TW201311252A - Methods of treatment, pharmaceutical compositions and uses thereof - Google Patents

Abstract

The invention relates to methods for preventing, slowing the progression of, delaying or treating metabolic disorders induced in patients by the treatment with neuroleptic agents comprising administering to the patients an SGLT2 inhibitor.

Description

Therapeutic methods, pharmaceutical compositions and uses thereof

The present invention relates to a method of preventing metabolic disorders induced by the treatment of a neuroleptic in a patient, slowing the progression of such metabolic disorders, delaying or treating such metabolic disorders, comprising administering to such patients SGLT2 inhibitors.

A neuroleptic (also known as an antipsychotic) is a drug that improves the symptoms of psychosis, including symptoms of schizophrenia, delusions, and psychotic depression. Some types of neuroleptics are also used to treat non-psychiatric conditions, such as Tourette syndrome and Asperger syndrome. There are two types of psychoactive drugs: the typical antipsychotic, which was first discovered in the 1950s; and the atypical antipsychotic, which was developed in the 1970s and used since then. Atypical neuroleptics are generally considered to be more effective than typical neuroleptics and are less likely to cause side effects such as extrapyramidal syndrome (EPS). Studies have indicated that psychotic episodes are associated with an excess of neurotransmitters called dopamine. Both typical neuroleptics and atypical neuroleptics work by blocking dopamine receptors in the brain, reducing dopamine activity and thereby alleviating psychosis. Although both classes of drugs work in a similar manner, it has been noted that typical antipsychotic drugs are less selective in the type of dopamine receptor they block. This lack of selectivity has been shown to cause an increase in the range and severity of side effects (especially EPS) caused by typical neuroleptics.

The neuroleptic contains a group of 7 drugs: phenothiazine, further divided into aliphatic, piperidine and piperazine; sulfur (Thioxanthenes) (eg, droperidol); phenylbutanone (eg, haloperidol); dibenzoxazolidine (eg, loxapine); indanone (eg Moldinone; diphenylbutyl piperidine (e.g., pimozide); benzisoxazole (e.g., risperidone).

Metabolic side effects are one of the undue side effects observed with mental stabilizers, especially atypical neuroleptics. Such side effects include glucose disorders, insulin resistance, hyperlipidemia, weight gain, and hypertension, and can put patients at risk for cardiac metabolic disorders (see, for example, Boyda et al. (2000) Trends in Pharmacological Sciences 31:484- 497).

Accordingly, there is a need for methods, medicaments, and pharmaceutical compositions that are effective in treating psychiatric disorders while reducing or avoiding side effects associated with antipsychotic treatment, particularly metabolic side effects.

It is an object of the present invention to provide a method of preventing metabolic disorders in a patient receiving treatment of a psychiatric disorder, particularly a patient treated with a neuroleptic, a process of slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder, and a pharmaceutical composition.

Another object of the present invention is to provide for the prevention of diabetes and diabetic complications in patients treated with psychotic disorders, especially those treated with a neuroleptic, to slow the progression of the diabetes and diabetic complications, to delay or treat the diabetes and diabetes concurrently. Methods and pharmaceutical compositions.

Another object of the present invention is to provide a method and a medical combination for preventing type II diabetes in a patient receiving treatment of a mental disorder (especially a patient treated with a neuroleptic), slowing the progression of the type II diabetes, delaying or treating the type II diabetes Things.

Another object of the present invention is to provide a method and pharmaceutical composition for preventing weight gain, delaying the progression of weight gain, delaying or treating the weight gain in a patient receiving treatment for a psychiatric condition, particularly a patient treated with a neuroleptic.

Another object of the present invention is to provide a method and pharmaceutical composition for improving glycemic control in a patient receiving treatment for a psychiatric condition, particularly a patient treated with a neuroleptic.

Another object of the present invention is to provide a method of preventing hyperglycemia, a process of slowing down the hyperglycemia, delaying or treating the hyperglycemia, and a pharmaceutical combination for preventing a patient receiving treatment of a mental disorder (especially a patient treated with a neuroleptic) Things.

Another object of the present invention is to provide patients with anti-glycemic tolerance (IGT), fasting blood glucose abnormality (IFG), insulin resistance and / or methods and pharmaceutical compositions for the development of metabolic syndrome to type 2 diabetes.

Another object of the present invention is to provide a method and pharmaceutical composition for reducing or preventing interruption of treatment of the neuroleptic in a patient treated with a neuroleptic.

Other objects of the present invention will become apparent to those skilled in the art from the description of the <RTIgt;

The present invention achieves the above objects and needs by providing a method of preventing a metabolic disorder induced by a patient using a neuroleptic treatment, slowing the progression of such metabolic disorders, delaying or treating such metabolic disorders, and the methods include administering a patient SGLT2 inhibitors, for example, are combined or alternately or sequentially administered with a neuroleptic. The present invention also achieves the above objectives and needs by providing SGLT-2 inhibitors for preventing metabolic disorders induced by the use of neuroleptics in patients, slowing the progression of such metabolic disorders, delaying or treating such metabolic disorders. It is, for example, combined with a neuroleptic or alternately or sequentially. The present invention also achieves the above objects and needs by providing a pharmaceutical composition comprising a neuroleptic and an SGLT-2 inhibitor.

SGLT2 inhibitors represent a novel class of agents developed to treat or ameliorate glycemic control in patients with type 2 diabetes. An example of a SGLT-2 inhibitor is a glucone-substituted benzene derivative, for example, as in WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489, WO 2006/064033, WO 2006 /117359, WO 2006/117360, WO 2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940 . A benzyl derivative substituted with a grape glucopyranyl group is proposed as an inducer of urinary glucose excretion and as a drug for treating diabetes.

Accordingly, in one embodiment, the present invention provides a method of preventing a metabolic disorder induced in a patient by treating a patient with a neuroleptic, slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder, the method comprising administering Inhibitors with SGLT2 in this patient.

In one aspect, the SGLT2 inhibitor is selected from the group consisting of a glucone-substituted benzene derivative of formula (I). Wherein R ¹ represents Cl, methyl or cyano, R ² represents H, methyl, methoxy or hydroxy, and R ³ represents ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran- 3-yloxy or (S) -tetrahydrofuran-3-yloxy; or a prodrug thereof.

In one aspect, the SGLT2 inhibitor is 1-chloro-4-(β-D-glucopyran-1-yl)-2-[4-( (S) -tetrahydrofuran-3-yloxy)- Benzyl]-benzene, also known as empagliflozin.

In one aspect, the SGLT-2 inhibitors are dapagliflozin, canagliflozin, luseogliflozin, tofogliflozin, ipragliflozin ), ertugliflozin, atigliflozin or remogliflozin.

In another aspect, the SGLT inhibitor is a compound of the formula:

In one aspect, the neuroleptic is a typical neuroleptic or atypical neuroleptic.

In one aspect, the neuroleptic is phenothiazine, sulfur , benzophenone, dibenzoxazil, indanone, diphenylbutyl piperidine or benzisoxazole.

In one aspect, the neuroleptic is olanzapine, risperidone, quetiapine (or quetiapine) Fumarate)), amisulpiride, aripiprazole, haloperidol, clozapine, ziprasidone, zotepine, paliperidone (paliperidone) or oxanetant. In one aspect, the neuroleptic is olanzapine. In one aspect, the neuroleptic is clozapine.

In one aspect, the metabolic disorder induced by treating the patient with a neuroleptic in this patient is weight gain.

In one aspect, the metabolic disorder induced in the patient by treatment with the neuroleptic is hyperglycemia.

In one aspect, the SGLT-2 inhibitor and the neuroleptic agent are administered in combination or alternately or sequentially to the patient.

In another embodiment, the invention provides a method of treating a psychiatric disorder in a diabetic patient, the method comprising administering to the patient a SGLT-2 inhibitor and a neuroleptic.

In one aspect, the SGLT-2 inhibitor and the neuroleptic agent are administered in combination or alternately or sequentially to the patient.

In one aspect, the patient: (1) is an individual diagnosed with one or more conditions selected from the group consisting of overweight, obesity, visceral obesity, and abdominal obesity; or (2) for displaying one or two Or more than two individuals in the following conditions: (a) fasting blood glucose or serum glucose concentration greater than 100 mg/dL, especially greater than 125 mg/dL; (b) postprandial plasma glucose equal to or greater than 140 mg/dL; (c) HbA1c A value equal to or greater than 6.5%, in particular equal to or greater than 8.0%; or (3) an individual in which one, two, three or more of the following conditions are present: (a) obesity, visceral obesity and/or abdominal obesity (b) triglyceride blood content 150 mg/dL; (c) HDL-cholesterol blood content <40 mg/dL in female patients and HDL-cholesterol blood content <50 mg/dL in male patients; (d) systolic blood pressure 130 mm Hg and diastolic blood pressure 85 mm Hg; (e) fasting blood glucose levels 100 mg/dL.

In one aspect, the SGLT2 inhibitor is selected from the group consisting of a glucone-substituted benzene derivative of formula (I). Wherein R ¹ represents Cl, methyl or cyano, R ² represents H, methyl, methoxy or hydroxy, and R ³ represents ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran- 3-yloxy or (S) -tetrahydrofuran-3-yloxy; or a prodrug thereof.

In one aspect, the SGLT2 inhibitor is 1-chloro-4-(β-D-glucopyran-1-yl)-2-[4-( (S) -tetrahydrofuran-3-yloxy)- Benzyl]-benzene, also known as acegliflozin.

In one aspect, the SGLT-2 inhibitor is dapagliflozin, cangliflozin, lugliflozin, togliflozin, iglitazone, ergrenide or repaglinide.

In another aspect, the SGLT inhibitor is a compound of the formula:

In one aspect, the neuroleptic is a typical neuroleptic or atypical neuroleptic.

In one aspect, the neuroleptic is phenothiazine, sulfur , benzophenone, dibenzoxazil, indanone, diphenylbutyl piperidine or benzisoxazole.

In one aspect, the neuroleptic is olanzapine, risperidone, quetiapine (or quetiapine fumarate), amisulpride, aripiprazole, haloperidol, clozapine , ziprasidone, zotiapine, paliperidone or oxatanide. In one aspect, the neuroleptic is olanzapine. In one aspect, the neuroleptic is clozapine.

In another embodiment, the invention provides a method of reducing body weight, reducing body fat, preventing weight gain, or alleviating weight gain in a patient receiving treatment of a psychotic condition, the method comprising administering to the patient an SGLT2 inhibitor and a neuroleptic.

In another embodiment, the invention provides a method of treating, alleviating, preventing or ameliorating hyperglycemia exacerbations in a patient receiving treatment of a psychiatric disorder, the method comprising administering to the patient an SGLT2 inhibitor and a neuroleptic.

In another embodiment, the invention provides a treatment, amelioration, prevention or A method of alleviating overweight or obesity in a patient receiving treatment for a psychiatric condition, the method comprising administering to the patient an SGLT2 inhibitor and a neuroleptic.

In another embodiment, the invention provides a method of treating, ameliorating, preventing or ameliorating pre-diabetes in a patient receiving treatment of a psychiatric disorder, the method comprising administering to the patient an SGLT2 inhibitor and a neuroleptic.

In another embodiment, the invention provides a method of treating, ameliorating, preventing or ameliorating type 2 diabetes in a patient treated for a psychiatric condition, the method comprising administering to the patient an SGLT2 inhibitor and a neuroleptic.

In another embodiment, the invention provides a method of treating, ameliorating, preventing or ameliorating hypertension associated with weight gain in a patient treated with a psychotic disorder, the method comprising administering to the patient an SGLT2 inhibitor and a neuroleptic.

In another embodiment, the invention provides a method of reducing or preventing interruption of a neuroleptic treatment in a patient receiving treatment for a psychiatric condition, the method comprising administering to the patient an SGLT2 inhibitor.

In another embodiment, the invention provides the use of an SGLT2 inhibitor to reduce body weight, reduce body fat, prevent weight gain, or alleviate weight gain in a patient treated with a neuroleptic.

In another embodiment, the invention provides the use of a SGLT2 inhibitor to treat, alleviate, prevent or ameliorate hyperglycemia in a patient treated with a neuroleptic.

In another embodiment, the invention provides the use of a SGLT2 inhibitor to treat, alleviate, prevent or ameliorate overweight or obesity in a patient treated with a neuroleptic.

In another embodiment, the invention provides the use of a SGLT2 inhibitor to treat, alleviate, prevent or ameliorate pre-diabetes in a patient treated with a neuroleptic.

In another embodiment, the invention provides the use of a SGLT2 inhibitor to treat, alleviate, prevent or ameliorate Type II diabetes in a patient treated with a neuroleptic.

In another embodiment, the invention provides the use of a SGLT2 inhibitor to treat, alleviate, prevent or ameliorate hypertension associated with weight gain in a patient treated with a neuroleptic.

In another embodiment, the invention provides the use of a SGLT-2 inhibitor to reduce body weight, reduce body fat, prevent weight gain, or alleviate weight gain in a patient treated with a neuroleptic.

In another embodiment, the invention provides the use of an SGLT-2 inhibitor to reduce or prevent treatment discontinuation in a patient treated with a neuroleptic.

In another embodiment, the invention provides a combination of an SGLT-2 inhibitor and a neuroleptic for the treatment of a psychiatric disorder in a diabetic patient.

In another embodiment, the invention provides a combination of an SGLT-2 inhibitor and a neuroleptic for use in reducing weight, reducing body fat, preventing weight gain, or alleviating weight gain in a patient suffering from a psychiatric condition.

In another embodiment, the present invention provides an SGLT2 inhibitor for preventing a metabolic disorder induced by treating a patient with a neuroleptic in a patient, slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder .

In one aspect, in the above methods, uses, compounds or compositions, the SGLT2 inhibitor is selected from the group consisting of glucone-substituted benzene derivatives of formula (I). Wherein R ¹ represents Cl, methyl or cyano, R ² represents H, methyl, methoxy or hydroxy, and R ³ represents ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran- 3-yloxy or (S) -tetrahydrofuran-3-yloxy; or a prodrug thereof.

In one aspect, in the above methods, uses, compounds or compositions, the SGLT2 inhibitor is 1-chloro-4-(β-D-glucopyran-1-yl)-2-[4-( ( S) -Tetrahydrofuran-3-yloxy)-benzyl]-benzene, also known as iglitavir.

In one aspect, the SGLT-2 inhibitor is dapagliflozin, cangliflozin, lugliflozin, togliflozin, iglitazone, ergrenide or repaglinide.

In another aspect, the SGLT inhibitor is a compound of the formula:

In one aspect, the neuroleptic is a typical neuroleptic or atypical neuroleptic in the above methods, uses, compounds or compositions.

In one aspect, in the above methods, uses, compounds or compositions, the neuroleptic is phenothiazine, sulfur , benzophenone, dibenzoxazil, indanone, diphenylbutyl piperidine or benzisoxazole.

In one aspect, in the above methods, uses, compounds or compositions, the neuroleptic is olanzapine, risperidone, quetiapine (or quetiapine fumarate), amisulpride, ar Riprazole, haloperidol, clozapine, ziprasidone, zotiapine, paliperidone or oxatanide. In one aspect, the neuroleptic is olanzapine. In one aspect, the neuroleptic is clozapine.

In one aspect, in the above methods, uses, compounds or compositions, the compositions are suitable for combination or simultaneous or sequential use of SGLT2 inhibitors and neuroleptics.

In another embodiment, the invention provides a pharmaceutical composition comprising (a) an SGLT2 inhibitor and (b) a neuroleptic.

In one aspect, the SGLT2 inhibitor is selected from the group consisting of a glucone-substituted benzene derivative of formula (I). Wherein R ¹ represents Cl, methyl or cyano, R ² represents H, methyl, methoxy or hydroxy, and R ³ represents ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran- 3-yloxy or (S) -tetrahydrofuran-3-yloxy; or a prodrug thereof.

In one aspect, the SGLT2 inhibitor is 1-chloro-4-(β-D-glucopyran-1-yl)-2-[4-( (S) -tetrahydrofuran-3-yloxy)- Benzyl]-benzene, also known as acegliflozin.

In one aspect, the SGLT-2 inhibitor is dapagliflozin, cangliflozin, lugliflozin, togliflozin, iglitazone, ergrenide or repaglinide.

In another aspect, the SGLT inhibitor is a compound of the formula:

In one aspect, the neuroleptic is a typical neuroleptic or atypical neuroleptic.

In one aspect, the neuroleptic is phenothiazine, sulfur , benzophenone, dibenzoxazil, indanone, diphenylbutyl piperidine or benzisoxazole.

In one aspect, the neuroleptics are olanzapine, risperidone, quetiapine (quetiapine fumarate), amisulpride, aripiprazole, haloperidol, clozapine, Ziprasidone, zotipin, paliperidone or oxatanide. In one aspect, the neuroleptic is olanzapine. In one aspect, the neuroleptic is clozapine.

In one aspect, the compositions are suitable for combination or simultaneous or sequential use of SGLT2 inhibitors and neuroleptics.

In one aspect, the above and below psychiatric disorders are schizophrenia. In one aspect, the above and below patients are individuals who are treated for a psychiatric disorder, such as schizophrenia.

In another aspect, the patient in the context of the present invention is an individual treating a manic episode associated with type I bipolar disorder. In another aspect, the patient is an individual who treats a mixed episode associated with type I bipolar disorder. In one other aspect, the patient is an individual who treats a manic episode or a mixed episode associated with type I bipolar disorder. In another aspect, the patient is an acute agitation individual associated with schizophrenia and type I bipolar mania. In another aspect, the patient is an individual treating a depressive episode associated with type I bipolar disorder. In another aspect, the patient is an individual receiving treatment for depression.

According to another aspect of the present invention, there is provided a method of preventing a condition or condition of a patient receiving treatment of a psychiatric condition, such as a patient treated with a neuroleptic, slowing the progression of the condition or condition, delaying or treating the condition or A method of a condition selected from the group consisting of complications of diabetes such as cataracts and microvascular and macrovascular diseases such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, arteries Sclerosing, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmia and vascular restenosis, the method is characterized by a neuroleptic and The SGLT2 inhibitor is administered, for example, in combination or alternately or sequentially to the patient. In particular, one or more aspects of diabetic nephropathy (such as hyperperfusion, proteinuria, and albuminuria) can be treated, slowed down, or delayed or prevented. The term "tissue ischemia" includes, inter alia, diabetic macroangiopathy, diabetic microangiopathy, poor wound healing, and diabetic ulcer. The terms "microvascular and macrovascular disease" and "microvascular and macrovascular complications" are used interchangeably in this application.

According to another aspect of the present invention, there is provided a method of preventing a metabolic disorder in a patient treated with a psychotic disorder (for example, a patient treated with a neuroleptic), slowing the progression of the metabolic disorder, delaying or treating the metabolic disorder, the metabolism The disorder is selected from the group consisting of type 2 diabetes, abnormal glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, gestational diabetes, and In the case of cystic fibrosis-associated diabetes, the method is characterized in that a neuroleptic and an SGLT2 inhibitor are administered, for example, in combination or alternately or sequentially to the patient.

According to another aspect of the present invention, there is provided a method of improving blood glucose control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated red blood in a patient receiving treatment for a psychotic condition (for example, a patient treated with a neuroleptic) A method of a hormone (HbA1c) characterized in that a neuroleptic and an SGLT2 inhibitor are administered, for example, in combination or alternately or sequentially to the patient.

According to another aspect of the present invention, there is provided a method for preventing, slowing, delaying or reversing a patient receiving treatment of a psychotic disorder (for example, a patient treated with a neuroleptic) from glucose tolerance abnormality (IGT), fasting blood glucose abnormality (IFG) A method of developing insulin resistance and/or self-metabolic syndrome to type 2 diabetes characterized by administering a neuroleptic and an SGLT2 inhibitor, for example, in combination or alternation or sequentially to the patient.

According to another aspect of the present invention, there is provided a method of reducing body weight and/or body fat, or preventing weight and/or body fat, or promoting body weight, in a patient receiving treatment for a psychotic condition (for example, a patient treated with a neuroleptic) A method of reducing body fat, characterized in that a neuroleptic and an SGLT2 inhibitor are administered, for example, in combination or alternately or sequentially to the patient.

Another aspect of the invention provides a method of maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or insulin resistance in a patient receiving treatment for a psychiatric condition, such as a patient treated with a neuroleptic. The method is characterized in that the neuroleptic and the SGLT2 inhibitor are administered, for example, in combination or alternately or sequentially to the patient.

According to another aspect of the present invention, there is provided a use of an SGLT2 inhibitor for the manufacture of a medicament for use in a patient receiving a psychiatric condition (for example, a patient treated with a neuroleptic) for the treatment of diabetes; A condition or disorder of a group consisting of a diabetic complication, slowing the progression of the condition or condition, delaying or treating the condition or condition; preventing a metabolic disorder selected from the group consisting of, slowing down the progression of the metabolic disorder, delaying Or treating the metabolic disorder: type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, and gestational diabetes; Or - improve glycemic control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin (HbA1c); or - prevent, slow, delay or reverse from glucose tolerance abnormal (IGT), fasting blood glucose Abnormal (IFG), insulin resistance and/or progression from metabolic syndrome to type 2 diabetes; or - prevention of a condition or condition selected from the group consisting of, slowing down the condition or condition The progression, delay or treatment of the condition or condition: complications of diabetes such as cataracts and microvascular and macrovascular diseases such as nephropathy, Retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, stroke, and peripheral arterial obstructive disease; or - reduce body weight and / or body fat, or prevent weight and / or body fat increase, or promote weight and / Or a reduction in body fat; or - preventing, slowing, delaying or treating a disease or condition attributed to abnormal accumulation of ectopic fat; or - maintaining and/or improving insulin sensitivity and/or treating or preventing hyperinsulinemia and/or Or insulin resistance; - treatment of diabetes associated with cystic fibrosis; characterized in that the SGLT2 inhibitor is for example administered in combination or alternately or sequentially with a neuroleptic.

According to another aspect of the invention, there is provided the use of a pharmaceutical composition of the invention for the manufacture of a medicament for use in a therapeutic and prophylactic method as described above and below.

definition

The term of the present invention "neuroleptic" or "antipsychotic agent" means calm and not calm psychotropic substances, which include mainly used to control psychotic delusions, hallucinations or thought disorder, the particular conditions such as schizophrenia.

The term " psychotic disorder " or " psychotic disorder " as used in the present invention means an abnormally conscious condition. It is a general psychiatric term that is generally described as a mental state involving "loss of connection with reality." The term psychiatric disorder indicates a more severe form of psychotic disorder during which hallucinations and delusions and loss of insight may occur. Individuals suffering from mental illness may exhibit hallucinations or delusional beliefs and may exhibit personality changes and mental disorders. Depending on the severity of the mental illness, it can be accompanied by abnormal or peculiar behavior, as well as social difficulties and obstacles to performing daily activities.

The term " active ingredient " of the pharmaceutical composition of the present invention means an SGLT2 inhibitor and/or a neuroleptic of the present invention.

The term " body mass index " or " BMI " of a human patient is defined as the weight (kg) divided by the height (meter) square, so the BMI has a unit of kg/m ² .

The term " overweight " is defined as the condition that the individual has a BMI greater than 25 kg/m ² and less than 30 kg/m ² . The terms "overweight" and "pre-obesity" are used interchangeably.

The term " obesity " is defined as the condition in which the individual's BMI is equal to or greater than 30 kg/m ² . According to the WHO definition, the term obesity can be classified as follows: The term "type I obesity" is a condition in which the BMI is equal to or greater than 30 kg/m ² but less than 35 kg/m ² ; the term "type II obesity" is a BMI equal to or greater than 35 kg/ m ² but less than 40 kg/m ² ; the term "type III obesity" is a condition in which the BMI is equal to or greater than 40 kg/m ² .

The term " visceral obesity " is defined as a condition in which a male waist-to-hip ratio is greater than or equal to 1.0 and a female waist-to-hip ratio is greater than or equal to 0.8. It defines the risk of insulin resistance and the development of pre-diabetes.

The term " abdominal obesity " is generally defined as a condition in which a male waist circumference is >40 吋 or 102 cm and a female waist circumference is >35 吋 or 94 cm. For Japanese ethnicity or Japanese patients, abdominal obesity can be defined as male waist circumference. 85 cm and female waist 90 cm (see, for example, the investigating committee for the diagnosis of metabolic syndrome in Japan).

The term " normal blood glucose " is defined as the condition in which the individual's fasting blood glucose concentration is within the normal range, ie greater than 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L). The term "fasting" has the usual meaning as a medical term.

The term " hyperglycemia " is defined as the condition in which an individual's fasting blood glucose concentration is above the normal range, ie greater than 100 mg/dL (5.6 mmoI/L). The term "fasting" has the usual meaning as a medical term.

The term " hypoglycemia " is defined as an individual whose blood glucose concentration is below the normal range, especially below 70 mg/dL (3.89 mmol/L) or even below 60 mg/dl.

The term " postprandial hyperglycemia " is defined as a condition in which an individual has a 2-hour postprandial blood glucose or serum glucose concentration greater than 200 mg/dL (11.1 mmol/L).

The term " fasting glucose abnormality " or " IFG " is defined as the individual's fasting blood glucose concentration or fasting serum glucose concentration ranging from 100 mg/dl to 125 mg/dl (ie 5.6 mmol/l to 6.9 mmol/l), especially Greater than 110 mg/dL and less than 126 mg/dl (7.00 mmol/L). Individuals with "normal fasting glucose" have a fasting glucose concentration of less than 100 mg/dl, which is less than 5.6 mmol/l.

The term " glucose tolerance abnormality " or " ITT " is defined as a condition in which an individual has a 2-hour postprandial blood glucose or serum glucose concentration greater than 140 mg/dl (7.8 mmol/L) and less than 200 mg/dL (11.11 mmol/L). Abnormal glucose tolerance (i.e., 2 hours postprandial blood glucose or serum glucose concentration) can be measured by blood glucose levels expressed in milligrams per minute (dL) of plasma glucose after 2 hours after fasting of 75 g of glucose. Individuals with "normal glucose tolerance" had a 2-hour postprandial blood glucose or serum glucose concentration of less than 140 mg/dl (7.8 mmol/L).

The term " hyperinsulinemia " is defined as the fasting or postprandial serum or plasma insulin concentration of an individual with insulin resistance and with or without blood glucose normality is higher than non-insulin resistance and waist-to-hip ratio <1.0 (male) or < The condition of a normal thin individual of 0.8 (female).

The terms " insulin sensitization ", "improvement of insulin resistance" or "reduced insulin resistance" are synonymous and are used interchangeably.

The term " insulin resistance " is defined as a state in which a circulating insulin content is required to exceed a normal response to glucose load to maintain normal blood glucose (Ford ES et al, JAMA . (2002) 287 :356-9). One method for determining insulin resistance is the euglycaemic-hyperinsulinaemic clamp test. The ratio of insulin to glucose is determined in the context of a combined insulin-glucose fusion technique. If glucose uptake is less than 25% of the background population studied, insulin resistance is considered to be present (WHO definition). The so-called minimal model is much simpler than the clamp test, in which the insulin and glucose concentrations in the blood are measured at regular intervals during the intravenous glucose tolerance test and insulin resistance is calculated from these concentrations. . In this way it is not possible to distinguish between hepatic insulin resistance and peripheral insulin resistance.

In addition, insulin resistance, response to therapy in patients with insulin resistance, insulin sensitivity, and hyperinsulinemia can be assessed by a reliable indicator of insulin resistance - "Hystatometric Model Assessment of Insulin Resistance (HOMA-IR) The score was quantified (Katsuki A et al., Diabetes Care 2001; 24: 362-5). Further reference is made to a method for determining the HOMA index of insulin sensitivity ( Matthews et al, Diabetologia 1985 , 28: 412-19 ), a method for determining the ratio of intact proinsulin to insulin ( Forst et al, Diabetes 2003 , 52 (Supp. 1): A459 ) and normal blood glucose clamp research. In addition, plasma adiponectin levels can be monitored as a potential replacement for insulin sensitivity. Estimation of insulin resistance by the steady-state evaluation model (HOMA)-IR score was calculated using the following formula (Galvin P et al, Diabet Med 1992; 9: 921-8): HOMA-IR = [fasting serum insulin (μU/mL) ]×[fasting plasma glucose (mmol/L)/22.5].

In general, other parameters are used in daily clinical practice to assess insulin resistance. Preferably, for example, the patient's triglyceride concentration is used because the increase in triglyceride content is significantly associated with the presence of insulin resistance.

Patients with a propensity to develop IGT or IFG or type 2 diabetes are those with hyperinsulinemia and defined as insulin resistant with normal blood glucose. Typical patients with insulin resistance are usually overweight or obese, but this is not always the case. If insulin resistance can be detected, this is a particularly powerful indication of the presence of pre-diabetes. Thus, to maintain glucose homeostasis, an individual may produce 2-3 times as much endogenous insulin as a healthy individual, which would otherwise lead to any clinical symptoms.

The method for studying pancreatic beta cell function is similar to the above method for insulin sensitivity, hyperinsulinemia or insulin resistance: HOMA index can be determined, for example, by measuring beta cell function ( Matthews et al, Diabetologia 1985 , 28: 412). -19 ), the ratio of intact proinsulin to insulin ( Forst et al, Diabetes 2003 , 52 (suppl. 1): A459 ), oral glucose tolerance test or insulin/C-peptide secretion after dietary tolerance test, or borrow Measurement of beta cell function by minimal blood glucose clamp studies and/or minimal modeling after frequent sampling of intravenous glucose tolerance tests ( Stumvoll et al, Eur J Clin Invest 2001, 31:380-81 ) improve.

" Pre-diabetes " is a generic term referring to the intermediate stage between normal glucose tolerance (NGT) and dominant type 2 diabetes (T2DM), also known as intermediate hyperglycemia. Thus, it represents three groups of individuals, individuals with only glucose tolerance abnormalities (IGT), individuals with only fasting glucose abnormalities (IFG), or individuals with both IGT and IFG. IGT and IFG usually have different pathophysiological causes, however, mixed conditions with both characteristics may also be present in patients. Thus, in the context of the present invention, a patient diagnosed with "pre-diabetes" is an individual diagnosed with IGT or an individual diagnosed with IFG or an individual diagnosed with both IGT and IFG. Following the definition of the American Diabetes Association (ADA) and in the context of the present invention, patients diagnosed with "pre-diabetes" are the following individuals: a) fasting plasma glucose (FPG) concentration <100 mg/dL [ 1 mg/dL = 0.05555 mmol/L], and the 2-hour plasma glucose (PG) concentration range measured by the 75 g oral glucose tolerance test (OGTT) was between Between 140 mg/dL and <200 mg/dL (ie IGT); or b) fasting plasma glucose (FPG) concentration is between 2-hour plasma glucose (PG) concentration <140 mg/dL (ie IFG) measured between 100 mg/dL and <126 mg/dL and measured by the 75 g oral glucose tolerance test (OGTT); or c Fasting plasma glucose (FPG) concentration is between 2-hour plasma glucose (PG) concentration range between 100 mg/dL and <126 mg/dL and measured by the 75 g oral glucose tolerance test (OGTT) Between 140 mg/dL and <200 mg/dL (ie both IGT and IFG).

Patients with "pre-diabetes" are individuals who tend to develop type 2 diabetes. Pre-diabetes expands the definition of IGT to include fasting blood glucose Individuals within the normal range of 100 mg/dL (JB Meigs et al., Diabetes 2003; 52: 1475-1484). Explained in the Positional State of the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases entitled "The Prevention or Delay of Type 2 Diabetes" (Position Statemen) Identify pre-diabetes as the scientific and medical basis for serious health threats (Diabetes Care 2002; 25: 742-749).

The term " type 1 diabetes " is defined as the condition in which an individual has a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol/L) in the presence of autoimmunity against pancreatic beta cells or insulin. If glucose tolerance testing is performed, in the presence of autoimmune immunity to pancreatic beta cells or insulin, diabetics will have a blood glucose level of more than 200 mg of glucose per deciliter of plasma 2 hours after fasting 75 g of glucose (11.1 mmol). /l). In the glucose tolerance test, 75 g of glucose was orally administered to the patients tested after 10-12 hours of fasting, and blood glucose levels were recorded immediately before glucose intake and 1 hour and 2 hours after glucose uptake. By detecting circulating islet cell autoantibodies [1A type diabetes], ie at least one of the following: GAD65 [glutamic acid decarboxylase-65], ICA [islet cell cytoplasm], IA-2 [tyrosine] Cytoplasmic domain of phosphatase-like protein IA-2], ZnT8 [zinc carrier-8] or anti-insulin; or detection of other autoimmune signs [1B type diabetes] in the absence of typical circulating autoantibodies, That is, the presence of autoimmune to pancreatic beta cells is observed as detected by pancreatic biopsy or imaging. There is usually a genetic predisposition (such as HLA, INS VNTR, and PTPN22 ), but this is not always the case.

The term " type 2 diabetes " is defined as the condition in which an individual has a fasting blood glucose or a serum glucose concentration greater than 125 mg/dL (6.94 mmoI/L). Blood glucose measurements are standard procedures in routine medical analysis. If the glucose tolerance test is performed, the blood glucose level of diabetic patients after 2 days of fasting intake of 75 g of glucose will exceed 200 mg of glucose per ml of plasma (11.1 mmol/l). In the glucose tolerance test, 75 g of glucose was orally administered to the patients tested after 10-12 hours of fasting, and blood glucose levels were recorded immediately before glucose intake and 1 hour and 2 hours after glucose uptake. In healthy individuals, blood glucose levels will be 60 mg to 110 mg per deciliter of plasma before glucose uptake, less than 200 mg/dL 1 hour after glucose uptake and less than 140 mg/dL after 2 hours. If the value is 140 mg to 200 mg after 2 hours, this is considered abnormal glucose tolerance.

The term " late type 2 diabetes " includes patients with secondary drug failure, insulin therapy indications, and development of microvascular and macrovascular complications such as diabetic nephropathy or coronary heart disease (CHD).

The term " HbA1c " refers to the non-enzymatic glycosylation product of the heme B chain. The determination of HbA1c is well known to those skilled in the art. HbA1c values are especially important in monitoring diabetes treatment. Because the production of HbA1c is basically dependent on blood sugar levels and red blood cell life, HbA1c reflects the average blood glucose level in the first 8-12 weeks in the sense of "blood sugar memory." Diabetic patients whose HbA1c values are always well regulated by intensive diabetes therapy (ie, less than 6.5% of total hemoglobin in the sample) are significantly better protected against diabetic microangiopathy. For example, metformin itself has an average improvement in HbA1c values for diabetic patients of about 1.0-1.5%. In all diabetic patients, this reduction in HbA1C value is not sufficient to achieve the desired target range of HbA1c < 6.5% and preferably < 6%.

In the context of the present invention, the term " insufficient blood glucose control " or "insufficient blood glucose control" means that the patient shows a HbA1c value above 6.5%, especially above 7.0%, even more preferably above 7.5%, especially above 8%. situation.

" Metabolic syndrome ", also known as "X syndrome" (when used in the case of metabolic disorders), also known as "metabolic disorder syndrome", is characterized by a syndrome of insulin resistance (Laaksonen DE) Et al, Am J Epidemiol 2002; 156 :1070-7). According to the ATP III/NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) JAMA: Journal of the American Medical Association (2001) 285 : 2486-2497), diagnosed with metabolic syndrome when there are three or more of the following risk factors:

1. Abdominal obesity, defined as a male waist circumference > 40 吋 or 102 cm and a female waist circumference > 35 吋 or 94 cm; or in the case of a Japanese race or Japanese patient, defined as a male waist circumference 85 cm and female waist 90 cm; 2. Triglyceride: 150 mg/dL; 3. Male HDL-cholesterol <40 mg/dL; 4. Blood pressure 130/85 mm Hg (SBP 130 or DBP 85); 5. Fasting blood sugar 100 mg/dL.

The NCEP definition has been verified (Laaksonen DE et al, Am J Epidemiol. (2002) 156 : 1070-7). Triglycerides and HDL cholesterol in the blood can also be determined by standard methods in medical analysis and are described, for example, in Thomas L (eds.): "Labor und Diagnose", TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000. .

According to the commonly used definition, hypertension is diagnosed if the systolic blood pressure (SBP) exceeds the value of 140 mm Hg and the diastolic blood pressure (DBP) exceeds the value of 90 mm Hg. If the patient develops manifest diabetes, it is currently recommended to reduce systolic blood pressure to less than 130 mm Hg and to reduce diastolic blood pressure to less than 80 mm Hg.

The term " gestational diabetes " (gestational diabetes) refers to a form of diabetes that occurs during pregnancy and usually stops immediately after production. Gestational diabetes is diagnosed by a screening test conducted between the 24th week and the 28th week of pregnancy. It is usually a simple test to measure blood glucose levels 1 hour after administration of 50 g glucose solution. If the content is higher than 140 mg/dl for 1 hour, it is suspected of gestational diabetes. Final confirmation can be obtained by standard glucose tolerance testing, for example using 75 g glucose.

Within the scope of the present invention, the term " SGLT2 inhibitor " relates to a compound which exhibits an inhibitory effect on sodium-glucose transporter 2 (SGLT2), in particular human SGLT2, in particular a glucomannan-based derivative, i.e., having glucosinolate a compound of the glycosyl moiety. Inhibition of hSGLT2 IC ₅₀ to measure preferably less than 1000 nM, and even more preferably less than 100 nM, most preferably less than 50 nM. IC SGLT2 inhibitor of ₅₀ values generally greater than 0.01 nM, or even greater than or equal to 0.1 nM. The inhibition of hSGLT2 can be determined by methods known in the literature, in particular as described in the application WO 2005/092877 or WO 2007/093610 (page 23/24), which are incorporated by reference in their entirety. Into this article. The term "SGLT2 inhibitor" also encompasses any pharmaceutically acceptable salts, hydrates and solvates thereof, including the individual crystalline forms.

The term " treatment " encompasses a patient whose therapeutic treatment has developed a condition, especially in a dominant form. Therapeutic treatment may be symptomatic treatment to alleviate the symptoms of a particular indication, or treatment for the cause to reverse or partially reverse the condition of the indication or to halt or slow the progression of the disease. Thus, the compositions and methods of the invention are useful, for example, for therapeutic treatments over a period of time as well as for long-term therapies.

The terms " prophylactic treatment " and "prevention" are used interchangeably and include treating a patient at risk of developing the conditions described above to reduce the risk.

Aspects of the invention (particularly methods and uses) relate to SGLT2 inhibitors and neuroleptics.

In other mechanisms, renal filtration and resorption of glucose contributes to steady-state plasma glucose concentrations and is therefore useful as an anti-diabetic target. Re-absorption of filtered glucose through renal epithelial cells is carried out along a sodium gradient via a sodium-dependent glucose co-carrier (SGLT) located in the brush border membrane of the tubule. There are at least three SGLT isoforms, and their performance patterns and physicochemical properties are not with. SGLT2 is only expressed in the kidney, while SGLT1 is additionally expressed in other tissues such as the intestine, colon, bone and heart muscle. In the case of normal blood glucose levels, glucose is completely reabsorbed by the SGLT in the kidney, and at glucose concentrations above 10 mM, the renal resorption capacity is saturated, leading to diabetes (this is the "diabetes" concept). This threshold concentration may be reduced due to inhibition of SGLT2. In experiments using the SGLT inhibitor phlorizin, inhibition of SGLT has been shown to partially inhibit glucose reabsorption from the glomerular filtrate into the blood, resulting in diabetes and subsequent reduction in blood glucose concentration.

In one aspect, the SGLT2 inhibitor is selected from the group consisting of : dapagliflozin, cangliflozin, agliflozin, iglegine, togliflozin, lugliflozin, ug Column, repagide, sergliflozin and compounds of the formula And a phenanthrene-substituted benzene derivative of the formula (I), Wherein R ¹ represents Cl, methyl or cyano, R ² represents H, methyl, methoxy or hydroxy, and R ³ represents ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran- 3-Proxy or (S) -tetrahydrofuran-3-yloxy; or a prodrug of one of the aforementioned SGLT2 inhibitors.

The compounds of the formula (I) and their synthetic processes are described, for example, in the following patent applications: WO 2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO 2006/064033, WO 2007/031548, WO 2007 /093610, WO 2008/020011, WO 2008/055870, WO 2011/039107 and WO 2011/039108.

Among the glucopicanyl-substituted benzene derivatives of the above formula (I), the following substituents are preferably defined.

R ¹ preferably represents chlorine or a cyano group, especially chlorine.

R ² preferably represents H.

R ³ preferably represents ethyl, cyclopropyl, ethynyl, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy. R ³ even more preferably represents cyclopropyl, ethynyl, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy. R ³ preferably represents an ethynyl group, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy.

The glucone-substituted benzene derivative of the preferred formula (I) is selected from the group consisting of the compounds (I.1) to (I.11):

According to an embodiment of the invention, the SGLT2 inhibitor is selected from the group consisting of the compounds of the formula (I) above, G1a . The group G1a is even more preferably a grape glucopyranosyl group of the formula (I) selected from the compounds (I.6), (I.7), (I.8), (I.9) and (I.11). Substituted benzene derivative composition. A preferred example of the SGLT2 inhibitor of the group G1a is the compound (I.9), also known as iglitavir.

According to another embodiment of the invention, the SGLT2 inhibitor is selected from the group consisting of dapagliflozin, cangliflozin, agliflozin, iglegine, lugliflozin, ergrenide, and togliflozin. Groups, especially dagliflozin or cangliflozin.

In accordance with the present invention, it is to be understood that the definitions of the SGLT2 inhibitors listed above include glucosamine-substituted benzene derivatives of formula (I), as well as hydrates, solvates thereof and polymorphic forms thereof, and Prodrug. With regard to the preferred compound (I.7), a favorable crystalline form is described in the international patent application WO 2007/028814, which is hereby incorporated herein in its entirety. With regard to the preferred compound (I.8), a favorable crystalline form is described in International Patent Application No. WO 2006/117360, the entire disclosure of which is hereby incorporated herein. With regard to the preferred compound (I.9), the advantageous crystalline forms are described in the international patent application WO 2006/117359 and WO 2011/039107, the entire contents of each of which are hereby incorporated by reference. With regard to the preferred compound (I.11), a favorable crystalline form is described in International Patent Application No. WO 2008/049923, the entire disclosure of which is hereby incorporated herein. These crystalline forms have good solubility properties which give the SGLT2 inhibitors good bioavailability. In addition, the crystalline form is physicochemically stable and thus provides good shelf life stability of the pharmaceutical composition.

The preferred crystalline form of the compound (I.9) (I.9X) can be characterized by an X-ray powder diffraction pattern comprising peaks at 18.84, 20.36 and 25.21 degrees 2Θ (±0.1 degrees 2Θ), wherein the X-ray powder is wound. The image (XRPD) was obtained using CuK _α1 radiation.

In particular, the X-ray powder diffraction pattern comprises peaks at 14.69, 18.84, 19.16, 19.50, 20.36, and 25.21 degrees 2 Θ (± 0.1 degrees 2 Θ), wherein the X-ray powder diffraction pattern uses CuK _α1 radiation. obtain.

In detail, the X-ray powder diffraction pattern comprises peaks at 14.69, 17.95, 18.43, 18.84, 19.16, 19.50, 20.36, 22.71, 23.44, 24.81, 25.21, and 25.65 degrees 2 Θ (± 0.1 degrees 2 Θ), wherein The X-ray powder diffraction pattern is obtained using CuK _α1 radiation.

More specifically, the crystalline form (I.9X) is characterized by an X-ray powder diffraction pattern obtained using CuK _α1 radiation, which contains the degree 2 in the Table 1 (±0.1 degrees 2Θ) ) The peak. Peaks with a relative intensity I/I ₀ greater than 20 are particularly characteristic.

Even more specifically, the crystalline form (I.9X) is characterized by an X-ray powder diffraction pattern obtained using CuK _α1 radiation, the X-ray powder diffraction pattern comprising as shown in Figure 1 of WO 2006/117359. The peak at 2 Θ (± 0.1 degrees 2 Θ).

Further, the crystalline form (I.9X) is characterized by a melting point of about 149 ° C ± 5 ° C (determined by DSC; from the initial temperature evaluation; heating rate 10 K / min). The DSC curve obtained is shown in Figure 2 of WO 2006/117359.

Within the scope of the present invention, a position sensitive detector (OED) and a Cu anode are used as an X-ray source (CuK _α1 radiation, λ=1.54056 , 40 kV, 40 mA) transmission mode STOE-STADI P diffractometer to record X-ray powder diffraction pattern. In the above Table 1, the value "2Θ[°]" represents the diffraction angle (degrees) and the value "d[ ]" indicates the specified distance between the lattice faces ( ). The intensity shown in Figure 1 of WO 2006/117359 is expressed in units of cps (counts per second).

In order to take into account experimental errors, the above 2Θ values should be considered to be accurate to ±0.1 degrees 2Θ, especially ±0.05 degrees 2Θ. That is, when the predetermined crystal of the compound (I.9) is evaluated When the product is in the crystalline form of the present invention, if the value of the Θ value of the experimental observation sample is within the above-mentioned characteristic value ± 0.1 degree 2 ,, especially if it is within the eigenvalue ± 0.05 degree 2 ,, it should be considered to be the same as the characteristic value.

The melting point was determined by DSC (differential scanning calorimetry) using DSC 821 (Mettler Toledo).

In one embodiment, the pharmaceutical composition or dosage form of the invention comprises Compound (I.9) wherein at least 50% by weight of the compound (I.9) is in the form of its crystalline form (I.9X) as defined above . In the composition or dosage form, preferably at least 80% by weight, more preferably at least 90% by weight of the compound (I.9) is in the form of its crystalline form (I.9X) as defined above.

The term "davigliflozin" as used herein refers to dapagliflozin, including hydrates and solvates thereof, and crystalline forms thereof. This compound and its synthesis are described, for example, in WO 03/099836. Preferred hydrates, solvates and crystalline forms are described, for example, in the patent applications WO 2008/116179 and WO 2008/002824.

The term "cangliflozin" as used herein refers to cangliflozin, including hydrates and solvates thereof, and crystalline forms thereof, and has the following structure:

Such compounds and methods for their synthesis are described, for example, in WO 2005/012326 and WO 2009/035969. Preferred hydrates, solvates and crystalline forms This is described, for example, in the patent application WO 2008/069327.

The term "agliflozin" as used herein refers to aglilipin, including hydrates and solvates thereof, and crystalline forms thereof, and has the following structure:

This compound and its synthesis are described, for example, in WO 2004/007517.

The term "egliflozin" as used herein refers to ezetetide, including hydrates and solvates thereof, and crystalline forms thereof, and has the following structure:

This compound and its synthesis are described, for example, in WO 2004/080990, WO 2005/012326 and WO 2007/114475.

The term "tuglipide" as used herein refers to togliflozin, including hydrates and solvates thereof, and crystalline forms thereof, and has the following structure:

This compound and its synthesis are described, for example, in WO 2007/140191 and WO 2008/013280.

The term "lugliflozin" as used herein refers to lugliflozin, including hydrates and solvates thereof, and crystalline forms thereof, and has the following structure:

The term "erglipidem" as used herein refers to erglistine, including hydrates and solvates thereof, and crystalline forms thereof, and has the following structure: It is described, for example, in WO 2010/023594. formula The compounds are described, for example, in WO 2008/042688 or WO 2009/014970.

As used herein, the term "restaglian" refers to repaglinide and repaglinide prodrugs, in particular remogliflozin etabonate, including hydrates and solvates thereof and their crystallization. form. The synthesis of this compound is described, for example, in the patent applications EP 1213296 and EP 1354888.

The term "shegliflozin" as used herein refers to gliclamide and sigridinol prodrugs, in particular sergliflozin etabonate, including hydrates and solvates thereof and their crystallization. form. Processes for the production of such compounds are described, for example, in the patent applications EP 1 344 780 and EP 1 489 089.

For the avoidance of any doubt, the disclosures of each of the foregoing references to the above-referenced SGLT2 inhibitors are specifically incorporated herein by reference.

Mental stabilizers suitable for combination with SGLT-2 inhibitors in the present invention include, but are not limited to, typical and atypical antipsychotics, including phenothiazine, further divided into aliphatic, piperidine and piperazine; sulfur (eg, droperidol); phenylbutanone (eg, haloperidol); dibenzoxazin (eg, loxapine); indanone (eg, fluorenone); diphenylbutyl piperidine (eg, piperazine); and typical antipsychotics, including benzisoxazole (eg, risperidone), olanzapine, quetiapine, oxathatin, and ziprasidone.

Thus, suitable neuroleptics for use in combination with the SGLT-2 inhibitors of the invention include phenylbutanone such as haloperidol, piperazine and droperidol. Suitable examples of phenothiazine include chlorpromazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, triflupromazine. (thiflupromazine), prochlorperazine, thioridazine, and acetophenazine. sulfur Suitable examples include tevothiazide (thiothixene) and chloropyrazine (chlorprothixene).

Suitable neuroleptics for use in combination with the SGLT-2 inhibitors of the invention also include thienobenzodiazepines, dibenzodiazepines, benzisoxazoles, dibenzothiazepines, imidazolidinone, Benzoisothiazolyl-piperazine.

Suitable neuroleptics for use in combination with the SGLT-2 inhibitors of the invention also include triazines such as lamotrigine; dibenzoxazidines such as loxapine; indanones, such as? Anthrone; aripiprazole.

Suitable neuroleptics for use in combination with the SGLT-2 inhibitors of the invention also include dibenzoazepines, such as clozapine.

Other neuroleptics for use in combination with the SGLT-2 inhibitors of the invention also include sulpiride.

Particularly suitable for use in the present invention is a neuroleptic selected from the group consisting of olanzapine, risperidone, quetiapine, amisulpride, aripiprazole, haloperidol, and chlorine. Nitrogen, ziprasidone, zotipine, paliperidone and oxatanide. Particularly useful neuroleptics of the invention are olanzapine, clozapine, risperidone and quetiapine.

Haloperidol has the following structure:

Clozapine has the following structure:

Olanzapine has the following structure:

Risperidone has the following structure:

Quetiapine has the following structure:

Amiciride has the following structure:

Sulpiride has the following structure:

Other suitable neuroleptics for use in combination with the SGLT-2 inhibitors of the invention also include a neuroleptic selected from the group consisting of: asenapine, bonnanserin, ipanley Ketone (iloperidone), lurasidone, mosapramine, paliperidone, pericyazine, perospirone, promazine, and chloramphenicol alcohol (zuclopenthixol).

Other suitable neuroleptics for use in combination with the SGLT-2 inhibitors of the invention also include combinations of two or more of the foregoing neuroleptics, or one or more of the above-described neuroleptics and one or more other compounds (eg, Nitrogen is combined with fluoxetine or phenazoline and amitriyptyline.

The chemical names of the selected compounds used in the context of the present invention are shown below (group G2):

It will be appreciated that when used in combination with a SGLT-2 inhibitor, the neuroleptic may be in the form of a pharmaceutically acceptable salt such as chlorpromazine hydrochloride, mesodazine benzenesulfonate, thioridazine hydrochloride, butylene Bismuthrazine dihydrochloride, fluphenazine hydrochloride, fluphenazine hydrochloride, fluphenazine citrate, trifluoperazine hydrochloride, telfalotazine hydrochloride , haloperidol citrate, loxapine succinate and chlorphenone hydrochloride. Phenazine, chloropyrazine , clozapine, haloperidol, piperazine and risperidone are usually used in non-salt form.

Unless otherwise noted, it is to be understood in accordance with the present invention that the definitions of active agents (including SGLT2 inhibitors and neuroleptics) mentioned above and below may also encompass pharmaceutically acceptable salts and prodrugs thereof. , hydrates, solvates and polymorphic forms. In particular, the term therapeutic agent as used herein refers to the respective active agents. With regard to their salts, hydrates and polymorphic forms, particular reference is made to the salts, hydrates and polymorphic forms thereof as referred to herein.

In another embodiment, the combinations, compositions, methods, and uses of the invention involve the SGLT2 inhibitor being selected from the group G1 and the neuroleptic agent being selected from the group G2.

In another embodiment, the combinations, compositions, methods, and uses of the invention involve the SGLT2 inhibitor being selected from the group G1 and the neuroleptic agent being selected from the group of G2a.

In another embodiment, the combinations, compositions, methods, and uses of the invention involve the SGLT2 inhibitor being selected from the group G1 and the neuroleptic agent being selected from the group of G2b.

In another embodiment, the combinations, compositions, methods, and uses of the invention involve the SGLT2 inhibitor being selected from the group G1a and the neuroleptic agent being selected from the group G2.

In another embodiment, combinations, compositions, methods, and uses of the invention The SGLT2 inhibitor is selected from the group G1a and the neuroleptic is selected from the group of G2a.

In another embodiment, the combinations, compositions, methods, and uses of the invention involve the SGLT2 inhibitor being selected from the group G1a and the neuroleptic agent being selected from the group of G2b.

In a particular embodiment, the combinations, compositions, methods, and uses of the invention involve a combination of a SGLT2 inhibitor that is a compound of formula (I.9) (also known as acegliflozin).

In another aspect, the combinations, compositions, methods, and uses of the invention relate to the following combinations of SGLT2 inhibitors and neuroleptics:

In another aspect, the combinations, compositions, methods, and uses of the invention relate to the following combinations of SGLT2 inhibitors and neuroleptics:

In another aspect, the combinations, compositions, methods, and uses of the invention relate to the following combinations of SGLT2 inhibitors and neuroleptics:

Thus, in the context of the present invention, the SGLT-2 inhibitors of the present invention are useful for counteracting the side effects, particularly metabolic side effects, caused by administration of a patient's neuroleptic. In one aspect, the SGLT-2 inhibitor of the present invention can be adapted to counteract the weight gain of a patient caused by administration of a patient's neuroleptic. In another aspect, the SGLT-2 inhibitor of the present invention can be adapted to counteract hyperglycemia in a patient caused by administration of a patient's neuroleptic. As described above, by using the method of the present invention or administering the pharmaceutical composition of the present invention and especially in view of the action of the SGLT2 inhibitor, the weight gain due to administration of the neuroleptic can be reduced, or the body weight can be reduced. Increase or even lose weight. In some cases, the metabolic side effects treated with certain neuroleptics may be an increase in blood pressure associated with weight gain, such as an increase in systolic blood pressure or an increase in diastolic blood pressure or both. In such cases, the SGLT-2 inhibitors of the present invention may be adapted to counteract an increase in blood pressure (systolic or diastolic blood pressure or both) of a patient caused by administration of a patient's neuroleptic. Accordingly, in one aspect, the present invention provides a method of treating, ameliorating, preventing or ameliorating hypertension associated with weight gain in a patient treated with a psychotic disorder, the method comprising administering to the patient an SGLT2 inhibitor and a neuroleptic . In another aspect, the invention provides a SGLT2 inhibitor for the treatment, alleviation, prevention or amelioration of mental stability Use of high blood pressure associated with weight gain in a patient treated with a drug.

In another aspect, the SGLT-2 inhibitors of the invention can be used in patients treated with a neuroleptic to reduce or prevent interruption of the neuroleptic treatment.

In the present invention, metabolic disorders include type 2 diabetes, abnormal glucose tolerance (IGT), fasting blood glucose abnormality (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, gestational diabetes, and Cystic fibrosis-related diabetes. In the present invention, metabolic disorders also include weight gain. In the present invention, metabolic disorders also include pre-diabetes. In the present invention, the metabolic disorder may also be hypertension associated with weight gain.

In another aspect, the treatment or prevention of the present invention is advantageously adapted to a patient in need of such treatment or prevention, such as a patient treated with a neuroleptic, which is diagnosed with one or more conditions selected from the group consisting of: Overweight and obesity, especially class I obesity, class II obesity, class III obesity, visceral obesity and abdominal obesity. In addition, the treatment or prevention of the present invention is advantageously adapted to patients who have contraindications to weight gain.

When the present invention relates to a patient in need of treatment or prevention, the present invention is primarily directed to human treatment and prevention, but the methods and pharmaceutical compositions of the present invention may also be used in veterinary medicine in mammals accordingly. Within the scope of the present invention, the term "patient" encompasses adults (age 18 or older), adolescents (10 to 17 years old) and children (6-9 years old).

In one aspect of the invention, the psychiatric condition is schizophrenia. In one aspect of the invention, the patient is an individual treated for a psychiatric disorder, such as schizophrenia.

In one aspect of the invention, PANSS is used (positive and negative symptoms) Scale) scores measure the severity of symptoms or psychosis in individuals with schizophrenia. PANSS scores are well known in the art.

In one aspect of the invention, the patient in the combination, composition, method or use of the invention is an individual for treating one of the following conditions: - psychosis, - acute and chronic psychosis, - acute psychosis, - severe depression Mental illness, - agitation in schizophrenia or bipolar disorder, - anti-therapeutic schizophrenia, - acute agitation in schizophrenia, - 谵妄, - AIDS AIDS.

In another aspect of the invention, the patient in the combination, composition, method or use of the invention is an individual receiving treatment for depression. In another aspect, the patient is an individual who treats one of the following conditions: - agitation depression, - an accessory condition in severe depression, - a bad mood, - bipolar disorder, - a manic phase of bipolar disorder, - double Autism.

In another aspect of the invention, a patient in a combination, composition, method or use of the invention is for treating a manic episode associated with type I bipolar disorder body. In another aspect, the patient is an individual who treats a mixed episode associated with type I bipolar disorder. In one other aspect, the patient is an individual who treats a manic episode or a mixed episode associated with type I bipolar disorder. In another aspect, the patient is an acute agitation individual associated with schizophrenia and type I bipolar mania. In another aspect, the patient is an individual treating a depressive episode associated with type I bipolar disorder.

In another aspect of the invention, the patient in the combination, composition, method or use of the invention is an individual who treats the following other mental states that cause mental confusion or mental dysfunction: - insomnia, - itching, - preparation of anesthesia ,- Suicidal behavior, - Anxiety disorders, - Post-traumatic stress disorder (PTSD), - Autism, - Stress and anxiety associated with alcohol withdrawal, - Epileptic irritability, - Severe anxiety disorder.

According to an embodiment of the present invention, there is provided a method of improving glycemic control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin (HbA1c) in a patient treated with a neuroleptic agent, the patient Diagnosis of impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance, metabolic syndrome, and/or type 1 diabetes or type 2 diabetes, The method is characterized in that the neuroleptic and SGLT2 inhibitors, as defined above and below, are administered, for example, in combination or alternately or sequentially to the patient.

Furthermore, the methods, uses, and pharmaceutical compositions of the present invention are particularly suitable for treating patients treated with a neuroleptic agent that is diagnosed with one or more of the following conditions: (a) Obesity (including Class I, Class II, and/or III) Obesity), visceral obesity and/or abdominal obesity; (b) triglyceride blood content 150 mg/dL; (c) HDL-cholesterol blood content <40 mg/dL in female patients and HDL-cholesterol blood content <50 mg/dL in male patients; (d) systolic blood pressure 130 mm Hg and diastolic blood pressure 85 mm Hg; (e) fasting blood glucose levels 100 mg/dL.

It is conceivable that patients treated with neuroleptics and diagnosed with impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolic syndrome develop cardiovascular disease (such as myocardial infarction, coronary heart disease) The risk of cardiac insufficiency and thromboembolic events increases. The blood glucose control of the present invention can reduce the side effects induced by the neuroleptic, including cardiovascular risk. The method or pharmaceutical composition of the present invention may be particularly suitable for the long-term treatment or prevention of a disease as described above and below for a patient having type 2 diabetes and treated with a neuroleptic (such as a typical or atypical neuroleptic) and/or Or a condition, especially suitable for long-term glycemic control.

The term "long-term" as used above and hereinafter means treating a patient or administering a drug to a patient for a period of longer than 12 weeks, preferably longer than 25 weeks, or even better than one year.

Accordingly, a particularly preferred embodiment of the present invention provides a therapy, preferably oral therapy, for use in ameliorating, particularly long-term, patients with type 2 diabetes, particularly patients with advanced type 2 diabetes, In addition, diagnose blood glucose in patients who are overweight, obese (including Class I, Class II, and/or Class III obesity), visceral obesity, and/or abdominal obesity and who are treated with a neuroleptic (such as a typical or atypical neuroleptic) control.

The preferred ranges of amounts of SGLT2 inhibitors and neuroleptics used in the pharmaceutical compositions and methods and uses of the present invention are described below. These ranges refer to the daily dose administered to an adult patient, especially a person weighing, for example, about 70 kg, and may be adjusted accordingly for 1 or 2 daily doses and for other routes of administration and for patient age. The range of doses and amounts is calculated for individual active fractions.

A preferred dosage range for the SGLT2 inhibitor is from 0.5 mg to 500 mg per day, such as from 0.5 mg to 200 mg, such as from 1 mg to 100 mg, such as from 1 mg to 50 mg. Oral administration is preferred. Thus, the dosage form of the SGLT-2 inhibitor may comprise the amounts mentioned above, especially from 1 mg to 50 mg or from 1 mg to 25 mg. Specific dose concentrations (eg, per lozenge or capsule) are, for example, 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg or 50 mg of a compound of formula (I), especially Compound (I.9). The active ingredient can be administered once, twice or three times a day, preferably once a day.

Typical doses of aglilipin are 10 mg and 25 mg once daily. Typical doses of dapagliflozin are 1 mg, 2.5 mg, 5 mg, and 10 mg once daily; and 2.5 mg and 5 mg twice daily. Typical doses of cangliflozin are 100 mg and 300 mg once daily; or 50 mg or 150 mg, twice daily Times.

The minimum dose of the neuroleptic will vary depending on the choice of agent, but will generally be about 0.5 mg per day for the most effective compound or about 20 mg per day for the less effective compound. The maximum dose of a neuroleptic is typically 30 mg per day for the most effective compound or 200 mg per day for the less effective compound. The compound is administered once to three times a day, preferably once or twice daily, and especially once daily.

Examples of routes of administration, forms, and dosage ranges for exemplary neuroleptics are disclosed below.

Clozapine is usually administered orally in the form of a lozenge and in a dosage range of 12.5-900 mg/day or 300-900 mg/day, especially 350-420 mg/day.

Olanzapine is usually administered orally in the form of a lozenge and in a dose range of 5-25 mg/day, 10-25 mg/day or 5-20 mg/day. Typical doses of olanzapine are 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg once daily.

Ziprasidone is usually administered orally in the form of a capsule and a dose of 20-80 mg/dose twice or 80-160 mg/day.

Risperidone is usually administered orally in the form of a solution or lozenge and in a dose range of 2-16 mg/day, especially 2-4 mg/day or 4-12 mg/day, or intravenously in a long-acting injectable form. versus. Quetiapine fumarate is usually administered orally in the form of a lozenge and in a dosage range of 50-900 mg/day or 300-900 mg/day oral lozenge.

Sertindole is usually administered in a dose range of 4-24 mg/day.

Haloperidol is usually in the form of a lozenge and 1-100 mg/day or 1-15 mg/ A daily dose range of 5-15 mg/day is administered orally.

Haloperidol citrate is usually administered orally by parenteral injection.

Chlorpromazine is usually administered from a rectal suppository in the range of 30-800 mg/day or 200-500 mg/day, or orally by capsule, solution or lozenge, or by parenteral injection.

Flurazine is usually administered in a dose range of 0.5-40 mg/day or 1-5 mg/day.

Flupheniramine citrate is usually administered by parenteral injection.

Tivothiazide It is usually administered orally in the form of a capsule and a dose ranging from 6 to 60 mg/day or 8 to 30 mg/day.

Tivothiazide hydrochloride They are usually administered orally or parenterally in the form of a solution or an injection.

Trifluoperazine is usually administered in a dose range of 2-40 mg/day.

The phenazine is usually administered orally in the form of a solution or lozenge and in a dose range of 12-64 mg/day or 16-64 mg/day.

Thioridazine is usually administered orally in the form of a suspension, solution or lozenge and in a dosage range of 150-800 mg/day or 100-300 mg/day.

Mesodarazine is usually administered in a dose range of 30-400 mg/day.

The ketone is usually administered in a dose range of 50-225 mg/day or 15-150 mg/day.

The morphine hydrochloride is usually administered orally in the form of a solution.

Loxapine is usually administered in a dose range of 20-250 mg/day or 60-100 mg/day.

Loxapine hydrochloride is usually administered orally or parenterally in the form of a solution or injection. versus.

Loxapine succinate is usually administered orally in the form of a capsule.

Piperazine is usually administered in a dose range of 1-10 mg/day.

In the methods and uses of the invention, the neuroleptic and SGLT2 inhibitors are administered in combination or alternately or sequentially. The term "combination administration" means that the active ingredients are administered simultaneously or substantially simultaneously. The term "alternating administration" means first administering one of two active ingredients (ie, a SGLT2 inhibitor or a neuroleptic) and administering another active ingredient (ie, a neuroleptic or SGLT2 inhibitor) after a period of time. ), wherein the administration process can be repeated one or more times. The period of time between administration of the first active ingredient and the second active ingredient may range from 1 minute to 12 hours. The combination or alternating administration may be once, twice, three times or four times a day, preferably one or two times a day. The term "sequential" means that the first active ingredient (in detail, a neuroleptic) is administered to the patient one or more times during the first time period, and then the second active ingredient of the patient is administered in the second time period (in detail, the SGLT2 inhibitor One or more times. In other words, the term "sequence" includes the first therapy, in particular the use of a neuroleptic in the first period; followed by a second therapy, in particular the use of the SGLT2 inhibitor in the second period.

Pharmaceutical compositions in the form of separate dosage forms or multiple dosage forms, preferably in divided portions, are suitable for combination therapy to flexibly adapt to the individual therapeutic needs of the patient.

The pharmaceutical compositions can be formulated for oral, parenteral (including subcutaneous) or other routes of administration in liquid or solid form. Oral administration of the SGLT2 inhibitor is preferred. Suitably, the formulations are in individual dosage units and may be prepared by any methods known in the art of pharmacy. All methods include the following steps: The active ingredient is associated with one or more pharmaceutically acceptable carriers, such as a liquid carrier or a finely divided solid carrier or both, and, if necessary, the product is shaped into the desired formulation. An example of a pharmaceutical composition comprising a SGLT2 inhibitor compound (I.9) is described in WO 2010/092126, which is incorporated herein in its entirety.

The pharmaceutical composition can be formulated into a solution, a suspension, an emulsion, a tablet, a granule, a fine granule, a powder, a capsule, a capsule, a soft capsule, a pill, an oral solution, a syrup, a dry syrup, a chewable tablet, a sugar-coated tablet, an effervescent Tablets, drops, instant tablets, oral rapid dispersion tablets. The pharmaceutical composition of the SGLT2 inhibitor is preferably in the form of a tablet.

The pharmaceutical compositions and dosage forms preferably comprise one or more pharmaceutically acceptable carriers. Preferred carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Examples of pharmaceutically acceptable carriers are known to those skilled in the art.

The pharmaceutical compositions may also be formulated for parenteral administration (for example by injection, such as bolus injection or continuous infusion), and may be presented in unit dosage form in ampoules with preservatives, prefilled syringes, small volume infusion containers or more In the dose container. The compositions may be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and may contain a formulation such as a suspending, stabilizing and/or dispersing agent. Alternatively, the active ingredient may be in the form of a powder, which is obtained by sterile separation of sterile solids or by lyophilization from solution for reconstitution with a suitable vehicle (for example, sterile pyrogen-free water) before use.

Injectable formulations may be formulated according to known techniques, for example, using a liquid carrier (which usually comprises sterile water) and optionally other additives. It is prepared, for example, as a preservative, a pH adjusting agent, a buffering agent, an isotonic agent, a dissolution aid, and/or a surfactant (tenside) or an analog thereof to obtain an injectable solution or suspension. Additionally, injectable formulations may contain other additives which delay the release of the drug, such as salts, solubilizers or precipitants.

For further details regarding dosage forms, formulations and administration of the SGLT2 inhibitors of the invention and/or the neuroleptic of the invention, reference is made to the scientific literature and/or published patent documents, in particular to the scientific literature and/or publications cited herein. Patent documents.

Pharmaceutical compositions (or formulations) can be packaged in a variety of ways. In general, articles for dispensing include one or more containers containing one or more pharmaceutical compositions in a suitable form. Tablets are typically packaged in a suitable primary package for ease of handling, dispensing and storage, and to ensure proper stability of the composition during prolonged contact with the environment during storage. The primary container of the tablet can be in a bottle or blister pack.

The injectable solution can be utilized in a typical form for presentation, such as vials, cartridges or prefilled (disposable) pens, which can be further encapsulated.

The article may further comprise a label or package insert, which is generally included in a commercial package of the therapeutic product and may contain information regarding indications, usage, dosage, dosing, contraindications and/or warnings associated with the use of the therapeutic product. Instructions. In one embodiment, the label or package insert indicates that the composition can be used to achieve any of the objectives described above or below.

Methods of making the SGLT2 inhibitors of the invention and prodrugs thereof are known to those skilled in the art. The compounds of the invention are preferably prepared using synthetic methods as described in the literature, including the patent applications cited above. Production method It is described in WO 2006/120208 and WO 2007/031548. With regard to the preferred compound (I.9), the advantageous crystalline forms are described in the International Patent Applications WO 2006/117359 and WO 2011/039108, the entireties of each of each of

The active ingredient can be in the form of a pharmaceutically acceptable salt. The active ingredient or a pharmaceutically acceptable salt thereof may be in the form of a solvate such as a hydrate or an alcohol adduct.

Any of the above combinations and methods can be tested using animal models known in the art within the scope of the present invention.

For example, the methods of the invention can be tested in genetically hyperinsulinemia or diabetic animals, such as db/db mice, ob/ob mice, Zucker Fatty (fa/fa) rats or Zucker Zucker Diabetic Fatty (ZDF) rats. Furthermore, it can be tested in animals with experimentally induced diabetes, such as Han Wistar rat or Sprague Dawley rat pretreated with streptozotocin.

The effect of the methods and compositions of the present invention on glycemic control can be tested in an oral glucose tolerance test after a single administration of the SGLT2 inhibitor and the neuroleptic alone and in combination in the animal model described above. . The blood glucose time course can be followed after oral glucose challenge in fasting overnight animals. In addition, after administration of the SGLT2 inhibitor and the neuroleptic agent alone and in combination in the animal model described above, the effect on blood glucose control can be determined by measuring the HbA1c value in the blood. In these experiments, body weight, blood pressure, and various metabolic markers can also be measured. Therefore, Animal models were used to assess the effects of long-term administration of SGLT-2 inhibitors and neuroleptics, alone and in combination, on body weight, food and water intake, blood pressure, and various metabolic markers.

The invention is further described in the following examples which are not intended to limit the scope of the invention.

Pharmacological example Example 1: Oral glucose tolerance test in ZDF rats

Oral glucose tolerance tests were performed in 9-week-old male Zucker Diabetic Obesity (ZDF) rats (ZDF/Crl-Lepr ^fa ) overnight. A pre-dose blood sample is obtained by tail blood sampling. Blood glucose was measured with a blood glucose meter and animals were randomized for blood glucose analysis (n=5 per group). Subsequently, each group received a single oral administration of a vehicle or a neuroleptic in the presence or absence of a SGLT-2 inhibitor. Animals received an oral glucose load (2 g/kg) 30 minutes after administration of the compound. Blood glucose in the tail blood was measured 30 minutes, 60 minutes, 90 minutes, 120 minutes, and 180 minutes after glucose challenge. Glucose fluctuations were quantified by calculating the reactive glucose AUC. Data are expressed as mean ± SEM. Two-sided unpaired Student t-test was used to statistically compare the control group with the active group.

In a glucose tolerance test, the SGLT-2 inhibitor was a compound (I.9) and the neuroleptics were olanzapine, risperidone, quetiapine, amisulpride, aripiprazole, and fluphene. Pyridinol, clozapine, ziprasidone, zotipine or oxatanide.

Example 2: Acute effects of antipsychotics on glucose levels during the glucose tolerance test

Female rats after fasting overnight (n=8 per group) were treated with vehicle (control) or low dose and high dose atypical neuroleptic in the presence or absence of SGLT-2 inhibitor. Fasting plasma glucose (time 0) was measured for each animal prior to treatment with a neuroleptic. The glucose content was then tested at 60 minutes, 180 minutes and 360 minutes after administration. Immediately after the last glucose test, the animals were tested for glucose tolerance by, for example, intraperitoneal challenge injection of 1 g/ml/kg glucose. Thereafter, the glucose content was measured every 15 minutes for 2 hours.

In a glucose tolerance test, the SGLT-2 inhibitor was a compound (I.9) and the neuroleptics were olanzapine, risperidone, quetiapine, amisulpride, aripiprazole, and fluphene. Pyridinol, clozapine, ziprasidone, zotipine or oxatanide.

Example 3: Treatment of hyperglycemia or type 2 diabetes

A patient treated with a neuroleptic agent and having an elevated blood glucose level or even a dominant type 2 diabetes is treated by the method of the present invention. The patient's blood glucose level was determined and the effect of the SGLT2 inhibitor was compared to placebo or different therapies. According to the present invention, this effect can be observed in patients treated for a long period of time (e.g., 3 months to 1 year or even 1 to 6 years). For example, fasting glucose and/or HbA1c values are observed.

Example 4: Oral glucose tolerance test

The goal of this study was to evaluate selected neuroleptics (clozapine, olanzapine, haloperidine) alone or in combination with selected SGLT-2 inhibitors (dapagide, cangliflozin, and aceclovir). Alcohol) Acute effects in the oral glucose tolerance test (OGTT).

animal

Female Wistar rats (when arriving at a weight range of 250-300 g) were obtained from Janvier (Le Genest Saint Isle-France, France) at a temperature of 21 ± 4 ° C and a humidity of 55 ± 20% Bring two or three together. The animals were maintained in an inverse phase-dark cycle (8 hours off at 09.30-17.30), during which time the room was illuminated by a red light. Prior to the Oral Glucose Tolerance Test (OGTT) experiment, animals were housed and free access to fat diets and tap water until the end of the night.

Oral glucose tolerance tests were performed in fasted overnight animals. A pre-dose blood sample (t0-90 min) was obtained by tail blood sampling. Blood glucose was measured with a blood glucose meter and animals were randomized for blood glucose analysis (n=8 per group). Subsequently, each group received a single oral administration of a vehicle or a neuroleptic in the presence or absence of a SGLT-2 inhibitor. Animals received an oral glucose load (2 g/kg) 60 minutes after administration of the compound. Blood glucose in the tail blood was measured at 15 minutes, 30 minutes, 60 minutes, 120 minutes, and 180 minutes after glucose challenge. Glucose fluctuations were quantified by calculating the reactive glucose AUC. Data are expressed as mean ± SEM. The two-way unpaired Studden's t test was used to statistically compare the control group with the active group.

In these experiments, the SGLT-2 inhibitors dapagliflozin, cangliflozin, and aglitazone were administered at a dose of 10 mg/kg orally (oral route, 5 ml/kg, in Natrosol 0.5%). Or in combination with three different neuroleptics: olanzapine (8 mg/kg, subcutaneous) and clozapine (8 mg/kg, subcutaneous) for subcutaneous injection (in 5% acetic acid + 7.5% 10 M NaOH solution) ), or intraperitoneally administered haloperidol (4 mg / kg in 0.9% NaCl solution).

As illustrated in Figure 1A, clozapine, olanzapine, and haloperidol caused abnormal glucose tolerance. Glucose AUC was significantly (p < 0.001) increased relative to controls using a neuroleptic (Figure 1 B). The number on each bar graph in Figure 1B indicates the percent increase in AUC over the control.

In another set of experiments, SGLT-2 inhibitors were combined with a neuroleptic. Figure 2A illustrates OGTT in combination with olanzapine and an SGLT-2 inhibitor. All SGLT-2 inhibitors tested significantly reduced AUC glucose compared to olanzapine alone (Figure 2B). The number on each bar graph in Figure 2B indicates the percent increase in AUC over the control.

The OGTT in combination with clopidogrel inhibitor and clozapine is presented in Figure 3A. The SGLT-2 inhibitor in combination with clozapine improved AUC glucose compared to clozapine alone (Fig. 3B). The number on each bar graph indicates the percentage increase in AUC over the control.

A similar effect has been observed with haloperidol (Fig. 4A). However, since haloperidol degraded OGTT less significantly than olanzapine and clozapine, the improvement in glucose tolerance was less pronounced when combined with the .SGLT-2 inhibitor (Fig. 4B).

Example of a formulation

The following examples of formulations which may be obtained in a manner similar to those known in the art are used to more fully illustrate the invention without limiting the invention to the examples. The term "active substance" means an SGLT-2 inhibitor of the invention, especially a compound of formula (I), for example a compound of formula (I.9) or a crystalline form thereof (I.9X).

Use a suitable grinder (such as a pin before making a pharmaceutical composition or dosage form) The bar grinder or jet mill) grinds the active pharmaceutical ingredient or active substance, i.e., compound (I.9), preferably in crystalline form (I9.X), to obtain the desired particle size distribution.

The following table shows examples of typical particle size distribution values X90, X50 and X10 of the preferred active pharmaceutical ingredients of the present invention.

Typical particle size distribution results

Example 1 : Dry ampules containing 50 mg of active substance per 10 ml

composition:

preparation: The active substance and mannitol are dissolved in water. The solution was freeze dried after encapsulation. To prepare a ready-to-use solution, the product is dissolved in water for injection.

Example 2 : Dry ampoules containing 25 mg of active substance per 2 ml

composition:

preparation: The active substance and mannitol are dissolved in water. Freeze drying after encapsulation Solution. To prepare a ready-to-use solution, the product is dissolved in water for injection.

Example 3 : Lozenges containing 50 mg of active substance

composition:

preparation: (1), (2), and (3) were mixed together and granulated using the aqueous solution of (4). (5) is added to the dried granulated material. The mixture was pressed from this mixture, and both sides were embossed on both sides with slits on one side.

Tablet diameter: 9 mm.

Example 4 : Capsules containing 50 mg of active substance

composition:

preparation: (3) Wet grinding (1). This wet abrasive was added to the mixture of (2) and (4) with vigorous mixing. Fill this powder mixture to No. 3 in a capsule filling machine Hard gelatin capsules.

Example 5 : Lozenges containing 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg of active substance

Example 6 : Lozenge manufacturing process

Example 7 : Pharmaceutical composition containing other fillers

The copovidone is dissolved in purified water at ambient temperature to produce a granulating liquid. Blending glucosamine-substituted benzene derivatives, mannitol, pregelatinized starch and jade of the present invention in a suitable mixer Rice starch produces a premix. The premix is wetted with a granulating liquid and subsequently granulated. The wet granules are sieved through a suitable sieve. The granules were dried in a fluid bed dryer at an inlet air temperature of about 60 ° C until the dry loss value was 1-4%. The dried granules were sieved through a sieve having a mesh size of 1.0 mm.

Magnesium stearate was passed through a sieve to deblock and added to the granules. The final blend was then prepared by final blending for 3 minutes in a suitable blender and compressed into a tablet core.

Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are suspended in purified water at a suitable temperature in a mixer to prepare a coating suspension. The tablet core was coated with a coating suspension until the weight gain was about 3%, thereby producing a film-coated tablet. The following formulation variants are available:

Example 8 : Pharmaceutical composition containing other disintegrants

The copolycytonone is dissolved in purified water at ambient temperature to produce a granulated liquid. Blending the grape glucopyranyl group of the present invention in a suitable mixer The benzene derivative, mannitol, pregelatinized starch and corn starch produce a premix. The premix is wetted with a granulating liquid and subsequently granulated. The wet granules are sieved through a suitable sieve. The granules were dried in a fluid bed dryer at an inlet air temperature of about 60 ° C until the drying loss value was 1-4%. The dried granules were sieved through a sieve having a mesh size of 1.0 mm.

The crospovidone was added to the dried granules and mixed for 5 minutes to prepare a main blend. Magnesium stearate was passed through a sieve to deblock and added to the main blend. Subsequently, the final blend was prepared by final blending for 3 minutes in a suitable blender and compressed to a 8 mm round lozenge core with a compressive force of 16 kN.

The coating suspension is prepared by suspending hydroxypropylmethylcellulose, polyethylene glycol, talc, titanium oxide and iron oxide in purified water at a suitable temperature in a mixer. The tablet core was coated with a coating suspension until the weight gain was about 3%, thereby producing a film-coated tablet. The following formulation variants are available:

The tablet hardness, brittleness, content uniformity, disintegration time, and dissolution properties were determined as described above.

Example 9 : Direct compression formulation

1. The active ingredient, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose or polyethylene glycol powder are sieved through a 20 mesh hand sieve.

2. Add the above items to the high shear mixer and mix for 2 minutes.

3. Prepare a premix of about lactose and colloidal cerium oxide (about 1/1).

4. The premix was screened through a 20 mesh hand screen and added to the mixer.

5. The remaining lactose was sieved through a 20 mesh hand sieve and added to the mixer.

6. Mix the components in the mixer for 2 minutes.

7. Screen the magnesium stearate by hand through a 30 mesh screen and add to the mixer.

8. Mix for 1 minute and 30 seconds to obtain the final blend.

9. Press the final blend onto a suitable press.

10. Apply the film to the core of the tablet as appropriate.

Example 10 : Lozenges containing 0.5 mg, 5 mg, 25 mg, 100 mg of active substance

The active substance (for example, compound (I.9), preferably in crystalline form (I.9X)), hydroxypropylcellulose and croscarmellose sodium are mixed in a blender. This premix is mixed with monohydrated lactose and a portion of microcrystalline cellulose. The resulting blend was granulated using purified water. When needed, depending on the batch and the equipment used, individual tablet batches can produce multiple particle-forming portions.

Remove the granules on the dryer tray and dry. The particles are then ground. The remaining microcrystalline cellulose (as a premix with colloidal ceria for all strengths except 0.5 mg) was added to the milled granules and mixed. Magnesium stearate is premixed with a portion of the blend, sieved into the remaining granules and mixed.

The final tablet blend is compressed into a tablet using a tablet press. The finished tablet is packaged using a suitable container closure system.

Example 11 : Lozenges containing 1 mg, 5 mg, 25 mg of active substance

The active substance (for example compound (I.9), preferably in crystalline form (I.9X)) is passed through a sieve and added to a blender or high shear granulator. The hydroxypropylcellulose and croscarmellose sodium were passed through a sieve, added to the drug substance, and mixed. The intragranular portion of the microcrystalline cellulose is passed through a sieve to a high shear granulator and mixed with the drug substance premix. This material is then added by passing the lactose through a sieve into a granulator and mixing. The resulting blend was granulated using purified water. For larger batches, individual tablet batches can produce multiple particle-forming fractions, depending on the batch and equipment used, as needed.

Remove the granules on the dryer tray and dry. The granules are then passed through a grinder to the blender. The colloidal ceria is premixed with a portion of the extragranular microcrystalline cellulose. This premix is passed through a mill to a blender, and the remaining extragranular microcrystalline cellulose is then passed through a mill to a blender and mixed with the milled granules. Magnesium stearate is premixed with a portion of the blend, passed through a grinder to the remaining granules and mixed.

The final tablet blend is compressed into a tablet using a tablet press. The finished tablet is packaged using a suitable container closure system.

Figure 1A : Oral glucose tolerance test for selected neuroleptics.

Figure 1B : Area under the glucose curve (AUC) of the selected neuroleptic.

Figure 2A : Oral glucose tolerance test in combination with olanzapine and selected SGLT-2 inhibitors.

Figure 2B : Glucose AUC in combination with olanzapine and a selected SGLT-2 inhibitor.

Figure 3A : Oral glucose tolerance test of clozapine in combination with a selected SGLT-2 inhibitor.

Figure 3B : Glucose AUC in combination with clozapine and a selected SGLT-2 inhibitor.

Figure 4A : Oral glucose tolerance test of haloperidol in combination with a selected SGLT-2 inhibitor.

Figure 4B : Glucose AUC in combination with haloperidol in combination with a selected SGLT-2 inhibitor.

Claims (33)

A use of an SGLT2 inhibitor for the manufacture of a medicament for preventing, slowing progression, delaying or treating a metabolic disorder induced by a patient with a neuroprotective agent. The use of claim 1, wherein the SGLT2 inhibitor is selected from the group consisting of a glucone-substituted benzene derivative substituted by the formula (I), Wherein R ¹ represents Cl, methyl or cyano, R ² represents H, methyl, methoxy or hydroxy, and R ³ represents ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran- 3-yloxy or (S) -tetrahydrofuran-3-yloxy; or a prodrug thereof. The use of claim 2, wherein the SGLT2 inhibitor is 1-chloro-4-(β-D-glucopyran-1-yl)-2-[4-( (S) -tetrahydrofuran-3-yloxy Base)-benzylidene-benzene. The use of claim 1, 2 or 3, wherein the neuroleptic is a typical neuroleptic or an atypical neuroleptic. The use of claim 1, 2 or 3, wherein the neuroleptic is phenothiazine, sulfur (Thioxanthane), phenylbutanone, dibenzoxazine, indanone, diphenylbutylpiperidine or benzisoxazole. The use of claim 1, 2 or 3, wherein the neuroleptic is olanzapine (olanzapine), risperidone, quetia-pine, amisulpiride, aripiprazole, haloperidol, clozapine ), ziprasidone, zotepine, paliperidone or osanetant. The use of any one of claims 1 to 3, wherein the metabolic disorder induced by the patient to be treated with a neuroleptic is weight gain. The use of any one of claims 1 to 3, wherein the metabolic disorder induced by the patient to be treated with a neuroleptic is hyperglycemia. The use of any one of claims 1 to 3, wherein the SGLT-2 inhibitor and the neuroleptic agent are administered in combination or alternately or sequentially to the patient. Use of an SGLT2 inhibitor for the manufacture of a medicament for the treatment of a psychiatric condition in a diabetic patient, wherein the medicament further comprises or is used in combination with a neuroleptic. The use of claim 10, wherein the SGLT-2 inhibitor and the neuroleptic agent are administered in combination or alternately or sequentially to the patient. The use of claim 10 or 11, wherein the patient: (1) is an individual diagnosed with one or more conditions selected from the group consisting of overweight, obesity, visceral obesity, and abdominal obesity; or (2) for display Individuals with one, two or more of the following conditions: (a) fasting blood glucose or serum glucose concentration greater than 100 mg/dL, especially greater than 125 mg/dL; (b) postprandial plasma glucose equal to or greater than 140 mg/dL; (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 8.0%; or (3) an individual in which one, two, three or more of the following conditions are present: (a) obesity, visceral obesity and/or Or abdominal obesity; (b) triglyceride blood content 150 mg/dL; (c) HDL-cholesterol blood content <40 mg/dL in female patients and HDL-cholesterol blood content <50 mg/dL in male patients; (d) systolic blood pressure 130 mm Hg and diastolic blood pressure 85 mm Hg; (e) fasting blood glucose levels 100 mg/dL. The use of claim 10 or 11, wherein the SGLT2 inhibitor is selected from the group consisting of a glucone-substituted benzene derivative substituted by the formula (I), Wherein R ¹ represents Cl, methyl or cyano, R ² represents H, methyl, methoxy or hydroxy, and R ³ represents ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran- 3-yloxy or (S) -tetrahydrofuran-3-yloxy; or a prodrug thereof. The use of claim 10 or 11, wherein the SGLT2 inhibitor is 1-chloro-4-(β-D-glucopyran-1-yl)-2-[4-( (S) -tetrahydrofuran-3-氧基oxy)-benzyl]-benzene. The use of claim 10 or 11, wherein the neuroleptic is a typical spirit Stabilizer or atypical neuroleptic. The use of claim 10 or 11, wherein the neuroleptic is phenothiazine, sulfur , benzophenone, dibenzoxazil, indanone, diphenylbutyl piperidine or benzisoxazole. The use of claim 10 or 11, wherein the neuroleptic is olanzapine, risperidone, quetiapine, amisulpride, aripiprazole, haloperidol, clozapine, ziprasidone, Zotidine, paliperidone or oxatanide. Use of an SGLT2 inhibitor for the manufacture of a medicament for reducing weight, reducing body fat, preventing weight gain or slowing weight gain in a patient receiving treatment for a psychotic condition, wherein the medicament further comprises a neuroleptic or a neuroleptic The agents are used in combination. Use of an SGLT2 inhibitor for the manufacture of a medicament for the treatment, reduction, prevention or alleviation of hyperglycemia in a patient receiving treatment for a psychotic condition, wherein the medicament further comprises a neuroleptic or a combination with a neuroleptic use. A use of an SGLT2 inhibitor for the manufacture of a medicament for reducing weight, reducing body fat, preventing weight gain or slowing weight gain in a patient treated with a neuroleptic. A use of an SGLT2 inhibitor for the manufacture of a medicament for treating, reducing, preventing or slowing the exacerbation of hyperglycemia in a patient treated with a neuroleptic. The use according to any one of claims 18 to 21, wherein the SGLT2 inhibitor is selected from the group consisting of a glucone-substituted benzene derivative of the formula (I). Wherein R ¹ represents Cl, methyl or cyano, R ² represents H, methyl, methoxy or hydroxy, and R ³ represents ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran- 3-yloxy or (S) -tetrahydrofuran-3-yloxy; or a prodrug thereof. The use according to any one of claims 18 to 21, wherein the SGLT2 inhibitor is 1-chloro-4-(β-D-glucopyran-1-yl)-2-[4-( (S) - Tetrahydrofuran-3-yloxy)-benzyl]-benzene. The use of any one of claims 18 to 21, wherein the neuroleptic is a typical neuroleptic or an atypical neuroleptic. The use of any one of claims 18 to 21, wherein the neuroleptic is phenothiazine, sulfur , benzophenone, dibenzoxazil, indanone, diphenylbutyl piperidine or benzisoxazole. The use according to any one of claims 18 to 21, wherein the neuroleptic is olanzapine, risperidone, quetiapine, amisulpride, aripiprazole, haloperidol, clozapine, Laxethin, zotipin, paliperidone or oxatanide. The use of any one of claims 18 to 21, wherein the composition is suitable for use in combination or simultaneous or sequential use of the SGLT2 inhibitor and the neuroleptic. A pharmaceutical composition comprising (a) a neuroleptic and (b) an SGLT2 inhibitor. The pharmaceutical composition according to claim 28, wherein the SGLT2 inhibitor is selected from the group consisting of a glucone-substituted benzene derivative substituted by the formula (I). Wherein R ¹ represents Cl, methyl or cyano, R ² represents H, methyl, methoxy or hydroxy, and R ³ represents ethyl, cyclopropyl, ethynyl, ethoxy, (R) -tetrahydrofuran- 3-yloxy or (S) -tetrahydrofuran-3-yloxy; or a prodrug thereof. The pharmaceutical composition according to claim 29, wherein the SGLT2 inhibitor is 1-chloro-4-(β-D-glucopyran-1-yl)-2-[4-((S)-tetrahydrofuran-3-氧基oxy)-benzyl]-benzene. The pharmaceutical composition of claim 28, 29 or 30, wherein the neuroleptic is a typical neuroleptic or an atypical neuroleptic. The pharmaceutical composition of claim 28, 29 or 30, wherein the neuroleptic is phenothiazine, sulfur , benzophenone, dibenzoxazil, indanone, diphenylbutyl piperidine or benzisoxazole. The pharmaceutical composition of claim 28, 29 or 30, wherein the neuroleptic is olanzapine, risperidone, quetiapine, amisulpride, aripiprazole, haloperidol, clozapine, Laxethin, zotipin, paliperidone or oxatanide.