FIELD OF THE INVENTION
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The present invention relates to glucokinase activators containing heteroaryloxy quinazoline derivatives as active ingredients. The present invention further relates to novel heteroaryloxy quinazoline derivatives.
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OF THE INVENTION
Glucokinase (GK) (ATP: D-hexose 6-phosphotransferase, EC 184.108.40.206) is one of four mammalian hexokinases (hexokinase IV). Hexokinases are enzymes in the first step of the glycolytic pathway and catalyze the reaction from glucose to glucose-6-phosphate. Glucokinase is expressed principally in the liver and pancreatic beta cells and plays an important role in whole-body glucose metabolism by controlling the rate-determining step in glucose metabolism in these cells. The glucokinases expressed in the liver and pancreatic beta cells differ in the sequence of the 15 N-terminal amino acids due to a difference in splicing, respectively, whereas their enzymatic characteristics are identical. The enzyme activities of the three hexokinases (I, II, and III) other than the glucokinase become saturated at a glucose concentration of 1 mM or lower, whereas the Km of glucokinase to glucose is 8 mM, which is close to the physiological blood glucose level. Accordingly, glucokinase-mediated intracellular glucose metabolism is accelerated in response to blood glucose level changes by postprandial glucose level increase (10-15 mM) from normal glucose (5 mM).
It has been hypothesized for around 10 years that glucokinase serves as a glucose sensor for pancreatic beta cells and the liver (for example, see non-patent document 1). Recent results in glucokinase gene-manipulated mice have confirmed that glucokinase does in fact play an important role in systemic glucose homeostasis. Mice lacking a functional glucokinase gene die shortly after birth (for example, see non-patent document 2), while healthy and diabetic mice overexpressing glucokinase have lower blood glucose levels (for example, see non-patent document 3). With glucose level increase, the reactions of pancreatic beta- and liver cells, while differing, both act toward lowering blood glucose. Pancreatic beta cells secrete more insulin, while the liver takes up glucose and stores it as glycogen while also reducing glucose release.
Such variation in glucokinase enzyme activity is important for liver and pancreatic beta cell-mediated glucose homeostasis in mammals. A glucokinase gene mutation has been found in a case of diabetes which occurs in youth, referred to as MODY2 (maturity-onset diabetes of the young), and the reduced glucokinase activity has been shown to be responsible for blood glucose increase (for example, see non-patent document 4). In contrast, families having a mutation increasing the glucokinase activity has been found, and such individuals exhibit hypoglycemia (for example, see non-patent document 5).
These suggest that in humans as well, glucokinase functions as a glucose sensor and thus plays an important role in glucose homeostasis. Glucose regulation utilizing a glucokinase sensor system is likely to be possible to achieve in most patients with type II diabetes mellitus. Since glucokinase activators should have effects of accelerating insulin secretion by pancreatic beta cells and of promoting glucose uptake and inhibiting glucose release by the liver, they are likely to be useful as therapeutic agents for patients with type II diabetes mellitus.
In recent years, it has been found that pancreatic beta cell glucokinase is expressed locally in rat brain, particularly in the ventromedial hypothalamus (VMH). Around 20% of VMH neurons are referred to as “glucose-responsive neurons”, and these have long been considered to play an important role in body weight control. Administration of glucose into rat brain reduces feeding consumption, whereas inhibition of glucose metabolism by intracerebral administration of glucose analog glucosamine produces hyperphagia. Electrophysiological experiments have indicated that glucose-responsive neurons are activated in response to physiological glucose level changes (5-20 mM) but that their activation is inhibited with glucose metabolism inhibition by, e.g., glucosamine. The glucose level-detecting system in the VMH is intended to be based on a glucokinase-mediated mechanism similar to that for insulin secretion by pancreatic beta cells. Accordingly, substances which activate glucokinase in the VMH in addition to the liver and pancreatic beta cells not only exhibit a glucose rectifying effect but can also potentially rectify obesity, which is a problem for most patients with type II diabetes mellitus.
The above description indicates that compounds having glucokinase-activating effects are useful as therapeutic and/or prophylactic agents for diabetes mellitus, as therapeutic and/or prophylactic agents for chronic complications of diabetes mellitus, such as retinopathy, nephropathy, neurosis, ischemic heart disease and arteriosclerosis, and further as therapeutic and/or prophylactic agents for obesity.
As a compound associated with a heteroaryloxy quinazoline derivative according to the present invention, for example, a compound represented by the following formula (A):
is disclosed in patent document 1.
Although there is a commonality of having GK activity between the compound represented by the formula (A) and a compound according to the present invention, the compound represented by the formula (A) has no dimethylaminoethoxy group as an essential substituent on a pyridine ring.
patent document 1: WO2005/090332
non-patent document 1: Garfinkel D. et al., Computer modeling identifies glucokinase as glucose sensor of pancreatic beta-cells, American Journal Physiology, vol. 247 (3Pt2) 1984, pp. 527-536
non-patent document 2: Grupe A. et al., Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis, Cell, vol. 83, 1995, pp. 69-78
non-patent document 3: Ferre T. et al., Correction of diabetic alterations by glucokinase, Proceedings of the National Academy of Sciences of the U.S.A, vol. 93, 1996, pp. 7225-7230
non-patent document 4: Vionnet N. et al., Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus, Nature Genetics, vol. 356, 1992, pp. 721-722
non-patent document 5: Glaser B. et al., Familial hyperinsulinism caused by an activating glucokinase mutation, New England Journal Medicine, vol. 338, 1998, pp. 226-230
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OF THE INVENTION
It is desirable to provide therapeutic and/or prophylactic agents for diabetes mellitus that bind to glucokinase to increase glucokinase activity; and to provide anti-obesity agents that stimulate and act on satiety center by activating glucokinase. The present invention also provides compounds having drug efficacy and/or more excellent properties as medicaments. Further provided are glucokinase activators comprising compounds according to the present invention or pharmaceutically acceptable salts thereof as active ingredients. Also provided are treatments and/or therapeutic agents for diabetes mellitus comprising compounds according to the present invention or pharmaceutically acceptable salts thereof as active ingredients. Also provided are pharmaceutical compositions comprising compounds according to the present invention or pharmaceutically acceptable salts thereof as active ingredients. In addition, the present invention also provides pharmaceutical compositions comprising: compounds according to the present invention used for treating, preventing and/or delaying onset of type 2 diabetes mellitus; other drugs; and pharmaceutically acceptable carriers.
The present inventors undertook thorough research to find that introduction of a dimethylaminoethoxy group or the like as a substituent on a quinazoline ring into quinazoline compounds having GK activation action in related art results in great improvement in drug efficacy and/or properties such as solubility compared to quinazoline compounds in related art, and the invention was thus accomplished.
Specifically, the present invention relates to:
(1) a compound represented by a formula (I):
[wherein the A ring represents a 5- or 6-membered heteroaryl ring that is selected from the group consisting of pyrazolyl, pyrazinyl, thiadiazolyl, thiazolyl, pyridinyl, thiatriazolyl, triazolyl, tetrazolyl, imidazolyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl and isoxazolyl groups, which may have one or two groups selected from the group consisting of lower alkyl, lower alkoxy, halogen, hydroxy, C3-7 cycloalkyl and lower alkyl having 1-3 identical or different lower alkoxy groups, halogen atoms or hydroxy groups, or represents a ring in which the 5- or 6-membered heteroaryl ring and a benzene or pyridine ring are condensed;
the B ring represents a 5- or 6-membered heteroaryl group having 1-3 identical or different hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms;