HK1170171A

HK1170171A - Combination therapy for the treatment of diabetes

Info

Publication number: HK1170171A
Application number: HK12110952.1A
Authority: HK
Inventors: Yin Liang; John Ryan; Abraham B. Woldu; Lisa E. Wu
Original assignee: Janssen Pharmaceutica, N.V.
Priority date: 2009-07-08
Filing date: 2010-07-07
Publication date: 2013-02-22

Description

Combination therapy for the treatment of diabetes

Cross reference to related patent applications

This patent application claims the benefit of U.S. provisional patent application 61/223,881 filed on 7/8/2009, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to co-therapies (co-therapies) and methods for the treatment and prevention of glucose-related disorders such as type 2diabetes and syndrome X. The invention further relates to pharmaceutical compositions for use in the synergistic treatments and methods described herein.

Background

Diabetes is a medical term that exists for elevated blood glucose. A diabetic patient either fails to produce insulin, produces too little insulin, or fails to respond to insulin, resulting in the accumulation of glucose in the blood. The most common form of diabetes is type 2diabetes, once referred to as adult-onset diabetes or non-insulin dependent diabetes mellitus (NIDDM), which accounts for > 90% of diabetes in adults. However, type 2diabetes is becoming increasingly prevalent in adolescents and children as younger populations become increasingly overweight or obese. Diabetes may also refer to gestational diabetes, type 1 diabetes, or autoimmune diabetes, once referred to as juvenile onset diabetes and 11/2 diabetes, also known as latent autoimmune diabetes adult or LADA. Diabetes may occur as a result of poor eating habits or lack of physical activity (e.g., sedentary lifestyle), genetic mutation, pancreatic damage, drug (e.g., AIDS therapy) or chemical (e.g., steroid) exposure or disease (e.g., cystic fibrosis, down syndrome, cushing's syndrome). Two rare types of genetic defects that cause diabetes are termed juvenile adult onset diabetes (MODY) and Atypical Diabetes (ADM).

Type 2diabetes (non-insulin dependent diabetes mellitus or NIDDM) is a metabolic disorder involving dysregulation of glucose metabolism and insulin resistance and long-term complications involving the eyes, kidneys, nerves and blood vessels. Type 2diabetes usually develops in adulthood (middle or later) and is described by the inability of the human body to produce sufficient insulin (abnormal insulin secretion) or its inability to utilize insulin efficiently (resistance to insulin action in target organs and tissues). More specifically, patients with type 2diabetes have a relative insulin deficiency. That is, in these patients, plasma insulin levels are normal to high in an absolute sense, although they are lower than expected for the presence of plasma glucose levels.

Type 2diabetes is characterized by the following clinical signs or symptoms: sustained elevated plasma glucose concentration or hyperglycemia; polyuria; polydipsia and/or polyphagia; chronic microvascular complications such as retinopathy, nephropathy and neuropathy; and macrovascular complications such as hyperlipidemia and hypertension that can lead to blindness, end stage renal disease, amputation, and myocardial infarction.

Syndrome X, also known as Insulin Resistance Syndrome (IRS), metabolic syndrome or X metabolic syndrome, is a disorder that makes it possible to develop type 2diabetes and cardiovascular diseases including glucose intolerance, hyperinsulinemia and insulin resistance, hypertriglyceridemia, hypertension and obesity.

Diagnosis of type 2diabetes involves assessment of symptoms and measurement of glucose in the urine and blood. Blood glucose level determination is essential for accurate diagnosis. More specifically, fasting blood glucose level determination is the standard method used. However, the Oral Glucose Tolerance Test (OGTT) is considered to be more sensitive than fasting blood glucose levels. Type 2diabetes is associated with abnormal Oral Glucose Tolerance (OGT). OGTT may thus help in diagnosing Type 2Diabetes, but in general is not necessary for Diabetes diagnosis (Emancopator K, Am J Clin Pathol 1999, 11 months; 112 (5): 665-74; Type 2Diabetes mellitis, precision Resources Inc., 2000, 3 months). OGTT allows the estimation of pancreatic beta cell secretory function and insulin sensitivity, which aids in the diagnosis of type 2diabetes and in the assessment of the severity or progression of the disease (e.g., Caumo A, Bergman RN, Cobelli C, J Clin Endocrinol Metab 2000, 85 (11): 4396-402). More specifically, the OGTT contributes to determining the degree of hyperglycemia in patients with multiple borderline fasting blood glucose levels who have not yet been diagnosed with diabetes. In addition, OGTT can be used to test patients with type 2diabetes symptoms who have to be definitively confirmed or rejected for possible diagnosis of abnormal carbohydrate metabolism.

Thus, impaired glucose tolerance is diagnosed in individuals who have fasting blood glucose levels below those required to diagnose type 2diabetes, but have a plasma glucose response between normal and diabetic during the OGTT. Glucose tolerance abnormalities are considered to be a pre-diabetic state, and glucose tolerance abnormalities (defined by OGTT) are a strong predictor of the development of type 2diabetes (Haffner SM, Diabet Med 1997 month 8; 14Suppl 3: S12-8).

Type 2diabetes is a progressive disease that is exacerbated by increased plasma glucose levels associated with decreased pancreatic function and/or a decrease in other insulin-related processes. Thus, type 2diabetes typically has a long-term pre-diabetic stage and a variety of pathophysiological mechanisms can lead to pathological hyperglycemia and abnormal glucose tolerance, such as abnormal glucose utilization and efficiency, insulin action, and/or insulin production in the pre-diabetic state (Goldberg RB, Med Clin North Am, 1998; 82 (4): 805-21).

Pre-Diabetes associated with glucose intolerance may also be associated with abdominal obesity, insulin resistance, hyperlipidemia and hypertension, and syndrome X (Groop L, Forsborm C, Lehtovirta M, Am J Hypertens 1997 7 months; 10(9Pt 2): 172S-180S; Haffner SM, J Diabetes Compounds 1997 3-4 months; 11 (2): 69-76; Beck-Nielsen H, Henriksen JE, Alford F, Hother-Nielson O, Diabetes Med1996 9 months; 13(9Suppl 6): S78-84).

Thus, defective carbohydrate metabolism is critical for the onset of type 2diabetes and impaired glucose tolerance (Dinneen SF, Diabet Med 1997, 8 months; 14Suppl 3: S19-24). Indeed, conditions that continue from abnormal glucose tolerance and abnormal fasting glucose to eventual type 2diabetes are present ((Ramlo-suspended BA, Edelman SV, Prim Care 1999 month 12; 26 (4): 771-89).

Early intervention in individuals at risk of developing type 2diabetes, focused on reducing pathological hyperglycemia or impaired glucose tolerance, may prevent or delay progression to type 2diabetes and associated complications and/or syndrome X. Thus, by effectively treating oral glucose tolerance abnormalities and/or elevated blood glucose levels, progression of the disorder to type 2diabetes or syndrome X can be prevented or inhibited.

Typical treatments for glucose disorders, including type 2diabetes and syndrome X, focus on maintaining blood glucose levels as close to normal as possible, and include diet and exercise, as well as, where necessary, treatment with anti-diabetic agents, insulin, or combinations thereof. Type 2diabetes mellitus that cannot be controlled by dietary management is treated with oral antidiabetic agents, including but not limited to: sulfonylureas (e.g., without limitation, the first generation: chlorpropamide, tolazamide (tolazamide), tolbutamide, the second generation: glyburide (glyburide), glipizide (glipizide), and the third generation: glimepiride), biguanides (e.g., metformin), thiazolidinediones (e.g., rosiglitazone, pioglitazone, troglitazone), alpha-glucosidase inhibitors (e.g., acarbose, miglitol), meglitinides (e.g., repaglinide), other insulin sensitizing compounds, and/or other anti-obesity agents (e.g., orlistat or sibutramine). Anti-diabetic agents are additionally combined with pharmacological agents for the treatment of concomitant comorbidities (e.g. antihypertensive agents for hypertension, hypolipidemic agents for hyperlipidemia) for syndrome X.

First line therapy typically includes metformin and sulfonylureas as well as thiazolidinediones. Metformin monotherapy is the first line of choice, particularly for the treatment of type 2diabetes patients who are also obese and/or dyslipidemia. Lack of adequate response to metformin is usually followed by treatment with metformin in combination with sulfonylureas, thiazolidinediones or insulin. Sulfonylurea monotherapy (including all generations of drugs) is also a common first line of choice. Another first-line therapy option may be thiazolidinediones. For patients who do not respond properly to oral anti-diabetic monotherapy, a combination of these agents is administered. Insulin therapy is used as monotherapy or in combination with oral antidiabetics when glycemic control cannot be maintained with oral antidiabetics alone. These same strategies, optionally in combination with additional strategies (e.g., anti-hypertensive agents), can be used to treat syndrome X.

Anti-diabetic agents include, but are not limited to:

(a) sulfonylureas, which increase insulin production by stimulating pancreatic β cells, thus acting as insulin secretagogues. The primary mechanism of action of sulfonylureas is to close ATP-sensitive potassium channels in the plasma membrane of the beta cell, thereby initiating a cascade of events leading to insulin release. Suitable examples of sulfonylureas include, but are not limited to, chlorpropamide, tolazamide, tolbutamide, glyburide, glipizide, glimepiride, and the like.

(b) Meglitinide, another class of insulin secretagogues, has a mechanism of action different from that of sulfonylureas. Suitable examples of meglitinides include, but are not limited to, repaglinide.

(c) Agents that can modify insulin secretion such as glucagon-like peptide 1(GLP-1) and mimetics thereof, Glucose Insulinotropic Peptide (GIP) and mimetics thereof, Exendin (Exendin) and mimetics thereof, and dipeptidyl protease inhibitors (DPPIV).

(d) Biguanides, which can reduce hepatic glucose production and increase glucose uptake. Suitable examples include, but are not limited to, metformin.

(e) Thiazolidinediones, which are insulin-sensitizing drugs that can reduce peripheral insulin resistance by enhancing the action of insulin at a target organ or tissue. These agents bind to and activate nuclear receptors, the peroxisome proliferator-activated receptor gamma (PPAR- γ), which increases transcription of specific insulin responsive genes. Suitable examples of PPAR-agonists are thiazolidinediones, which include, but are not limited to, rosiglitazone, pioglitazone, troglitazone, ixabeglitazone (designated MCC-555), 2- [2- [ (2R) -4-hexyl-3, 4-dihydro-3-oxo-2H-1, 4-benzoOxazin-2-yl]Ethoxy radical]-phenylacetic acid and the like. In addition, non-thiazolesThe alkanediones can also be used as insulin sensitizers, including but not limited to GW2570 and the like.

(f) retinoid-X receptor (RXR) modulators (also insulin sensitizers) including, but not limited to, tagretin (targretin), 9-cis-retinoic acid, and the like.

(g) Other insulin sensitizers include, but are not limited to, INS-1, PTP-1B inhibitors, GSK3 inhibitors, glycogen phosphorylase a inhibitors, fructose-1, 6-bisphosphatase inhibitors, and the like.

(h) An alpha-glucosidase inhibitor which acts to inhibit alpha-glucosidase. Alpha-glucosidase converts fructose to glucose and thus these inhibitors may delay the digestion of sugars. Undigested carbohydrates are subsequently broken down in the intestine, thereby lowering the postprandial blood glucose peak. Suitable examples include, but are not limited to, acarbose and miglitol.

(i) Insulin, including regular or fast acting, intermediate and long acting, inhaled and insulin analogues such as insulin molecules with subtle differences in the natural amino acid sequence. These modified insulins may have a faster onset of action and/or a shorter duration of action.

(j) Small molecule mimetics of insulin, including but not limited to L-783281, TE-17411, and the like.

(k) Sodium-glucose cotransporter inhibitors that inhibit the reabsorption of glucose by the kidney, such as T-1095, T-1095A, phlorizin, and the like.

(l) Amylin (Amylin) agonists, including but not limited to pramlintide and the like.

(k) Glucagon antagonists such as AY-279955 and the like.

In addition to antidiabetic agents, therapy may include additional treatment with antiobesity agents, such as orlistat, which is a pancreatic lipase inhibitor that prevents lipolysis and absorption; or sibutramine, which is an appetite suppressant and a reuptake inhibitor of serotonin, norepinephrine and dopamine in the brain. Other potential additional anti-obesity agents include, but are not limited to: appetite suppressants acting through an adrenergic mechanism, such as benzphetamine, phenmetrazine, phentermine, bupropion, mazindol, sibutramine, norephedrine or ephedrine; appetite suppressants acting through a 5-hydroxytryptamine-capable mechanism, such as quinazine, fluoxetine, sertraline, fenfluramine or dexfenfluramine; appetite suppressants acting through dopamine mechanisms, such as apomorphine; appetite suppressants that act through histaminergic mechanisms (e.g., histamine mimetics, H3 receptor modulators); energy expenditure enhancers such as beta-3 adrenergic agonists and uncoupling protein function stimulators; leptin and leptin mimetics; a Y neuropeptide antagonist; melanocortin-1, 3 and 4 receptor modulators; a cholecystokinin agonist; glucagon-like peptide-1 (GLP-1) mimetics and analogs (e.g., exendin); androgens (e.g., dehydroepiandrosterone and its derivatives such as native cholanonene), testosterone, anabolic hormones (e.g., oxandrolone), and steroid hormones; galanin receptor antagonists; cytokine agents such as ciliary neurotrophic factor; an amylase inhibitor; enterostatin agonists/mimetics; orexin/hypothalamin antagonists; a urocortin antagonist; bombesin agonists; a protein kinase a modulator; corticotropin-releasing factor mimetics; cocaine-and amphetamine-regulated transcript mimetics; calcitonin gene-related peptide mimetics; and fatty acid synthase inhibitors.

There remains a need to provide effective treatments for glucose-related disorders such as elevated blood glucose, type 2diabetes, syndrome X, and the like. There also exists a need to provide an effective treatment for glucose-related disorders that also slows or prevents the progression and/or progression of type 2 diabetes.

Disclosure of Invention

The present invention relates to a method of co-therapy for the treatment and prevention of glucose related disorders, said method comprising administering to a subject in need thereof a therapeutically effective amount of co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I)

Wherein ring a and ring B are one of:

(1) ring a is an optionally substituted unsaturated monocyclic heterocycle, ring B is an optionally substituted unsaturated monocyclic heterocycle, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring; or

(2) Ring a is an optionally substituted benzene ring, ring B is an optionally substituted unsaturated monocyclic heterocycle, or an optionally substituted unsaturated fused heterobicyclic ring, wherein Y is connected to the heterocycle of the fused heterobicyclic ring; or

(3) Ring a is an optionally substituted unsaturated fused heterobicyclic ring, wherein both the sugar moiety X- (sugar) and the moiety-Y- (ring B) are located on the same heterocyclic ring of the fused heterobicyclic ring, ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring;

x is a carbon atom or a nitrogen atom; and

y is- (CH)₂)_n- (wherein n is 1 or 2);

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

The present invention also relates to a method of co-therapy for the treatment and prevention of glucose-related disorders, said method comprising administering to a subject in need thereof a therapeutically effective amount of co-therapy comprising (a) glyburide and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also relates to the use of (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with (b) metformin or a pharmaceutically acceptable salt thereof for the treatment and prevention of glucose related disorders.

The present invention also relates to the use of (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with (b) metformin or a pharmaceutically acceptable salt thereof and (c) a sulfonylurea, preferably glibenclamide, or a pharmaceutically acceptable salt thereof for the treatment and prevention of glucose related disorders.

The present invention also relates to a method of co-therapy for the treatment and prevention of glucose-related disorders, said method comprising administering to a subject in need thereof a therapeutically effective amount of co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (c) a sulfonylurea (preferably glyburide) or a pharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition comprising (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient. An example of the present invention is a pharmaceutical composition prepared by mixing (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient. Exemplified herein is a process for preparing a pharmaceutical composition comprising admixing (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient.

The invention also relates to a pharmaceutical composition comprising (a) a sulfonylurea, preferably glibenclamide, or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient. An example of the present invention is a pharmaceutical composition prepared by mixing (a) a sulfonylurea (preferably glibenclamide) or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient. Exemplified herein is a process for preparing a pharmaceutical composition comprising mixing (a) a sulfonylurea (preferably glibenclamide) or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient.

The present invention also relates to a pharmaceutical composition comprising (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, (c) a sulfonylurea or a pharmaceutically acceptable salt thereof, and (d) a pharmaceutically acceptable excipient. One example of the present invention is a pharmaceutical composition prepared by mixing (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of the formula (I) or a pharmaceutically acceptable salt thereof, (c) a sulfonylurea or a pharmaceutically acceptable salt thereof, and (d) a pharmaceutically acceptable excipient. Exemplified herein is a process for preparing a pharmaceutical composition comprising mixing (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, (c) a sulfonylurea or a pharmaceutically acceptable salt thereof, and (d) a pharmaceutically acceptable excipient.

Detailed Description

The present invention relates to a method for the treatment and prevention of glucose related disorders, said method comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I)

Wherein ring a, ring B, X, and Y are as defined herein; or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) are shown to have inhibitory activity against sodium-dependent glucose transporters such as SGLT 2. The compounds of formula (I) are shown to have inhibitory activity against sodium-dependent glucose transporters present in the intestine and kidney of mammalian species, and are also shown to have blood glucose lowering effect. The compounds of formula (I) may be prepared according to methods disclosed in the following documents: nomura, s, et al, published on 10/20/2005, U.S. patent publication US 2005/0233988a1, which is incorporated herein by reference.

In one embodiment, the present invention relates to a method of treating and preventing a glucose-related disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I-X)

Or a pharmaceutically acceptable salt thereof. In certain preferred embodiments, the compound of formula (I-X) is a crystalline form of the hemihydrate of the compound of formula (I-X), as described in WO 2008/069327, the disclosure of which is incorporated herein by reference in its entirety.

In another embodiment, the present invention relates to a method of treating or preventing a glucose-related disorder comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I-Y)

Or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating and preventing glucose-related disorders, said method comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) a sulfonylurea, preferably glyburide, or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I)

Wherein ring a, ring B, X, and Y are as defined herein; or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a method of treating or preventing a glucose-related disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) a sulfonylurea, preferably glyburide, or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I-X), or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a method of treating or preventing a glucose-related disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) a sulfonylurea (preferably glyburide), or a pharmaceutically acceptable salt thereof, and (b) a compound of formula (I-Y), or a pharmaceutically acceptable salt thereof.

Metformin, more particularly metformin hydrochloride (also known under the trade names GLUCOPHAGE, RIOMET, fortame, glucetza, OBIMET, dienen, DIABEX, diammin, and the like) is a biguanide type oral antidiabetic agent. Metformin is a first line therapy for type 2diabetes, particularly in overweight and obese people. In the united states and some countries, metformin (e.g., as a metformin hydrochloride tablet) is typically administered as a starting dose of 500mg twice daily or 850mg once daily, with a meal. The daily dose may be increased in increments of 500mg per week or 850mg per 2 weeks, up to a total of 2000mg per day, given in divided doses. Patient doses may also be escalated from 500mg twice daily to 850mg twice daily after 2 weeks. For those patients requiring additional glycemic control, a daily maximum dose of metformin to 2550mg per day may be administered. Doses in excess of 2000mg are better tolerated within three meals per day. Preferably, the metformin or a pharmaceutically acceptable salt thereof is metformin hydrochloride.

Glibenclamide (also known under the trade names DIABETA, GLYNASE, PRESTAB, MICRONASE, etc.) is a sulfonylurea type of oral antidiabetic agent. Glibenclamide is used in the treatment of type II diabetes by inhibiting ATP-sensitive potassium channels in pancreatic beta cells. This inhibition causes depolarization of the cell membrane, which causes voltage-dependent calcium channels to open, which in turn causes an increase in intracellular calcium in the beta cell, which stimulates insulin release. The starting dose of glibenclamide is typically 2.5mg to 5mg (1.5 gm to 3mg if administered as micronized glibenclamide) taken daily with a meal. If desired, the glibenclamide dose may be escalated (with an increase of 2.5mg or less per week) up to 20mg per day (or up to 12mg per day if administered as micronized glibenclamide). Glibenclamide may also be administered in combination with metformin, which is available under the trade names GLUCOVANCE and GLIBOMET.

The present invention also relates to a method of treating and preventing glucose related disorders comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (c) a sulfonylurea or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention relates to a method of treating and preventing a glucose-related disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I-X) or a pharmaceutically acceptable salt thereof and (c) a sulfonylurea or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to a method of treating or preventing a glucose-related disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I-Y) or a pharmaceutically acceptable salt thereof and (c) a sulfonylurea or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating and preventing a glucose-related disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (c) glibenclamide.

In another embodiment, the present invention relates to a method of treating or preventing a glucose-related disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I-X) or a pharmaceutically acceptable salt thereof and (c) glibenclamide.

In another embodiment, the present invention relates to a method of treating or preventing a glucose-related disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I-Y) or a pharmaceutically acceptable salt thereof and (c) glyburide.

Sulfonylureas are a class of compounds that can be used by stingingA pharmaceutical compound which stimulates pancreatic beta cells to increase insulin production and thereby acts as an insulin secretagogue. The primary mechanism of action of sulfonylureas is to close ATP-sensitive potassium channels in the plasma membrane of the beta cell, thereby initiating a cascade of events leading to insulin release. Suitable examples of sulfonylureas include, but are not limited to, chlorpropamide, tolazamide, tolbutamide, glyburide, glipizide, glimepiride, and the like. The dosage and administration of the sulfonylurea can be readily determined by one skilled in the art by consulting the PDR (physics's Desk Reference) and/or FDA-mandated drug literature including the agent. For example, chlorpropamideA representative dose of (a) is 100-250mg once a day; tulasulfenuronA representative dose of 250mg once a day or twice a day; tolbutamideA representative dose of 1000mg twice a day or three times a day; glimepirideA representative dose of (a) is 2mg once a day; glipizideThe representative dose of (a) is 5-10mg once a day or twice a day; and glibenclamideA representative dose of (a) is 2.5-5mg once a day or twice a day.

In one embodiment of the invention, the sulfonylurea is selected from chlorpropamide, tolazamide and tolbutamide; wherein the sulfonylurea is present (administered) in an amount ranging from about 100mg to about 3000mg or any amount or range within that range, preferably in an amount ranging from about 100mg to about 1000mg or any amount or range within that range. In another embodiment of the invention, the sulfonylurea is selected from glibenclamide, glipizide, and glimepiride; and is present in an amount ranging from about 0.1mg to about 50mg or any amount or range within that range, preferably in an amount ranging from about 1.0mg to about 50mg, more preferably in an amount ranging from about 2.0mg to about 25mg or any amount or range within that range.

In another embodiment of the invention, the sulfonylurea is glibenclamide; wherein the glibenclamide is present in an amount in the range of from about 1.0mg to about 20mg per day or any amount or range within that range; preferably in an amount in the range of from 2.5mg to about 20mg per day or any amount or range within that range, more preferably in an amount in the range of from 2.5mg to about 10mg per day or any amount or range within that range, and more preferably in an amount in the range of from 2.5mg to about 5mg per day or any amount or range within that range.

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a co-therapy comprising (a) metformin or a pharmaceutically acceptable salt thereof; and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a co-therapy comprising (a) glibenclamide; and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition comprising (a) metformin or a pharmaceutically acceptable salt thereof; (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (c) a sulfonylurea or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention relates to a pharmaceutical composition comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I-X) or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is directed to a pharmaceutical composition comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I-Y) or a pharmaceutically acceptable salt thereof. In another embodiment of the present invention, the pharmaceutical composition is an immediate release dosage form. In another embodiment of the present invention, the pharmaceutical composition is an extended release dosage form wherein the dosage form releases the one or more active ingredients over a period of time ranging from about 8 to about 24 hours or any amount and range within this range.

In one embodiment, the present invention relates to a pharmaceutical composition comprising (a) glibenclamide and (b) a compound of formula (I-X), or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention relates to a pharmaceutical composition comprising (a) glibenclamide and (b) a compound of formula (I-Y), or a pharmaceutically acceptable salt thereof. In another embodiment of the present invention, the pharmaceutical composition is an immediate release dosage form. In another embodiment of the present invention, the pharmaceutical composition is an extended release dosage form wherein the dosage form releases the one or more active ingredients over a period of time ranging from about 8 to about 24 hours or any amount and range within this range.

In one embodiment, the present invention relates to a pharmaceutical composition comprising (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I-X) or a pharmaceutically acceptable salt thereof, and (c) a sulfonylurea or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I-Y) or a pharmaceutically acceptable salt thereof, and (c) a sulfonylurea or a pharmaceutically acceptable salt thereof. In another embodiment of the present invention, the pharmaceutical composition is an immediate release dosage form. In another embodiment of the present invention, the pharmaceutical composition is an extended release dosage form wherein the dosage form releases the one or more active ingredients over a period of time ranging from about 8 to about 24 hours or any amount and range therein, preferably over a period of time ranging from about 8 to about 12 hours or any amount and range therein.

In one embodiment, the present invention relates to a pharmaceutical composition, wherein the metformin or a pharmaceutically acceptable salt thereof is metformin hydrochloride. In another embodiment, the present invention relates to a pharmaceutical composition, wherein the metformin hydrochloride is present in a dose ranging from about 100mg to about 2000mg, preferably from about 250mg to about 1000mg, or any amount or range within said range. In another embodiment, the present invention relates to a pharmaceutical composition, wherein the metformin hydrochloride is present in a dose selected from the group consisting of 250mg, 500mg, 750mg, 850mg, 1000mg, 1700mg and 2000 mg.

In another embodiment, the invention relates to a pharmaceutical composition, wherein the glibenclamide is present in a dose ranging from about 1.0mg to about 20.0mg, preferably from about 2.5mg to about 20.0mg, more preferably from about 2.5mg to about 10.0mg, or any amount or range within said range. In another embodiment, the present invention relates to a pharmaceutical composition, wherein the glibenclamide is present in a dose selected from 1.0, 1.5, 2.5, 5.0, 7.5, 10, 12.5, 15 and 20 mg.

In one embodiment, the present invention relates to a pharmaceutical composition wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I-X) or a pharmaceutically acceptable salt thereof; and a compound of formula (I-Y) or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a pharmaceutical composition wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-X) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to a pharmaceutical composition wherein the compound of formula (I-X) or a pharmaceutically acceptable salt thereof is present in a dose ranging from about 1mg to about 500mg, preferably from about 1mg to about 300mg, preferably from about 25mg to about 300mg, or any amount or range within said range. In another embodiment, the present invention relates to a pharmaceutical composition wherein the compound of formula (I-X) or a pharmaceutically acceptable salt thereof is present in a dose ranging from about 25mg to about 300mg, preferably a dose selected from 50mg, 100mg, 150mg, 200mg and 300 mg.

In another embodiment, the present invention relates to a pharmaceutical composition wherein the compound of formula (I-Y) or a pharmaceutically acceptable salt thereof is present in a dose ranging from about 1mg to about 500mg, preferably from about 1mg to about 100mg, preferably from about 1mg to about 50mg, or any amount or range within said range. In another embodiment, the present invention is directed to a pharmaceutical composition wherein the compound of formula (I-Y) or a pharmaceutically acceptable salt thereof is present in a dose selected from 1mg, 5mg, 10mg, 25mg, 50mg, and 100 mg.

In another embodiment, the present invention relates to a pharmaceutical composition comprising:

(a) metformin or a pharmaceutically acceptable salt thereof;

(b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from a compound of formula (I-X) or a pharmaceutically acceptable salt thereof; and a compound of formula (I-Y) or a pharmaceutically acceptable salt thereof;

wherein the metformin or a pharmaceutically acceptable salt thereof is present in an amount in the range of from about 100mg to about 2000mg, preferably from about 500mg to about 1000mg or any amount or range within this range; and is

Wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 1mg to about 1000mg or any amount or range within that range (preferably in an amount ranging from about 1mg to about 500mg or any amount or range within that range, more preferably in an amount ranging from about 10mg to about 300mg or any amount or range within that range).

(a) glibenclamide; wherein the glibenclamide is present in an amount in the range of about 1.0mg to about 20mg, preferably in an amount in the range of about 2.5mg to about 20mg or any amount or range within this range; and

(b) a compound of formula (I) or a pharmaceutically acceptable salt thereof (wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I-X) or a pharmaceutically acceptable salt thereof; and a compound of formula (I-Y) or a pharmaceutically acceptable salt thereof); wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 1mg to about 1000mg or any amount or range within that range (preferably in an amount ranging from about 1mg to about 500mg or any amount or range within that range, more preferably in an amount ranging from about 10mg to about 300mg or any amount or range within that range).

In one embodiment of the invention, the compound of formula (I) is a compound of formula (I-X) and is present in an amount ranging from about 1mg to about 1000mg or any amount or range within that range, preferably in an amount ranging from about 50mg to about 300mg or any amount or range within that range. In another embodiment of the invention, the compound of formula (I) is a compound of formula (I-Y) and is present in the pharmaceutical composition in an amount ranging from about 1mg to about 1000mg or any amount or range therein, preferably in an amount ranging from about 1mg to about 100mg or any amount or range therein, more preferably in an amount ranging from about 10mg to about 50mg or any amount or range therein.

(a) metformin or a pharmaceutically acceptable salt thereof; wherein the metformin or a pharmaceutically acceptable salt thereof is present in an amount in the range of from about 100mg to about 2000mg, preferably from about 500mg to about 1000mg or any amount or range within this range;

(b) a compound of formula (I) or a pharmaceutically acceptable salt thereof (wherein the compound of formula (I) is selected from a compound of formula (I-X) or a pharmaceutically acceptable salt thereof; and a compound of formula (I-Y) or a pharmaceutically acceptable salt thereof); wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 1mg to about 1000mg or any amount or range within that range (preferably in an amount ranging from about 1mg to about 500mg or any amount or range within that range, more preferably in an amount ranging from about 10mg to about 300mg or any amount or range within that range); and

(c) glibenclamide; wherein the glibenclamide is present in an amount in the range of about 1.0mg to about 20mg, preferably in an amount in the range of about 2.5mg to about 20mg or any amount or range within this range.

In one embodiment, the present invention relates to a pharmaceutical composition comprising (a) metformin hydrochloride; (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from a compound of formula (I-X) or a pharmaceutically acceptable salt thereof; and a compound of formula (I-Y) or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, disintegrants, binders, diluents, lubricants, stabilizers, antioxidants, surfactants, colorants, plasticizers, coating agents, and the like. More specifically, suitable pharmaceutical excipient packagesContaining one or more of the following substances: (i) diluents such as lactose, microcrystalline cellulose, dicalcium phosphate, starch, and the like; (ii) binder such as polyvinylpyrrolidone (such as POVIDONE), methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (such as METHOCEL)^TME-5), and the like; (iii) disintegrating agents such as sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and the like; (iv) wetting agents such as surfactants, e.g., sodium lauryl sulfate, polysorbate 20, and the like; (v) lubricants such as magnesium stearate, sodium stearyl fumarate, talc, and the like; (vi) flow promoters or glidants such as colloidal silicon dioxide, talc, and the like; and other excipients known to be useful in the preparation of pharmaceutical compositions. Additional suitable pharmaceutical excipients and their properties can be found, for exampleHandbook of Pharmaceutical Excipients，R.C.Rowe，P.J.Sheskey&Weller (ed.), fourth edition (published by Pharmaceutical Press, a Division of Royal Pharmaceutical Society of Great Britain). In another embodiment, the present invention relates to the above pharmaceutical composition, further comprising a sulfonylurea or a pharmaceutically acceptable salt thereof.

Fillers or diluents for use in the pharmaceutical compositions of the present invention include fillers or diluents commonly used in formulating pharmaceutical formulations. Examples of fillers or diluents for use according to the present invention include, but are not limited to, sugars such as lactose, dextrose, glucose, sucrose, cellulose, starch and sugar derivatives, polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol and sorbitol), cyclodextrins, calcium carbonate, magnesium carbonate, microcrystalline cellulose, combinations thereof and the like.

The binders used in the pharmaceutical compositions of the present invention include binders that are commonly used in formulating pharmaceutical formulations. Examples of binders for use according to the present invention include, but are not limited to, cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose), glycols, sucrose, dextrose, corn syrup, polysaccharides (including gum arabic, tragacanth gum, guar gum, alginates, and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene glycol, combinations thereof, and the like.

Disintegrants for use in the pharmaceutical compositions of the invention include disintegrants commonly used in the formulation of pharmaceutical formulations. Examples of disintegrants for use in accordance with the invention include, but are not limited to, starch and cross-linked starch, cellulose and polymers, combinations thereof and the like. Representative disintegrants include microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, cellulose, agar and related gums, sodium carboxymethyl starch, corn starch, potato starch, sodium carboxymethyl starch, Veegum HV, methylcellulose, agar, bentonite, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid, guar gum, combinations thereof and the like.

The lubricant, glidant, or anti-adherent used in the pharmaceutical composition of the present invention includes lubricants, glidants, and anti-adherents commonly used in formulating pharmaceutical formulations. Examples for use according to the present invention include, but are not limited to, magnesium carbonate, magnesium lauryl sulfate, calcium silicate, talc, fumed silica, combinations thereof and the like. Other useful lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, magnesium silicate, mineral oil, hydrogenated vegetable oil, wax, glyceryl behenate, polyethylene glycol, combinations thereof, and the like.

Surfactants useful in the pharmaceutical compositions of the present invention include surfactants commonly used in formulating pharmaceutical formulations. Examples of surfactants for use according to the present invention include, but are not limited to, ionic and non-ionic surfactants or wetting agents commonly used in formulating pharmaceutical formulations, such as ethoxylated castor oil, polyglycolized glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, docusate sodium, sodium lauryl sulfate, cholic acid or derivatives thereof, lecithin, phospholipids, combinations thereof, and the like.

Other polymers commonly used as excipients in pharmaceutical compositions include, but are not limited to, Methylcellulose (MC), Ethylcellulose (EC), Hydroxyethylcellulose (HEC), Methylhydroxyethylcellulose (MHEC), Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and the like.

The pharmaceutical composition may further comprise an antioxidant and a chelating agent. For example, the pharmaceutical formulation may comprise Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), Propyl Gallate (PG), sodium metabisulfite, ascorbyl palmitate, potassium metabisulfite, disodium ethylenediaminetetraacetate (ethylenediaminetetraacetic acid; also known as disodium edetate), EDTA, tartaric acid, citric acid monohydrate, and sodium sulfite.

The pharmaceutical composition may optionally further comprise one or more flow modifiers (glidants). The flow modifier may be present in the form of a powder or granules and is blended in order to increase the flowability of the composition during the manufacturing process, in particular during the manufacture of tablets by compressing powders or granules. Flow modifiers that may be used include, but are not limited to, highly dispersed silica (Aerosil) or dry starch.

One skilled in the art will readily recognize that suitable pharmaceutical excipients may be selected such that they are compatible with the other excipients and do not bind to the pharmaceutical compound (active ingredient) or cause degradation of the drug.

The tablet composition may optionally further comprise a coating agent. Suitable coating agents include, but are not limited to, film-forming polymers such as those from the group: cellulose derivatives, dextrins, starches, natural gums (e.g. gum arabic, xanthan gum, alginates), polyvinyl alcohols, polymethacrylates and derivatives thereof such asThese materials can be applied to the tablets as solutions or suspensions by a variety of conventional pharmaceutical methods, such as film coating. The coating agent is typically applied as a solution/suspension which may contain, in addition to any film-forming polymer present, one or more adjuvants such as hydrophilic agents, plasticizers, surfactants, dyes and white pigments such as titanium dioxide.

In certain embodiments of the present invention, the pharmaceutical composition preferably comprises between about 5% to about 50% by weight diluent (relative to the total weight of the composition or composition layer), more preferably between about 5% to about 25% by weight diluent, and still more preferably about 7% diluent.

In further embodiments of the invention, the pharmaceutical composition preferably comprises between about 1% to about 10% by weight of binder (relative to the total weight of the composition or composition layer), more preferably between about 3% to about 5% by weight of binder, and still more preferably about 4% of binder.

In further embodiments of the invention, the pharmaceutical composition preferably comprises between about 1% to about 10% by weight of disintegrant (relative to the total weight of the composition or composition layer), more preferably between about 2% to about 5% by weight of disintegrant, and still more preferably about 3% of disintegrant.

In further embodiments of the present invention, the pharmaceutical composition preferably comprises between about 0% to about 5% by weight of a wetting agent (relative to the total weight of the composition or composition layer), more preferably between about 0.1% to about 2% by weight of a wetting agent, and still more preferably about 0.3% of a wetting agent.

In further embodiments of the invention, the pharmaceutical composition preferably comprises between about 0% to about 3% by weight of the lubricant (relative to the total weight of the composition or composition layer), more preferably between about 0.1% to about 2% by weight of the lubricant, and still more preferably about 0.5% of the lubricant.

Definition of

The term "halogen atom" or "halogen" means chlorine, bromine, fluorine and iodine, chlorine and fluorine being preferred.

The term "alkyl" means a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms. A linear or branched alkyl group having 1 to 6 carbon atoms is preferable, and a linear or branched alkyl group having 1 to 4 carbon atoms is more preferable. Examples are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl and their various branched isomers. Further, the alkyl group may be optionally and independently substituted with 1 to 4 substituents listed below, if necessary.

The term "alkylene group" or "alkylene" means a straight or branched divalent saturated hydrocarbon chain having 1 to 12 carbon atoms. Preferred are linear or branched alkylene groups having 1 to 6 carbon atoms, and more preferred are linear or branched alkylene groups having 1 to 4 carbon atoms. Examples thereof are methylene, ethylene, 1, 2-propylene, 1, 3-propylene and the like. If necessary, the alkylene group may also be optionally substituted in the same manner as the above-mentioned "alkyl group". When alkylene groups as defined above are attached to two different carbon atoms of the phenyl ring, they form, together with the carbon atoms to which they are attached, a fused five-, six-or seven-membered carbocyclic ring, and may be optionally substituted by one or more substituents as defined below.

The term "alkenyl group" means a straight or branched monovalent hydrocarbon chain having 2 to 12 carbon atoms and at least one double bond. Preferred alkenyl groups are linear or branched alkenyl groups having 2 to 6 carbon atoms, more preferably linear or branched alkenyl groups having 2 to 4 carbon atoms. Examples thereof are vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4, 8, 12-tetradecatrienyl and the like. The alkenyl group may be optionally and independently substituted with 1 to 4 substituents described below, if necessary.

The term "alkenylene" means a straight or branched divalent hydrocarbon chain having 2 to 12 carbon atoms and at least one double bond. Preferred is a linear or branched alkenylene group having 2 to 6 carbon atoms, and more preferred is a linear or branched alkenylene group having 2 to 4 carbon atoms. Examples thereof are pentenylene, propenylene, butadienylene and the like. The alkylene group may be optionally substituted with 1 to 4 substituents described below, if necessary. When alkenylene groups as defined above are attached to two different carbon atoms of the phenyl ring, they form, together with the carbon atoms to which they are attached, a fused five-, six-or seven-membered carbocyclic ring (e.g. a fused phenyl ring), and may be optionally substituted by one or more substituents as defined below.

The term "alkynyl group" means a straight or branched monovalent hydrocarbon chain having at least one triple bond. Preferred alkynyl groups are straight or branched chain alkynyl groups having 2 to 6 carbon atoms, more preferably straight or branched chain alkynyl groups having 2 to 4 carbon atoms. Examples thereof are 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecenyl, 4-dodecenyl and the like. The alkynyl group may be optionally and independently substituted with 1 to 4 substituents described below, if necessary.

The term "cycloalkyl" means a monocyclic or bicyclic monovalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and more preferably a monocyclic saturated hydrocarbon group having 3 to 7 carbon atoms. Examples thereof are monocycloalkyl and bicycloalkyl radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. These groups may be optionally and independently substituted with 1 to 4 substituents described below, if necessary. The cycloalkyl group may be optionally combined with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring₂) The fused, fused saturated hydrocarbon ring and the fused unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents described below.

The term "cycloalkylene" means a monocyclic or bicyclic divalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and preferably a monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms. Examples thereof are monocyclic alkylene and bicycloalkylene such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and the like. These groups may be optionally and independently substituted with 1 to 4 substituents described below, if necessary. Further, the cycloalkylene group may be optionally combined with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring₂) The fused, and fused saturated hydrocarbon ring and unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents mentioned below.

The term "cycloalkenyl" means a monocyclic or bicyclic monovalent unsaturated hydrocarbon ring having 4 to 12 carbon atoms and having at least one double bond. Preferred cycloalkenyl groups are monocyclic unsaturated hydrocarbon groups having 4 to 7 carbon atoms. Examples thereof are monocyclic alkenyl groups such as cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group and the like. These groups may be optionally and independently substituted with 1 to 4 substituents described below, if necessary. Further, the cycloalkenyl group may be optionally combined with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO within the ring₂) The fused, and fused saturated hydrocarbon ring and unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents described below.

The term "cycloalkynyl" means a monocyclic or bicyclic unsaturated hydrocarbon ring having 6 to 12 carbon atoms and having at least one triple bond. Preferred cycloalkynyl groups are monocyclic unsaturated hydrocarbon groups having 6 to 8 carbon atoms. Examples thereof are monocyclic alkynyl groups such as cyclooctynyl, cyclodecynyl. These groups may be optionally substituted with 1 to 4 substituents described below, if necessary. Further, the cycloalkynyl group may be optionally and independently bonded to a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring, if necessary₂) The fused, and fused saturated or unsaturated hydrocarbon ring may be optional andindependently by 1 to 4 substituents described below.

The term "aryl" means a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples thereof are phenyl group, naphthyl group (including 1-naphthyl group and 2-naphthyl group). These groups may be optionally and independently substituted with 1 to 4 substituents described below, if necessary. Further, the aryl group may be optionally combined with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring₂) The fused, and fused saturated hydrocarbon ring or unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents described below.

The term "unsaturated monocyclic heterocyclic ring" means an unsaturated hydrocarbon ring containing 1 to 4 hetero atoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the preferred unsaturated monocyclic heterocyclic ring is a 4-to 7-membered saturated or unsaturated hydrocarbon ring containing 1 to 4 hetero atoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof are pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, pyrazole,Oxazole, isoAzole, 4, 5-dihydroOxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, and the like. Wherein the pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, pyridine, pyrazine, furan, thiophene, pyrrole, imidazole, thiophene, pyrrole, and thiophene,Azole and thiazole can be preferably used. The "unsaturated monocyclic heterocycle" may be optionally and independently substituted with 1 to 4 substituents described below, if necessary.

The term "unsaturated fused heterobicyclic ring" means a hydrocarbon ring composed of a saturated or unsaturated hydrocarbon ring fused with the above-mentioned unsaturated monocyclic heterocyclic ring, whereinIf necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring₂. "unsaturated fused heterobicyclic ring" includes, for example, benzothiophene, indole, tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene, thienopyridine, quinoline, indoline, isoindoline, benzothiazole, benzophenonOxazoles, indazoles, dihydroisoquinolines, and the like. In addition, "heterocycle" also includes their possible N-or S-oxides.

The term "heterocyclyl" means a monovalent radical of an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring as mentioned above, and a monovalent radical of a saturated form of an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring as mentioned above. The heterocyclic group may be optionally and independently substituted with 1 to 4 substituents mentioned below, if necessary.

The term "alkanoyl" means formyl and the group formed by bonding an "alkyl" group to a carbonyl group.

The term "alkoxy" means a group formed by bonding an "alkyl" group to an oxygen atom.

Substituents for each of the above groups include, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), nitro group, cyano group, oxo group, hydroxyl group, mercapto group, carboxyl group, sulfo group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidene methyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkenyloxy group, cycloalkynyloxy group, aryloxy group, heterocyclic oxy group, alkanoyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, cycloalkynylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, alkoxycarbonyl group, alkenyloxycarbonyl group, alkynyloxycarbonyl group, cycloalkoxycarbonyl group, cycloalkenyloxycarbonyl group, cycloalkynyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group, alkanoyloxy group, alkenylcarbonyloxy group, alkynylcarbonyloxy group, cycloalkylcarbonyloxy group, cycloalkenylcarbonyloxy group, cycloalkynylcarbonyloxy group, Arylcarbonyloxy, heterocyclylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkanoylamino, mono-or di-alkoxycarbonylamino, mono-or di-arylcarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono-or di-alkylcarbamoyl, mono-or di-arylcarbamoyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, heterocyclylsulfinyl, alkoxycarbonylamino, Alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl and heterocyclylsulfonyl. Each of the above groups may be optionally substituted with these substituents.

Further, terms such as haloalkyl, halogenated lower alkyl, halogenated alkoxy, halogenated lower alkoxy, halogenated phenyl or halogenated heterocyclic group mean that alkyl, lower alkyl, alkoxy, lower alkoxy, phenyl or heterocyclic group (hereinafter referred to as alkyl and the like) are respectively substituted with one or more halogen atoms. Preferred are alkyl groups substituted with 1 to 7 halogen atoms and the like, and more preferred are alkyl groups substituted with 1 to 5 halogen atoms and the like. Likewise, terms such as hydroxyalkyl, hydroxy-lower alkyl, hydroxyalkoxy, hydroxy-lower alkoxy, and hydroxyphenyl mean alkyl substituted with one or more hydroxy groups, and the like. Preferred are alkyl groups substituted with 1 to 4 hydroxyl groups and the like, and more preferred are alkyl groups substituted with 1 to 2 hydroxyl groups and the like. Further, terms such as alkoxyalkyl, lower alkoxyalkyl, alkoxy-lower alkyl, lower alkoxy-lower alkyl, alkoxyalkoxy, lower alkoxyalkoxy, alkoxy-lower alkoxy, lower alkoxy-lower alkoxy, alkoxyphenyl, and lower alkoxyphenyl mean alkyl substituted with one or more alkoxy groups, and the like. Preferred are alkyl groups substituted with 1 to 4 alkoxy groups, etc., and more preferred are alkyl groups substituted with 1 to 2 alkoxy groups, etc.

The terms "aralkyl" and "arylalkoxy" used alone or as part of another group refer to the alkyl and alkoxy groups described above with an aryl substituent.

Unless otherwise defined, the term "lower" used in the definition of chemical formula in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms. More preferably, it means a straight or branched carbon chain having 1 to 4 carbon atoms.

Examples of the optionally substituted unsaturated monocyclic heterocyclic ring of the present invention include unsaturated monocyclic heterocyclic rings which may be optionally substituted with 1 to 5 substituents selected from the group consisting of: halogen atom, nitro group, cyano group, oxo group, hydroxyl group, mercapto group, carboxyl group, sulfo group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylenemethyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkenyloxy group, aryloxy group, heterocyclic oxy group, alkanoyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, cycloalkenylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, alkoxycarbonyl group, alkenyloxycarbonyl group, alkynyloxycarbonyl group, cycloalkoxycarbonyl group, cycloalkenyloxycarbonyl group, cycloalkynyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group, alkanoyloxy group, alkenylcarbonyloxy group, alkynylcarbonyloxy group, cycloalkylcarbonyloxy group, cycloalkenylcarbonyloxy group, cycloalkynylcarbonyloxy group, arylcarbonyloxy group, heterocyclic carbonyloxy group, alkylthio group, Alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkanoylamino, mono-or di-alkoxycarbonylamino, mono-or di-arylcarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono-or di-alkylcarbamoyl, mono-or di-arylcarbamoyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, heterocyclylsulfonyl, heterocyclylsulfonylamino, heterocycl, Cycloalkynylsulphonyl, arylsulphonyl and heterocyclosulphonyl groups, wherein each substituent may also be optionally substituted by these substituents.

Examples of the optionally substituted unsaturated fused heterobicyclic ring of the present invention include unsaturated fused heterobicyclic rings which may be optionally substituted with 1 to 5 substituents selected from the group consisting of: halogen atom, nitro group, cyano group, oxo group, hydroxyl group, mercapto group, carboxyl group, sulfo group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylenemethyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkenyloxy group, aryloxy group, heterocyclic oxy group, alkanoyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, cycloalkenylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, alkoxycarbonyl group, alkenyloxycarbonyl group, alkynyloxycarbonyl group, cycloalkoxycarbonyl group, cycloalkenyloxycarbonyl group, cycloalkynyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group, alkanoyloxy group, alkenylcarbonyloxy group, alkynylcarbonyloxy group, cycloalkylcarbonyloxy group, cycloalkenylcarbonyloxy group, cycloalkynylcarbonyloxy group, arylcarbonyloxy group, heterocyclic carbonyloxy group, alkylthio group, Alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkanoylamino, mono-or di-alkoxycarbonylamino, mono-or di-arylcarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono-or di-alkylcarbamoyl, mono-or di-arylcarbamoyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, heterocyclylsulfonyl, heterocyclylsulfonylamino, heterocycl, Cycloalkynylsulphonyl, arylsulphonyl and heterocyclosulphonyl groups, wherein each substituent may also be optionally substituted by these substituents.

Examples of the benzene ring which may be optionally substituted in the present invention include benzene rings which may be optionally substituted with 1 to 5 substituents selected from the group consisting of: halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, carboxyl group, sulfonic group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkoxy group, cycloalkenyloxy group, cycloalkynyloxy group, aryloxy group, heterocyclic oxy group, alkanoyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, cycloalkenylcarbonyl group, cycloalkynylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, alkoxycarbonyl group, alkenyloxycarbonyl group, alkynyloxycarbonyl group, cycloalkoxycarbonyl group, cycloalkenyloxycarbonyl group, cycloalkynyloxycarbonyl group; aryloxycarbonyl, heterocyclyloxycarbonyl, alkanoyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, cycloalkynylcarbonyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkanoylamino, mono-or di-alkoxycarbonylamino, mono-or di-arylcarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono-or di-alkylcarbamoyl, mono-or di-arylcarbamoyl, alkylsulfinyl, alkenylsulfinyl, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, cycloalkynylcarbonyloxy, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkanoylamino, mono-or di-, Alkynylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylene, alkyleneoxy, alkylenedioxy, and alkenylene, wherein each substituent may be optionally further substituted by these substituents. Further, examples of the optionally substituted benzene ring include a benzene ring substituted with an alkylene group to form a condensed carbocyclic ring together with the attached carbon atom, and a benzene ring substituted with an alkenylene group to form a condensed carbocyclic ring together with the attached carbon atom, such as a condensed benzene ring.

Preferred examples of the optionally substituted unsaturated monocyclic heterocyclic ring include unsaturated monocyclic heterocyclic rings which may be optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen atom, hydroxyl group, alkoxy group, alkyl group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, alkoxyalkyl group, alkoxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, cycloalkenyl group, cycloalkoxy group, aryl group, aryloxy group, arylalkoxy group, cyano group, nitro group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkanoyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, heterocyclic group, and oxo group.

Preferred examples of the optionally substituted unsaturated fused heterobicyclic ring include unsaturated fused heterobicyclic rings which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, alkoxy group, alkyl group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, alkoxyalkyl group, alkoxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, cycloalkenyl group, cycloalkoxy group, aryl group, aryloxy group, arylalkoxy group, cyano group, nitro group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkanoyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, heterocyclic group, and oxo group.

Preferred examples of the optionally substituted benzene ring include benzene rings which may be optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen atom, hydroxyl group, alkoxy group, alkyl group, haloalkyl group, haloalkoxy group, hydroxyalkyl group, alkoxyalkyl group, alkoxyalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylenemethyl group, cycloalkenyl group, cycloalkoxy group, aryl group, aryloxy group, arylalkoxy group, cyano group, nitro group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkanoyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, heterocyclic group, alkylene group, alkyleneoxy group, alkylenedioxy group, and alkenylene group.

Preferably, the optionally substituted unsaturated monocyclic heterocycle is an unsaturated monocyclic heterocycle which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group and oxo group;

the optionally substituted unsaturated fused heterobicyclic ring is an unsaturated fused heterobicyclic ring which may be optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, sulfamoyl group, mono-or di-alkyl-sulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkanoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group and oxo group; and is

The optionally substituted benzene ring is a benzene ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group, alkylene group and alkenylene group;

wherein each of the above substituents on the unsaturated monocyclic heterocycle, unsaturated fused heterobicyclic ring and benzene ring may be further substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, mono-or di-alkylamino group, carboxyl group, alkoxycarbonyl group, phenyl group, alkyleneoxy group, alkylenedioxy group, oxo group, carbamoyl group, and mono-or di-alkylcarbamoyl group.

Preferably, the optionally substituted unsaturated monocyclic heterocycle is an unsaturated monocyclic heterocycle which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono-or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, a phenyl group, a heterocyclic group and an oxo group;

an optionally substituted unsaturated fused heterobicyclic ring is an unsaturated fused heterobicyclic ring that may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono-or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, a phenyl group, a heterocyclic group and an oxo group; and is

The optionally substituted benzene ring is a benzene ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, cyano group, alkyl group, alkoxy group, alkanoyl group, mono-or di-alkylamino group, alkanoylamino group, alkoxycarbonylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, phenyl group, heterocyclic group, alkylene group and alkenylene group;

wherein each of the above substituents on the unsaturated monocyclic heterocycle, unsaturated fused heterobicyclic ring and benzene ring may be further substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, cyano group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkanoyl group, mono-or di-alkylamino group, carboxyl group, hydroxyl group, phenyl group, alkylenedioxy group, alkyleneoxy group, alkoxycarbonyl group, carbamoyl group and mono-or di-alkylcarbamoyl group.

In a preferred embodiment of the invention, in the compounds of formula (I),

(1) ring a is an unsaturated monocyclic heterocycle optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group and oxo group, and

ring B is an unsaturated monocyclic heterocycle, an unsaturated fused heterobicyclic ring, or a benzene ring, each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group, alkylene group, and alkenylene group;

(2) ring a is a benzene ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, alkanoylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group, alkylene group and alkenylene group, and

ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono-or di-alkylamino group, a sulfamoyl group, a mono-or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, an alkylsulfonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclic group, an alkylene group; and

(3) ring a is an unsaturated fused heterobicyclic ring that may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylidenemethyl group, alkoxy group, alkanoyl group, alkylthio group, alkylsulfonyl group, alkylsulfinyl group, amino group, mono-or di-alkylamino group, sulfamoyl group, mono-or di-alkylsulfamoyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, mono-or di-alkylcarbamoyl group, alkylsulfonylamino group, phenyl group, phenoxy group, phenylsulfonylamino group, phenylsulfonyl group, heterocyclic group and oxo group, and

ring B is an unsaturated monocyclic heterocycle, an unsaturated fused heterobicyclic ring, or a benzene ring, each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono-or di-alkylamino group, a sulfamoyl group, a mono-or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, an alkylsulfonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclic group, an alkylene group;

wherein each of the above substituents on ring a and ring B may be further optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, cyano group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkanoyl group, mono-or di-alkylamino group, carboxyl group, hydroxyl group, phenyl group, alkylenedioxy group, alkyleneoxy group, alkoxycarbonyl group, carbamoyl group and mono-or di-alkylcarbamoyl group.

In another preferred embodiment of the invention, in the compounds of formula (I), ring A and ring B are

(1) Ring a is an unsaturated monocyclic heterocycle which may be optionally substituted with: halogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxy group or oxo group, ring B is (a) a benzene ring which may be optionally substituted with: a halogen atom; a cyano group; a lower alkyl group; a halogenated lower alkyl group; lower alkoxy; halo-lower alkoxy; mono-or di-lower alkylamino; phenyl which may be optionally substituted by a halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy, or mono-or di-lower alkylamino; or a heterocyclic group which may be optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group or a mono-or di-lower alkylamino group; (b) an unsaturated monocyclic heterocycle which may optionally be substituted with: a halogen atom; a cyano group; a lower alkyl group; a halogenated lower alkyl group; lower alkoxy; halo-lower alkoxy; mono-or di-lower alkylamino; phenyl which may be optionally substituted by a halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy, or mono-or di-lower alkylamino; and a heterocyclic group which may be optionally substituted by a group selected from a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a mono-or di-lower alkylamino group; or (c) an unsaturated fused heterobicyclic ring which may be optionally substituted with: a halogen atom; a cyano group; a lower alkyl group; a halogenated lower alkyl group; lower alkoxy; halo-lower alkoxy; mono-or di-lower alkylamino; phenyl which may be substituted by halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy, or mono-or di-lower alkylamino; and a heterocyclic group which may be optionally substituted by a group selected from a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a mono-or di-lower alkylamino group;

(2) ring a is a benzene ring which may be optionally substituted with: halogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, phenyl group or lower alkenylene group, ring B is (a) an unsaturated monocyclic heterocycle which may be optionally substituted with: a halogen atom; a cyano group; a lower alkyl group; a halogenated lower alkyl group; phenyl-lower alkyl; lower alkoxy; halo-lower alkoxy; mono-or di-lower alkylamino; phenyl which may be optionally substituted by a halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy, mono-or di-lower alkylamino or carbamoyl; or a heterocyclic group which may be optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a mono-or di-lower alkylamino group or a carbamoyl group; (b) an unsaturated fused heterobicyclic ring which may be optionally substituted with a group selected from: a halogen atom; a cyano group; a lower alkyl group; a halogenated lower alkyl group; phenyl-lower alkyl; lower alkoxy; halo-lower alkoxy; mono-or di-lower alkylamino; phenyl which may be substituted by halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy or mono-or di-lower alkylamino; and a heterocyclic group which may be optionally substituted by a group selected from a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, or a mono-or di-lower alkylamino group; or

(3) Ring a is an unsaturated fused heterobicyclic ring which may be optionally substituted with a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or an oxo group, and ring B is (a) a benzene ring which may be optionally substituted with a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group; phenyl which may be optionally substituted by a halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy or mono-or di-lower alkylamino; and heterocyclyl which may be optionally substituted by a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group or mono-or di-lower alkylamino group; (b) an unsaturated monocyclic heterocycle which may be optionally substituted with: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group; phenyl which may be optionally substituted by a halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy or mono-or di-lower alkylamino; or a heterocyclic group which may be optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a mono-or di-lower alkylamino group; or (c) an unsaturated fused heterobicyclic ring which may be optionally substituted with a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group; phenyl which may be substituted by halogen atom, cyano, lower alkyl, halogeno-lower alkyl, lower alkoxy or mono-or di-lower alkylamino; and heterocyclyl which may be optionally substituted by a group selected from: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group or mono-or di-lower alkylamino group.

In another preferred embodiment, in the compounds of formula (I), Y is-CH₂-and is attached to ring a at the 3-position and X is at the 1-position, ring a being a phenyl ring substituted with 1 to 3 substituents selected from the group consisting of: lower alkyl, halogenated lower alkyl, halogen atom, lower alkoxy, phenyl and lower alkenylene, ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each substituted with 1 to 3 substituents selected from the group consisting of: lower alkyl, halogenated lower alkyl, phenyl-lower alkyl, halogen atom, lower alkoxy, halogenated lower alkoxy, phenyl, halophenyl, cyanophenyl, lower alkylphenyl, halogenated lower alkylphenyl, lower alkoxyphenyl, halogenated lower alkoxyphenyl, lower alkylenedioxyphenyl, lower alkyleneoxyphenyl, mono-or di-lower alkylaminophenyl, carbamoylphenyl, mono-or di-lower alkylaminophenylFormylphenyl group, heterocyclic group, halogenoheterocyclic group, cyanoheterocyclic group, lower alkylheterocyclic group, lower alkoxyheterocyclic group, mono-or di-lower alkylaminocyclyl group, carbamoylheterocyclic group, and mono-or di-lower alkylcarbamoyl group.

In another more preferred embodiment, in the compound of formula (I), Y is-CH₂-and is attached to ring a at the 3-position and X is at the 1-position, ring a being an unsaturated monocyclic heterocycle which may be substituted with 1 to 3 substituents selected from: lower alkyl, halogen atom, lower alkoxy and oxo, ring B is a benzene ring which may be substituted with 1 to 3 substituents selected from the group consisting of: lower alkyl, halogenated lower alkyl, halogen atom, lower alkoxy, halogenated lower alkoxy, phenyl, halogenated phenyl, cyanophenyl, lower alkylphenyl, halogenated lower alkylphenyl, lower alkoxyphenyl, heterocyclic group, halogenated heterocyclic group, cyanoheterocyclic group, lower alkylheterocyclic group and lower alkoxyheterocyclic group.

Furthermore, in another preferred embodiment, in the compounds of formula (I), Y is-CH₂-and is attached to ring a at the 3-position and X is at the 1-position, ring a being an unsaturated monocyclic heterocycle which may be substituted with 1 to 3 substituents selected from: lower alkyl, halogen atom, lower alkoxy and oxo, ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each of which may be substituted with 1 to 3 substituents selected from the group consisting of: lower alkyl, halogenated lower alkyl, halogen atom, lower alkoxy, halogenated lower alkoxy, phenyl, halogenated phenyl, cyanophenyl, lower alkylphenyl, halogenated lower alkylphenyl, lower alkoxyphenyl, halogenated lower alkoxyphenyl, heterocyclic group, halogenated heterocyclic group, cyanoheterocyclic group, lower alkylheterocyclic group and lower alkoxyheterocyclic group. In a more preferred embodiment of the invention, X is a carbon atom and Y is-CH₂-。

In addition, in another preferred embodiment, in the compounds of formula (I), ring A and ring B are

(1) Ring a is a phenyl ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, lower alkyl optionally substituted by halogen atom or lower alkoxy, lower alkoxy optionally substituted by halogen atom or lower alkoxy, cycloalkyl, cycloalkoxy, phenyl and lower alkenylene, and

ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with halogen atom, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen atom or lower alkoxy; a cycloalkyl group; a cycloalkoxy group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy, or carbamoyl; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group, or a carbamoyl group; and an oxo group, and a pharmaceutically acceptable salt thereof,

(2) ring a is an unsaturated monocyclic heterocycle which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atom, lower alkyl optionally substituted by lower alkoxy, lower alkoxy optionally substituted by halogen atom or lower alkoxy, cycloalkyl, cycloalkoxy and oxo, and

ring B is a benzene ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with halogen atom, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen atom or lower alkoxy; a cycloalkyl group; a cycloalkoxy group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group; lower alkylene;

(3) ring a is an unsaturated monocyclic heterocycle which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a lower alkyl group optionally substituted with a halogen atom or a lower alkoxy group, a lower alkoxy group optionally substituted with a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloalkoxy group and an oxo group,

ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with a halogen atom, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen atom or lower alkoxy; a cycloalkyl group; a cycloalkoxy group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy; a heterocyclic group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group; and an oxo group;

(4) ring a is an unsaturated fused heterobicyclic ring that may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a lower alkyl group optionally substituted with a lower alkoxy group, a lower alkoxy group optionally substituted with a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloalkoxy group and an oxo group,

ring B is a benzene ring which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with halogen atom, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen atom or lower alkoxy; a cycloalkyl group; a cycloalkoxy group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group; and lower alkylene; or

(5) Ring a is an unsaturated monocyclic heterocycle which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom, a lower alkyl group optionally substituted with a lower alkoxy group, a lower alkoxy group optionally substituted with a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloalkoxy group and an oxo group,

ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring each of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with halogen atom, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen atom or lower alkoxy; a cycloalkyl group; a cycloalkoxy group; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group; and an oxo group.

In another preferred embodiment of the invention, in the compounds of formula (I), Y is attached to ring A at the 3-position and X is at the 1-position, ring A being a phenyl ring optionally substituted with the following substituents: halogen atom, lower alkyl optionally substituted by halogen atom, lower alkoxy or phenyl, ring B is an unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring which may be optionally substituted by 1 to 3 substituents independently selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with a halogen atom or phenyl; lower alkoxy; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl or lower alkoxy; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group or a lower alkoxy group; and an oxo group.

In another preferred embodiment of the invention, in the compound of formula (I), Y is attached to ring a at the 3-position and X is at the 1-position, ring a being an unsaturated monocyclic heterocycle which may optionally be substituted by a substituent selected from the group consisting of: halogen atom, lower alkyl group and oxo group, ring B is a benzene ring which may be optionally substituted with a substituent selected from the group consisting of: a halogen atom; lower alkyl optionally substituted with a halogen atom or phenyl; lower alkoxy; phenyl optionally substituted by a halogen atom, cyano, lower alkyl, halogenated lower alkyl or lower alkoxy; a heterocyclic group optionally substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group or a lower alkoxy group; and lower alkylene.

Preferred examples of the unsaturated monocyclic heterocyclic ring include 5-or 6-membered unsaturated heterocyclic rings containing 1 or 2 hetero atoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms. More specifically, furan, thiophene, and,Oxazole, isoAzoles, triazoles, tetrazoles, pyrazoles, pyridines, pyrimidines, pyrazines, dihydroisoindolesOxazole, dihydropyridine, and tetrazole. Preferred unsaturated fused heterobicyclic rings include 9-or 10-membered unsaturated fused heterocyclic rings containing 1 to 4 heteroatoms independently selected from nitrogen atoms, oxygen atoms, and sulfur atoms. More specifically, indoline, isoindoline, benzothiazole, and benzo are preferableAzoles, indoles, indazoles, quinolines, isoquinolines, benzothiophenes, benzofurans, thienothiophenes, and dihydroisoquinolines.

In a more preferred embodiment, in the compound of formula (I), ring a is a phenyl ring which may be optionally substituted by a substituent selected from the group consisting of: halogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxy group and phenyl group, ring B is a heterocyclic ring selected from the group consisting of: thiophene, furan, benzofuran, benzothiophene, and benzothiazole, wherein the heterocycle may be optionally substituted with a substituent selected from the group consisting of: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, phenyl-lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, phenyl group, halogenated phenyl group, lower alkylphenyl group, lower alkoxyphenyl group, thienyl group, halogenated thienyl group, pyridyl group, halogenated pyridyl group and thiazolyl group.

In a further preferred embodiment, in the compounds of formula (I), Y is-CH₂-, Ring A is a group selected fromAn unsaturated monocyclic heterocycle or an unsaturated fused heterobicyclic ring of the group: thiophene, dihydroisoquinoline, dihydroisoOxazole, triazole, pyrazole, dihydropyridine, indoline, indole, indazole, pyridine, pyrimidine, pyrazine, quinoline and isoindoline, wherein the heterocycle may be optionally substituted with a substituent selected from the group consisting of: halogen atom, lower alkyl group and oxo group, ring B is a benzene ring which may be optionally substituted with a substituent selected from the following group: halogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxy group and halogenated lower alkoxy group.

In a further preferred embodiment, in the compound of formula (I), ring a is a benzene ring substituted with a halogen atom or lower alkyl group, and ring B is thienyl substituted with a phenyl group or a heterocyclic group, wherein the phenyl group and the heterocyclic group are substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group and halogenated lower alkoxy group.

In addition, in another aspect of the present invention, preferred examples of the compound of formula (I) include compounds wherein: wherein ring A is

Wherein R is^1a、R^2a、R^3a、R^1b、R^2bAnd R^3bEach independently is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkoxy group, a phenyl group, a phenylalkoxy group, a cyano group, a nitro group, an amino group, a mono-or di-alkylamino group, an alkanoylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, a phenylsulfonylamino group, an alkylsulfinyl group, anA sulfonyl group, and

ring B is

Wherein R is^4aAnd R^5aEach independently is a hydrogen atom; a halogen atom; a hydroxyl group; an alkoxy group; an alkyl group; a haloalkyl group; a haloalkoxy group; a hydroxyalkyl group; an alkoxyalkyl group; a phenylalkyl group; an alkoxy group; a hydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkyl group; cycloalkylidenemethyl; a cycloalkenyl group; a cycloalkoxy group; a phenoxy group; a phenylalkoxy group; a cyano group; a nitro group; an amino group; mono-or di-alkylamino; an alkanoylamino group; a carboxyl group; an alkoxycarbonyl group; a carbamoyl group; mono-or di-alkylcarbamoyl; an alkanoyl group; an alkylsulfonylamino group; a phenylsulfonylamino group; an alkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; phenyl optionally substituted by a halogen atom, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylenedioxy, alkyleneoxy or mono-or di-alkylamino; or a heterocyclic group optionally substituted by a halogen atom, cyano group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, carbamoyl group or mono-or di-alkylcarbamoyl group, or R^4aAnd R^5aBonded to each other at their ends to form an alkylene group; and is

R^4b、R^5b、R^4cAnd R^5cEach independently is a hydrogen atom; a halogen atom; a hydroxyl group; an alkoxy group; an alkyl group; a haloalkyl group; a haloalkoxy group; a hydroxyalkyl group; an alkoxyalkyl group; a phenylalkyl group; an alkoxy group; a hydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkyl group; cycloalkylidenemethyl; a cycloalkenyl group; a cycloalkoxy group; a phenoxy group; a phenylalkoxy group; a cyano group; a nitro group; an amino group; mono-or di-alkylamino; an alkanoylamino group; a carboxyl group; an alkoxycarbonyl group; a carbamoyl group; mono-or di-alkylcarbamoyl; an alkanoyl group; an alkylsulfonylamino group; a phenylsulfonylamino group; an alkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; by halogen atomsCyano, alkyl, haloalkyl, alkoxy, haloalkoxy, methylenedioxy, ethyleneoxy or mono-or di-alkylamino optionally substituted phenyl; or a heterocyclic group optionally substituted with a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group.

More preferred are compounds of formula (I): wherein R is^1a、R^2a、R^3a、R^1b、R^2bAnd R^3bEach independently is a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a phenyl group;

R^4aand R^5aEach independently is a hydrogen atom; a halogen atom; a lower alkyl group; a halogenated lower alkyl group; phenyl-lower alkyl; phenyl optionally substituted by a halogen atom, cyano group, lower alkyl group, halogeno-lower alkyl group, lower alkoxy group, halogeno-lower alkoxy group, methylenedioxy group, ethyleneoxy group or mono-or di-lower alkylamino group, carbamoyl group or mono-or di-lower alkylcarbamoyl group; or a heterocyclic group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a carbamoyl group, or a mono-or di-lower alkylcarbamoyl group; or R^4aAnd R^5aBonded to each other at their ends to form a lower alkylene group; and is

R^4b、R^5b、R^4cAnd R^5cEach independently is a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group.

Also preferred are compounds of formula (I) wherein ring B is a ring of the structure

Wherein R is^4aIs optionally substituted by halogen atom, cyano group, lower alkyl group, halogeno-lower alkyl group, lower alkoxy group, halogeno-lower alkoxy group, methylenedioxy group, ethyleneoxy group,Mono-or di-lower alkylamino, carbamoyl or mono-or di-lower alkylcarbamoyl substituted phenyl; or a heterocyclic group optionally substituted by a halogen atom, cyano group, lower alkyl group, lower alkoxy group, carbamoyl group or mono-or di-lower alkylcarbamoyl group, and

R^5ais a hydrogen atom, or

R^4aAnd R^5aBonded to each other at their ends to form a lower alkylene group.

Even more preferred are compounds of formula (I) wherein ring A is

Wherein R is^1aIs a halogen atom, a lower alkyl group or a lower alkoxy group, and R^2aAnd R^3aIs a hydrogen atom; and ring B is

Wherein R is^4aIs phenyl optionally substituted with a substituent selected from the group consisting of: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, mono-or di-lower alkylamino group, carbamoyl group and mono-or di-lower alkylcarbamoyl group; or a heterocyclic group optionally substituted by a halogen atom, cyano group, lower alkyl group, lower alkoxy group, carbamoyl group and mono-or di-lower alkylcarbamoyl group, and R^5aIs a hydrogen atom, and Y is-CH₂-。

In a more preferred embodiment, in the compounds of formula (I), R^4aIs phenyl optionally substituted by halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy or halogenated lower alkoxy; or is optionally substituted by halogen atoms, cyano, lower alkylOr lower alkoxy-substituted heterocyclic group.

In another embodiment, preferred compounds of formula (I) may be represented by formula (IA) below:

wherein R is^AIs a halogen atom, a lower alkyl group or a lower alkoxy group; r^BIs phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen atom, cyano group, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, halogenated lower alkoxy group, methylenedioxy group, ethyleneoxy group, mono-or di-lower alkylamino group, carbamoyl group and mono-or di-lower alkylcarbamoyl group; or a heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group, a mono-or di-lower alkylamino group, a carbamoyl group and a mono-or di-lower alkylcarbamoyl group; r^CIs a hydrogen atom; or R^BAnd R^CTaken together are fused benzene rings which may be substituted with halogen atoms, lower alkyl groups, halogenated lower alkyl groups, lower alkoxy groups or halogenated lower alkoxy groups.

In a preferred embodiment, in the compounds of formula (I), R^AIs a halogen atom or a lower alkyl group, R^CIs a hydrogen atom, and R^BIs a phenyl group substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, a mono-or di-lower alkylamino group, a carbamoyl group and a mono-or di-lower alkylcarbamoyl group; or a heterocyclic group substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group, a mono-or di-lower alkylamino group, a carbamoyl group and a mono-or di-lower alkylcarbamoyl group. The chemical structure of such compounds can be represented by the following formula (IA'):

wherein R is^AIs a halogen atom, or a lower alkyl group, and ring C is a phenyl group substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, a mono-or di-lower alkylamino group, a carbamoyl group, and a mono-or di-lower alkylcarbamoyl group; or a heterocyclic group substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkoxy group, a mono-or di-lower alkylamino group, a carbamoyl group and a mono-or di-lower alkylcarbamoyl group.

In a more preferred embodiment, in the compounds of formula (I), ring C is phenyl substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, cyano, lower alkyl, halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy and mono-or di-lower alkylamino; or a heterocyclic group substituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group and a halogenated lower alkoxy group.

Among them, preferred are those wherein ring C is a phenyl group substituted with a halogen atom, a cyano group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group; or a heterocyclic group substituted by a halogen atom, a cyano group, a lower alkyl group or a lower alkoxy group.

Preferred heterocyclic groups include 5-or 6-membered heterocyclic groups containing 1 or 2 heteroatoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms, or 9-or 10-membered heterocyclic groups containing 1 to 4 heteroatoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms. In particular, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, quinolinyl, tetrazolyl andan azole group.

In a further preferred embodiment, in the compounds of formula (I), ring C is phenyl substituted by halogen atom or cyano or pyridyl substituted by halogen atom.

In another embodiment, preferred are compounds of formula (I) wherein ring A is

Wherein R is^4bAnd R^5bEach independently is a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a halogenated lower alkoxy group.

In another aspect of the present invention, preferred examples of the compound of formula (I) include compounds represented by the following formula (IB):

wherein R is⁸、R⁹And R¹⁰Each independently is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkoxy group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono-or di-alkylamino groupA group, alkylcarbonylamino, carboxyl, alkoxycarbonyl, carbamoyl, mono-or di-alkylcarbamoyl, alkanoyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfinyl, alkylsulfonyl or arylsulfonyl; and a group represented by:

wherein R is^6aAnd R^7aEach independently is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkoxy group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono-or di-alkylamino group, an alkylcarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono-or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group^6bAnd R^7bEach independently a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group or an alkoxy group.

Among the compounds represented by formula (IB), more preferred are compounds: wherein R is⁸、R⁹And R¹⁰Each independently is a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy-lower alkyl group, a halogenated lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkoxy group, a cycloalkoxy group, a halogenated lower alkoxy group or a lower alkoxy-lower alkoxy group, and a group represented by:

wherein R is^6a、R^7aEach independently is a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy-lower alkyl group, a halogenated lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkoxy group, a cycloalkoxy group, a halogenated lower alkoxy group or a lower alkoxy-lower alkoxy group, or a group represented by the formula:

wherein R is^6bAnd R^7bEach independently is a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group or a lower alkoxy group.

In another aspect, preferred embodiments of compounds of formula (I) include compounds represented by formula (IC) below:

wherein ring B' is an optionally substituted benzene ring, an optionally substituted unsaturated monocyclic heterocycle, or an optionally substituted unsaturated fused heterobicyclic ring.

Preferred examples of the ring B' include a benzene ring and a heterocyclic ring, both of which may have a substituent selected from the group consisting of: a halogen atom; a cyano group; lower alkyl optionally substituted by halogen atom; lower alkoxy optionally substituted by halogen atom; a lower alkanoyl group; mono-or di-lower alkylamino; a lower alkoxycarbonyl group; a carbamoyl group; mono-or di-lower alkylcarbamoyl; phenyl optionally substituted with a substituent selected from: a halogen atom, a cyano group, a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group optionally substituted with a halogen atom, a lower alkanoyl group, a mono-or di-lower alkylamino group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono-or di-lower alkylcarbamoyl group; heterocyclyl optionally substituted with a substituent selected from: a halogen atom, a cyano group, a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group optionally substituted with a halogen atom, a lower alkanoyl group, a mono-or di-lower alkylamino group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono-or di-lower alkylcarbamoyl group; an alkylene group; and an oxo group.

More preferred examples of the ring B' include benzene rings which may be substituted with a substituent selected from the group consisting of: a halogen atom; a cyano group; lower alkyl optionally substituted by halogen atom; lower alkoxy optionally substituted by halogen atom; mono-or di-lower alkylamino; phenyl optionally substituted with: halogen atom, cyano group, lower alkyl group optionally substituted by halogen atom, lower alkoxy group optionally substituted by halogen atom; heterocyclyl optionally substituted with: halogen atom, cyano group, lower alkyl group optionally substituted by halogen atom, lower alkoxy group optionally substituted by halogen atom.

Preferred compounds of formula (I) may be selected from:

1- (β -D-glucopyranosyl) -4-chloro-3- (6-ethylbenzo [ b ] thiophen-2-ylmethyl) benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (5-thiazolyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- (5-phenyl-2-thienyl-methyl) benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (2-pyrimidinyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (2-pyrimidinyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (3-cyanophenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (4-cyanophenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (6-fluoro-2-pyridinyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2-pyridinyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (3-difluoromethyl-phenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (3-cyanophenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-cyanophenyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridinyl) -2-thienylmethyl ] benzene;

1- (β -D-glucopyranosyl) -4-fluoro-3- (5- (3-cyanophenyl) -2-thienylmethyl) benzene;

a pharmaceutically acceptable salt thereof; and prodrugs thereof.

Particularly preferred compounds of formula (I) include:

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (3-cyano-phenyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-cyano-phenyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluoro-phenyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (3-cyano-phenyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-methyl-3- [5- (6-fluoro-2-pyridinyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2-pyridinyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

1- (β -D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridinyl) -2-thienylmethyl ] benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and

1- (β -D-glucopyranosyl) -4-fluoro-3- (5- (3-cyanophenyl) -2-thienylmethyl) benzene, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Pharmaceutically acceptable salts of the compounds of formula (I) include, for example: salts with alkali metals such as lithium, sodium, potassium, and the like; salts with alkaline earth metals such as calcium, magnesium, etc.; salts with zinc or aluminum; salts with organic bases such as ammonium, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris (hydroxymethyl) aminomethane, N-methylglucamine, triethanolamine and dehydroabietylamine; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc.; or salts with acidic amino acids such as aspartic acid, glutamic acid, and the like.

The term "prodrug" means an ester or carbonate formed by reacting one or more of the hydroxyl groups of a compound of formula (I) with an acylating agent substituted with an alkyl, alkoxy, or aryl group using conventional methods to produce an acetate, pivalate, dimethyl carbonate, benzoate, and the like. In addition, prodrugs also include esters or amides, which are similarly formed by reacting one or more of the hydroxy groups of the compounds of formula (I) with an α -amino acid or β -amino acid, and the like, using conventional methods, using condensing agents.

The compounds of formula (I) also include mixtures of stereoisomers or each pure or substantially pure isomer. For example, the present compounds may optionally have one or more asymmetric centers located at carbon atoms containing any of the substituents. Thus, the compounds of formula (I) may exist as enantiomers or diastereomers or mixtures thereof. When the compound of formula (I) contains a double bond, the present compound may exist in the form of geometric isomers (cis compound, trans compound), and when the compound of formula (I) contains an unsaturated bond such as carbonyl, the present compound may exist in the form of tautomers, and the present compound also includes these isomers or mixtures thereof. The starting compounds may be used in the preparation of the present compounds in the form of racemic mixtures, enantiomers or diastereomers. When the present compounds are obtained in diastereomeric or enantiomeric forms, they can be separated by conventional methods such as chromatography or fractional crystallization.

Furthermore, the compounds of formula (I) include intramolecular salts, hydrates, solvates or polymorphs thereof.

The methods of the invention relate to the treatment and or prevention (including delay of progression or onset) of a "glucose-related disorder". As used herein, the term "glucose-related disorder" shall be defined as any disorder characterized by or developed as a result of elevated glucose levels. Glucose related disorders shall include diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glucose, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, or hypertension. In particular, the "glucose-related disorder" is diabetes (type 1 and type 2diabetes, etc.), diabetic complications (such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), obesity, or postprandial hyperglycemia.

In one embodiment of the invention, the glucose related disorder is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, and hypertension.

In another embodiment of the invention, the glucose related disorder is selected from the group consisting of type 1 diabetes, type 2diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, obesity and postprandial hyperglycemia. In another embodiment of the invention, the glucose related disorder is selected from the group consisting of type 1 diabetes, type 2diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, obesity and delayed wound healing. In another embodiment of the invention, the glucose related disorder is selected from the group consisting of poor glycemic control, type 2diabetes, syndrome X, gestational diabetes, insulin resistance, hyperglycemia. In another embodiment of the invention, the glucose related disorder is type 2 diabetes.

In another embodiment, the glucose-related disorder is selected from the group consisting of elevated glucose levels, pre-diabetes, impaired oral glucose tolerance, poor glycemic control, type 2diabetes, syndrome X (also known as metabolic syndrome), gestational diabetes, insulin resistance, and hyperglycemia.

Treatment of glucose-related disorders includes lowering blood glucose levels, improving glycemic control, reducing insulin resistance, and/or preventing the development of glucose-related disorders (e.g., preventing the development of type 2diabetes in patients with impaired oral glucose tolerance or elevated blood glucose levels).

As used herein, the terms "syndrome X", "metabolic syndrome" and "metabolic syndrome X" shall mean disorders that make it possible to develop type 2diabetes and cardiovascular disease as well as disorders characterized by insulin resistance and hyperinsulinemia and that may be accompanied by one or more of the following symptoms: (a) glucose intolerance, (b) type 2diabetes, (c) dyslipidemia, (d) hypertension, and (e) obesity.

The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the target of treatment, observation or experiment.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

As used herein, unless otherwise indicated, the terms "treatment", "treating", "treatment", and the like shall include the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present invention to prevent the onset of, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder.

As used herein, unless otherwise indicated, the term "preventing" shall include (a) reducing the frequency of one or more symptoms; (b) reducing the severity of one or more symptoms; (c) delay or avoid the development of additional symptoms; and/or (d) delaying or avoiding the development of the disorder or condition.

One skilled in the art will recognize that, in the context of a method of prevention wherein the present invention is directed to a subject in need thereof (i.e., a subject in need of prevention), any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Furthermore, a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who does not exhibit any symptoms of the disorder, disease or condition to be prevented, but who is deemed by a physician, clinician or other medical professional to be at risk of developing the disorder, disease or condition. For example, the subject may be considered at risk of developing a disorder, disease, or condition (and thus in need of prophylactic or preventative treatment) due to the subject's medical history, including but not limited to family history, predisposition to the disease, co-existing disorder or condition (with concurrent morbidity), genetic testing, and the like.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

Wherein the invention relates to co-therapy or combination therapy comprising the administration of (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, by "therapeutically effective dose" is meant the amount of the combination of agents taken together such that the combined effect elicits the desired biological or pharmaceutical response. For example, a therapeutically effective amount of a co-therapy comprising administering (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof will be an amount of (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof that have a combined effect that is therapeutically effective when taken together or continuously. Additionally, and as will be recognized by those skilled in the art, in the case of a synergistic therapy having a therapeutically effective amount, as in the above examples, (a) the amount of metformin or a pharmaceutically acceptable salt thereof and/or (b) the amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone may or may not be therapeutically effective.

One skilled in the art will also recognize that the term "therapeutically effective amount" comprising a co-therapy of (a) glyburide and (b) a compound of formula (I), or a pharmaceutically acceptable salt thereof, shall mean an amount of glyburide and an amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, that when taken together or consecutively have a therapeutically effective combined effect; and it will also be recognized that the amounts of each of the components may or may not be therapeutically effective alone.

One skilled in the art will also recognize that the term "therapeutically effective amount" which includes the co-therapy of administering (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (c) a sulfonylurea (preferably glyburide), or a pharmaceutically acceptable salt thereof, shall mean the amount of each of the components described which, when taken together or consecutively, has a therapeutically effective combined effect; and it will also be recognized that the amounts of each of the components may or may not be therapeutically effective alone.

As used herein, the terms "co-therapy" and "combination therapy" shall mean the treatment of a subject in need thereof by administering (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally (c) a sulfonylurea (preferably glyburide) or a pharmaceutically acceptable salt thereof, wherein (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally (c) a sulfonylurea (preferably glyburide) or a pharmaceutically acceptable salt thereof, are administered by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical dosage form. Wherein (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof and optionally (c) a sulfonylurea (preferably glyburide) or a pharmaceutically acceptable salt thereof are administered in separate dosage forms, the number of doses of each compound administered per day may be the same or different. (a) Metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof and optionally (c) a sulfonylurea (preferably glibenclamide) or a pharmaceutically acceptable salt thereof may be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, and rectal. The compounds may also be administered directly to the nervous system, including but not limited to intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal and/or perimedullary routes of administration, by delivery via intracranial or intraspinal needles and/or catheters with or without pump devices. The (a) metformin or a pharmaceutically acceptable salt thereof, (b) the compound of formula (I) or a pharmaceutically acceptable salt thereof and optionally (c) a sulfonylurea (preferably glyburide) or a pharmaceutically acceptable salt thereof may be administered according to a simultaneous or alternating dosing regimen, either simultaneously in separate or single forms, at the same or at different times during the course of treatment. One skilled in the art will also recognize that the discussion above regarding "co-therapy" and "combination therapy" will apply analogously to the treatment of glucose-related disorders comprising administering to a subject in need thereof (a) glyburide and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof.

To provide a more accurate description, certain quantitative expressions herein are recited as ranges from about X to about Y. It should be understood that if a range is recited, the range is not limited to the recited upper and lower limits, but includes all ranges from about X to about Y, or any amount or range therein.

To provide a more concise description, some of the quantitative expressions given herein are not modified by the term "about". It is understood that each quantity given herein is meant to refer to the actual given value, whether or not the term "about" is used explicitly, and is also intended to refer to the approximation to such given value that would reasonably be inferred according to ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.

The present invention also includes pharmaceutical compositions comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The pharmaceutical compositions of the present invention, described herein as active ingredients, can be prepared according to conventional pharmaceutical compounding techniques by intimately mixing (a) metformin or a pharmaceutically acceptable salt thereof and (b) the compound of formula (I) or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients.

The invention also includes pharmaceutical compositions comprising (a) glibenclamide and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The pharmaceutical compositions of the present invention, described herein as the active ingredient, can be prepared according to conventional pharmaceutical compounding techniques by intimately mixing (a) glibenclamide and (b) the compound of formula (I) or a pharmaceutically acceptable salt thereof, with pharmaceutically acceptable excipients.

The present invention also relates to a pharmaceutical composition comprising (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, (c) a sulfonylurea or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The pharmaceutical compositions of the present invention, described herein as active ingredients, can be prepared according to conventional pharmaceutical compounding techniques by intimately mixing (a) metformin or a pharmaceutically acceptable salt thereof, (b) the compound of formula (I) or a pharmaceutically acceptable salt thereof, and (c) the sulfonylurea or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients.

The pharmaceutically acceptable excipient may take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable excipients and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations such as powders, capsules and tablets, suitable excipients and additives include diluents, granulating agents, lubricants, binders, disintegrating agents, hydrophilic polymers to control drug release, hydrophobic polymers to control drug release, wetting agents and the like. The solid oral formulations may also be coated with sugar, cellulose ether and acrylic polymers for extended release, or may be enteric coated to regulate the primary site of absorption. For parenteral administration, the excipients will typically consist of sterile water and other ingredients may be added to increase solubility or preserve. Injectable suspensions or solutions may also be prepared using aqueous excipients in conjunction with appropriate additives.

To prepare the pharmaceutical compositions of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof and (a) metformin or a pharmaceutically acceptable salt thereof and/or (b) a sulfonylurea (preferably glyburide) or a pharmaceutically acceptable salt thereof as active ingredients are intimately mixed according to conventional pharmaceutical compounding techniques with pharmaceutically acceptable excipients which may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral administration such as intramuscular injection. In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable excipients and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as powders, capsules and tablets (including caplets), suitable excipients and additives include diluents, granulating agents, lubricants, binders, disintegrants, hydrophilic polymers to control drug release, hydrophobic polymers to control drug release, wetting agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical excipients are obviously employed. Tablets may be sugar-coated or enteric-coated, if desired, using standard techniques. For parenteral dosage forms, the excipients will typically comprise sterile water, but may also comprise other ingredients, for example for purposes such as to aid dissolution or for preservation. Suspensions for injection may also be prepared, in which case appropriate liquid excipients, suspending agents and the like may be employed. The pharmaceutical compositions described herein will contain an amount of the active ingredient per dosage unit (e.g., per tablet, per capsule, per powder, per injection, per teaspoonful, etc.) sufficient to deliver an effective dosage as described above. The pharmaceutical compositions herein will independently contain per dosage unit (e.g., per tablet, per capsule, per powder, per injection, per suppository, per teaspoonful, etc.) from about 0.01 to about 2,000mg or any amount or range therein of each of (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and/or (c) a sulfonylurea, preferably glyburide, or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions described herein may be administered in an appropriately selected therapeutically effective dose, which may vary depending on the requirements of the patient, the severity of the condition being treated and the compound being administered. Daily administration or post-cycle administration (post-periodic dosing) may be employed.

Preferably, these pharmaceutical compositions are in unit dosage forms, such as tablets, pills, capsules, powders, granules, parenteral sterile solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the pharmaceutical composition may be presented in a form suitable for once weekly or once monthly administration; for example, insoluble salts of the active compound (e.g., caprate) may be suitable for providing depot formulations for intramuscular injection.

To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutically acceptable excipient (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums) and other pharmaceutically acceptable diluents (e.g., water) to form a solid dosage composition containing a mixture of the active ingredients. Tablets or pills of the pharmaceutical compositions of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, a tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating covering the former. The two components may be separated by an enteric layer which serves to prevent disintegration in the stomach, thereby allowing the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acid materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms which may be incorporated into the pharmaceutical compositions of the present invention for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils (cottonseed, sesame, coconut or peanut oil), as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums, for example tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

Advantageously, the pharmaceutical compositions of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily. In addition, the pharmaceutical compositions of the present invention may be administered intranasally by topical application of a suitable intranasal vehicle or by transdermal patches well known to those of ordinary skill in the art. Administration is in the form of a transdermal delivery system, and dosing will, of course, be continuous rather than intermittent throughout the dosing regimen.

In certain embodiments, for oral administration in the form of tablets or capsules, the active pharmaceutical ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert excipient (e.g., ethanol, glycerol, water, and the like). In addition, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture, as desired or necessary. Suitable binders include, but are not limited to, starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth) or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, methylcellulose, agar, bentonite, xanthan gum, and the like. The liquid forms are suitably flavored suspending or dispersing agents, such as synthetic and natural gums, e.g., tragacanth, acacia, methylcellulose, and the like. For parenteral administration, sterile suspensions and solutions are desirable. When intravenous administration is desired, isotonic formulations, which typically contain suitable preservatives, are employed.

The pharmaceutical compositions of the present invention may be prepared according to known methods and using known methods and equipment, as disclosed, for example, in the following documents:Pharmaceutical Sciencesremington, 17 th edition, p.1585-1594 (1985);Chemical Engineers Handbookperry, 6 th edition, pages 21-13 to 21-19 (1984); j. the design is a squareournal of Pharmaceutical SciencesParrot, Vol.61, No. 6, p.813-829 (1974); andChemical Engineerhixon, pages 94-103 (1990).

The particles of the pharmaceutical composition of the invention may be prepared, for example, by comminution which will yield the active ingredient in the desired size and any accompanying pharmaceutically acceptable excipients of the desired size. Suitable means for producing the desired particles include, but are not limited to, granulation, spray drying, sieving, lyophilization, crushing, grinding, jet milling, micronization, and fine cutting to produce the desired particle size. This process may be accomplished by a size reduction device such as a micro mill, fluid energy mill, grinder, roller mill, hammer mill, attritor, roller mill, ball mill, vibratory ball mill, impact mill, centrifugal mill, coarse crusher, and fine crusher. The size of the particles can be determined by screening, including grizzlies, flat screens, vibrating screens, rotary screens, shaker screens, vibrating screens, and reciprocating screens. The granules are then compressed, for example according to known methods, to obtain tablets.

As another optionThe granules of the pharmaceutical composition of the present invention may be produced according to wet granulation techniques. In the wet granulation technique, solid particles are wetted and bound together with a binder solution consisting essentially of a granulating solvent, a binder, and optionally other excipients. The active ingredient (e.g. a compound of formula (I-X) or a pharmaceutically acceptable salt thereof) may be granulated with or without other solid excipients into solid particles or partially dissolved in a binder solution. The solid particles may be mixed by mechanical agitation (using, for example, low and high shear mixers) or they may be fluidized by a gas (as in fluidized bed granulation). The granulation fluid is added until a wet blend is produced, and then the wet weight blend is forced through a predetermined screen and dried in a fluid bed dryer. The blend is dried in a forced air oven at a temperature ranging from about 24 ℃ to about 35 ℃ for about 18 to about 24 hours. The dried granules are then classified according to known methods. The dried granules were then classified. Next, magnesium stearate or other suitable lubricant (if desired) and other excipient materials (as appropriate) are added to the granulation, and the granulation is placed in a grinding jar on a porcelain ball mill jar for 10 minutes. For the preparation of tablets, e.g. inThe resulting mixture is pressed into layers in a press or a Korsch LCT press. In one example, the speed of the press is set at 15rpm and the maximum load is set at 4 tons.

Alternatively, the active ingredient and excipients may be blended in a fluid bed granulator as powdered ingredients. After dry-blending the powdered ingredients in the granulator, a granulating fluid, such as an aqueous solution of polyvinylpyrrolidone, is sprayed onto the powder. The resulting agglomerated material was then dried in a granulator. The process granulates all the ingredients present therein while adding the granulation fluid. After the granules are dried, a lubricant such as stearic acid or magnesium stearate is mixed into the granulated mass using a blender such as a V-blender or a tote blender (toteblend). The granules are then compressed and coated in the manner described above.

Exemplary solvents suitable for manufacturing the components of the pharmaceutical composition include aqueous or inert solvents that do not adversely affect the materials used in the system. The solvent broadly includes a member selected from the group consisting of: aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic materials, aromatic materials, heterocyclic solvents, and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropanol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether acetate, methylene chloride, ethylene dichloride, dichloropropane, carbon tetrachloride nitroethane, nitropropane tetrachloroethane, diethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1, 4-diacetone, methyl propyl ketone, n-butyl acetate, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether acetate, methylene chloride, ethylene dichloride, dichloropAlkanes, tetrahydrofuran, diglyme, water, aqueous solvents containing inorganic salts such as sodium chloride, calcium chloride, and the like, and mixtures thereof such as acetone and water, acetone and methanol, acetone and ethanol, dichloromethane and methanol, and dichloroethane and methanol.

If desired, a pan coating may be used to provide the finished dosage form. In pan coating systems, the coating composition is deposited by continuous spray coating onto compressed tablets, with tumbling in a rotating coating pan. Pan coaters (pan coaters) are commonly used due to their availability on a commercial scale. Other techniques may be used to coat the tablets. Once coated, the tablets are dried, for example, in a forced air oven or in an oven with controlled temperature and humidity to release the solvent dosage form used in the manufacturing process. Drying conditions are conventionally selected according to the available equipment, environmental conditions, solvents, coating agents, coating thickness, etc.

Other coating techniques may also be employed. For example, one alternative technique uses an air-suspension method. The method comprises suspending and tumbling the tablets in an air stream until coatedThe agent is applied. The air suspension method is described, for example, in U.S. patent No.2,799,241; in J.am.pharm.Assoc., volume 48, page 451-459 (1959); and as above, volume 49, pages 82-84 (1960). It is also possible to use, for example, dichloromethane methanol as a cosolvent for the coating materialThe tablets were coated by an air suspension coater. Can be used by using a cosolventAn air suspension coating machine.

Where treatment of a glucose related disorder is desired, a synergistic therapy of the present invention comprising (a) metformin or a pharmaceutically acceptable salt thereof and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in any of the compositions described above and according to a dosing regimen established in the art.

Where treatment of glucose related disorders is desired, a synergistic therapy of the present invention comprising (a) glibenclamide and (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, can be administered in any of the compositions described above and according to dosing regimens established in the art.

Where treatment of glucose related disorders is desired, a co-therapy of the present invention comprising (a) metformin or a pharmaceutically acceptable salt thereof, (b) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (c) a sulfonylurea (preferably glyburide) or a pharmaceutically acceptable salt thereof, may be administered in any of the above compositions and according to dosing regimens established in the art.

In one embodiment, for oral administration, the composition is preferably provided in the form of a tablet containing 50, 100, 150, 200, 250, 500, 750, 850, 1000, 1500 or 2000mg of metformin or a pharmaceutically acceptable salt thereof (preferably metformin hydrochloride); and further comprises 1, 5, 10, 25, 50, 100, 150, 200, 250, 300 or 500mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, for oral administration, the composition is preferably provided in the form of a tablet containing 1.0, 2.5, 5.0, 7.5, 10.0, 12.5, 15 or 20 milligrams of glyburide; and further comprises 1, 5, 10, 25, 50, 100, 150, 200, 250, 300 or 500mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, for oral administration, the composition is preferably provided in the form of a tablet containing 50, 100, 150, 200, 250, 500, 750, 850, 1000, 1500 or 2000mg of metformin or a pharmaceutically acceptable salt thereof (preferably metformin hydrochloride); and further contains 1, 5, 10, 25, 50, 100, 150, 200, 250, 300 or 500mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably a compound of formula (I-X) or a pharmaceutically acceptable salt thereof or a compound of formula (I-Y) or a pharmaceutically acceptable salt thereof, and further contains 1.0, 2.5, 5.0, 7.5, 10.0, 12.5, 15, 20, 25, 50, 100, 250, 500 or 1000mg of a sulfonylurea or a pharmaceutically acceptable salt thereof.

Preferably, metformin or a pharmaceutically acceptable salt thereof (more preferably, metformin hydrochloride) is administered at a dosage level of about 0.01mg/kg body weight to about 200mg/kg body weight per day, or about 0.5mg/kg body weight to about 50mg/kg body weight per day, or any amount or range therein. Preferably, the range is from about 1.0 to about 50.0mg/kg body weight per day, or any amount or range therein, more preferably, from about 5mg/kg to about 30mg/kg, or any amount or range therein, more preferably, from about 5 to about 20mg/kg body weight per day, or any amount or range therein. In one embodiment, the effective amount of metformin, or a pharmaceutically acceptable salt thereof, is provided at a dosage level of 250mg, 500mg, 750mg, 1000mg or 2000mg, or any amount or range therein.

Preferably, the glyburide is administered at a dosage level of about 0.01mg/kg body weight to about 0.5mg/kg body weight per day, or about 0.01mg/kg body weight to about 0.3mg/kg body weight per day, or any amount or range therein. In one embodiment, an effective amount of glyburide is provided at a dosage level of 1.0mg, 2.5mg, 5.0mg, 7.5mg, 10.0mg, 12.5mg, 15mg, or 20mg, or any amount or range therein.

Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dosage level of about 0.01mg/kg body weight to about 500mg/kg body weight per day, or about 0.01mg/kg body weight to about 200mg/kg body weight per day, or any amount or range therein. Preferably, the range is from about 0.01 to about 50mg/kg body weight per day, or any amount or range therein, more preferably, from about 0.05mg/kg to about 10mg/kg, or any amount or range therein, more preferably, from about 1 to about 5mg/kg body weight per day, or any amount or range therein. In one embodiment, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided at a dosage level of 10mg, 25mg, 50mg, 100mg, 150mg, or 300mg, or any amount or range therein. Preferably, the sulfonylurea, or a pharmaceutically acceptable salt thereof, is administered at a dosage level of about 0.01mg/kg body weight to about 200mg/kg body weight, or any amount or range therein, per day. Preferably, the range is from about 0.01 to about 50mg/kg body weight per day. In one embodiment, the effective amount of the sulfonylurea, or a pharmaceutically acceptable salt thereof, is provided at a dosage level of 1.0mg, 2.5mg, 5.0mg, 10mg, 25mg, 50mg, 100mg, 150mg, 250mg, 500mg, 100mg, or any range or amount therein. The co-therapy of the present invention may be administered on a regimen of 1 to 4 times per day.

The optimal dosage to be administered can be readily determined by one skilled in the art and will vary with, for example, the mode of administration, the strength of the formulation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust the dosage.

One skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and generally accepted cell and/or animal models can predict the ability of a test compound to treat or prevent a given disorder. Those skilled in the art will also recognize that human clinical trials (including human first use trials, dose exploration trials, and efficacy trials) conducted in healthy patients and/or patients with a given disease may be accomplished according to methods well known in the clinical and medical arts.

The following examples are given to aid in the understanding of the present invention and are not intended to, and should not be construed to, limit in any way the invention set forth in the claims that follow thereafter.

The ability and unexpected synergistic effect of metformin and compounds of formula (I) in the treatment of glucose related disorders such as type 2diabetes and syndrome X is based on the following animal studies.

Example 1: in vivo mouse study

Male C57BL/6 mice (100 mice in total) were fed with a high fat diet from 3 to 6 weeks of age (3 weeks total). After 3 weeks on a high fat diet, all mice received a single intraperitoneal injection of Streptozotocin (STZ) (100mg/kg in 0.05mol/L citric acid, pH4.5, 10 mg/ml). All mice were then kept on the high fat diet for an additional 3 weeks. Those mice with fasting blood glucose levels > 7mM and < 15mM were selected for the study.

At the beginning of the pre-dose cycle, each mouse was assigned a pre-dose number, shown on its cage card. After assignment to the dose group, each mouse was assigned a unique study identification number (which will be shown on its cage card) and determined by permanent marking of its tail. Mice were housed in stainless steel cages 5 per cage. The study room was maintained for a 12 hour light/dark cycle (the light/dark cycle may be interrupted for study related activities) at a temperature range of 64 ° F to 79 ° F with a relative humidity range of 30% to 70%. The temperature and humidity ranges will be monitored by a hygrothermograph. Mice were fed ad libitum (unless otherwise indicated) a high fat diet prepared at Southern University (Southern University). Water is optionally supplied through the water bottle.

Research and design:

the quarantine period is 5 days. Test compounds or vehicle were administered by gavage. The dose level was chosen to represent a range of exposures with pharmacological effects.

Mice were selected based on pre-dose evaluation on day-1 and randomized to groups based on body weight and fasting blood glucose levels using a computer generated randomization procedure. The mean values of body weight and fasting blood glucose levels were similar for each group (with < 5% variation).

Mice were randomly assigned to six test groups of 10 mice each. Each group was treated by oral administration for 3 weeks using one of the following regimens: (a) a solvent; (b) 1mg/kg of a compound of formula (I-Y); (c) 10mg/kg of a compound of formula (I-Y); (d) metformin, 500 mg/kg; (e)1mg/kg of a combination of a compound of formula (I-Y) and 500mg/kg of metformin; and (f)10mg/kg of a combination of a compound of formula (I-Y) and 500mg/kg of metformin.

On day 1 (first day of dosing), dosing at all dose levels began. All groups were then dosed for an additional 20 days. The following pharmacological parameters were measured during and at the end of the study: (a) post-prandial blood glucose was measured on days 1, 7, 14 and 21 prior to dosing; (b) the body weight of each mouse was measured after blood glucose measurements on day-1 (for grouping), days 1, 7, 14 and 21; and (c) 24 hour food intake (average of 5 mice per cage) was measured on days 1, 7, 14 and 20.

On day 18 of treatment, mice were fasted overnight (5 pm-8 am) after changing to a new cage. The next morning, basal fasting blood glucose levels were determined. Then, a glucose solution (20% glucose, 2g/kg body weight, 1ml/100g body weight, freshly prepared before Oral Glucose Tolerance Test (OGTT)) was administered by oral gavage. Blood glucose levels were measured with tail blood 30, 60 and 120 minutes after glucose challenge. Food was changed after the last blood glucose measurement time point.

The pharmacological significance of any result is determined based on statistical analysis and historical control data. Statistical analysis was performed using graphpadpism.

The compounds of formula (I-Y) alone and in combination with metformin were tested according to the procedure described above and the results are listed in Table 1 below.

Table 1: in vivo mouse assay results

Example 2: in vivo mouse study

Male ob/ob mice (8 weeks old, about 50g) were housed in 2 mice per cage in a temperature controlled room with a 12 hour light/dark cycle. The mice were allowed to obtain water and food ad libitum (a commercially provided diet). Mice were divided into 6 test groups based on their body weight and post-prandial blood glucose levels, as recorded in table 2 below.

Table 2: mouse treatment group

Design of research：

On the first morning, mice were grouped as indicated above and fed glucose. The mice were then given either vehicle or test compound by gavage once daily at 4:00 pm daily for 22 days. The compounds of formula (I-X) were administered at 1mg/kg or 10mg/kg (as illustrated in the results table below), with or without treatment with metformin hydrochloride at a dose of 250 mg/kg.

Body weight, food intake and post-prandial blood glucose levels were measured weekly. After an overnight fast, the mice were subjected to an Oral Glucose Tolerance Test (OGTT) on day 18. At t₀(before glucose administration), corresponding to t 30, 60 and 120 minutes after administration₃₀、t₆₀And t₁₂₀Glucose concentration at 0.5g/kg body weight and blood glucose level of OGTT were measured with a Glucometer (Glucometer). The blood glucose solution administered was prepared with 12.5% glucose at 0.5g/kg body weight, 1ml/250g body weight.

After completion of the study, final body weight and blood glucose levels were collected and mice in each group were sacrificed to collect blood for biochemical analysis including post-prandial blood glucose levels, fasting blood glucose levels, blood glucose levels during the OGTT, plasma insulin and body weight changes.

The compounds of formula (I-X) alone and in combination with metformin were tested according to the procedure described above and the results are listed in Table 3 below.

Table 3: in vivo ob/ob mouse assay results

The results in Table 3 above show that 10mg/kg of the compound of formula (I-X) significantly reduced blood glucose levels and improved glucose excursions during the OGTT. The results also show no additive or synergistic effect in mice treated with the combination of metformin and the compound of formula (I-X). In addition, the results show that 250mg/kg of metformin has no effect on glycemic control, indicating that ob/ob mice are not a suitable animal model to demonstrate metformin activity (in view of the mechanism by which metformin acts on blood glucose levels). The lack of additive and/or synergistic potentiation of the combination of the compound of formula (I-X) and metformin is therefore believed to be a result of the limitations of this model in demonstrating the known anti-diabetic activity.

Example 3

Pharmaceutical composition-combination of metformin hydrochloride and compound of formula (I-X)

Pharmaceutical compositions comprising metformin hydrochloride and the compound of formula (I-X) were prepared as follows, and the components of the formulations are listed in Table 4 below. Metformin hydrochloride is commercially available as Drug Substance (DS) from Solmag s.p.a. melazzano (Via Della vitaria 89, 26837Cassino d' Alberi, melazzano, italy).

Table 4: combination tablet formulation

Metformin hydrochloride, the compound of formula (I-X), microcrystalline cellulose (MCC) and croscarmellose sodium were sieved and blended in a Bohle bin blender (L.B Bohle Maschinen + Verfhren GmbH, Enniger loh, Germany). The resulting material was fluidized in a Glatt fluidized bed processor (Glatt Air technologies, Ramsay, NJ) with a 1.0mm nozzle and a hood set at 2. A binder (povidone K29/32) was then sprayed onto the resulting granules, in a 6% w/w solids solution in water. Moisture content and particle growth were monitored during this process, and samples were taken every 10 minutes of treatment. A moisture scale was used to determine Loss On Drying (LOD).

The dried granules were then lubricated with sieved magnesium stearate in a bohle bin blender. The final blend was compressed into tablets on a rotary press Fette 1200i (Fette GmbH, Schwarzenbek, germany) equipped with a 0.830 "x 0.4095" D-die and a low feeder. Two stations were used to press the batch to the target tablet weight. Five different compression profiles (compression profiles) were used for producing tablets.

For these five compression profiles in batches, the tablet weight variation was less than 1% and the friability was less than 0.5%. Tablet hardness increases with pressure, increasing from 16kp at 14.6KN to 25kp at 31.3KN, with a corresponding tablet thickness decreasing from 7.32 ± 0.3mm at 14.6KN to 6.84 ± 0.3mm at 31.3 KN. The disintegration time increased with pressure from about 4:50 minutes at 14.6KN to about 9:40 minutes at 31.3 KN. Measurements of the dissolution rate showed that between about 85% and about 93% of the compound of formula (I-X) was released and between about 94% and about 99% of the metformin hydrochloride was released at 30 minutes.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the appended claims and their equivalents.

Claims

1. A method of treating a glucose-related disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising

(a) Metformin or a pharmaceutically acceptable salt thereof; and

(b) a compound of formula (I)

Wherein ring a and ring B are one of:

(1) ring a is an optionally substituted unsaturated monocyclic heterocycle, and ring B is an optionally substituted unsaturated monocyclic heterocycle, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring; or

(2) Ring a is an optionally substituted phenyl ring, and ring B is an optionally substituted unsaturated monocyclic heterocycle, or an optionally substituted unsaturated fused heterobicyclic ring, wherein Y is connected to the heterocycle of the fused heterobicyclic ring; or

x is a carbon atom or a nitrogen atom; and

y is- (CH)₂)_n- (wherein n is 1 or 2);

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the glucose-related disorder is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glucose, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, and hypertension.

3. The method of claim 1, wherein the glucose related disorder is type 2 diabetes.

4. The method of claim 1, wherein the compound of formula (I) is a compound of formula (I-X)

Or a pharmaceutically acceptable salt thereof.

5. The process of claim 4, wherein the compound of formula (I-X) is a crystalline hemihydrate.

6. The method according to claim 1, wherein the metformin or a pharmaceutically acceptable salt thereof is metformin hydrochloride; and wherein the metformin hydrochloride is administered in a dose of between about 100mg to about 2000 mg.

7. The method of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 50mg to about 500 mg.

8. A method of treating a glucose-related disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a co-therapy comprising

(a) Metformin hydrochloride; and

(b) a compound of formula (I-X)

Or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the glucose-related disorder is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glucose, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, and hypertension.

10. The method of claim 9, wherein the glucose related disorder is type 2 diabetes.

11. The method according to claim 8, wherein the metformin hydrochloride is administered in a dose of between about 100mg to about 2000 mg.

12. The method of claim 8, wherein the compound of formula (I-X) or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 50mg to about 500 mg.

13. A pharmaceutical composition comprising

(a) Metformin hydrochloride;

(b) a compound of formula (I-X)

Or a pharmaceutically acceptable salt thereof; and

(c) a pharmaceutically acceptable excipient.

14. The pharmaceutical composition according to claim 13, wherein the metformin hydrochloride is present in an amount in the range of from about 100mg to about 2000 mg; and wherein the compound of formula (I-X) or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 50mg to about 500 mg.

15. The pharmaceutical composition according to claim 13, wherein the metformin hydrochloride is present in an amount of about 250mg, about 500mg, about 750mg, about 850mg or about 1000 mg; and wherein the compound of formula (I-X) or a pharmaceutically acceptable salt thereof is present in an amount of about 100mg, about 150mg, or about 300 mg.

16. A pharmaceutical composition comprising

(a) Metformin or a pharmaceutically acceptable salt thereof;

(b) a compound of formula (I-X)

Or a pharmaceutically acceptable salt thereof

(c) A sulfonylurea or a pharmaceutically acceptable salt thereof; and

(d) a pharmaceutically acceptable excipient.

17. The pharmaceutical composition of claim 16, wherein the sulfonylurea is selected from chlorpropamide, tolazamide, tolbutamide, glyburide, glipizide, and glimepiride.

18. The pharmaceutical composition according to claim 16, wherein the metformin or a pharmaceutically acceptable salt thereof is metformin hydrochloride; and wherein the sulfonylurea is glibenclamide.

19. The pharmaceutical composition of claim 16, wherein

The metformin hydrochloride is present in an amount in the range of from about 100mg to about 2000 mg;

the compound of formula (I-X) or a pharmaceutically acceptable salt thereof is present in an amount ranging from about 50mg to about 500 mg;

and the glibenclamide is present in an amount in the range of about 2.5mg to about 20 mg.