CN104628612B - One class itrile group benzol sulfohydrazide class GPR119 agonist, preparation method and its usage - Google Patents
One class itrile group benzol sulfohydrazide class GPR119 agonist, preparation method and its usage Download PDFInfo
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Abstract
The present invention relates to the pharmaceutical field relevant to diabetes B. Specifically, the present invention relates to the GPR119 agonist of a class itrile group benzol sulfohydrazide structure, its preparation method and in the application prepared in diabetes B medicine.
Description
Technical field
The present invention relates to the pharmaceutical field of the treatment of diabetes B. More particularly, the present invention relates to the GPR119 agonist of the class nitrile group-containing benzol sulfohydrazide structure that diabetes B is had therapeutic action, its preparation method, and the purposes in pharmacy.
Background technology
Diabetes threaten the health of the mankind day by day seriously. In the current U.S., nearly 1,600 ten thousand people suffer from the misery that diabetes are brought. One patients with type �� DM is also referred to as insulin-dependent diabetes mellitus, belongs to autoimmune disorder. It causes owing to the pancreatic islet p-cells that can produce Regular Insulin is destroyed by self immune system, and at present in the world to this sick not cure method, therefore patient must accept injection of insulin treatment. If not insulin injection, cell cannot absorb glucose and obtain energy. The related symptoms of one patients with type �� DM usually occur in Childhood and adolescence. Owing to the course of disease is usually relatively anxious, illness is obvious, and patient can be impelled initiatively to seek the help of medical procedure. Type-II diabetes is also referred to as non insulin dependent diabetes, shows as patient and lacks enough capability control own blood glucose levels. Type-II diabetes its be not enough by insulin secretion or insulin resistant (referring to that the Regular Insulin of body internal secretion can not appropriately be responded by bodily tissue) causes, that is type-II diabetes patient or be that the Regular Insulin of self secretion is insufficient, or is the Regular Insulin that can not effectively use self to secrete. Several factors can cause appearance and the development of insulin resistant, comprises heredity, obesity, advanced age and long-term hyperglycemia etc. Although type-II diabetes may appear at all age group, but generally occurs in it grownup, so it is also called maturity-onset diabetes sometimes. However, it should be noted that, the sickness rate of type-II diabetes is soaring in children population in recent years.
With it diabetic subject, in blood and urine, the content of glucose raises, and causes many urine, thirsty, hungry and a series of problem such as fat and protein metabolism. If not diagnosis and treatment in addition, diabetes can cause blind, gangrenous, and even the various complication jeopardizing life such as renal failure and heart trouble.
Type-II diabetes patient accounts for greatly the 90%-95% of diabetic subject's sum. In current Western society, about there is the grownup of 6% to suffer from type-II diabetes, cause the death of 193,000 people in the U.S. every year, in all causes of death, occupy the 7th. Worldwide, it is subject to the puzzlement of diabetes B more than 1.5 hundred million people, and this numeral is estimated to be doubled in 2025. Although some people easily suffers from diabetes, riseing mainly by the mode of life sat for a long time, full diet of current case because of the factor of heredity, and obesity general in developed country is caused. The type-II diabetes patient of general 80% is significantly overweight. The youngster suffering from now this disease increases just day by day. Current type-II diabetes has been acknowledged as in 21st century in the world to one of significant threat of human health.
At present, the treatment plan that type-II diabetes is had degree different by people. The most basic scheme is the combination of diet and exercise, can also coordinate pharmacological agent on this basis. The medicine used for the treatment of diabetes at present, except Regular Insulin, also has following several: Insulin secretagogues, such as sulfonylureas specifically, and it can improve the amount of pancreas beta cell excreting insulin; Hypoglycemic agents, such as metformin, it can reduce the amount of liver output glucose; Peroxisome proliferator-activated receptors-�� (PPAR-��) agonist, such as glitazone medicine, it can strengthen the effect of Regular Insulin; Also having alpha-glucosidase inhibitor, it can hinder the output of glucose in intestines. But, existing medicine also has the aspect of some shortcomings, comprises the side effect of hypoglycemia, and body weight increases, the appearance of resistance, gastrointestinal problems, and oedema. The type-II diabetes needs of patients oral drug therapy of general 49%, the needs of patients insulin injection of general 40% also may use oral pharmaceutical simultaneously, and then the patient of general 10% can only use a diet and temper symptom management.
In order to can new more effective therapy be introduced to the market, the research in several fields is had to carry out at present. Its direction mainly comprises: the excessive production reducing glycogen, strengthen the path that Regular Insulin absorbs glucose signals to cell transmission, increase the insulin secretion of the liver beta cell promoted by glucose, and try hard to solve fat and adjoint metabolism of fat and accumulation aspect problem.
GPR119 is a special target spot, and it is a member in rhodopsin family in g protein coupled receptor. Except being referred to as " GPR119 ", it also has other to identify, and includes but not limited to RUP3, Snorf25,19AJ, AXOR20 and PS1. The beta Cell of islet that GPR119 is mainly expressed in pancreatic tissue and PP cell, and enteron aisle L cell (secretion GLP-1) and K cell [secreting glucose-dependent-insulinotropic polypeptide (GIP)]. Scientific experiment confirms, exciting GPR119 can improve intracellular loops adenosine phosphate (cAMP) concentration, the stimulation in activated cell-secretion coupling, thus increases the GLP-1 of glucose dependency and the secretion of Regular Insulin. See T.Sogaetal., BiochemicalandBiophysicalResearchCommunications, 2005,326,744-751, the inside some have the document about GPR119. Also having science to report recently, GPR119 agonist can reduce withering of people's enteron aisle L cell and die.
Type-II diabetes patient with it in, although the secretory volume of GLP-1 decreases, GLP-1 still keeps for the activity of beta cell, therefore has much research for GLP-1 recently. These researchs indicate GLP-1 except stimulating body glucose dependency ground excreting insulin, also has other hypoglycemic mechanism, this includes but not limited to: the secretion suppressing pancreas hyperglycemic hormone after the meal, reduce and absorb nutrition to the speed in blood, and help control body weight by reducing appetite. Result of study shows, the therapy improving GLP-1 secretory volume can be applicable to various symptom and imbalance, include but not limited to metabolism disorder, gastrointestinal disturbance, inflammation, mental illness, depression, and neuropsychiatric disease includes but not limited to diabetes (type and two types), metabolic syndrome, obesity, poor appetite/excessively prosperous, becomes thin, anxiety, irritability, myocardial ischemia/reperfusion injury, senile dementia, and the disease of other central nervous systems.
But, owing to GLP-1 can be degraded by proteolytic enzyme DPP-IV rapidly, the application of external source GLP-1 on clinical treatment is very limited. According to reported in literature, having several analogue being used for treating the GLP-1 of type-II diabetes to be in the development phase, they are all through the polypeptide of modification, have the longer transformation period and activity is similar than the GLP-1 of people self secretion. Taking BYETTA be wherein trade(brand)name sell medicine be in this kind new medicine first by FDA approval listing. But, these analogues need to be used by injection, and this certainly too late oral medicine that can increase GLP-1 secretion is more satisfactory. Truly having oral DPP-IV inhibitor on the market, it can reduce the degraded of GLP-1 thus improve GLP-1 level, such as is the sitagliptin that trade(brand)name renders to market taking JANUVIA. If but there is a medicine can act on L-cell and beta cell simultaneously, promotes the endogenous property secretion of GLP-1 and Regular Insulin, the treatment of type-II diabetes is had more benefits, more promising.
Present invention finds the agonist of a class GPR119, it is by improving the level of GIP, GLP-1 and Regular Insulin, thus improves body to a certain extent to the processing power of glucose. Moreover, research shows GPR119 agonist, such as, molecule in the present invention, can promote to non-glucose dependency the secretion of incretin. Polypeptide GIP and GLP-1 is incretin, in 20 years of the past, has a large amount of paper report GIP and GLP-1 to have diversified physiological action. Such as see Perry, T.etal., Curr.AlzheimerRes., 2005,377-385. After human body takes in nutritive substance, enteroendocrine cell K and L cell can secrete GIP and GLP-1 respectively. Although the mechanism of control GLP-1 secretion it be unclear that, the nerve conduction of the hormonal stimulation that perhaps rapid rise of GLP-1 level can participate in owing to GIP in the dining rear short period of time, and after for some time, perhaps the lasting rising of GLP-1 level is the direct activation of L-cell caused by the nutritive substance in distal small intestine and colon. GIP and GLP-1 is potent promotor, can strengthen the reaction that the blood sugar raised is made by health, it is to increase the secretion of Regular Insulin. But, at type-II diabetes, patient demonstrates with it, although the effect of GLP-1 insulin secretion accelerating still keeps, and the promoting insulin secretion decline of GIP. Puzzling is, the GIP that volume is injected by type-II diabetes patient still has good reaction, just lose susceptibility (Meieretal. to continuing a small amount of mode injected, Diabetes, 2004,53, S220-S224), so the exact cause of GIP activity decrease it be not immediately clear. Nearest research also shows, continues to use the derivative of fatty acid 14 days of a kind of long-acting GIP to ob/ob mouse, contributes to the homeostasis (IrwinN.etal.J.Med.Chem., 49,1047-1054) that it maintains glucose.
It thus is seen that GPR119 agonist has the value being applied in treatment diabetes and being associated in symptom, especially for type-II diabetes, fat, glucose intolerance, insulin resistant, Metabolic syndrome X, hyperlipidemia, blood lipidol of gallbladder is too much, and arteriosclerosis.
The present invention discloses the glucokinase activators of a class nitrile group-containing benzol sulfohydrazide structure, and these compounds can be used for preparing the medicine for the treatment of diabetes B.
Summary of the invention
It is an object of the present invention to provide the GPR119 agonist of a kind of excellent activity with general formula I.
It is a further object to provide the method that preparation has the compound of general formula I.
It is also another object of the present invention to provide the compound containing general formula I and treat the application in diabetes B as effective constituent.
Now content of the present invention is specifically described by object in conjunction with the present invention.
The compound that the present invention has general formula I has following structural formula:
The compound of preferred formula I has following structure,
Compound of Formula I of the present invention is synthesized by following route:
Compound I I and compound III, in generation addition reaction, generate compound IV; There is addition reaction in compound IV and compound V, generates I.
Compound of Formula I of the present invention has the agonism of GPR119, can be used as the medicine of effective constituent for the preparation of diabetes B. The activity of compound of Formula I of the present invention is verified by receptor binding assays.
The compound of Formula I of the present invention is effective in quite wide dosage range. The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times. The actual dosage taking compound of Formula I of the present invention can be determined according to relevant situation by doctor.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated. It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention. Those skilled in the art all should within the protection domain required by the application's claim according to the various changes that the teachings of the present invention is made.
The synthesis of embodiment 1 Compound I-1
A. the synthesis of compound IV-1
Compound I I-11.81g (10mmol) and compound III 4.80g (30mmol) is dissolved in the THF of 20mL drying, temperature rising reflux 3 hours, and TLC finds that reaction completes. Reaction mixture pours in 100mL frozen water, it may also be useful to the CH of 50mL �� 32Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying. Taking out and filter siccative, filtrate is steamed dry on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound IV-1, white solid, ESI-MS, m/z=342 ([M+H]+)��
B. the synthesis of Compound I-1
Compound IV-10.68g (2mmol) and compound V-10.40g (2mmol) is dissolved in the THF of 10mL drying, temperature rising reflux 3 hours, and TLC finds that reaction completes. Reaction mixture pours in 100mL frozen water, it may also be useful to the CH of 50mL �� 32Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying. Taking out and filter siccative, filtrate is steamed dry on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound I-1, white solid, ESI-MS, m/z=540 ([M+H]+)��
Embodiment 2-3
With reference to the method for embodiment 1, synthesize compound listed in Table.
The preparation of embodiment 4 reference compound D-1
For the useful effect of the compounds of this invention is described further, applicant describes applicant's research but not yet disclosed Compound D-1 and pharmacological datum.
A. the synthesis of compound IV-4
Compound I I-41.47g (10mmol) and compound III 4.80g (30mmol) is dissolved in the THF of 20mL drying, temperature rising reflux 3 hours, and TLC finds that reaction completes. Reaction mixture pours in 100mL frozen water, it may also be useful to the CH of 50mL �� 32Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying. Taking out and filter siccative, filtrate is steamed dry on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound IV-4, white solid, ESI-MS, m/z=308 ([M+H]+)��
B. the synthesis of Compound D-1
Compound IV-40.61g (2mmol) and compound V-40.34g (2mmol) is dissolved in the THF of 10mL drying, temperature rising reflux 3 hours, and TLC finds that reaction completes. Reaction mixture pours in 100mL frozen water, it may also be useful to the CH of 50mL �� 32Cl2Extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying. Taking out and filter siccative, filtrate is steamed dry on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound D-1, white solid, ESI-MS, m/z=480 ([M+H]+)��
The external exciting experiment to GPR119 of embodiment 5 compound
People-mouse chimera GPR119 the expression construct of amino acid whose for the C-terminal 137 of coding FLAG epitope tag, front 198 amino acid of people GPR119 and mouse receptor 3 copies are cloned into tsiklomitsin can in inducible vectors pcDNA5/FRT/TO (Invitrogen#V6520-20), and it comprises the marker of hygromycin resistance. By in the genome that this construct stable integration is extremely expressed specific host cell system Flp-In-T-Rex-HEK293 (Invitrogen) of tetracycline repressor, it is achieved the expression of receptor of precise hard_drawn tuhes. Once produce the clone of stable hygromycin resistance, cell being maintained at 37 DEG C and adds wet 5%CO2In atmosphere and substratum. This substratum is improved Eagle's medium (Dulbecco ' smodifiedEagle ' smedium) (DMEM, Invitrogen) by the Da Erbaike being supplemented with 2mML-glutamine, 10% foetal calf serum, 200 �� g/ml hygromycin B and 15 �� g/ml rice pest element (blasticidin) and is formed.
Measure before 48 hours carrying out cAMP accumulation, by the cell of chimeric for stably express people/mouse GPR119 construct with 4 �� 103The density of cells/well is seeded in the white plate of solid (No. 35-6661st, BD) of 384 hole poly-D-Lys coatings, and makes it add wet 5%CO in 37 DEG C2Atmosphere grows to bring out expression of receptor with being supplemented with in the substratum of 1 �� g/ml tsiklomitsin. Measuring the same day, remove substratum and adding wet 5%CO in 37 DEG C2Atmosphere and 20 �� l/ holes measure damping fluid and (have Ca2+And Mg2+Phosphate buffered salt solution, 12mM glucose, 0.1mM isobutyl-methyl-xanthine, 0.1% not fatty acids bovine serum albumin) in by cell incubation 50min, this mensuration damping fluid has expects that the compound added from the Concentrated stocks being dissolved in methyl-sulphoxide (DMSO) of concentration to obtain the final concentration of 1%DMSO in mensuration. Using CisBio homogeneous phase time discrimination fluorescence (HTRF) to measure test kit, the code following manufacturers measures cAMP accumulation. In brief, in each hole, add 10 �� lcAMP-HTRF luciferase assay reagents separately, and by sample in incubated at room 40min. Envision instrument (PerkinElmer) is used to measure at 320nm fluorescence excitation and at 665nm and 620nm. Calculate 665/620 fluorescence ratio and by the nanomolar concentration of the cAMP that is translated in each hole from cAMP typical curve interpolation. Excel/XLfit software (Microsoft and IDBS) is adopted to utilize four parameter logarithmic curve-fitting Equation for Calculating concentration-response curve and EC50��
Test result sees the following form.
| Compound | EC50(nM) |
| Reference compound D-1 | 20.9 |
| Compound I-1 | 9.4 |
| Compound I-2 | 10.2 |
| Compound I-3 | 10.7 |
From upper table result it may be seen that the compound of the present invention is good GPR119 agonist.
Claims (3)
1. the compound with general formula I,
2. the compound of Formula I that claim 1 defines, is selected from:
3. the application of the compound of Formula I that one of claim 1-2 defines in preparation treatment diabetes B medicine.
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Denomination of invention: Nitrile benzenesulfonylhydrazine type GPR119 agonist, preparation method and application thereof Effective date of registration: 20170816 Granted publication date: 20160601 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
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