CN101658673A

CN101658673A - Method of treating diabetes

Info

Publication number: CN101658673A
Application number: CN200910171670A
Authority: CN
Inventors: 安德鲁·沃尔夫; 马库斯·耶林
Original assignee: CV Therapeutics Inc
Current assignee: Gilead Sciences Inc
Priority date: 2002-05-21
Filing date: 2003-05-21
Publication date: 2010-03-03

Abstract

Methods are provided for treating diabetes, lowering plasma level of HbA1c, glucose plasma levels, total cholesterol plasma level, and/or triglyceride plasma level while increasing HDL cholesterol levels and delaying onset of diabetic retinopathy in a diabetic, pre-diabetic, or non-diabetic mammal while minimizing undesirable side effects. The invention comprises administration of a partial fattyacid inhibitor such as ranolazine.

Description

The method of treatment diabetes

The application is that the application number of submitting on May 21st, 2003 is 03811323.6 (former PCT application number is PCT/US2003/016277), and denomination of invention is divided an application for the application for a patent for invention of " methods of treatment diabetes ".The application requires the priority of No. the 60/382nd, 781, the U.S. Provisional Application of submitting on May 21st, 2002 and the U.S. Provisional Application of submitting on March 31st, 2003 the 60/459th, No. 332, and the full content of its disclosure is hereby expressly incorporated by reference.

Technical field

The invention provides and be used for the treatment of diabetes, the blood plasma level, glucose plasma level, T-CHOL blood plasma level and/or the triglyceride blood plasma level that reduce HbA1c increase the HDL cholesterol levels simultaneously, and the method for minimum degree is reduced to undesirable side effect in the outbreak that postpones diabetic retinopathy in diabetes, prediabetes or non-diabetic mammal simultaneously.

Background technology

Diabetes are a kind of diseases, it is characterized in that: hyperglycemia; The metabolism of lipid, carbohydrate and proteinic change; And the danger that increases from the complication of angiopathy.Diabetes are public health problem that increase day by day, because it is relevant with the age and the obesity that increase day by day.

The diabetes that two kinds of main types are arranged: 1) I type, be also referred to as insulin-dependent diabetes (IDDM), and 2) the II type, be also referred to as noninsulindependent diabetes (NIDDM).Two types diabetes all reduce the reaction of insulin owing to circulation insulin in shortage and peripheral tissue.

Type i diabetes is owing to health can not produce insulin, " unlatching " somatic hormone, allow glucose to enter and supply with their fuel to cause.The complication of type i diabetes comprises: heart disease and outbreak; Retinopathy (ophthalmic); Kidney disease (nephropathy); Neuropathy (nerve injury); And good skin, be enough to and the keeping of oral health.

Type ii diabetes is can not produce enough insulins or cell can not utilize the insulin by the natural generation of health to cause owing to health.This health can not utilize the state of insulin to be called insulin resistance best.Type ii diabetes often is attended by hypertension and this may exert an influence to heart disease.In suffering from the patient of type ii diabetes, stress, infection and medicine (as 17-hydroxy-11-dehydrocorticosterone) also can cause serious hyperglycemia level.Be attended by dehydration, in suffering from the patient of type ii diabetes, serious blood sugar increasing can cause the increase (hypertonicity state) of blood osmol concentration.This state can cause stupor.

Stimulate the picked-up of glucose and the concentration that the metabolism insulin can reduce glucose in the blood by muscle and fatty tissue.The insulin stimulating glucose is housed in the liver as glycogen, and is housed in the fatty tissue as triglyceride.Insulin also promotes to be used for the utilization of the muscle glucose of energy.Thereby insufficient insulin level or the sensitivity to insulin that reduces in blood produce the glucose and the triglyceride of high level in can blood.

The early symptom of untreated diabetes is lost in the urine relevant with the blood sugar level of raising and glucose.A large amount of glucoses can cause the urine discharge of increase and cause dehydration in urine.Dehydration can cause the thirsty sense and the water consumption of increase.Although can not utilize glucose can be able to finally cause losing weight appetite increase.Some untreated diabeticss are also complained fatigue, are felt sick and vomiting.The patient who suffers from diabetes is easy to occur the infection of bladder, skin and vaginal area.The fluctuation of blood sugar level can cause blurred vision.High glucose level can cause drowsiness and stupor (diabetic coma).

The people of glucose level between normal and diabetes has carbohydrate tolerance and reduces (IGT).This state is also referred to as prediabetes or insulin resistance syndrome.People with IGT does not suffer from diabetes, is diagnosed as diabetes but have to be higher than normal blood sugar level but also not to be high enough to.Their increasing insulin of health manufacturing, but owing to organizing it is not reacted, thereby their health can not suitably utilize sugar.Nearest studies show that, IGT self can be the risk factor that heart disease occurs.According to estimates, suffers from the danger that prediabetic people and the people with euglycemia relatively have 1.5 times cardiovascular disease.The danger that the people who suffers from diabetes suffers from cardiovascular disease increases by 2 to 4 times.

High-caliber glucose and triglyceride can cause thickening of capillary tube basement membrane in the blood, and it causes the carrying out property of tube chamber to narrow down.These angiological pathology features cause that such as the such disease of diabetic retinopathy, it can cause the ulcer and the gangrene of the blindness, coronary heart disease, intercapillary glomerulosclerosis, neuropathy and limbs.

The toxic action of the excessive blood plasma level of glucose comprises the glycosylation of cell and tissue.Glycation product is accumulated in the tissue and can finally forms crosslinking protein, and these crosslinking proteins are called high glycosylation effect end-product.The glycosylation of non-enzyme may directly cause the expansion of vascular stroma and the vascular complication of diabetes.For example, the glycosylation of collagen causes excessive crosslinked, and then causes the atherosclerotic blood vessel.And macrophage stimulates inflammatory cytokine before these emiocytosises to the picked-up of glycosylated protein.Activation or induced degradation and the propagation cascade in mesenchymal cell and endotheliocyte respectively of these cytokines.

The glycosylation of hemoglobin provides the short-cut method of the aggregative index of definite glucemia state.The level of glycosylated protein has reflected the level of glucose in a period of time and has been to be called the basis that HbA1 (HbA1c) is measured.

The weighed average of blood sugar level in 120 days before HbA1c is reflected in; Plasma glucose in the pro-30 days is about 50% to the final result contribution that HbA1c measures.The test of A1c (being also referred to as HbA1c, glycohemoglobin or glycosylated hemoglobin) shows how controlled well diabetes are in nearest some months.A1c is more near 6%, and the control of diabetes is good more.The every increase of A1c blood glucose 30mg/dl, then A1c increases by 1%, and then the danger of complication increases.

The another kind of the toxic action of hyperglycemia is explained and is comprised that Sorbitol forms.Be reduced into its corresponding sugar alcohol, Sorbitol by glucose in the aldose reductase born of the same parents; The generation speed of Sorbitol is determined by concentration of glucose on every side.Thereby, the Sorbitol that tissue has high concentration as crystalline lens, retina, arterial wall and peripheroneural neurilemma cell.

Hyperglycemia is also damaged the function of nervous tissue, because glucose and inositol competition cause the reduction of cell concentration, and then the function of nervous system and the neuropathy that change.

The triglyceride levels that increases also is the result of insulin deficit disease.The high triglyceride level is also relevant with angiopathy.

Thereby blood sugar control and triglyceride levels are desirable therapeutic goals.Many oral antihyperglycemics are known.The medicine that increases the insulin output by pancreas comprises that sulfonylurea (comprises chlorpropamide

Tolbutamide

Glibenclamide

Glipizide

And glimepiride

) and meglitinides (comprise repaglinide

And Nateglinide

).The medicine that reduces the amount of hepatogenous glucose comprises that biguanides (comprises metformin

).The increase cell comprises that to the medicine of the sensitivity of insulin thiazolidinediones (comprises troglitazone

Pioglitazone

And rosiglitazone

).Minimizing absorbs carbohydrate from intestinal medicine comprises that alpha-glucosidase inhibitor (comprises acarbose

And miglitol

).

With

Can change the hdlc mode of diabetics.HDL (or good cholesterol) strengthens these medicines.

Influence intestinal; Its effect is to aid in diabetes medicament, and it acts on other positions, as sulfonylurea.ACE inhibitor can be used for controlling hypertension, treatment heart failure and prevention injury of kidney in the crowd who suffers from hypertension or diabetes.The bonded products of ACE inhibitor or ACE inhibitor and diuretic, as hydrochlorothiazide, available on market.Yet these treatments are unsatisfactory.

Controlling of blood pressure can reduce cardiovascular disease (for example, myocardial infarction and outbreak) about 33% to 50% and can reduce microvascular disease (eye, kidney and sacred disease) about 33%.Center for Disease Control (CDC) finds, every reduction by 10 millimeter of mercuries of systolic blood pressure (mm Hg), and the risk of any complication relevant with diabetes then reduces 12%.The control to cholesterol and lipid (for example, HDL, LDL and triglyceride) that improves can reduce cardiovascular complication 20% to 50%.

T-CHOL should be less than 200mg/dl.The target level of high density lipoprotein (HDL or " well " cholesterol) is to be higher than 45mg/dl and to be to be higher than 55mg/dl for the Ms for the man, and low density lipoprotein, LDL (LDL or " bad " cholesterol) should keep below 100mg/dl.For Ms and man's target triglyceride level less than 150mg/dl.

About 50% the patient who suffers from diabetes to a certain degree diabetic retinopathy can occur in diabetes after 10 years, and 80% diabetics suffered from retinopathy after 15 years.

In the research of being undertaken by diabetes and digestive tract and kidney disease institute (NIDDK) (DCCT research), shown to keep blood sugar level as far as possible near the outbreak and the progress that normally can slow down the eye, kidney and the sacred disease that cause by diabetes.

2 (II) type diabetes in diabetes mellitus prevention plan (DPP) clinical trial, have been studied.DPP discovers that during the research in 3 years, diet and motion significantly reduce the probability that diabetes appear in the people who suffers from IGT.Give metformin

Also reduce danger, though not too remarkable.

DCCT studies show that, has dependency between HbA1c and average blood sugar.DPP studies show that HbA1c and disadvantageous danger as a result are closely related.

At a series of prevention meeting VI: in the report of diabetes and cardiovascular disease, have report to think that about 2/3rds diabetics dies from heart or angiopathy at last from American Heart Association.Research shows that also the increase of the cardiovascular disease danger relevant with diabetes can alleviate by the risk factor of controlling the individual, as obesity, hypercholesterolemia and hypertension.

The danger that diabetics reduces complication is important, as cardiovascular disease, retinopathy, nephropathy and neuropathy.Diabetics reduces T-CHOL and triglyceride levels also is important to reduce cardiovascular complication.It also is important reducing these possible complication danger for the patient who suffers from IGT (prediabetes).

Therefore,, then can reduce the danger of complication,, or postpone its outbreak as cardiovascular disease, retinopathy, nephropathy and neuropathy if can control HbA1c and blood sugar level.If can hypercholesterolemia reducing and triglyceride levels, so just can reduce cardiovascular complication.

United States Patent (USP) the 4th, 567, No. 264 (its description is hereby expressly incorporated by reference) disclosed some chemical compounds, and it has demonstrated is partial fatty acid oxidation inhibitors.A kind of chemical compound of Pi Luing wherein, (±)-N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group)-propyl group]-1-piperazine acetamide (being called ranolazine) just treating anginal clinical trial.Find that also ranolazine can be used for treating congestive heart failure and arrhythmia.During utilizing ranolazine to carry out the angina pectoris clinical trial, shockingly find, with ranolazine angina pectoris is not only effectively treated in the treatment of diabetic patient with angina pectoris, and reduces HbA1 (HbA1c) level, and in long-time the triglyceride reducing level.Find that also ranolazine can reduce ND's triglyceride levels.Find that also ranolazine can reduce the glucose plasma level, and in long-time the hypercholesterolemia reducing level, increase the HDL cholesterol levels simultaneously.Therefore, ranolazine provides the method for treatment diabetes, prediabetes or non-diabetic state, and it is by reducing level and/or the minimizing and the diabetes complications associated with arterial system of genotoxic potential metabolite in the blood.Ranolazine can also reduce for having cardiovascular problems and diabetes or the necessary medication amount of prediabetic patient.

Summary of the invention

An object of the present invention is to provide a kind of effective ways for the treatment of mammal diabetes degree that simultaneously undesirable side effect minimized.Correspondingly,, the present invention relates to a kind of method for the treatment of the mammal diabetes, comprise partial fatty acid oxidation (pfox) inhibitor that gives the effective therapeutic dose of mammal of its needs aspect first.

Aspect second, the present invention relates to a kind of method for the treatment of the mammal diabetes, comprise the partial fatty acid oxidation inhibitors of the Formula I that gives effective therapeutic dose:

Formula I

Wherein:

R ¹, R ², R ³, R ⁴And R ⁵Each is the alkyl amido of hydrogen, low alkyl group, lower alkoxy, cyano group, trifluoromethyl, halogen, lower alkylthio, low alkyl group sulfinyl, low alkyl group sulfonyl or the optional replacement of N-independently, if work as R ¹When being methyl, R ⁴It or not methyl;

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶, R ⁷, R ⁸, R ⁹And R ¹⁰Each is hydrogen, lower acyl, aminocarbonyl methyl, cyano group, low alkyl group, lower alkoxy, trifluoromethyl, halogen, lower alkylthio, low alkyl group sulfinyl, low alkyl group sulfonyl or two elementary alkyl amido independently; Or

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

The chemical compound of Formula I is disclosed in United States Patent (USP) the 4th, 567 in more detail, and in No. 264, the content of its disclosure is hereby expressly incorporated by reference.Preferred compounds of the invention are ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

The 3rd aspect of the present invention is the method for treatment mammal diabetes, comprises the ranolazine that gives effective therapeutic dose.

The 4th aspect of the present invention relates to a kind of method for the treatment of the mammal diabetes, comprises the partial fatty acid oxidation inhibitors of the Formulae II that gives effective therapeutic dose:

Formulae II

Wherein:

R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, and R ⁸Be hydrogen, low alkyl group or-C (O) R; Wherein R is-OR ⁹Or-NR ⁹R ¹⁰, R wherein ⁹And R ¹⁰Be hydrogen or low alkyl group; Or

R ¹And R ², R ³And R ⁴, R ⁵And R ⁶, R ⁷And R ⁸, and if connected carbon together, then be carbonyl; Or

R ¹And R ⁵, or R ¹And R ⁷, or R ³And R ⁵, or R ³And R ⁷, when a time-out then forms bridging group-(CR ¹²R ¹³) _n-, wherein n is 1,2 or 3, and R ¹²And R ¹³Then be hydrogen or low alkyl group independently; But the maximum number of palpus carbonyl is 2;-C (O) NR ⁹R ¹⁰The maximum number of group is 1; And the maximum number of bridging group is 1;

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

X ¹Be the aryl of the cycloalkyl of the low alkyl group of hydrogen, optional replacement, optional replacement, optional replacement or the heteroaryl of optional replacement;

X ²Be the aryl of optional replacement or the heteroaryl of optional replacement;

Y is the bicyclic heteroaryl of optional replacement; And

Z ¹And Z ²Be the alkylidene of 1-4 carbon atom of optional replacement independently.

The chemical compound of Formulae II is disclosed in U.S. Provisional Patent Application the 60/306th, No. 621 in (being No. the 10/198th, 237, U.S. Patent application now) in more detail, and the content of its disclosure is hereby expressly incorporated by reference.

The 5th aspect of the present invention is the method for treatment diabetes, comprise the partial fatty acid oxidation inhibitors that gives effective therapeutic dose, be 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

The 6th aspect of the present invention is to reduce the method for mammal HbA1c blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

The 7th aspect of the present invention is to reduce the method for mammal HbA1c blood plasma level, comprises the partial fatty acid oxidation inhibitors that gives effective therapeutic dose, and wherein partial fatty acid oxidation inhibitors is the chemical compound of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

The 8th aspect of the present invention is to reduce the method for mammal HbA1c blood plasma level, comprise the partial fatty acid oxidation inhibitors that gives effective therapeutic dose, wherein partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

The 9th aspect of the present invention is to reduce the method for mammal HbA1c blood plasma level, comprises the partial fatty acid oxidation inhibitors that gives effective therapeutic dose, and wherein partial fatty acid oxidation inhibitors is the chemical compound of Formulae II:

Formulae II

Wherein:

R ¹And R ⁵, or R ¹And R ⁷, or R ³And R ⁵, or R ³And R ⁷, if a time-out then forms bridging group-(CR ¹²R ¹³) _n-, wherein n is 1,2 or 3, and R ¹²And R ¹³Then be hydrogen or low alkyl group independently; But the maximum number of palpus carbonyl is 2;-C (O) NR ⁹R ¹⁰The maximum number of group is 1; And the maximum number of bridging group is 1;

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

The of the present invention ten aspect is to reduce the method for mammal HbA1c blood plasma level, comprise the partial fatty acid oxidation inhibitors that gives effective therapeutic dose, wherein the partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

The 11 aspect of the present invention is to reduce the method for mammal triglyceride blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

The 12 aspect of the present invention is to reduce the method for mammal triglyceride blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is the chemical compound of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

The 13 aspect of the present invention is to reduce the method for mammal triglyceride blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

The 14 aspect of the present invention is to reduce the method for mammal triglyceride blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is the chemical compound of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

The 15 aspect of the present invention is to reduce the method for mammal triglyceride blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein the partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

The 16 aspect of the present invention is to reduce the method for mammal glucose plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

The 17 aspect of the present invention is to reduce the method for mammal glucose plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is the chemical compound of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

The 18 aspect of the present invention is to reduce the method for mammal glucose plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

Nineteen of the present invention aspect is to reduce the method for mammal glucose plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is the chemical compound of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

The 20 aspect of the present invention is to reduce the method for mammal glucose plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein the partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

The 21 aspect of the present invention is to reduce the method for mammal T-CHOL blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

The 22 aspect of the present invention is to reduce the method for mammal T-CHOL blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is the chemical compound of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

The 23 aspect of the present invention is to reduce the method for mammal T-CHOL blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

The 24 aspect of the present invention is to reduce the method for mammal T-CHOL blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is the chemical compound of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

The 25 aspect of the present invention is to reduce the method for mammal T-CHOL blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein the partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

The 26 aspect of the present invention is the method that postpones the outbreak of mammal diabetic retinopathy, wherein mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

The 27 aspect of the present invention is the method that postpones the outbreak of mammal diabetic retinopathy, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is the chemical compound of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

The 28 aspect of the present invention is the method that postpones the outbreak of mammal diabetic retinopathy, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

The second nineteen aspect of the present invention is the method that postpones the outbreak of mammal diabetic retinopathy, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is the chemical compound of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

The 30 aspect of the present invention is the method that postpones the outbreak of mammal diabetic retinopathy, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein the partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

A hentriaconta-of the present invention aspect is to improve the method for mammal HDL cholesterol blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

The 32 aspect of the present invention is to improve the method for mammal HDL cholesterol blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is the chemical compound of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

The 33 aspect of the present invention is to improve the method for mammal HDL cholesterol blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

The 34 aspect of the present invention is to improve the method for mammal HDL cholesterol blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is the chemical compound of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

The 35 aspect of the present invention is to improve the method for mammal HDL cholesterol blood plasma level, wherein mammal is diabetes, non-diabetic or prediabetic, comprise the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs, wherein the partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

The 36 aspect of the present invention is the method for treatment mammal diabetes, comprise partial fatty acid oxidation (pfox) inhibitor that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is to give as immediate release dosage form.

The 37 aspect of the present invention is the method for treatment mammal diabetes, comprises partial fatty acid oxidation (pfox) inhibitor that gives the effective therapeutic dose of mammal of its needs, and wherein partial fatty acid oxidation inhibitors is to give as slow release formulation.

The 38 aspect of the present invention is the method for treatment mammal diabetes, comprise partial fatty acid oxidation (pfox) inhibitor that gives the effective therapeutic dose of mammal of its needs, wherein partial fatty acid oxidation inhibitors is to give with a kind of dosage form, and it has and discharges immediately and lasting release aspect.

The 3rd nineteen aspect of the present invention is the method for treatment mammal diabetes, comprises partial fatty acid oxidation (pfox) inhibitor that gives the effective therapeutic dose of mammal of its needs, and wherein partial fatty acid oxidation inhibitors is a ranolazine.

The 40 aspect of the present invention is the method for treatment mammal diabetes, comprise partial fatty acid oxidation (pfox) inhibitor that gives the effective therapeutic dose of mammal of its needs, wherein the blood plasma level of the ranolazine that in 24 hours, provides of slow release formulation 550 and 7500ng substrate (base)/ml between.

The 41 aspect of the present invention is the method for treatment mammal diabetes, comprise partial fatty acid oxidation (pfox) inhibitor that gives the effective therapeutic dose of mammal of its needs, wherein the blood plasma level of the ranolazine that in 24 hours, provides of slow release formulation 550 and 7500ng substrate/ml between, wherein slow release formulation comprises:

Component	Weight range (%)	Preferred ranolazine dosage form (mg)
Component	Weight range (%)	Preferred ranolazine dosage form (mg)	Ranolazine	??75	??500
Microcrystalline Cellulose (filler)	??10.6	??70.7	Ranolazine	??75	??500
Microcrystalline Cellulose (filler)	??10.6	??70.7	Methacrylic acid copolymer	??10.0	??66.7
Sodium hydroxide	??0.4	??2.7	Methacrylic acid copolymer	??10.0	??66.7
Sodium hydroxide	??0.4	??2.7	Hydroxypropyl emthylcellulose	??2.0	??13.3
Magnesium stearate	??2.0	??13.3	Hydroxypropyl emthylcellulose	??2.0	??13.3

The 42 aspect of the present invention is the method for treatment mammal diabetes, comprises the chemical compound that gives the mammal Formula I, and wherein dosage is from twice of about 250mg every day to about 2000mg every day twice.

The 43 aspect of the present invention is the method for treatment mammal diabetes, comprises that twice of about 250mg every day is to twice ranolazine about 2000mg every day.

The 44 aspect of the present invention is to reduce the method for the negative effect of diabetes, comprises giving ranolazine.

The 45 aspect of the present invention is the method that postpones the diabetes outbreak, comprises giving ranolazine.

The 46 aspect of the present invention is the method that postpones the initiation of insulinize, comprises giving ranolazine.

The 47 aspect of the present invention is to reduce patient's HbA1c level and do not cause hypoglycemic method, comprises giving ranolazine.

Description of drawings

Fig. 1 shows the influence of ranolazine to the HbA1c level.

Fig. 2 shows the initial terminal point of CARISA: the exercise duration at the trough place.This figure shows that diabetes and ND use the variation (unit second) from baseline of twice of placebo, 750mg ranolazine every day or 1000mg ranolazine twice back every day.

Fig. 3 shows CARISA: the exercise duration at the crest place.This figure shows that diabetes and ND use the variation (unit second) from baseline of twice of placebo, 750mg ranolazine every day or 1000mg ranolazine twice back every day.

Fig. 4 shows CARISA: to the movement time of angina pectoris attacks.This figure is presented at trough and crest place diabetes and ND and uses the variation (unit second) from baseline of twice of placebo, 750mg ranolazine every day or 1000mg ranolazine twice back every day.

Fig. 5 shows the variation (all diabetics) of CARISA:HbA1c from baseline.This figure is presented at the percent that baseline and last research value place diabetics use the HbA1c after twice of twice of placebo, 750mg ranolazine every day or 1000mg ranolazine every day.

Fig. 6 shows the variation (dependency and noninsulindependent diabetes patient) of CARISA:HbA1c from baseline.This figure is presented at the percent that baseline and last research value place's insulin-dependent and noninsulindependent diabetes patient use the HbA1c after twice of twice of placebo, 750mg ranolazine every day or 1000mg ranolazine every day.

The specific embodiment

The invention provides a kind of method, preferably with the chemical compound of Formula I or Formulae II with partial fatty acid oxidation inhibitors treatment diabetes.

Diabetes as herein defined, are a kind of morbid states, it is characterized in that: hyperglycemia; The metabolism of lipid, carbohydrate and proteinic change; And the danger that increases from the complication of angiopathy.

The glucemia regulation and control are adjustings of blood sugar level.

Hemoglobin is carried out glycosylation to form the glycosyl valine adduct of hemoglobin (HbA1c) at its amino terminal valine residue.The toxic action of hyperglycemia may be the result that this class non-enzymatic glycation product gathers.The covalent reaction of glucose and hemoglobin also provides easy method to measure the aggregative index of glucemia state.For example, the half-life of DCLHb equals the erythrocytic half-life (about 120 days).Because the amount of glycosylated protein was directly proportional with the time that concentration of glucose and protein are exposed to glucose, so the glucemia state in (4 to 12 week) over a long time before the reflection of the concentration of HbA1c is taken a sample in circulation.Thereby HbA1c rises to doubling for a long time of 10% prompting average blood sugar concentration from 5%.

With respect to the chemical compound of Formula I, following word and phrase generally have implication as described below, unless other implications of expression in the context that they use therein.

The group that " aminocarbonyl methyl " refers to have following structure:

Wherein A represents junction point.

" halogen " or " halogen " refers to fluorine-based, chloro, bromo or iodo.

" lower acyl " refers to have the group of following structure:

Wherein R is a low alkyl group as herein defined, and A represents junction point, and comprises such group, as acetyl group, propiono, positive bytyry and similar group.

" low alkyl group " refers to the unbranched saturated hydrocarbon chain of 1-4 carbon atom, as methyl, ethyl, n-pro-pyl and normal-butyl.

" lower alkoxy " refer to-the OR group, and wherein R is a low alkyl group as herein defined.

" low-grade alkyl sulphur " refer to-the SR group, and wherein R is a low alkyl group as herein defined.

" low alkyl group sulfinyl " refers to the group of following chemical formula:

Wherein R is a low alkyl group as herein defined, and A represents junction point.

" low alkyl group sulfonyl " refers to the group of following chemical formula:

The group that " alkyl amido of the optional replacement of N-" refers to have following structure:

Wherein R is that hydrogen or low alkyl group and R ' are low alkyl groups as herein defined independently, and A represents junction point.

With respect to the chemical compound of Formulae II, following word and phrase generally have implication as described below, unless other implications of expression in the context that they use therein.

Term " alkyl " refers to have the unit price base side chain or the unbranched saturated hydrocarbon chain of 1-20 carbon atom.This term can be with illustrating such as groups such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-hexyl, positive decyl, uncle's decyls.

Term " alkyl of replacement " refers to:

1) as above-mentioned defined alkyl group; has 1 to 5 substituent group; preferred 1 to 3 substituent group, these substituent groups are selected from by alkenyl; alkynyl; alkoxyl; cycloalkyl; cycloalkenyl; acyl group; acylamino-; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amino; azido; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; thiol; alkylthio group; aryl; aryloxy group; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alcoxyl amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO ₂-alkyl ,-SO ₂-aryl and-SO ₂The group that-heteroaryl is formed.Unless definition has qualification in addition, all substituent groups are all further replaced by 1-3 substituent group alternatively, be selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF3, amino, replacement amino, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2; Perhaps

2) alkyl as defined above inserts 1-5 atom or group, and it is to be selected from oxygen, sulfur and NR independently _a-, R wherein _aBe selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic radical.Unless definition has qualification in addition, all substituent groups can further be replaced by 1-3 substituent group alternatively, and it is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2; Perhaps

3) as above-mentioned defined alkyl, it contains 1 to 5 as above-mentioned defined substituent group and insertion as an above-mentioned defined 1-5 atom or group.

Term " low alkyl group " refers to have the side chain of 1-6 carbon atom or the unit price base of unbranched saturated hydrocarbon chain.This term can be by illustrating such as groups such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-hexyls.

Term " low alkyl group of replacement " refers to as above-mentioned defined low alkyl group, has 1 to 5 substituent group, preferred 1 to 3 substituent group, as the alkyl that replaces is defined, perhaps refer to low alkyl group as defined above, it perhaps refers to low alkyl group as defined above as to the defined insertion of alkyl that replaces 1 to 5 atom as defined above, has as defined above 1 to 5 substituent group and inserts 1 to 5 atom as defined above again.

Term " alkylidene " refers to the double-basis of side chain or unbranched saturated hydrocarbon chain, and it has 1 to 20 carbon atom, preferably has 1-10 carbon atom, more preferably 1 to 6 carbon atom.This term can be by such as methylene (CH ₂-), ethylidene (CH ₂CH ₂-), the propylidene isomer is (as ,-CH ₂CH ₂CH ₂-and-CH (CH ₃) CH ₂-) etc. group illustrate.

Term " low-grade alkylidene " refers to the double-basis of side chain or unbranched saturated hydrocarbon chain, preferably has 1 to 6 carbon atom.

Term " alkylidene of replacement " refers to:

(1) as above-mentioned defined alkylidene; have 1 to 5 substituent group, these substituent groups are selected from by alkyl; alkenyl; alkynyl; alkoxyl; cycloalkyl; cycloalkenyl; acyl group; acylamino-; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amino; azido; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; thiol; alkylthio group; aryl; aryloxy group; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alcoxyl amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO ₂-alkyl ,-SO ₂-aryl and-SO ₂The group that-heteroaryl is formed.Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2; Perhaps

(2) as above-mentioned defined alkylidene, it is inserted into 1 to 5 atom or group, and it independently is selected from oxygen, sulfur and NR _a-, R wherein _aBe selected from alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and the heterocyclic radical of hydrogen, optional replacement or be selected from carbonyl, carboxyl ester, Carboxylamide and sulfonyl; Perhaps

(3) alkylidene as defined above, it has as above-mentioned defined 1 to 5 substituent group, and by as an above-mentioned defined 1-20 atom separated.The example of the alkylidene that replaces has chlorine methylene (CH (Cl)-), amino ethylidene (CH (NH ₂) CH ₂-), methylamino ethylidene (CH (NHMe) CH ₂-), 2-carbonyl propylidene isomer (CH ₂CH (CO ₂H) CH ₂-), ethoxyethyl group (CH ₂CH ₂O-CH ₂CH ₂-), ethylmethylamino ethyl (CH ₂CH ₂N (CH ₃) CH ₂CH ₂-), 1-ethyoxyl-2-(2-ethyoxyl-ethyoxyl) ethane (CH ₂CH ₂O-CH ₂CH ₂-OCH ₂CH ₂-OCH ₂CH ₂-) and analog.

Term " aralkyl " refers to be covalently attached to the aryl of alkylidene, and wherein aryl and alkylidene define at this paper." aralkyl of optional replacement " refers to be covalently attached to the aryl of optional replacement of the alkylidene of optional replacement.This class aralkyl is by being illustrated such as benzyl, phenethyl, 3-(4-methoxyphenyl) propyl group and similar group.

Term " alkoxyl " refers to radicals R-O-, wherein R is the alkyl of optional replacement or the cycloalkyl of optional replacement, or R is group-Y-Z, wherein Y is that the alkylidene and the Z of optional replacement are the alkynyl of the alkenyl of optional replacement, optional replacement or the cycloalkenyl of optional replacement, wherein alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl such as in this article definition.Preferred alkoxyl is the alkyl-O-of optional replacement and comprises, as an example as: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, positive hexyloxy, 1,2-dimethyl butoxy, trifluoromethoxy and similar group.

Term " alkylthio group " refers to radicals R-S-, and wherein R is as defining at alkoxyl.

Term " alkenyl " refers to unit price base side chain or unbranched unsaturated alkyl, preferably has 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, 2 to 6 carbon atoms and have 1 to 6 most preferably, preferred 1, two keys (vinyl).Preferred alkenyl comprises ethylidene or vinyl (CH=CH ₂), 1-propylidene or pi-allyl (CH ₂CH=CH ₂), isopropylidene (C (CH ₃)=CH ₂), dicyclo [2.2.1] heptene and similar group.Under alkenyl and situation that nitrogen links to each other, two keys can not be in the α position of nitrogen.

Term " low-grade alkenyl " refers to as above-mentioned defined alkenyl with 2 to 6 carbon atoms.

Term " alkenyl of replacement " refers to as above-mentioned defined alkenyl; has 1 to 5 substituent group; and preferred 1 to 3 substituent group is selected from by alkyl; alkenyl; alkynyl; alkoxyl; cycloalkyl; cycloalkenyl; acyl group; acylamino-; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amino; azido; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; thiol; alkylthio group; aryl; aryloxy group; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO ₂-alkyl ,-SO ₂-aryl and-SO ₂The group that-heteroaryl is formed.Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.

Term " alkynyl " refers to the unit price base of unsaturated hydrocarbons, better has 2 to 20 carbon atoms, better has 2 to 10 carbon atoms, preferably has 2 to 6 carbon atoms, and has at least 1, the unsaturated position of preferred 1 to 6 acetylene (triple bond).Preferred alkynyl comprises acetenyl (C ≡ CH), propargyl (or third-1-alkynes-3-base ,-CH ₂C ≡ CH) and analog.Be connected at alkynyl under the situation of nitrogen, triple bond can not be in the α position of nitrogen.

Term " alkynyl of replacement " refers to as above-mentioned defined alkynyl; has 1 to 5 substituent group; preferred 1 to 3 substituent group is selected from by alkyl; alkenyl; alkynyl; alkoxyl; cycloalkyl; cycloalkenyl; acyl group; acylamino-; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amino; azido; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; thiol; alkylthio group; aryl; aryloxy group; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO ₂-alkyl ,-SO ₂-aryl and-SO ₂The group that-heteroaryl is formed.Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.

Term " aminocarbonyl " refers to group-C (O) NRR, and wherein each R is hydrogen, alkyl, aryl, heteroaryl, heterocyclic radical independently, or wherein two R groups in conjunction with to form heterocyclic group (for example, morpholino).Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.

Term " acylamino-" refers to group-NRC (O) R, and wherein each R is hydrogen, alkyl, aryl, heteroaryl or heterocyclic radical independently.Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.

Term " acyloxy " refer to group-O (O) C-alkyl ,-O (O) C-cycloalkyl ,-O (O) C-aryl ,-O (O) C-heteroaryl and-O (O) C-heterocyclic radical.Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.

Term " aryl " refers to the aromatic carbocyclic group of 6 to 20 carbon atoms, have monocycle (as, phenyl) or multi-ring (as, xenyl) or a plurality of condensing (thick) ring (as, naphthyl or anthryl).Preferred aryl groups comprises phenyl, naphthyl and similar group.

Unless the substituent group for aryl has qualification in addition in definition; this class aryl can be replaced alternatively by 1 to 5 substituent group; preferred 1 to 3 substituent group is selected from by alkyl; alkenyl; alkynyl; alkoxyl; cycloalkyl; cycloalkenyl; acyl group; acylamino-; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amino; azido; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; thiol; alkylthio group; aryl; aryloxy group; heteroaryl; amino-sulfonyl; amino carbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO ₂-alkyl ,-SO ₂-aryl and-SO ₂The group that-heteroaryl is formed.Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.

Term " aryloxy group " refers to group aryl-O-, and wherein aryl is as above-mentioned definition, and comprises the aryl of same as above-mentioned defined optional replacement.Term " arylthio " refers to radicals R-S-, and wherein R is as defining at aryl.

Term " amino " refers to group-NH ₂

Term " amino of replacement " refers to group-NRR, wherein each R is for independently by hydrogen, alkyl, cycloalkyl, carboxyalkyl (for example to be selected from, benzyloxycarbonyl group), the group of aryl, heteroaryl and heterocyclic radical composition, prerequisite is that two R groups are not hydrogen simultaneously, or group-Y-Z, wherein Y is the alkylidene of optional replacement, and Z is alkenyl, cycloalkenyl or alkynyl.Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.

Term " carboxyalkyl " refer to group-C (O) O-alkyl ,-C (O) O-cycloalkyl, wherein alkyl and cycloalkyl are as defined herein and alternatively further by alkyl, alkenyl, alkynyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group or-S (O) _nR replaces, and wherein R is alkyl, aryl or heteroaryl, and n is 0,1 or 2.

Term " cycloalkyl " refers to the cyclic hydrocarbon alkyl of 3 to 20 carbon atoms, has monocycle or condensed ring.This class cycloalkyl comprises, as an example, single ring architecture such as cyclopropyl, cyclobutyl, cyclopenta, ring octyl group and analog thereof, or condensed ring structure such as adamantyl and dicyclo [2.2.1] heptane or aryl-condensed thereon cycloalkyl, for example indane and analog.

Term " cycloalkyl of replacement " finger ring alkyl; has 1 to 5 substituent group; preferred 1 to 3 substituent group is selected from by alkyl; alkenyl; alkynyl; alkoxyl; cycloalkyl; cycloalkenyl; acyl group; acylamino-; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amino; azido; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; thiol; alkylthio group; aryl; aryloxy group; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO ₂-alkyl ,-SO ₂-aryl and-SO ₂The group that-heteroaryl is formed.Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.

That term " halogen " or " halogen " refer to is fluorine-based, bromo, chloro and iodo.

Term " acyl group " refers to group-C (O) R, and wherein R is the aryl of the heterocyclic radical of the cycloalkyl of the alkyl of hydrogen, optional replacement, optional replacement, optional replacement, optional replacement and the heteroaryl of optional replacement.

Term " heteroaryl " refers to aryl (that is, undersaturated), comprises 1 to 15 carbon atom and 1 to 4 hetero atom at least one ring, and these hetero atoms are selected from oxygen, nitrogen and sulfur.

Unless qualification is arranged in addition for the heteroaryl substituent definition; this class heteroaryl can be replaced alternatively by 1 to 5 substituent group; preferred 1 to 3 substituent group is selected from by alkyl; alkenyl; alkynyl; alkoxyl; cycloalkyl; cycloalkenyl; acyl group; acylamino-; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amino; azido; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; thiol; alkylthio group; aryl; aryloxy group; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO ₂-alkyl ,-SO ₂-aryl and-SO ₂The group that-heteroaryl is formed.Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.This class heteroaryl can have a monocycle (as, pyridine radicals, furyl, oxadiazole Ji, oxazolyl, isoxazolyl, pyrazolyl) or a plurality of condensed ring (as, such as indolizine base, benzoxazolyl, benzothiazolyl or benzothienyl and the such bicyclic heteroaryl of similar group).The example of nitrogen heterocyclic ring and heteroaryl includes but not limited to: pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, iso-indoles, indole, indazole, purine, quinolizine, isoquinolin, quinoline, 2, naphthyl pyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline and other contain the N-alkoxyl-nitrogen compound of heteroaryl.

Term " heteroarylidene " or " heteroaryl thiazolinyl (heteroarylenyl) " refer to the double-basis of heteroaryl as defined above.This term can pass through as 3,5-[1, and 2,4] oxadiazole thiazolinyls, 2,4-[1,3] oxazole thiazolinyls, 2,5-[1,3] oxazole thiazolinyls, 3,5-isoxazole thiazolinyl, 3,4-pyrazoles thiazolinyl, 3, groups such as 5-pyrazoles thiazolinyl are illustrated.For example, in the scope of the chemical compound of Formula I 3,5-[1,2,4] oxadiazole thiazolinyls are to be expressed as:

Unless qualification is arranged in addition for heteroaryl or heteroarylidene substituent definition; this class heteroarylidene group can be replaced alternatively by 1 to 5 substituent group; preferred 1 to 3 substituent group is selected from by alkyl; alkenyl; alkynyl; alkoxyl; cycloalkyl; cycloalkenyl; acyl group; acylamino-; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amino; azido; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; thiol; alkylthio group; aryl; aryloxy group; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO ₂-alkyl ,-SO ₂-aryl and-SO ₂The group that-heteroaryl is formed.Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.

Term " heteroaryloxy " refers to group heteroaryl-O-.

Term " heterocyclic radical " refers to the saturated or part unsaturated group of unit price, has monocycle or a plurality of condensed ring, has 1 to 40 carbon atom and 1 to 10 hetero atom in ring, preferred 1 to 4 hetero atom, and these hetero atoms are selected from nitrogen, sulfur, phosphorus and/or oxygen.

Unless the definition for heterocyclic substituent has qualification in addition; this class heterocyclic group can be replaced alternatively by 1 to 5 substituent group; preferred 1 to 3 substituent group is selected from by alkyl; alkenyl; alkynyl; alkoxyl; cycloalkyl; cycloalkenyl; acyl group; acylamino-; acyloxy; amino; aminocarbonyl; alkoxycarbonyl amino; azido; cyano group; halogen; hydroxyl; ketone group; thiocarbonyl; carboxyl; carboxyalkyl; arylthio; heteroarylthio; the heterocycle sulfenyl; thiol; alkylthio group; aryl; aryloxy group; heteroaryl; amino-sulfonyl; aminocarbonyl amino; heteroaryloxy; heterocyclic radical; heterocyclic oxy group; hydroxylamino; alkoxy amino; nitro;-SO-alkyl;-SO-aryl;-SO-heteroaryl;-SO ₂-alkyl ,-SO ₂-aryl and-SO ₂The group that-heteroaryl is formed.Unless definition has qualification in addition, otherwise all substituent groups further replace by 1-3 substituent group alternatively, is selected from alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxyl, halogen, CF ₃, amino, the amino that replaces, cyano group and-S (O) _nR, wherein R is that alkyl, aryl or heteroaryl and n are 0,1 or 2.Heterocyclic group can have a monocycle or a plurality of condensed ring.Preferred heterocycle comprises tetrahydrofuran base, morpholino, piperidyl and similar group.

Term " thiol (sulfydryl thiol) " refers to group-SH.

Term " alkylthio group of replacement " refers to the alkyl that group-S-replaces.

Term " heteroaryl thiol " refers to group-S-heteroaryl, and wherein, heteroaryl comprises the heteroaryl of optional replacement equally as defined above as defined above.

Term " sulfoxide " refers to group-S (O) R, and wherein R is alkyl, aryl or heteroaryl." sulfoxide of replacement " refers to group-S (O) R, and wherein R is the alkyl that replaces, the aryl of replacement or the heteroaryl that replaces, as defined herein.

Term " sulfone " refers to group-S (O) ₂R, wherein R is alkyl, aryl or heteroaryl." sulfone of replacement " refers to group-S (O) ₂R, wherein R is the alkyl that replaces, the aryl of replacement or the heteroaryl that replaces, as defined herein.

Term " ketone group " refer to group-C (O)-.Term " thiocarbonyl " refer to group-C (S)-.Term " carboxyl " refers to group-C (O)-OH.

" optionally " or " alternatively " refers to that incident or the situation described subsequently may take place or may not take place, and this description comprises example that wherein said incident or situation take place and the example that does not take place.

Term " chemical compound of Formula I " comprises as the chemical compound of the present invention that discloses and the prodrug of pharmaceutical salts, medicinal ester and this compounds.

" isomer " refers to have same atoms quality different chemical compound with atomic number but on one or more physics or chemical property.All isomers of the chemical compound of Formula I all within the scope of the invention.

Term " effectively therapeutic dose " refers to the amount of the chemical compound of Formula I, and when needing the mammal of this class treatment, it is enough to produce therapeutic effect, as following illustrated.Effectively therapeutic dose will depend on seriousness, administering mode of curee and the morbid state that will treat, curee's body weight and age, morbid state or the like, and it can easily be determined by those skilled in the art.

Term " treatment " or " processing " refer to any treatment to mammalian diseases, comprising:

(i) prevent disease promptly, does not manifest the clinical symptoms that causes disease;

(ii) suppress disease, that is, stop the development of clinical symptoms; And/or

(iii) alleviate disease, that is, clinical symptoms is disappeared.

Term " partial fatty acid oxidation inhibitors " refers to suppress the medicine or the chemical entities of mitochondrion fatty acid metabolism.Partial fatty acid oxidation inhibitors comprises from fatty acid metabolism and is displaced to glucose/lactate that the energy that will obtain from the inefficient relatively metabolism of fatty acid is transferred to by glucose and the Lactated energy that more the efficient oxidation produced." fatty acid oxidation inhibitors " also refers to chemical compound, and it suppresses to produce ATP from oxidation of fatty acids, produces ATP thereby stimulate from glucose and Lactated oxidation.In heart, it is need be by the metabolism of fatty acid that most of ATP produce.The metabolism of glucose and lactate provides the ATP than small scale.Yet with regard to oxygen consumption, the efficient that produces ATP from fatty acid is lower than the efficient that produces ATP from glucose and Lactated oxidation.Therefore, use fatty acid oxidation inhibitors to cause the oxygen molecule of each consumption to produce more energy, allowing more effectively provides energy to heart.Thereby fatty acid oxidation inhibitors especially can be used for treating the ischemic environment that the oxygen level is lowered.

In many cases, owing to have amino and/or carboxyl or similar group, chemical compound of the present invention can form acid and/or basic salt.Term " pharmaceutical salts (pharmaceutically acceptable salt) " is meant such salt, and it keeps the biological effect and the performance of the chemical compound of Formula I, and its be not on biology or others unfavorable.The medicinal basic addition salts can prepare by inorganic base and organic base.Salt derived from inorganic base comprises, only as an example, and sodium salt, potassium salt, lithium salts, ammonium salt, calcium salt and magnesium salt.Salt derived from organic base, include but not limited to primary amine, secondary amine, and the salt of tertiary amine, alkylamine for example, dialkylamine, trialkylamine, the alkylamine that replaces, two (alkyl of replacement) amine, three (alkyl of replacement) amine, alkenyl amine, two alkenyl amines, three alkenyl amines, the alkenyl amine that replaces, two (thiazolinyl of replacement) amine, three (thiazolinyl of replacement) amine, Cycloalkyl amine, two (cycloalkyl) amine, three (cycloalkyl) amine, the Cycloalkyl amine that replaces, dibasic Cycloalkyl amine, trisubstituted Cycloalkyl amine, cycloalkenyl group amine, two (cycloalkenyl group) amine, three (cycloalkenyl group) amine, the cycloalkenyl amine that replaces, dibasic cycloalkenyl amine, trisubstituted cycloalkenyl amine, arylamine, diaryl amine, triarylamine, heteroaryl amine, two heteroaryl amine, three heteroaryl amine, heterocyclic amine, two heterocyclic amines, three heterocyclic amines, blended diamidogen and triamine, wherein at least two substituent groups on amine are different and be selected from by alkyl, the alkyl that replaces, alkenyl, the alkenyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl, the cycloalkenyl that replaces, aryl, heteroaryl, heterocycle, and the group of analog composition.Also comprise following amine, promptly two or three substituent groups wherein with amino nitrogen, form heterocyclic radical or heteroaryl.

The particular instance that is fit to amine comprises, only as an example as, 2-aminopropane., trimethylamine, diethylamine, three (isopropyl) amine, three (n-pro-pyl) amine, ethanolamine, 2-dimethylaminoethanol, trimethylamine, lysine, arginine, histidine, caffeine, procaine, Hai Baming, choline, betanin, ethylenediamine, glycosamine, N-alkylated glucamine, theobromine, purine, piperazine, piperidines, morpholine, N-ethylpiperidine and analog.

Medicinal acid addition salt can prepare by mineral acid and organic acid.The salt that comprises hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid and analog derived from the salt of mineral acid.The salt that comprises acetic acid, propanoic acid, glycolic, acetone acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid and analog derived from organic acid salt.

" pharmaceutical carrier " used herein or " pharmaceutically acceptable carrier " comprise any He all solvents, disperse medium, coating, antibacterial and antifungal, etc. blend absorption delay agent and analog.This class aspect pharmaceutically active substance medium and the application of medicament be that the present technique field is known.Except in any and inconsistent conventional media of active component and medicament scope, it is contemplated that its application aspect therapeutic combination.The auxiliary activity composition also can be incorporated in the said composition.

Pharmaceutical composition and administration

Chemical compound of the present invention gives with the form of pharmaceutical composition usually.Therefore, the invention provides pharmaceutical composition, it contains: as active component, and one or more chemical compounds of the present invention or its medicinal salt or ester, and one or more pharmaceutical excipients; Carrier comprises inert solid diluent and filler; Diluent comprises aseptic aqueous solution and various organic solvent; Penetration enhancer; Solubilizing agent; And adjuvant.Chemical compound of the present invention can give separately or combine with the other treatment medicament and give.Such compositions with well-known mode in the pharmaceutical technology field be prepared (referring to, for example, Remington ' s PharmaceuticalSciences, Mace Publishing Co., Philadelphia, PA 17 ^ThEd. (1985) and " Modern Pharmaceutics ", Marcel Dekker, Inc.3 ^RdED. (G.S.Banker ﹠amp; C.T.Rhodes, Eds.)).

Chemical compound of the present invention can be by any acceptable administering mode with similar effectiveness, give with single dose or multiple dose, for example, as those as a reference patent and patent application described in, comprise rectum, the oral cavity, intranasal, with the percutaneous approach, by intra-arterial injection, intravenous administration, the intraperitoneal administration, the gastrointestinal tract external administration, intramuscular administration, subcutaneous administration, oral, topical, generally as inhalant, perhaps by dipping or apparatus for coating such as support (stent), for example, or the cylindrical polymeric administration of inserting tremulous pulse.

A kind of preferred administering mode is a parenteral, especially by injection.The novel compositions of the present invention can be incorporated into the form that wherein is used for drug administration by injection, comprise water or oil suspension or emulsion, adopt Oleum sesami, Semen Maydis oil, Oleum Gossypii semen or Oleum Arachidis hypogaeae semen and elixir, mannitol, dextrose or aseptic aqueous solution, and similar pharmaceutical carrier.Usually also saline solution is used for injection, but is less preferred in the present invention.Also can use ethanol, glycerol, propylene glycol, liquid polyethylene glycol and analog thereof (with and suitable mixture), cyclodextrin derivative and vegetable oil.Suitable flowability can keep by the following method, and for example, the use of coating as lecithin, passes through to keep needed particle size under dispersive situation, and by using surfactant.Can reach the effect of prophylaxis of microbial by using various antibacterial and antifungal, for example, parabens, chlorobutanol, phenol, sorbic acid, thiomersalate and analog thereof.

Being prepared as follows of injectable sterile solution: the composition adding of aequum is had in various other components appropriate solvent of (as above cited), if necessary, then pass through filtration sterilization.Generally, being prepared as follows of dispersant: various active component through sterilization are added in the sterile carrier, and it comprises basic disperse medium and above cited other required composition.Be used to prepare under the situation of injectable sterile solution at sterilized powder, preferred manufacturing procedure is to adopt vacuum drying and lyophilization technology, and its solution from previous aseptic filtration produces the powder of active component powder and any extra required composition.

Oral administration is another approach that gives these compositions.Administration can be passed through capsule or enteric coated tablet or analog.When preparation comprised a kind of pharmaceutical composition of chemical compound of Formula I at least or II, active component was usually with the excipient dilution and/or be encapsulated in such carrier, so that can present capsule, sachet, paper or other packing material form.When excipient was used as diluent, it can be solid, semisolid or fluent material (as mentioned above), and with regard to active component, it plays the effect of excipient, carrier or medium.Therefore, the form of said composition can be tablet, pill, powder, lozenge, sachet, cachet, elixir, suspending agent, Emulsion, solution, syrup, aerosol (as solid or in liquid medium), for example contain the powder up to ointment, soft capsule and hard capsule, injectable sterile solution and the sterile packaged of 10% weight active compound.

Some examples of appropriate excipients comprise lactose, dextrose, sucrose, Sorbitol, mannitol, starch, Radix Acaciae senegalis, calcium phosphate, alginate, tragacanth, gelatin, calcium silicates, microcrystalline Cellulose, polyvinylpyrrolidone, cellulose, sterilized water, syrup and methylcellulose.Prescription also comprises lubricant such as Pulvis Talci, magnesium stearate and mineral oil; Wetting agent; Emulsifying agent and suspending agent; Antiseptic such as methyl hydroxybenzoate and propyl hydroxybenzoate; Sweeting agent; And fumet.

By adopting method well known in the art can make compositions of the present invention, after to patient's administration, the quick, lasting of active component can be provided or delay release.The controlled-release administrating system that is used for oral administration comprises osmotic pump system and the dissolution system that contains polymer-coated storage capsule or drug-polymer matrix dosage form.The example of controlled release system is at United States Patent (USP) the 3rd, 845, No. 770, the 4th, 326, No. 525, the 4th, 902, No. 514, the 5th, 616, provides among No. 345 and the WO 0013687.Another prescription of using method of the present invention adopts transdermal drug delivery systems (" patch ").This class transdermal patch can be used for providing the continuous or discontinuous injection of The compounds of this invention under controlled quatity.The structure and the use that are used to pass the transdermal patch of medicine are well known in the art.For example, referring to United States Patent (USP) the 5th, 023, No. 252, the 4th, 992, No. 445 and the 5th, 001, No. 139.This class patch is configured for continuously, pulse or administration on demand.

These compositionss preferably are mixed with unit dosage forms.Term " unit dosage forms " refers to physically separated unit, be applicable to human subject and other mammiferous unit dose, each unit comprises the active material of scheduled volume, it is as calculated to produce needed treatment effect, and suitable drug excipient (for example, tablet, capsule and injection).The chemical compound of Formula I and II is effectively in wide dosage range, and gives the active drug amount usually.Preferably, for oral administration, each dosage unit contains the chemical compound of 10mg to 2g Formula I or II, better 10 to 1500mg, and better 10 to 1000mg, and best 10 to 700mg, and for the gastrointestinal tract external administration, the chemical compound of preferred 10 to 700mg Formula I or II, more preferably from about 50 to 200mg.Yet, it will be appreciated that, the amount of the chemical compound of actual Formula I that gives or II will comprise the order of severity and the analogue of the disease that will treat, the route of administration of selection, the pragmatize compound that gives and relative activity, each patient's age, body weight and reaction, patient's symptom by the doctor according to relevant situation decision.

In order to prepare the such solid composite of tablet, main active component mixes the solid preformulation composite that forms the homogeneous mixture that contains The compounds of this invention with drug excipient.When mentioning these pre-preparation compositions is equal phase time, and it is meant that active component is distributed in the whole compositions equably, thereby makes said composition can easily be subdivided into equivalent unit dosage forms, as tablet, pill and capsule.

Tablet of the present invention or pill can carry out coating or mix so that dosage form to be provided by alternate manner, and it has long action time, or are protected from the advantage of effect of the acid condition of stomach.For example, tablet or pill can comprise internal dose composition and outside dose components, and the latter wraps the former with the form of sealing.These two kinds of compositions can separate with enteric layer, this enteric layer be used to stop composition under one's belt disintegrate and make internal component send into duodenum intactly or be delayed to discharge.Various materials all can be used for enteric layer or coating, and these materials comprise the mixture of many polymer acids and polymer acid and lac (Lac), hexadecanol and cellulose acetate.

The compositions that is used for inhalant or insufflation comprises medical solution or organic solvent or its mixture and powder.The liquid or solid compositions can comprise suitable pharmaceutical excipient as indicated above.Preferably, these compositionss can give by the oral or nasal inhalation approach, produce the effect of part or system.The compositions that is present in the preferred medicinal solvent can atomize by using noble gas.The solution of atomizing can link to each other with face tent or batch (-type) positive pressure respirator by direct suction of atomising device or atomising device.Can give solution, suspending agent or powder composition from the device of sending composition in a suitable manner, preferred oral or intranasal administration.

The intravenous dosage form of ranolazine is to be prepared by aseptic fill method, and is specific as follows.In proper container, the dextrose monohydrate of aequum is dissolved in water for injection (WFI), it is approximately 78% of the weight that feeds intake for the last time.Under continuous stirring, with the ranolazine free alkali adding dextrose solution of aequum.In order to promote the dissolving of ranolazine, pH value of solution is adjusted to index 3.88-3.92 with 0.1N or 1N hydrochloric acid solution.In addition, 0.1NHCl or 1.0N NaOH can be used for solution finally is adjusted to index p H3.88-3.92.After the ranolazine dissolving, an inventory is adjusted to final weight with WFI.After the standard that confirms to have satisfied in the processing procedure, use by the aseptic filtration of two 0.2 μ m sterilizing filters the ranolazine bulk solution is sterilized.Thereafter, aseptic ranolazine bulk solution is filled into aseptic vial and clogs with aseptic stopper under aseptic condition under aseptic condition.Then the bottle that the clogs aluminum seal with the flip-top (flip-top) of cleaning is sealed.

The content of utilizing method well known to those skilled in the art and disclosing according to this patent, chemical compound of the present invention can infiltrate support by for example diffusion, or as coats support with gel form.

In a specific embodiment, can prepare preferred composition of the present invention, thereby give release, the especially slow release formulation that the patient provides the quick, lasting of active component later on or postpones.Most preferred compound of the present invention is a ranolazine, its called after (±)-N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, or its isomer or its effective pharmaceutical salts.Except as otherwise noted, the plasma ranolazine concentration of using in this description and embodiment refers to the ranolazine free alkali.

Preferred slow release formulation of the present invention is preferably the form of compressed tablets, the immixture that comprises the neutral pH dependency of chemical compound and part binding agent, wherein binding agent is at the rate of dissolution of scope inner control in aqueous medium of pH from stomach (usually about 2) pH (usually about 5.5) in the intestinal.An example of slow release formulation is disclosed in United States Patent (USP) the 6th, 303, and No. 607, the 6th, 479, No. 496, the 6th, 369, No. 062 and the 6th, 525, in No. 057, the content of its disclosure is hereby expressly incorporated by reference.

In order to guarantee the lasting release of chemical compound, can select the dissolution profiles of one or more pH dependency binding agents with the control chemical compound, like this when dosage form is passed through the harmonization of the stomach gastrointestinal tract, dosage form just can be slowly and is discharged medicine continuously.The dissolving control ability particular importance of pH dependency binding agent in slow release formulation, this is can cause adverse side effect because if chemical compound discharges the slow release formulation that too fast (" dosage is toppled over (dose-dumping) ") contain the chemical compound of enough administrations two next day so.

Correspondingly, be applicable to that pH dependency binding agent of the present invention is those binding agents, depressant thing is from the tablet rapid release during tablet is trapped in the stomach (pH is lower than about 4.5) herein for it, and it promotes to discharge from dosage form the chemical compound of therapeutic dose herein at bottom gastrointestinal tract (pH is usually greater than about 4.5).Many materials at the known conduct of pharmaceutical field " enteric " binding agent and coating material have needed pH solubility property.These materials comprise: the phthalic acid derivant of phthalic acid derivant such as polyvinyl and copolymer; Hydroxy alkyl cellulose, alkylcellulose, cellulose acetate, hydroxyalkyl cellulose acetate, cellulose ether, acetate alkyl cellulose and partial ester thereof; And the polymer of low alkyl group acrylic acid and lower alkyl acrylate and copolymer, and partial ester.

Can use the preferred pH dependency adhesive material to produce slow release formulation with chemical compound is methacrylic acid copolymer.Methacrylic acid copolymer is the copolymer of methacrylic acid and neutral acrylate or methacrylate (as ethyl acrylate or methyl methacrylate).Most preferred copolymer is methacrylic acid copolymer-C type USP (it is the copolymer of methacrylic acid and ethyl acrylate, has the methacrylic acid unit between 46.0% and 50.6%).Such copolymer can available from

Pharma, as

L 100-55 (as powder) or L30D-55 (as 30% dispersion in water).Other can use separately or comprise hydroxypropyl cellulose phthalate, hydroxypropylmethyl cellulose phthalate, CAP, Opaseal, polyvinylpyrrolidone phthalic acid ester and analog with pH dependency adhesive material that slow release formulation is united use.

One or more pH dependency binding agents can be used for slow release formulation in peroral dosage form.Should be noted that, pH dependency binding agent and viscosity intensifier, as hydroxypropyl emthylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral polymethacrylates and analog, they itself do not provide required dissolving control, and it is provided by discernible pH dependency binding agent.PH dependency binding agent is present in the dosage form of the present invention, and its quantitative range is from about 1 to about 10wt%, better from about 1 to about 3wt% and preferably about 2.0wt%.

As shown in table 1, it is insoluble relatively that preferred compound ranolazine of the present invention is higher than in about 6.5 the aqueous solution at pH, and begins remarkable increase being lower than about pH 6 dissolubility.

Table 1

PH value of solution	Dissolubility (mg/mL)	The USP solubility grade
PH value of solution	Dissolubility (mg/mL)	The USP solubility grade	??4.81	??161	Yi Rong
??4.89	??73.8	Solvable	??4.81	??161	Yi Rong
??4.89	??73.8	Solvable	??4.90	??76.4	Solvable
??5.04	??49.4	Solvable	??4.90	??76.4	Solvable
??5.04	??49.4	Solvable	??5.35	??16.7	Solvable slightly

??5.82	??5.48	Slightly soluble
??5.82	??5.48	Slightly soluble	??6.46	??1.63	Slightly soluble
??6.73	??0.83	Atomic molten	??6.46	??1.63	Slightly soluble
??6.73	??0.83	Atomic molten	??7.08	??0.39	Atomic molten
(7.59 non-buffered water)	??0.24	Atomic molten	??7.08	??0.39	Atomic molten
(7.59 non-buffered water)	??0.24	Atomic molten	??7.79	??0.17	Atomic molten
??12.66	??0.18	Atomic molten	??7.79	??0.17	Atomic molten

In dosage form, increase pH dependency binder content can reduce the slow release formulation of chemical compound when pH is lower than 4.5 (being the features of pH in the stomach) rate of release.The enteric coatings that is formed by binding agent is less soluble and can increase relative release rate being higher than pH 4.5, and wherein the dissolubility of chemical compound is lower.The suitable selection of pH dependency binding agent is convenient to that chemical compound has faster release rates from dosage form on pH4.5, the rate of release of appreciable impact simultaneously when low pH.The part neutralization of binding agent promotes that binding agent changes into latex shape thin film, and it forms around each granule.Correspondingly, select the type of pH dependency binding agent and the amount of quantity and part neutralization composition to control the rate of dissolution of chemical compound from dosage form with precision.

The pH dependency binding agent that dosage form of the present invention should have a capacity to be producing slow release formulation, can control the rate of release of chemical compound from this slow release formulation, so that significantly slack-off at low pHs (being lower than about 4.5) rate of dissolution.Methacrylic acid copolymer C type USP (

L 100-55) under the situation, the pH dependency binding agent of right quantity is between 5% and 15%.PH dependency binding agent has from about 1 to about 20% binding agent methacrylic acid usually, and wherein carboxyl is neutralized.Yet preferably, the scope of degree of neutralization is from about 3 to 6%.Slow release formulation also can contain the drug excipient with chemical compound and pH dependency binding agent intimately admixing.Pharmaceutical excipient can comprise, for example, pH dependency binding agent or film former such as hydroxypropyl emthylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral polymethacrylates (for example, the methyl methacrylate/ethyl acrylate copolymer, by

Pharma is at trade mark

Sell under the NE), starch, gelatin, saccharide, carboxymethyl cellulose and analog.Other useful drug excipients comprise: diluent such as lactose, mannitol, dried starch, microcrystalline Cellulose or the like; Surfactant such as polyoxyethylene sorbitol acid anhydride ester, sorbitan ester or the like; And coloring agent and fumet.Also there are lubricant (as Pulvis Talci and magnesium stearate) and other compression aids alternatively.

The compounds content of slow release formulation of the present invention calculate by weight be preferably about 50% to about 95% or more, better between about 70% to about 90% and preferably from about 70 to about 80%; PH dependency binder content is between 5% and 40%, preferably between 5% and 25% and more preferably between 5% and 15%; And the remainder of dosage form comprises pH dependency binding agent, filler and other optional excipient.Preferred slow release formulations more of the present invention are listed in following table 2.

Table 2

The most preferred weight of the preferred weight of weight

Composition

Scope (%) scope (%) scope (%)

Active component 0-95 70-90 75

Microcrystalline Cellulose (filler) 1-35 5-15 10.6

Methacrylic acid copolymer 1-35 5-12.5 10.0

Sodium hydroxide 0.1-1.0 0.2-0.6 0.4

Hydroxypropyl emthylcellulose 0.5-5.0 1-3 2.0

Magnesium stearate 0.5-5.0 1-3 2.0

Being prepared as follows of slow release formulation of the present invention: closely mix (dry blending) chemical compound and pH dependency binding agent and any optional excipient.Make dry mixed mixture become granule under the situation of strong alkali aqueous solution having then, wherein strong alkali aqueous solution is to be sprayed onto blended powder.Granule is dried, screens, mixes with optional lubricant (as Pulvis Talci or magnesium stearate), is pressed into tablet then.Preferred strong alkali aqueous solution is an alkali hydroxide soln, as sodium hydroxide or potassium hydroxide aqueous solution, and preferred sodium hydrate aqueous solution (containing alternatively) up to miscible solvent of 25% water such as lower alcohol.

The tablet that generates can be coated with optional film former, be used for identification, taste masking and make swallow easier.The quantitative range that film former usually exists be tablet weight 2% and 4% between.Suitable film former be well-known in the art and comprise hydroxypropyl emthylcellulose, cation methacrylate copolymer (dimethylaminoethyl methacrylate/methyl butyl methacrylate copolymer-

E,

Pharma) and analog.These film former can contain coloring agent, plasticizer and other auxiliary elements alternatively.

Preferably, compressed tablets has the hardness that is enough to the pressure of anti-8Kp.The big young pathbreaker of tablet depends primarily on the amount of chemical compound in tablet.These tablets will comprise 300 to 1100mg chemical compound free alkali.Preferably, the quantitative range of the contained chemical compound free alkali of these tablets is 400-600mg, 650-850mg and 900-1100mg.

In order to influence rate of dissolution, the time that wet mixed is contained the powder of chemical compound is controlled.Preferably, total powder mixes time, promptly powder is exposed to the time of sodium hydroxide solution, will be in 1-10 minute scope, and preferred 2-5 minute.After granulating, take out granule and be placed on from granulation machine and carry out drying about 60 ℃ fluidized bed dryer.

Have been found that, these methods produce slow release formulation, when chemical compound during as its free alkali rather than as dihydrochloride salts more common medicinal or as another salt or ester, these slow release formulations lower peak plasma level is provided after administration but the compounds effective plasma concentration up to 12 hours and longer.The use of free alkali provides at least one advantage: the ratio of chemical compound can increase in tablet, because the molecular weight of free alkali only is 85% of a dihydrochloride weight.By this way, can realize sending the chemical compound of effective dose, simultaneously the physics size of dose limitation unit.

Effectiveness and test

This method can effectively be treated diabetes.

Described in following examples, carry out activity test, and with conspicuous method for a person skilled in the art.

Following embodiment is used for illustrating the present invention.These embodiment never limit the scope of the invention, but show how to prepare and use chemical compound of the present invention.In these embodiments, all temperature all are Celsius temperatures

Embodiment 1-9 illustrates the preparation of the typical medicaments dosage form of the chemical compound that contains Formula I or II.

Embodiment 1

Preparation contains the hard capsules of following composition:

Quantity

Composition (mg/ capsule)

Active component 30.0

Starch 305.0

Magnesium stearate 5.0

Mix above composition and fill and enter in the regid gel capsule.

Embodiment 2

Prepare tablet with following composition:

Composition (mg/ tablet)

Active component 25.0

Cellulose, crystallite 200.0

Silica sol 10.0

Stearic acid 5.0

Composition mixed and extruding to form tablet.

Embodiment 3

Preparation contains the Foradil Aerolizer formoterol fumarate type of following composition:

Composition Weight %

Active component 5

Lactose 95

Active component is mixed with lactose, and mixture then adds powder inhaler

Embodiment 4

Each contains being prepared as follows of tablet of 30mg active component:

Quantity

Composition (mg/ tablet)

Active component 30.0mg

Starch 45.0mg

Microcrystalline Cellulose 35.0mg

Polyvinylpyrrolidone

4.0mg

(aseptic aqueous solution) as 10%

Carboxymethyl starch sodium 4.5mg

Magnesium stearate 0.5mg

Pulvis Talci 1.0mg

Amount to 120mg

Active component, starch and cellulose also mix up hill and dale by one 20 order U.S. sieve (No.20 meshU.S.sieve).The powder mixes of polyvinylpyrrolidonesolution solution and generation is then by one 16 order U.S. sieve (No.16 mesh U.S.sieve).So the granule of preparation is 50 ℃ to 60 ℃ dryings, and by one 16 order U.S. sieve.Before carboxymethyl starch sodium, magnesium stearate and the Pulvis Talci by 30 order U.S. sieves joined in the granule, and after the mixing, pushing to obtain each weight on tablet machine is the tablet of 120mg.

Embodiment 5

Each contains being prepared as follows of suppository of 25mg active component:

Composition Content

Active component 25mg

Saturated fatty acid glyceride reaches 2,000mg

Active component is by 60 order U.S. sieves and be suspended in the saturated fatty acid glyceride, and this fatty glyceride utilizes required minimum heat to melt.Then, mixture is injected the suppository mould of nominal 2.0g and make its cooling.

Embodiment 6

Each contains being prepared as follows of suspensoid of 50mg active component/5.0mL dosage:

Composition Content

Active component 50.0mg

Xanthan gum 4.0mg

Sodium carboxymethyl cellulose (11%)

50.0mg

Microcrystalline Cellulose (89%)

Sucrose 1.75g

Sodium benzoate 10.0mg

Spice and coloring agent are pressed quantum volueris

Purify waste water, reach 5.0mL

Active component, sucrose and xanthan gum are mixed, by 10 order U.S. sieves, then with the aqueous solution of the microcrystalline Cellulose and the sodium carboxymethyl cellulose of previous preparation.Stir the sodium benzoate, spice and the coloring agent that add dilute with water.Add enough water then to generate needed volume.

Embodiment 7

Subcutaneous dosage form can be prepared as follows:

Composition Quantity

Active component 5.0mg

Semen Maydis oil 1.0mL

Embodiment 8

The preparation injection preparation, it has following component:

Composition Content

Active component 2.0mg/ml

Mannitol, American Pharmacopeia (USP) 50mg/ml

Gluconic acid, American Pharmacopeia (USP) an amount of (pH5-6)

Water (distillation, aseptic) is in right amount to 1.0ml

Nitrogen, dispensatory of the United States of America (NF) is an amount of

Embodiment 9

Preparation topical preparation, it has following composition:

Composition Gram

Active component 0.2-10

Span (Span 60) 2.0

Tween (Tween 60) 2.0

Mineral oil 5.0

Vaseline 0.10

Methyl butex (methyl paraben) 0.15

Propyl parabene (propyl paraben) 0.05

BHA (butylated hydroxyanisol) 0.01

Water is in right amount to 100

Outside dewatering, merge all above-mentioned other compositions and be heated to 60 ℃, stir simultaneously.Then, at 60 ℃ of water that add capacity down, vigorous stirring so that composition is carried out emulsifying, adds an amount of water to 100g then simultaneously.

Embodiment 10

Preparation contains the slow releasing tablet of following component:

Composition	Weight range (%)	Preferred ranolazine dosage form (mg)
Composition	Weight range (%)	Preferred ranolazine dosage form (mg)	Ranolazine	??75	??500
Microcrystalline Cellulose (filler)	??10.6	??70.7	Ranolazine	??75	??500
Microcrystalline Cellulose (filler)	??10.6	??70.7	Methacrylic acid copolymer	??10.0	??66.7
Sodium hydroxide	??0.4	??2.7	Methacrylic acid copolymer	??10.0	??66.7
Sodium hydroxide	??0.4	??2.7	Hydroxypropyl emthylcellulose	??2.0	??13.3
Magnesium stearate	??2.0	??13.3	Hydroxypropyl emthylcellulose	??2.0	??13.3

Closely mix (dry blending) chemical compound and pH and rely on binding agent and any optional excipient.Make dry mixed mixture become granule under the situation of strong alkali aqueous solution having then, wherein strong alkali aqueous solution is to be sprayed onto blended powder.Granule is dried, screens, mixes with optional lubricant (as Pulvis Talci or magnesium stearate), be pressed into tablet then.Preferred strong alkali aqueous solution is an alkali hydroxide soln, as sodium hydroxide or potassium hydroxide aqueous solution, and preferred sodium hydrate aqueous solution (containing alternatively) up to miscible solvent of 25% water such as lower alcohol.

The tablet that generates can be coated with optional film former, be used for identification, taste masking and make swallow easier.The quantitative range that film former usually exists be tablet weight 2% and 4% between.Suitable film former be the present technique field known and comprise hydroxypropyl emthylcellulose, cation methacrylate copolymer (dimethylaminoethyl methacrylate/methyl butyl methacrylate copolymer-

E-

Pharma) and analog.These film former contain coloring agent, plasticizer and other helper components alternatively.

Compressed tablets preferably has the hardness that is enough to stand 8Kp pressure.The big young pathbreaker of tablet depends primarily on the amount of chemical compound in tablet.These tablets will comprise 300 to 1100mg chemical compound free alkali.Preferably, the quantitative range of the contained chemical compound free alkali of these tablets is 400-600mg, 650-850mg and 900-1100mg.

Embodiment 11

HbA1 c measures:

Measured HbA1c level (Componentsof total measurement error for hemoglobin A1c determination.Phillipov according to improving one's methods of Phillipov method, G., et al.Clin.Chem. (2001), 47 (10): 1851).(referring to Fig. 1)

Embodiment 12

Triglyceride levels

The test compound that is dissolved in DMSO and is suspended in 0.5% tylose gives Syria's gold hamster by means of the pharyngeal canal per os.In order to determine the CETP activity, before beginning experiment, pass through back socket of the eye puncture blood sample collection (approximately 250mu.l).Utilize the pharyngeal canal per os to give chemical compound thereafter.There is not the solvent of the same volume of chemical compound to give control animal.Then, animal is by fasting.Then at different time, after giving chemical compound 24 hours, by the back socket of the eye venous plexus blood sample collection that punctures.

Make blood sample coagulation by under 4 ℃, being incubated overnight.6000X.g centrifugal 10 minutes to blood sample.In the cholesterol in serum that generates and the concentration of triglyceride is to utilize commercial improve one's methods (modification) that obtains enzyme test to measure (cholesterol enzyme 14366Merck, triglyceride 14364Merck).

Embodiment 13

In order to study the antidiabetic effect of chemical compound, can i.v. injection STZ (60mg/kg, matched group can give saline vehicle) thus come to cause chemical damage to induce insulin-dependent diabetes to pancreas.The volume of injection is equivalent to the 0.1ml/100g body weight.Injection is delivered into the preceding intubate jugular vein (step is referring to following description) of the male Sprague Dawley of youth (190-220g) rat.Simultaneously subcutaneous implantable miniature osmotic pumps (step is referring to following description) with during studying with the constant rate of speed delivering drugs.The persistent period of depending on research, may need to implant second miniature osmotic pumps.

In order to confirm diabetic disease states, gather the blood sample (cutting the end of afterbody) of animal and measure its blood glucose from afterbody.The animal that blood sugar level surpasses 13mM is considered to diabetics and is divided into 4 groups at random.Accept two groups of every days subcutaneous injection of insulin to obtain part glucose control (glucose level on an empty stomach be approximately control of diabetes animal not 50%).One of part control of diabetes group is treated with test compound.In addition, comprise two non-diabetic groups, a winding then reception test chemical compound not of another group of chemical compound that is put to the test.Two non-diabetic group rats are not all accepted insulin.

On weekly basis, in the isoflurane anesthesia animal, gather 500 μ L blood samples, be used for measuring: the serum-concentration of blood glucose, the non-esterified free fatty of serum, serum triglycerides, HbA1c, serum insulin, T-CHOL, HDL cholesterol and test compound by back socket of the eye ophthalmorrhagia.Also measure body weight weekly.

In case reach stable HbA1c, then stop research.When this is established, then the carotid artery of animal is carried out intubate according to aseptic technique.The rat of anaesthetizing and waking is measured blood pressure.Second day, carry out oral glucose tolerance test.Oral glucose tolerance test relates to by gavage and gives 1g glucose/kg.

Before glucose excites, excite back 10,20,30 and 60 minutes and collect tremulous pulse blood sample (0.3ml), and separated plasma is used for glucose and insulin assay by jugular vein conduit (it before had been used to measure blood pressure) with glucose.

Induce STZ-diabetes and implantable miniature osmotic pumps.

Under isoflurane anesthesia, then clean rat tails with ethanol with warm water.Under anesthesia, utilize sterile needle and syringe and filtration sterilization solution, carry out tail vein injection STZ or saline.After the i.v. injection, it is hemorrhage to prevent that injection areas is exerted pressure, and animal is placed in the clean cage with aseptic bed Bed linens then.Except that STZ or saline injection, the anesthesia initial stage in the rat neck region subcutaneous implantable miniature pump.If research surpassed for 4 weeks, then carry out the second time and implant.Basically, the cervical region of small size is thinly sliced and thoroughly cleaned with iodine solution, utilize dissecting knife to make less 1cm otch and pump inserted the Sub-Q gap at aseptic first mouthful at skin layer.Then, when needs, use closed this otch of 1-2 surgery staple.

Implanting carotid duct is used to measure blood pressure and carries out oral glucose tolerance test

According to the condition of using aseptic technique and instrument, anesthetized rat is placed on its back, and wherein head is towards surgeon, and lubricated ointment is applied to two.Make midline incision to expose left common carotid artery along cervical region.Dorsal part tangent plane (it is come to the surface herein) at neck upward utilizes blunt dissection to make the tunnel for conduit in the subcutaneous pocket.Half crooked pincers is used for separating tremulous pulse and the flexible plastic tube that pass below the tremulous pulse rear portion flow into separated region with temporary transient prevention blood.The front portion of external carotid artery is carried out ligation with a 4-0 suture silk and is passed through at the fixing a pair of mosquito forceps in the end of suture material to produce slight tension force on tremulous pulse then.Half crosscut arteria carotis externa then inserts 0.033 or 0.040mm O.D. conduit, pushes aorta (approximately 2-3cm is dark) then to.Conduit is tied up to the appropriate location, is fixed in chest muscle and moves to prevent conduit, then the front portion of permanent ligation arteria carotis externa and the seepage of observing blood.Externally, conduit is tied up to nape and stitching thread around knot, stays about 2 inches long two ends, is used for fetching under skin.Nodular conduit is retracted under the skin preventing and is pulled out by rat.In order to measure blood pressure, conduit is connected in pressure transducer and data collecting system.In order to carry out the blood glucose tolerance test, conduit is connected in pin and syringe to collect blood sample.

Embodiment 14

In order to study the antidiabetic effect of chemical compound, can i.v. injection STZ (60mg/kg, matched group can give saline vehicle) thus come to cause chemical damage to induce insulin-dependent diabetes to pancreas.The volume of injection is equivalent to the 0.1ml/100g body weight.Be implanted in two conduits in jugular vein and the external carotid artery with surgery, injection is delivered into the preceding intubate jugular vein of the male Sprague Dawley of youth (280-300g) rat.In order to confirm diabetic disease states, gather the blood sample of animal and measure its blood glucose from intubate.The animal that blood sugar level surpasses 13mM is considered to diabetics.Preceding implantation catheter washes to keep open with heparinized saline every day.Inducing diabetes after one week, rat is carried out pharmacokinetic study with chemical compound of the present invention.Fetch under the skin animal on one's body conduit and test at open.Injection tied be connected to 19-gauge (gauge) IV device, fill with 0.1% heparinized saline, and syringe needle is inserted into conduit.Test compound is to give through the jugular vein conduit, by bolus injection or stable infusion, or through port lumen feeding (being respectively 1ml/kg and 2ml/kg).10 time points (using 5-6 animal), extract 300 μ l blood and pour into 300 μ l saline to replace blood volume from carotid narrow ridge (line).Be equivalent to total blood volume of about 10% at 10 time points from the 300 μ l blood of 300gm animal.If extract 24 hours blood samples, then with conduit in skin horizontal plane place knotting and allow animal get back in its cage.Then 24 hours anesthesia under by the bloodletting kill animals to collect last blood sample.If there are not 24 hours blood samples, then when last blood collecting, under anesthesia, pass through the bloodletting kill animals.

Embodiment 15

The exercise performance and the HbA1 c that suffer from the patient with angina pectoris of diabetes

The CARISA joint assessment of ranolazine (in the stable angina pectoris to) research is used diltiazem at random to 823 symptomatic chronic patient with angina pectoris in parallel, double blinding, the research in 12 weeks

Twice of twice of ranolazine 750mg every day, 1000mg every day or placebo are treated and added to atenolol or amlodipine.At baseline and at trough and peak plasma level after 2,6 and 12 weeks of treatment, the Bruce bicycle ergometor exercise of improveing.Used ranolazine dosage form is the dosage form that is shown among the embodiment 10 in this research.

In diabetes (D) and non-diabetic (ND) patient, to locate at trough (Fig. 2) and peak value (Fig. 3), ranolazine prolongs exercise duration (ED) similarly.Suffering from the ranolazine of 750mg dosage under the trough drug level and prolonging exercise duration in the patient with angina pectoris of diabetes and in the non-diabetic patient with angina pectoris, then prolonged exercise duration 22 seconds in 29 seconds.Suffering from the ranolazine of 1000mg dosage under the trough drug level and prolonging exercise duration in the patient with angina pectoris of diabetes and in the non-diabetic patient with angina pectoris, then prolonged exercise duration 21 seconds in 34 seconds.

Increasing (Fig. 4) angina pectoris frequency to the anginal time under the situation of ranolazine then reduces.D and ND patient compare, and the improvement of using ranolazine is not remarkable difference (treating p value 〉=0.26 by the diabetes interaction).Adverse events is similar: under the situation of using placebo, ranolazine 750 and 1000mg, having 25%, 25% and 34% D patient to have an adverse events at least respectively, then is 27%, 33% and 32% in ND patient.

At 12 whens week and placebo relatively, ranolazine 750 and 1000mg every day are attended by the average absolute reduction of HbA1c twice, are respectively 0.48 percentage point and 0.70 percentage point (p＜0.01) (Fig. 5).In the patient who uses insulin, descend bigger (being respectively 0.8 and 1.1 percentage point) (Fig. 6).The glucose of diabetics and triglyceride value are listed in table 1 in this research.

Table 1

Glucose and triglyceride value (all diabeticss)

Embodiment 16

Carbohydrate in MARISA and CARISA and lipid parameter

Ranolazine (RAN), partly suppress a member in the newtype medicine of fatty acid oxidation (pFOX), in chronic patient with angina pectoris, (MARISA N=191) and when adding background (background) antianginal therapy (uses atenolol, diltiazem in use separately

Or amlodipine) (CARISA N=823) has all increased the treadmill movement ability time.Ranolazine has reduced angina pectoris frequency and nitroglycerin consumption.Used ranolazine dosage form is the dosage form that is shown among the embodiment 10 in CARISA and MARISA research.The most continually Bao Dao adverse events (dizzy, constipation and feel sick) normally light-duty and betide less than among 10% the patient.The potential application of ranolazine in diabetics attracts people's attention, and this is because about 1/4th patient with angina pectoris all suffers from diabetes.

Under the situation of MARISA and CARISA, the effectiveness of ranolazine and toleration all are similar in diabetes and ND.Under the situation of CARISA (N=131), in diabetics, at 12 whens week and placebo relatively, ranolazine 750 and 1000mg every day are attended by the average absolute reduction of HbA1c twice, are respectively 0.48 percentage point and 0.70 percentage point (each p＜0.01).With placebo relatively, use respectively 750 and the situation of 1000mg every day twice (p＜0.02 and p＜0.01) under, bigger (N=31 descends in the patient who uses insulin; 0.84 and 1.05 percentage points).Under the situation of CARISA, ranolazine does not influence glucose on an empty stomach in diabetics, and is irrelevant with insulinize; Under the situation of using placebo and ranolazine, all report hypoglycemic episodes one time.After the month, in diabetics, HbA1c descends 1.1 percentage points from baseline at open-label treatment 12-24.Under the situation of CARISA, during initial 12 week of ranolazine treatment diabetics, average total and LDL cholesterol increase respectively and reach 16 and 11mg/dL; Yet, because the HDL cholesterol on average increases up to 5mg/dL, so the HDL/LDL ratio does not almost change.In bonded MARISA/CARISA diabetic population, during the open-label that surpasses 3 years was treated, total descended from baseline with the LDL cholesterol, and the HDL cholesterol then continues to increase.

Claims

1. a method for the treatment of the mammal diabetes comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

2. method according to claim 1, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

3. method according to claim 2, wherein said partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

4. method according to claim 1, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

5. method according to claim 4, wherein the described partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

6. method that reduces mammal HbA1c blood plasma level, wherein said mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

7. method according to claim 6, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

8. method according to claim 7, wherein said partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

9. method according to claim 6, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

Z ¹And Z ²Be the alkylidene with 1-4 carbon atom of optional replacement independently.

10. method according to claim 9, wherein the described partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

11. a method that reduces mammal triglyceride blood plasma level, wherein said mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

12. method according to claim 11, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formula I:

Formula I

Wherein:

R ¹, R ², R ³, R ⁴And R ⁵Each is the alkyl amido of hydrogen, low alkyl group, lower alkoxy, cyano group, trifluoromethyl, halogen, lower alkylthio, low alkyl group sulfinyl, low alkyl group sulfonyl or the optional replacement of N-independently, supposes to work as R ¹When being methyl, R ⁴It or not methyl;

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

13. method according to claim 12, wherein said partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

14. method according to claim 11, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

15. method according to claim 14, wherein the described partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

16. a method that reduces mammal glucose plasma level, wherein said mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

17. method according to claim 16, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

18. method according to claim 17, wherein said partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

19. method according to claim 16, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

20. method according to claim 19, wherein the described partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

21. a method that reduces mammal T-CHOL blood plasma level, wherein said mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

22. method according to claim 21, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

23. method according to claim 22, wherein said partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

24. method according to claim 21, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

25. method according to claim 24, wherein the described partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

26. method that is used to postpone the outbreak of mammal diabetic retinopathy, wherein said mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

27. method according to claim 26, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

28. method according to claim 27, wherein said partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

29. method according to claim 26, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

30. method according to claim 29, wherein the described partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

31. a method that improves mammal HDL cholesterol blood plasma level, wherein said mammal is diabetes, non-diabetic or prediabetic, comprises the partial fatty acid oxidation inhibitors that gives the effective therapeutic dose of mammal of its needs.

32. method according to claim 31, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formula I:

Formula I

Wherein:

Or R ²And R ³Formation-OCH together ₂O-;

R ⁶And R ⁷Formation-CH=CH-CH=CH-together; Or

R ⁷And R ⁸Formation-O-CH together ₂O-;

R ¹¹And R ¹²Each is hydrogen or low alkyl group independently; And

W is oxygen or sulfur;

Or its medicinal salt or ester or its isomer.

33. method according to claim 32, wherein said partial fatty acid oxidation inhibitors is a ranolazine, its called after N-(2, the 6-3,5-dimethylphenyl)-4-[2-hydroxyl-3-(2-methoxyl group phenoxy group) propyl group]-1-piperazine acetamide, as racemic mixture or its isomer or its pharmaceutical salts.

34. method according to claim 31, wherein said partial fatty acid oxidation inhibitors are the chemical compounds of Formulae II:

Formulae II

Wherein:

T is oxygen, sulfur or NR ¹¹, R wherein ¹¹Be hydrogen or low alkyl group;

V is-N＜,-CH＜or-N-CH＜;

Y is the bicyclic heteroaryl of optional replacement; And

35. method according to claim 34, wherein the described partial fatty acid oxidation inhibitors of Formulae II is 1-{4-[5-(4-trifluoromethyl)-[1,2,4]-oxadiazoles-3-ylmethyl]-piperazine-1-yl }-3-(2-methylbenzothiazole-1,5-base hydroxyl)-propan-2-ol; As racemic mixture or its isomer.

36. method according to claim 1, wherein said partial fatty acid oxidation inhibitors is to give as immediate release dosage form.

37. method according to claim 1, wherein said partial fatty acid oxidation inhibitors is to give as slow release formulation.

38. method according to claim 1, wherein said partial fatty acid oxidation inhibitors are to discharge immediately and the dosage form of lasting release aspect gives to have.

39. according to the described method of claim 37, wherein said partial fatty acid oxidation inhibitors is a ranolazine.

40. according to the described method of claim 39, the blood plasma level of the ranolazine that wherein said slow release formulation provided in 24 hours 550 and 7500ng substrate/ml between.

41. according to the described method of claim 40, wherein said slow release formulation comprises:

Composition weight scope (%)

Ranolazine 75

Microcrystalline Cellulose (filler) 10.6

Methacrylic acid copolymer 10.0

Sodium hydroxide 0.4

Hydroxypropyl emthylcellulose 2.0

Magnesium stearate 2.0.

42. according to the described method of claim 41, wherein said slow release formulation comprises:

Component ranolazine dosage form (mg)

Ranolazine 500

Microcrystalline Cellulose (filler) 70.7

Methacrylic acid copolymer 66.7

Sodium hydroxide 2.7

Hydroxypropyl emthylcellulose 13.3

Magnesium stearate 13.3.