.
  • Compounds of formula I may reduce the rate of cell proliferation when tested in an assay using a human breast cancer cell line (e.g. MDA-MB-231 ). The compounds may thus possess a beneficial inhibitory effect on the ability of tumors of this type, and of cancers generally, to survive. Compounds of formula I may also reduce the rate of cell proliferation when tested in other cancer cells lines such as MCF-7, PC-3, Jurkat, Skov- 3, HL60, MV4-11 , HT29, K562, MDA-MB231 , HCT116wt, HCT116P53-/-, A-549, DU- 145, LOVO, HCT-116 and PANC-1.
  • compounds of formula I are capable of inhibiting the proliferation of cancer cells.
  • proliferation we include an increase in the number and/or size of cancer cells.
  • compounds of formula I are capable of inhibiting metastasis of cancer cells.
  • metastasis we mean the movement or migration (e.g. invasiveness) of cancer cells from a primary tumor site in the body of a subject to one or more other areas within the subject's body (where the cells can then form secondary tumors).
  • the invention provides compounds and methods for inhibiting, in whole or in part, the formation of secondary tumors in a subject with cancer. It will be appreciated by skilled persons that the effect of a compound of formula I on "metastasis" is distinct from any effect such a compound may or may not have on cancer cell proliferation.
  • compounds of formula I may be capable of inhibiting the proliferation and/or metastasis of cancer cells selectively.
  • the combination product inhibits the proliferation and/or metastasis of cancer cells to a greater extent than it modulates the function (e.g. proliferation) of non-cancer cells.
  • the compound inhibits the proliferation and/or metastasis of cancer cells only.
  • cancer cells may be selected from the group consisting of cancer cells of the breast, bile duct, brain, colon, stomach, reproductive organs, thyroid, hematopoietic system, lung and airways, skin, gallbladder, liver, nasopharynx, nerve cells, kidney, prostate, lymph glands and gastrointestinal tract.
  • the cancer is selected from the group of colon cancer (including colorectal adenomas), breast cancer (e.g. postmenopausal breast cancer), endometrial cancer, cancers of the hematopoietic system (e.g.
  • the cancer is selected from the group of colon, prostate and, particularly, breast cancer.
  • the cancer is a non-solid tumor, it is preferably a hematopoietic tumor such as a leukemia (e.g. Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL).
  • AML Acute Myelogenous Leukemia
  • CML Chronic Myelogenous Leukemia
  • ALL Chronic Lymphocytic Leukemia
  • CLL Chronic Lymphocytic Leukemia
  • the cancer cells are breast cancer cells.
  • Compounds of formula I may also be of use in the treatment of a condition/disorder where fibrosis plays a role. Compounds of formula I may also be useful in the treatment of sexual dysfunction (e.g. the treatment of erectile dysfunction).
  • a condition/disorder where fibrosis plays a role includes (but is not limited to) cystic fibrosis or, preferably, scar healing, keloids, scleroderma, pulmonary fibrosis (including idiopathic pulmonary fibrosis), nephrogenic systemic fibrosis, and cardiovascular fibrosis (including endomyocardial fibrosis), systemic sclerosis, liver cirrhosis, eye macular degeneration, retinal and vitreal retinopathy, Crohn's/inflammatory bowel disease, post surgical scar tissue formation, radiation and chemotherapeutic-drug induced fibrosis, and cardiovascular fibrosis.
  • Compounds of formula I may also be of use in the treatment of osteoporosis.
  • Compounds of formula I may also be of use in the treatment of inflammation.
  • Compounds of formula I may also be of use in the treatment of sexual dysfunction.
  • Compounds of formula I may also be of use in the treatment of heart failure.
  • Compounds of formula I may also be of use in the treatment of lung disease.
  • Compounds of formula I may also be of use in the treatment of obesity.
  • Compounds of formula I may also be of use in the treatment of dry-type age-related macular degeneration.
  • Compounds of formula I may also be of use as an agent for cardioprotection.
  • Compounds of formula I may also be of use in the treatment of neurodegenerative diseases (e.g. Alzheimer ' s disease, Parkinson's disease and Huntington's disease, amyotrophic lateral sclerosis, polyglutamine disorders, such as spinal and bulbar muscular atrophy (SBMA), dentatorubral and pallidoluysian atrophy (DRPLA), and a number of spinocerebellar ataxias (SCA)).
  • neurodegenerative diseases e.g. Alzheimer ' s disease, Parkinson's disease and Huntington's disease, amyotrophic lateral sclerosis, polyglutamine disorders, such as spinal and bulbar muscular atrophy (SBMA), dentatorubral and pallidoluysian atrophy (DRPLA), and a number of spinocerebellar ataxias (SCA)).
  • neurodegenerative diseases e.g. Alzheimer ' s disease, Parkinson's disease and Huntington's disease, amyotrophic lateral sclerosis
  • compounds of formula I can be used in the treatment of diabetes, a disorder or condition where fibrosis plays a role, and hyperinsulinemia and associated conditions.
  • treatment include the therapeutic, or palliative, treatment of patients in need of, as well as the prophylactic treatment and/or diagnosis of patients which are susceptible to, the relevant disease states.
  • Patients include mammalian (including human) patients.
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient (e.g. sufficient to treat or prevent the disease).
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
  • compounds of formula I may be administered alone, but are preferably administered orally, intravenously, intramuscularly, cutaneously, subcutaneously, transm ⁇ cosally (e.g. sublingually or buccally), rectally, transdermal ⁇ , nasally, pulmonarily (e.g. tracheally or bronchially), topically, by any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharmaceutically acceptable dosage form.
  • Preferred modes of delivery include oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal delivery.
  • Compounds of formula I will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutically acceptable adjuvant diluent or carrier
  • Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.
  • Suitable pharmaceutical formulations may be found in, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995).
  • a parenterally acceptable aqueous solution may be employed, which is pyrogen free and has requisite pH, isotonicity, and stability. Suitable solutions will be well known to the skilled person, with numerous methods being described in the literature. A brief review of methods of drug delivery may also be found in e.g. Langer, Science (1990) 249, 1527.
  • Another aspect of the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in combination with a pharmaceutically acceptable excipient, such as an adjuvant, diluent or carrier.
  • the amount of compound of formula I in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
  • compounds of formula I may be administered at varying therapeutically effective doses to a patient in need thereof.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe.
  • the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
  • Administration may be continuous or intermittent (e.g. by bolus injection).
  • the dosage may also be determined by the timing and frequency of administration.
  • the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formula I (or, if employed, a corresponding amount of a pharmaceutically acceptable salt or prodrug thereof).
  • the medical practitioner or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the compounds of formula I may also be used or administered in combination with one or more additional drugs useful in the treatment of a disorder or condition ameliorated by the activation of AMPK, in combination therapy.
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • therapeutic agents useful in the treatment of a disorder or condition ameliorated by the activation of AMPK will be well known to those skilled in the art and include biguanides, glitazones (i.e. thiazolidinediones), oligomycins, AICAR (aminoimidazole carboxamide ribonucleotide), insulin, insulin secretagogues (such as sulphonylureas), peroxisome proliferator-activated receptor (PPAR) agonists (which also include thiazolidinediones), ⁇ -glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, exenatide, inhibitors of 11- ⁇ hydroxysteroid dehydrogenase type 1 , inhibitors of stearoyl- CoA desaturase 1 (SCD-1), A-769662, D942 (5-(3-(4-(2-(4-Fluorophenyl)ethoxy)- phenyl)prop
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a biguanide.
  • the agent may be selected from the group consisting of phenformin, buformin, and, most preferably, metformin.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise glitazones.
  • the agent may be selected from the group consisting of troglitazone, pioglitazone and rosiglitazone.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise an oligomycin.
  • the agent may be selected from the group consisting of oligomycin A, oligomycin B, oligomycin C, oligomycin D (rutamycin A), oligomycin E, oligomycin F, rutamycin B, 44-homooligomycin A and 44-homooligomycin B.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise AICAR.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise GLP-1 or a biologically active fragment, variant, fusion of derivative thereof.
  • the agent may be selected from the group consisting of Exendin-4 (exenatide; Byetta), exenatide long acting release (LAR), exenatide derivatives (such as ZP10 developed by Zealand Pharmaceuticals), native GLP-1, human GLP-1 derivatives (such as BIM51077 (Ipsen and Roche)), DPP-IV resistant GLP-1 analogues (for example LY315902 and LY30761 SR (Lilly)), long acting GLP-1 derivatives (such as NN2211 (Liraglutide; Novo Nordisk)) and complex proteins (such as the GLP-1 -albumin complex CJC-1131).
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a dipeptidyl peptidase IV (DPP-IV) inhibitor.
  • DPP-IV dipeptidyl peptidase IV
  • the agent may be selected from the group consisting of Vildagliptin (LAF237), MK-0431-Sitagliptin and Saxagliptin.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise gastric inhibitory polypeptide (GIP), or a biologically active fragment, variant, fusion of derivative thereof.
  • GIP gastric inhibitory polypeptide
  • GIP also known as glucose-dependent insulinotropic polypeptide, is a 42-amino acid peptide hormone synthesised in and secreted from K cells in the intestinal epithelium.
  • An important determinant of GIP action is the N-terminal cleavage of the peptide to the inactive GIP (3-42).
  • DPP-4 which also cleaves GLP-1 and GLP-2, rapidly inactivates GIP both in vitro and in vivo. Hence, it may be desirable to administer GIP in combination with a DPP-4 inhibitor.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a selective inhibitor of 11- ⁇ hydroxysteroid dehydrogenase type 1 (11 ⁇ -HSD1), an enzyme associated with conversion of cortisone to Cortisol in the liver and adipose tissue.
  • 11 ⁇ -HSD1 inhibitors/antagonists include AMG221 (developed by
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise an inhibitor of stearoyl- CoA desaturase 1 (SCD-1).
  • SCD-1 inhibitors include those described in US 2005/0019251 (e.g. 6-[4-(2-bromo-4-methoxy-benzoyl)-piperazin-1-yl]- N-(3-phenyl-propyl)-nicotinamide), those described in WO 2006/130986 (e.g.
  • the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a SIRT1 (also known as sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) activator.
  • SIRT1 activators include resveratrol and SRT-1720 (N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1 ,3]thiazol-6-yl]phenyl]quinoxal- ine-2-carboxamide).
  • Combination products as described herein provide for the administration of compound of formula I in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises compound of formula I 1 and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including compound of formula I and the other therapeutic agent).
  • compositions including a compound of formula I; another therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK; and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
  • kits of parts comprising components:
  • a pharmaceutical formulation including another therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • Components (a) and (b) of the kits of parts described herein may be administered simultaneously or sequentially.
  • a method of making a kit of parts as defined above comprises bringing component (a), as defined above, into association with a component (b), as defined above, thus rendering the two components suitable for administration in conjunction with each other.
  • components (a) and (b) of the kit of parts may be:
  • kit of parts comprising:
  • kits of parts described herein may comprise more than one formulation including an appropriate quantity/dose of compound of formula I 1 and/or more than one formulation including an appropriate quantity/dose of the other therapeutic agent, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of either compound, chemical composition(s) and/or physical form(s).
  • kits of parts as described herein by “administration in conjunction with”, we include that respective formulations comprising compound of formula I and the other therapeutic agent are administered, sequentially, separately and/or simultaneously, over the course of treatment of the relevant condition.
  • the term "administration in conjunction with” includes that the two components of the combination product (compound of formula I and the other therapeutic agent) are administered (optionally repeatedly), either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either a formulation comprising compound of formula I, or a formulation comprising the other therapeutic agent, are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person.
  • the term "in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration with the other component.
  • the terms “administered simultaneously” and “administered at the same time as” include that individual doses of compound of formula I and the other therapeutic agent are administered within 48 hours (e.g. 24 hours) of each other.
  • the compounds/combinations/methods/uses described herein may have the advantage that, in the treatment of the conditions described herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have better selectivity, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar compounds, combinations, methods (treatments) or uses known in the prior art for use in the treatment of those conditions or otherwise.
  • FIG. 1a which shows the effect of the compound of Example 1 on AMPK phosphorylation.
  • PC3 cells were cultured in serum-free medium overnight (16 h) and subsequently incubated with 5 ⁇ M (5) or 10 ⁇ M (10) of the compound of Example 1 or 0.1% DMSO (-) for 6 h.
  • Equal amounts of protein from total cell lysates were separated by 4-12% Bis-Tris polyacrylamide gel and the phosphorylation of AMPK was immunoblotted with a specific anti-phospho-Thr-172 AMPK ⁇ antibody as described under "Experimental Procedures".
  • Figure 1b which shows the effect of the compound of Example 3 and compounds (j) and (k) of Example 4 on eEF2 phosphorylation.
  • 1 ⁇ M or 5 ⁇ M of the compound of Example 3 and compounds (j) and (k) of Example 4 were added and incubated for an additional 4 h.
  • the figure provides representative immunoblots of eEF2 phosphorylation (p) by the compound of Example 3 and compounds (j) and (k) of Example 4.
  • the compound of Example 3 and Compounds (j) and (k) of Example 4 stimulate AMPK and eEF2 phosphorylation in PC3 cells.
  • Figure 1 c which shows the effect of the compounds of Example 4 on AMPK and eEF2 phosphorylation.
  • 5 ⁇ M of the compounds (a) to (i) of Example 4 were added and incubated for an additional 1 h.
  • the figure provides representative immunoblots of AMPK and eEF2 phosphorylation (p) by compounds (a) to (i) of Example 4.
  • Compounds (a) to (i) of Example 4 stimulate AMPK and eEF2 phosphorylation in PC3 cells.
  • Figure 1d which shows the effect of the compounds of Example 4 on AMPK and eEF2 phosphorylation.
  • FIG 2 which shows the effect of compound of Example 1 on blood glucose levels in ob/ob mice.
  • Ob/ob mice were administered compound of Example 1 (30 mg/kg, gray bars) or vehicle (black bars) by oral gavage twice daily for 20 days. Blood sampling was made on fed mice at day 0, 16 hours post dose of day 12 and day 20 of dosing.
  • Figure 3a which shows that treatment of tumor cell lines with Example 2 generates a dose dependent reduction in proliferation in MDA-MB-231 human breast cancer cell lines as measured by BrdU incorporation.
  • Figure 3b which shows that treatment of tumour cell lines with Example 1 generates a dose dependent reduction in proliferation in PC3 human prostate cancer cell lines as measured by BrdU incorporation.
  • Figure 4 which shows that the compound of Example 1 inhibits TGF- ⁇ -induced secretion of collagen IV in human primary mesangial cells, as indicated by the measurement of absorbance using the ELISA procedure.
  • FIG. 5 which shows that the compound of Example 1 (referred to as L201 in the Figure) does not affect plasma insulin levels in C57BL/6JBomTac mice after acute administration. Blood samples were analyzed for plasma insulin prior to administration of the compound of Example 1 and 10, 30 and 60 min after drug administration.
  • L201 the compound of Example 1
  • FIG. 6a which shows the effect of TGF- ⁇ 1 or TGF- ⁇ 1 and the compound of Example 3 on EDA-fibronectin expression and ⁇ SMA expression in WI-38 lung fibroblast cells.
  • Wl- 38 cells were incubated with TGF- ⁇ 1 (1 ng/mL) or TGF- ⁇ 1 (1 ng/mL) and the compound of Example 3 at 0.125 and 0.625 ⁇ M respectively) for 24 h.
  • FIG. 6b which shows the effect of TGF- ⁇ 1 or TGF- ⁇ 1 and the compound of Example 3 on AMPK and SMAD2 phosphorylation in WI-38 lung fibroblast cells.
  • WI-38 cells were incubated with TGF- ⁇ 1 (1 ng/mL) or TGF- ⁇ 1 (1 ng/mL) and the compound of Example 3 at 0.125 and 0.625 ⁇ M respectively) for 24 h.
  • the figure shows that the compound of Example 3 increases the phopshorylation of AMPK and decreases SMAD2 phosphorylation.
  • Figure 7 which shows that the compound of Example 5 suppress PP2C mediated dephosphorylation of p-T172 of AMPK in a cell free system, as measured by the relative levels of p-T172 of AMPK.
  • Figure 8 which showns that the treatment of normal human fibroblast cell line WI-38 with the compound of Example 5 increases steady state levels of phosphorylated AMPK and ACC.
  • THF tetrahydrofuran where no preparative routes are included, the relevant intermediate is commercially available (e.g. from Chemical Diversity, San Diego, CA, USA or other available commercial sources).
  • LC-MS was performed on a Sciex API 150 LC/ES-MS equipped with an ACE 3 C8 column (30 x 3.0 mm) using a flow of 1 ml_/min. Two gradient systems of acetonitrile in water (with 0.1% TFA) are used for elution: A) 5-100% under 10 min, then 2 min 100% isocratic or B) 90-100% under 2 min, then 2 min 100% isocratic.
  • Direct inlet ES-MS was also performed on a Bruker Esquire LC/ES-MS. 1 H nuclear magnetic resonance was recorded on a Bruker Avance DRX 400 spectrometer at 400.01 MHz using residual solvent as internal standard.
  • N-Thiourea-(3-trifluoromethylphenyl)-acetamicle (4.71 g) and methanesulfonic acid (1.2 ml_, 1.1 eq.) were added to toluene (100 mL) and the resultant mixture refluxed. After 3 h the reaction was complete according to LC-MS analysis indicate and the solvent was evaporated to give the crude methanesulfonic acid salt as a white solid (>90% purity). The salt was then triturated by stirring in EtOAc (150 mL) for about 40 min and was then collected by filtration (4.71 g (100% purity) 78% yield).
  • the salt was dissolved in EtOAc (200 mL) and 2M NaOH (75 mL) and the layers separated. The organic phase was washed twice with 2M NaOH (75 mL) and the combined water phase extracted with 4x150 mL EtOAc. The combined organic phase was washed with water (150 mL) followed by brine (150 mL), dried (MgSO 4 ) and the solvent removed under reduced pressure to give the desired product as a white solid (2.8 g, 64% yield).
  • the compounds of Example 8 are formed in a one step reaction from commercially available 2-amino-1 ,3,4-thiodiazoles and commercially available sulfonylchloride derivatives using the following method : 50 mg of the 2-amino-1,3,4-thiodiazole is dissolved in 2 mL dichloromethane (DCM) and chilled to 0 0 C. 0.4 equiv dimethylaminopyridine (DMAP) and 1.2 equiv. pyridine is added and stirred for 5 min. 1.2 equiv. of the sulfonylchloride is added dropwise to the mixture. The reaction mixture is stirred for 12 h at rt.
  • DCM dichloromethane
  • DMAP dimethylaminopyridine
  • pyridine 1.2 equiv. pyridine
  • reaction mixture is then quenched with 2 mL NaHCO 3 (aq.) followed by 2 mL water and extracted twice with DCM (2 mL). The residue is dried over Na 2 SO 4 and concentrated.
  • the product was purified by column chromatography using silica and petroleum ether and EtOAc as eluting solvent
  • Example 9 The compound of Example 9 was formed in a one step reaction from commercially available 2-amino-1 ,3,4-thiodiazoles and commercially available chloroformate derivatives using the method as described for Example 1d.
  • the 5-substituted 1 ,3,4-thiadiazol-2-ylhydrazines are formed from the corresponding 2- amino- 1 ,3,4-thiadiazole via the 2-chloro-1 ,3,4-thiadiazole using methods well-known to the person skilled in the art. For example methods described in Potts et al ⁇ J. Org. Chem. 1966, 31 , 3528-3531).
  • General protocol for the formation of benzohydrazides The hydrazine derivative (45 mg) was dissolved in 2 mL DCM and 2 equiv. of 1 -ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC), 0.05 equiv.
  • 1 ,3,4-thiadiazol-2-yl)hydrazine (formed as described in Example 10) is treated with sulfonic acid chlorides derivatives as described in Example 8 but with the use of potassium carbonate as base and acetonitrile as solvent to form the 1 ,3,4-thiadiazol-2- yl]-5- benzenesulfonohydrazide derivatives .
  • Table 1 The data presented in Table 1 below indicates the potency for a number of compounds of the examples that were tested in Tests A, I and J below.
  • the potency of the compounds to stimulate the phosphorylation of Thr-172 on the AMPK- ⁇ subunit was estimated by comparing the relative intensity of the Western blot for the compound in question to the Western blot obtained using the solvent vehicle as a control.
  • a "+” indicates a compound that is more potent than the control compound (with "+++” representing compounds that were significantly more potent).
  • cancer cell lines including source, tumor type, and morphology may be obtained from the American Type Culture Collection (ATCC) or its website (www.atcc.org).
  • ATCC American Type Culture Collection
  • www.atcc.org www.atcc.org
  • Example 1 The compounds of Examples 1 and 3 were obtained as described above and Compounds (a) to (k) and (I) to (n), (q), (x), (a1) and (b1), of Example 4 were obtained from VitasM-Laboratories or Interbioscreen. A stock solution of 10 mM was prepared by dissolving the compounds in 100% DMSO.
  • PC3 cells were purchased from LGC Promochem-ATCC (ATCC catalog no CRL- 1435). PC3 cells were maintained in Dulbecco's modified Eagle's medium (Gibco 21885) containing 5% fetal bovine serum (Gibco 10500-064), 25 ug/ml Gentamicin (Gibco 15750) and 1x non essential amino acids (Gibco 11140). The cells were incubated in a humidified atmosphere of 5% CO 2 at 37°C and passaged every 3 days by trypsinization.
  • PC3 cells were cultured in complete medium with 10% fetal bovine serum in 60-mm-diameter dishes, grown to 70-80% confluence and cultured in serum-free Dulbecco's modified Eagle's medium for 5 h. Cells were then treated for 1 h with the compounds of Examples 1 , 3 and compounds (a) to (i) of Example 4 or for 4h with compounds (j) and (k) of Example 4 that were dissolved in DMSO at the concentrations indicated in Figures 1a to 1d or above. Cells treated with compounds (I), (m), (n), (q), (x), (a1) and (b1), of Example 4 were handled in a corresponding manner to cells treated with compounds (j) and (k) of Example 4. The final concentration of DMSO did not exceed 0.1%, which did not affect AMPK or eEF2 phosphorylation. 0.1% DMSO was used as control.
  • PC3 cells were lysed in buffer (10OmM TRIS pH 6,8, 2%w/v Sodium dodecylsulfate (SDS), 1OmM NaF, 1OmM ⁇ -glycerophosphate, 1mM Na Vanadate). Cell debris is removed by centrifugation at 14,000 X g for 15 min at 4 0 C and the resulting supernatant is used for Western blotting. Protein concentrations of the lysates were measured using a BCA protein assay kit (Pierce #23225).
  • Filters were washed in 2OmM TRIS pH 7.5, 137mM NaCI, 25%v/v Tween20 for 3x5min. Filters were incubated in blocking solution with secondary antibody, peroxidase- conjugated Goat anti-rabbit IgG (Jackson immunoResearch #111-035-003) at room temperature for 1 h. Filters were washed as above for 3x10 min. Signal was developed with SuperSignal West Dura ECL kit (Pierce #1859024) and exposed to Hyperfilm ECL (Amersham #28906837).
  • the Western blot result showed that the compound of Example 3 stimulated the phosphorylation of Thr-172 of the AMPK ⁇ subunit. Moreover, AMPK activation by the compound of Example 3 in PC3 cells was further confirmed by enhanced phosphorylation of eEF2. These results indicate that the compound of Example 3 stimulated AMPK phosphorylation and downstream activity (see Figures 1b).
  • the Western blot result showed that compounds (a) to (k) of Example 4 stimulated the phosphorylation of Thr-172 of the AMPK ⁇ subunit. Moreover, AMPK activation by compounds (a) to (k) of Example 4 in PC3 cells was further confirmed by enhanced phosphorylation of eEF2. These results indicate that compounds (a) to (i) of Example 4 stimulate AMPK phosphorylation and downstream activity (see Fig 1c), as do compounds (j) and (k) of Example 4 (see Figures 1 b and 1d).
  • the potency of the compounds of Examples 1 , 3, 4(a), 4(b), 4(d), 4(e), 4(f), 4(h), 40), 4(k), 4(I), 4(m), 4(n), 4(q), 4(x), 4(a1), and 4(b1) to stimulate the phosphorylation of Thr-172 on the AMPK- ⁇ subunit was estimated by comparing the relative intensity of the Western blot obtained for the vehicle control to the Western blot obtained for the compound in question. As indicated in Table 1 of Example 13, the compounds were generally more potent than the control compound.
  • the aim of this study was to verify the efficacy of the compound of Example 1 in diabetic ob/ob mouse with regard to correction of the metabolic disorder hyperglycemia.
  • Ob/ob mice were gavaged twice daily with the compound of Example 1 and the effect of the compound on levels of blood glucose were assessed and the results were compared to a concurrent control group gavaged with vehicle.
  • mice Male B6.V-Lep ob /JBomTac (model number OB-M) mice were bred and delivered by Taconic. Animals were housed in Umea University animal facility in transparent polycarbonate cages, with wood chip bedding at a 12 h light/darkness cycle, a temperature of ⁇ 21°C, and a relative humidity of ⁇ 50% throughout the accommodation and dosing periods. Five animals were housed in each cage with free access to standard rodent chow (CRM(E)Rodent, Special Diets Services, Scanbur BK, Sweden) and tap water. All animal experiments were approved by the Local Ethics Review
  • mice Male ob/ob mice, 18 to 19 weeks of age were administered compound of Example 1 (30 mg/kg body weight) or vehicle (0.5% methylcellulose and 1% DMSO in PBS) by oral gavage twice daily (8:00-9:00 A.M. and 4:00-5:00 P.M.) for 20 days.
  • Mice were administered 5 ml/kg body weight of each emulsion using a teflon needle with silicone tip (Agnthos AB, Liding ⁇ , Sweden). Blood samples were drawn from the tail vein from fed animals 16 h post dose of day 12 and 20 of dosing for analysis of blood glucose.
  • Blood glucose levels were measured by using a Glucometer Elite (Bayer) according to the manufacturer's recommendations.
  • the compound of Example 1 was evaluated in diabetic ob/ob mice to test the effect of the compound of Example 1 on hyperglycemia. As shown in Figure 2, on day 12 of the treatment, the group treated with the compound of Example 1 showed a noticeable decrease in fed blood glucose when compared to mice treated with vehicle. At the end of the experiment (day 20), fed blood glucose levels in vehicle treated ob/ob mice were higher than those in the ob/ob mice treated with the compound of Example 1.
  • Example 2 in 0.2% DMSO in quadruplicate. After 18 h incubation, BrdU was added according to manufacturer's recommendations. After 6 h incubation in the presence of BrdU, the culture media was removed and BrdU incorporation was measured using "Cell Proliferation ELISA, BrdU colorimetric 11 Roche (11647229001) according to manufacturer's recommendations.
  • Proliferation rate of MDA-MB-231 cells are reduced by relevant concentrations of the test compounds as measured by BrdU incorporation (see Figure 3a).
  • the compound of Example 2 relative to the vehicle control (which displayed a BrdU incorporation of 1 unit) displayed the following (approximate) units of BrdU incorporations at different concentrations:
  • Proliferation rate of PC-3 cells are reduced by relevant concentrations of the test compounds as measured by BrdU incorporation (see Figure 3b).
  • the compound of Example 1 relative to the vehicle control (which displayed a BrdU incorporation of 1 unit) displayed the following (approximate) units of BrdU incorporations at different concentrations:

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Abstract

La présente invention concerne des composés de formule I dans laquelle les lignes pointillées, X, T, G, N, Y, A1 à A5 et D1 à D5 prennent les significations données dans la description. Ces composés sont utiles dans le traitement d'états ou de troubles améliorés par l'activation de l'AMPK, par exemple les maladies de la peau, les maladies pulmonaires, l'obésité, la dégénérescence maculaire liée à l'âge de type sec, la cardioprotection ou, de préférence, l'hyperinsulinémie, le diabète, le cancer, la fibrose, les maladies neurodégénératives, les dysfonctionnements sexuels, l'insuffisance cardiaque, l'inflammation et l'ostéoporose.
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Families Citing this family (1)

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US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2420434A (en) 1945-03-12 1947-05-13 Monsanto Chemicals 2-amino-5-alkenyl-1, 3, 4 thiadiazoles and process for making the same
US2511371A (en) 1945-03-12 1950-06-13 Monsanto Chemicals Sulfa derivatives of 2-amino-5-alkenyl-1, 3, 4-thiadiazoles
US2524729A (en) 1945-03-12 1950-10-03 Monsanto Chemicals 2-amino-5-benzyl-1, 3, 4-thiadiazole and acid salts thereof
US3720685A (en) 1970-07-15 1973-03-13 Squibb & Sons Inc 3-amino-5-benzyl-1,2,4-oxadiazoles
DE2652121A1 (de) 1975-12-01 1977-06-02 Merck Patent Gmbh Verfahren zur herstellung von 1,3,4-thiadiazol-5-thiolen
DE2611965A1 (de) 1976-03-20 1977-09-29 Merck Patent Gmbh Verfahren zur herstellung von 1,3,4- thiadiazol-5-thiolen
US4054665A (en) 1974-11-29 1977-10-18 Sandoz, Inc. 2-Amino-5-(trifluoromethylphenylalkyl)-1,3,4 thiadiazoles used in the treatment of insomnia and anxiety
JP3258771B2 (ja) 1992-11-16 2002-02-18 株式会社豊田製作所 ブレーキロータの面振れ測定用治具
WO2004004720A1 (fr) 2002-07-03 2004-01-15 Astex Technology Limited 3-(hetero) arylmethoxy pyridines et leurs analogues en tant qu'inhibiteurs de la p38 map kinase
WO2004103980A1 (fr) 2003-05-21 2004-12-02 Biovitrum Ab Inhibiteurs de 11-beta-hydroxy steroide deshydrogenase de type i
WO2005002673A1 (fr) 2003-07-03 2005-01-13 Astex Therapeutics Limited Inhibiteurs de raf kinase
US20050019251A1 (en) 2003-07-03 2005-01-27 The Regents Of The University Of California Methods for comparing relative flux rates of two or more biological molecules in vivo through a single protocol
WO2006130986A1 (fr) 2005-06-09 2006-12-14 Merck Frosst Canada Ltd. Derives d'azacyclohexane comme inhibiteurs de la stearoyl-coenzyme a delta-9 desaturase
WO2007010281A2 (fr) 2005-07-21 2007-01-25 Betagenon Ab Utilisation de derives et d'analogues de thiazole dans les troubles causes par les acides gras libres
WO2007044565A2 (fr) 2005-10-06 2007-04-19 University Of Massachusetts Composition et synthese de nouveaux reactifs pour inhiber la replication du vih
WO2008029266A1 (fr) 2006-09-08 2008-03-13 Glenmark Pharmaceuticals S.A. Inhibiteurs de la stéaroyl coa désaturase
WO2008062276A2 (fr) 2006-11-20 2008-05-29 Glenmark Pharmaceuticals S.A. Dérivés d'acétylène comme inhibiteurs de la stéaroyl coa désaturase
WO2008104524A1 (fr) 2007-02-28 2008-09-04 Smithkline Beecham Corporation Dérivés de thiadiazole, inhibiteurs de stéoryl-coa désaturase

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004009933A1 (de) * 2004-02-26 2005-09-15 Merck Patent Gmbh Verwendung von Thiadiazolharnstoffderivaten
US20080221088A1 (en) * 2005-06-23 2008-09-11 Vijay Kumar Potluri 3,4-Substituted Thiazoles as Ampk Activators
AU2008345225A1 (en) * 2007-12-21 2009-07-09 University Of Rochester Method for altering the lifespan of eukaryotic organisms

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2420434A (en) 1945-03-12 1947-05-13 Monsanto Chemicals 2-amino-5-alkenyl-1, 3, 4 thiadiazoles and process for making the same
US2511371A (en) 1945-03-12 1950-06-13 Monsanto Chemicals Sulfa derivatives of 2-amino-5-alkenyl-1, 3, 4-thiadiazoles
US2524729A (en) 1945-03-12 1950-10-03 Monsanto Chemicals 2-amino-5-benzyl-1, 3, 4-thiadiazole and acid salts thereof
US3720685A (en) 1970-07-15 1973-03-13 Squibb & Sons Inc 3-amino-5-benzyl-1,2,4-oxadiazoles
US4054665A (en) 1974-11-29 1977-10-18 Sandoz, Inc. 2-Amino-5-(trifluoromethylphenylalkyl)-1,3,4 thiadiazoles used in the treatment of insomnia and anxiety
DE2652121A1 (de) 1975-12-01 1977-06-02 Merck Patent Gmbh Verfahren zur herstellung von 1,3,4-thiadiazol-5-thiolen
DE2611965A1 (de) 1976-03-20 1977-09-29 Merck Patent Gmbh Verfahren zur herstellung von 1,3,4- thiadiazol-5-thiolen
JP3258771B2 (ja) 1992-11-16 2002-02-18 株式会社豊田製作所 ブレーキロータの面振れ測定用治具
WO2004004720A1 (fr) 2002-07-03 2004-01-15 Astex Technology Limited 3-(hetero) arylmethoxy pyridines et leurs analogues en tant qu'inhibiteurs de la p38 map kinase
WO2004103980A1 (fr) 2003-05-21 2004-12-02 Biovitrum Ab Inhibiteurs de 11-beta-hydroxy steroide deshydrogenase de type i
WO2005002673A1 (fr) 2003-07-03 2005-01-13 Astex Therapeutics Limited Inhibiteurs de raf kinase
US20050019251A1 (en) 2003-07-03 2005-01-27 The Regents Of The University Of California Methods for comparing relative flux rates of two or more biological molecules in vivo through a single protocol
WO2006130986A1 (fr) 2005-06-09 2006-12-14 Merck Frosst Canada Ltd. Derives d'azacyclohexane comme inhibiteurs de la stearoyl-coenzyme a delta-9 desaturase
WO2007010281A2 (fr) 2005-07-21 2007-01-25 Betagenon Ab Utilisation de derives et d'analogues de thiazole dans les troubles causes par les acides gras libres
WO2007010273A2 (fr) 2005-07-21 2007-01-25 Betagenon Ab Utilisation de derives et analogues de thiazole dans le traitement du cancer
WO2007044565A2 (fr) 2005-10-06 2007-04-19 University Of Massachusetts Composition et synthese de nouveaux reactifs pour inhiber la replication du vih
WO2008029266A1 (fr) 2006-09-08 2008-03-13 Glenmark Pharmaceuticals S.A. Inhibiteurs de la stéaroyl coa désaturase
WO2008062276A2 (fr) 2006-11-20 2008-05-29 Glenmark Pharmaceuticals S.A. Dérivés d'acétylène comme inhibiteurs de la stéaroyl coa désaturase
WO2008104524A1 (fr) 2007-02-28 2008-09-04 Smithkline Beecham Corporation Dérivés de thiadiazole, inhibiteurs de stéoryl-coa désaturase

Non-Patent Citations (79)

* Cited by examiner, † Cited by third party
Title
"Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
A. A. JALIL; N. KURONO; M. TOKUDA, SYNTHESIS, 2002, pages 2681 - 2686
A.-E. WANG; J.-H. XIE; L.-X. WANG; Q.-L. ZHOU, TETRAHEDRON, vol. 61, 2005, pages 259 - 266
ALEMAGNA ET AL., TETRAHEDRON, vol. 24, 1968, pages 3209 - 3217
AMTUL ET AL., BIOCHEM. BIOPHYS. COMMUN., vol. 319, 2004, pages 1053 - 1063
AVETISYAN ET AL., KHIRNIKA-FARMASEVTICHESKII ZHUMAL, vol. 15, no. 6, 1981, pages 416 - 418
BOKIN BOBAI, vol. 10, no. 8, 1982, pages 341 - 346
BOOTS ET AL., J. HET. CHEM., vol. 4, 1967, pages 274 - 283
BOOTS ET AL., J. HETEROCYCLIC CHEM., vol. 4, 1967, pages 272 - 283
BOVET, COMPTES RENDUS DES SEANCES DE LA SOCIETE DE BIOLOGIE ET DE SESTILIALES, vol. 138, 1944, pages 764 - 765
BRADLEY ET AL., LIQUID CRYSTALS TODAY, vol. 14, 2005, pages 15 - 18
BUNDEGAARD, H.: "Design of Prodrugs", 1985, ELESEVIER, pages: 1 - 92
CHUBB ET AL., CAN. J. CHEM., vol. 37, 1959, pages 1121 - 1123
DOBRZYN, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 101, no. 17, 2004, pages 6409 - 6414
EHRMANN ET AL., J. CLIN. ENDOCRINOL. METAB., vol. 91, no. 1, 2006, pages 48 - 53
EMBO JOURNAL, vol. 23, 2004, pages 1770 - 1781
ERLICH, ET AI, NEUROBIOL. OF DISEASE, vol. 26, no. 1, 2007, pages 86 - 93
F. O. ARP; G. C. FU, J. AM. CHEM. SOC., vol. 127, 2005, pages 10482 - 10483
FOROUMADI ET AL., ARCH. PH ARM. CHEM. LIFE. SCI., vol. 338, 2005, pages 112 - 116
FOROUMADI ET AL., ARCH. PHARM. CHEM. LIFE SCI., vol. 338, 2005, pages 112 - 116
FOROUMADI ET AL., ARCH. PHARM. CHEM. LIFE. SCI., vol. 338, 2006, pages 112 - 116
FOROUMADI ET AL., ARZNEIM. FORSCH., vol. 49, 1999, pages 1035 - 1038
FREEMAN, J. ET AL.: "Discovery of phenoxypiperidines as novel Stearoyl-CoA desaturase inhibitors: From Assay Validation to Lead Development", 233RD ACS NATIONAL MEETING, 2007
HEALY ET AL., BRITISH MEDICAL JOURNAL, 1960, pages 913 - 915
HOKFELT ET AL., J. MED. PHARM. CHEM., vol. 5, 1962, pages 247 - 257
HURST, D. T.; STACEY, A. D.; NETHERCLEFT, M.; RAHIM, A.; HAMDEN, M. R, AUST. J. CHEM., vol. 41, 1998, pages 1221
HURST, D. T.; STACEY, A. D.; NETHERCLEFT, M.; RAHIM, A.; HAMDEN, M. R., AUST. J. CHEM., vol. 41, 1998, pages 1221
INDIAN J. CHEM. SECT 8, vol. 478, 2008, pages 579
J. E. MILNE; S. L. BUCHWALD, J. AM. CHEM. SOC., vol. 126, 2004, pages 13028 - 13032
J. ZHOU; G. C. FU, J. AM. CHEM. SOC., vol. 125, 2003, pages 12527 - 12530
JANOVSKA A ET AL., MOL. CELL. ENDOCRINOLOGY, vol. 284, no. 1-2, 2008, pages 1 - 10
K6NIGHOF ET AL., SWISS MED WKLY, vol. 139, no. 39-40, 2009, pages 554 - 563
KANAZAWA ET AL., BIOCHEM. BIOPHYS. RES. COMMUN., vol. 375, no. 3, 2008, pages 414 - 419
KIDWAI ET AL., BIOORG. MED. CHEM, vol. 8, 2000, pages 69 - 72
KIDWAI ET AL., BIOORG. MED. CHEM., vol. 8, 2000, pages 69 - 72
KIM ET AL., J. ANDROLOGY, vol. 28, no. 4, 2007, pages 555 - 560
KLOSA ET AL., ARC. PHARM., vol. 287, 1954, pages 12 - 14
KOLA ET AL., J. CLIN.ENDOCRINOL. METAB., vol. 93, no. 12, 2008, pages 4969 - 4973
KRAMER ET AL., J. HET. CHEM., vol. 31, 1994, pages 1439 - 1443
KRAMER ET AL., J. HETEROCYCLIC CHEM., vol. 31, 1994, pages 1439 - 1443
KURKJY ET AL., J. AM. CHEM. SOC., no. 74, 1952, pages 6260 - 6262
KURKJY ET AL., J. AM. CHEM. SOC., vol. 74, 1952, pages 6260 - 6262
L. R. MOORE; K. H. SHAUGHNESSY, ORG. LETT., vol. 6, 2004, pages 225 - 228
LADWA ET AL., ORIENTAL J. CHEM., vol. 18, no. 1, 2002, pages 135 - 138
LANGER, SCIENCE, vol. 249, 1990, pages 1527
LIU ET AL., J. MED. CHEM., vol. 50, no. 13, 2007, pages 3086 - 3100
MAERTEN ET AL., TETRAHEDRON, vol. 63, no. 3, 2007, pages 682 - 689
MANETTI ET AL., J. MED. CHEM., vol. 49, 2006, pages 3278 - 3286
MELEY ET AL., J BIOL CHEM., vol. 281, no. 46, 17 November 2006 (2006-11-17), pages 34870 - 34879
MISHRA ET AL., J. BIOL. CHEM., vol. 283, 2008, pages 10461 - 10469
N. HADEI; E. A. B. KANTCHEV; C. J. O'BRIEN; M. G. ORGAN, ORG. LETT., vol. 7, 2005, pages 3805 - 3807
NAGANAWA ET AL., BIORG. MED. CHEM., vol. 14, 2006, pages 6628 - 6639
NATH ET AL., J. IMMUNOLOGY, vol. 182, 2009, pages 8005 - 8014
NESTLER, HUM. REPROD., vol. 1, 12 October 1997 (1997-10-12), pages 53 - 62
PHARMAZIE, vol. 34, no. 9, 1979, pages 537 - 538
PIPPICH ET AL., J. HETEROCYCLIC CHEMISTRY, vol. 34, 1997, pages 823 - 828
POTTS ET AL., J. ORG. CHEM., vol. 31, 1966, pages 3528 - 3531
QIN; DE VRIES, J. BIOL. CHEM., vol. 283, no. 11, 2008, pages 6744 - 6751
RADJAVI ET AL., FASEB J., vol. 22, 2008, pages 942.12
REMINGTON: "The Science and Practice of Pharmacy", 1995, MACK PRINTING COMPANY
S. HUO, ORG. LETT., vol. 5, 2003, pages 423 - 425
SAG ET AL., J. IMMUNOL., vol. 181, no. 12, 2008, pages 8633 - 8641
SARAFIDIS; RUILOPE, AM. J. NEPHROL., vol. 26, 2006, pages 232 - 244
SHAFIEE ET AL., J. HET. CHEM., vol. 13, 1976, pages 117 - 121
SHAFIEE ET AL., J. HETEROCYCLIC CHEM., vol. 13, 1976, pages 117 - 121
SHARMA ET AL., J. CLIN. INVEST., vol. 118, no. 5, 2008, pages 1645 - 1656
SPASI ET AL., THE NEUROSCIENTIST, vol. 15, no. 4, 2009, pages 309 - 316
T. A. WYNN, J. PATHOLOGY, vol. 214, 2008, pages 199 - 210
T.W. GREENE; P.G.M. WUTZ: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE
TOYOOKA ET AL., CHEM. PHARM. BULL., vol. 35, no. 3, 1987, pages 1030 - 1035
TOYOOKA ET AL., CHEM. PHARM. BULL., vol. 39, no. 11, 1991, pages 2837 - 2841
U. KIEHNE; J. BUNZEN; H. STAATS; A. LUTZEN, SYNTHESIS, 2007, pages 1061 - 1069
VAILLANCOURT ET AL., BIOORG. MED. CHEM. LETT., vol. 10, 2000, pages 2079 - 2081
WEI; FOLSTEIN, NEUROBIOLOGY OF AGING, vol. 27, 2006, pages 190 - 198
WONG ET AL., CLIN. SCI., vol. 116, 2009, pages 607 - 620
XIN ET AL., BIOORG. MED. CHEM. LETT., vol. 18, no. 15, 2008, pages 4298 - 4302
YAROVENKO ET AL., RUSSIAN JOUMAL OF ORGANIC CHEMISTRY, vol. 39, no. 8, 2003, pages 1133 - 1139
ZHAO ET AL., AM. J. PHYSIOL. LUNG CELL MOL. PHYSIOL., vol. 295, 2008, pages L497 - L504
ZWANENBURG ET AL., TETRAHEDRON LETT., vol. 50, 1973, pages 5009 - 5012

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