CN102250098A

CN102250098A - Pyrazinones compound

Info

Publication number: CN102250098A
Application number: CN2010101788324A
Authority: CN
Inventors: 殷建明; 朱惠霖
Original assignee: SUZHOU BORUI PARMACEUTICALS Inc
Current assignee: SUZHOU BORUI PARMACEUTICALS Inc
Priority date: 2010-05-21
Filing date: 2010-05-21
Publication date: 2011-11-23

Abstract

The invention relates to a pyrazinones compound which can be used as a dipeptidyl peptidase-4 (DDP-4) inhibitor. The pyrazinones compound has high activity and selectivity to the dipeptidyl peptidase-4. The compound provided by the invention can raise the level of endogenous incretin through inhibiting the DDP-4 and prolonging a half-life period of GLP-1 (Glucagonlike Peptide-1) and can completely perform the beneficial effects on adjusting the blood sugar so that the corresponding pharmacological effects are achieved. The pyrazinones compound or a pharmacological composition comprising the compound can be used for preventing or treating diabetes mellitus, especially II type diabetes mellitus, hyperglycemia, syndrome X, hyperinsulinemia, adiposity, atherosclerosis and various immunomodulatary diseases.

Description

The pyrazinones compound

Technical field

The present invention relates to pyrazinones compound and their medicinal application.

Background technology

Diabetes (diabetes mellitus) be by multiple environmental factors and inherited genetic factors interact and cause a kind of be the endocrine system disease of principal feature with the blood sugar metabolism disorder.Type ii diabetes is because histiocytic insulin resistant (is exactly that cell is no longer with the Regular Insulin combination, make and enter the glucose minimizing that cell interior participates in generating heat, the glucose of staying in the blood increases), β cell function decline or other multiple reason cause, be the coefficient result of h and E factor, account for more than 90% of diabetes total number of persons.。Type ii diabetes be more common in build overweight or fat in, the elderly, tangible familial inheritance is arranged.

Incretin (incretins) is the enteron aisle hormone, it mainly comprises glucose dependency insulin secretion accelerating polypeptide (glucose-dependent insulinotropic polypeptide or gastricinhibitory peptide, GIP) and glucagon-like-peptide-1 (glucagon-like peptide-1, GLP-1).Plasma insulin after incretin can be ingested by many approach and mechanism increase, this effect is called the incretin effect.GIP is mainly by the K emiocytosis that is present in the near-end enteron aisle, and GLP-1 is mainly by the L emiocytosis of distal gut.GIP can promote β grape cell sugar dependency ground uelralante, and promptly this kind promotes that Regular Insulin discharges, and to act on glucose level very obvious when raising, when glucose level is recovered just often then to disappear.GLP-1 not only can promote β grape cell sugar dependency ground uelralante, also can rely on mode suppression α emiocytosis glicentin by glucose, produces thereby suppress liver glucose.GLP-1 plays a role by the acceptor that belongs to g protein coupled receptor family.GLP-1 acceptor (GLP-1R) is at pancreas islet, kidney, heart, stomach, lung and reach central nervous system zone etc. on every side expression is all arranged, and rises by GLP-1R irritation cell inner gateway to promote or restraining effect.GLP-1 has multiple effect to many tissues and pancreatic endocrine, and it mainly acts on is the insulin secretion that strengthens the glucose mediation.

(Type 2 diabetes mellitus, T2DM) patient's GIP and GLP-1 activity and level have unusual performance to type ii diabetes.In T2DM patient, the incretin effect obviously reduces or even forfeiture.Thereby this variation prompting body of incretin effect causes glucose level to raise to the insulin response decline of the carbohydrate of absorption.Can (dipeptidyl peptidase-4 DPP-4) decomposes fast and loses its biological effect by dipeptidyl peptidase-4 after GIP and GLP-1 secrete in vivo.GIP and GLP-1 are about 2 to 7 minutes plasma half-life in vivo.GLP-1 has stronger promoting insulin secretion than GIP, have simultaneously suppress after the meal glucagon secretion, delay stomach emptying, the not available physiological action of GIP such as suppress to ingest.Other studies show that, type ii diabetes patient GIP level and healthy physiognomy after the meal works as, but the level of GLP-1 significantly is lower than healthy people, shows that these patients exist GLP-1 to lack.Research at present generally believes that the hypoglycemic mechanism of GLP-1 relates to the synthetic and secretion, the glucagon suppression that promote Regular Insulin to discharge, increase Regular Insulin and discharges and influence several aspects such as islet cells apoptosis, propagation and regeneration.Except that acting on pancreas islet, the GLP-1 acceptor also is distributed in the necleus of hypothalamus,paraventricular in close relations with appetite stimulator, hypophysis etc. and locates.Thereby, in case acceptor be activated, but depress appetite, the stomach emptying that slows down increases patient's the satiety and the food absorption that slows down, and then loses weight and reduce postprandial blood sugar.

Dipeptidyl peptidase-4 (DPP-4) is a kind of cell surface protein that relates to the various biological function, has important effect in vivo in the glucose metabolism.The enzymic activity of DPP-4 can be suppressed the efficient inhibition of agent institute, thereby the quick degraded of blocking-up GLP-1 and GIP, prolonged the plasma half-life of complete structure-preserved time of peptide quasi-molecule of GLP-1 and GIP and endogenous GLP-1 and GIP, and then the level of the endogenous incretin that raise, give full play to its beneficial effect in blood glucose regulation.Different is with sulfonylurea drugs, and the DPP-4 inhibitor can not only promote β cell uelralante, and can increase the synthetic of Regular Insulin in the β cell, also has the effect of the pancreas hyperglycemic-glycogenolytic factor (glucagons) of inhibition excretory.When blood sugar during near normal level, the burst size of Regular Insulin and the inhibition of hyperglycemic-glycogenolytic factor will reduce, thereby prevent to discharge or hyperglycemic-glycogenolytic factor suppresses the hypoglycemia (hypoglycemia) that excessively produces because of Regular Insulin.In a word, the DPP-4 inhibitor has the effect of protection cell function in lowering blood glucose, and can not cause side effects such as hypoglycemia and weight increase.

The DPP-4 inhibitor is compared own its original advantage with the traditions of the past antidiabetic drug, it can obtain the effect of lowering blood glucose by double mechanism, and it can also promote the more Regular Insulin of pancreatic secretion when having suppressed liver starch generation glucose total amount.On this point, the DPP-4 inhibitor still is positioned the treatment of type ii diabetes, because this type of diabetics's greatest problem is exactly to secrete enough pancreas islet interior blood sugar of decomposer usually.

Summary of the invention

Technical problem to be solved by this invention provides a kind of pyrazinones compound, and it is dipeptidyl peptidase-4 inhibitor of optionally target dipeptidyl peptidase-4.

For solving above technical problem, the present invention takes following technical scheme:

Compound with logical formula I:

In the formula I:

R ₀₁, R ₀₂, R ₀₃, R ₀₄, R ₀₅, R ₀₆, R ₀₇, R ₀₈, R ₀₉, R ₁₀, R ₁₁, R ₁₂, R ₁₃, be hydrogen or deuterium independently;

R _NFor being selected from a kind of in the following groups:

OH、CH ₂Ra、OCH ₂Ra、CORc、CHRdRi、(CH ₂)nRj、

And

Wherein:

Ra represents H; C1～C5 alkyl; C1～C8 alkyl that one or more fluorine atoms replace; Phenyl, it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for not replacing; Perhaps pyridyl, it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for replacing;

Rc represents H, CH ₂Ra, OCH ₂Ra, C2～C12 secondary amine, CHRd (NHRe), NReCHRd (COORg), 2-furyl, 1-connection hexahydropyridine base or 1-morpholinyl;

Rd is H or C1～C6 alkyl;

Re is H, CH ₂Rf, C1～C7 carbonyl or C1～C7 ester group;

Rg represents H or CH ₂Rf;

Rf represents C1～C5 alkyl; C1～C8 alkyl that one or more fluorine atoms replace; Phenyl, it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for not replacing; Perhaps Rf represents pyridyl, and it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for not replacing;

Ri represents NReCHRd (COORg), OCOCHRd (NHRe) or OCOORg;

Rj represents 2-furyl, 1-connection hexahydropyridine base or 1-morpholinyl;

N is the integer between 1～6, and Y represents C1～C6 alkyl.

According to the present invention, n is preferably 2 or 3.

According to the present invention, representational compound has the compound of formula II, formula III, formula IV, formula (V), formula VI, formula (VII) and formula (VIII) expression.

According to the present invention, described pharmacologically acceptable salt includes but not limited to hydrochloride, phosphoric acid salt, vitriol, acetate, maleate, benzene sulfonate, toluenesulfonate, fumarate, tartrate etc.

Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:

The pyrazinones compound that the present invention relates to has high activity and selectivity for dipeptidyl peptidase-4, by suppressing DPP-4, prolong the transformation period of endogenous GLP-1, and then the level of the endogenous incretin that raise, give full play to its beneficial effect in blood glucose regulation, thereby reach corresponding pharmacological action.Pyrazinones compound that the present invention relates to or the pharmaceutical composition that comprises this compounds can be used for prevention or treatment diabetes (especially type ii diabetes), hyperglycemia, X syndrome (capillary blood vessel stenocardia), hyperinsulinemia, obesity, atherosclerosis and various immunomodulatory disease.

Embodiment

The present invention will be further described in detail below in conjunction with specific embodiment, but the present invention is not limited to following examples.

Embodiment 1

The compound that present embodiment provides a kind of formula II to represent:

Embodiment 2

The compound that present embodiment provides a kind of formula III to represent

Embodiment 3

The compound that present embodiment provides a kind of formula IV to represent:

Embodiment 4

Present embodiment provides the compound of a kind of formula (V) expression:

Embodiment 5

The compound that present embodiment provides a kind of formula VI to represent:

Embodiment 6

Present embodiment provides the compound of a kind of formula (VII) expression:

Embodiment 7

Present embodiment provides the compound of a kind of formula (VIII) expression:

Claims

1. the compound and the pharmacologically acceptable salt thereof that have logical formula I:

In the formula I:

R ₀₁, R ₀₂, R ₀₃, R ₀₄, R ₀₅, R ₀₆, R ₀₇, R ₀₈, R ₀₉, R ₁₀, R ₁₁, R ₁₂, R ₁₃Be hydrogen or deuterium independently;

R _NFor being selected from a kind of in the following groups:

OH、CH ₂Ra、OCH ₂Ra、CORc、CHRdRi、(CH ₂)nRj、

And

Wherein:

Rd is H or C1～C6 alkyl;

Re is H, CH ₂Rf, C1～C7 carbonyl or C1～C7 ester group;

Rg represents H or CH ₂Rf;

Ri represents NReCHRd (COORg), OCOCHRd (NHRe) or OCOORg;

Rj represents 2-furyl, 1-connection hexahydropyridine base or 1-morpholinyl;

N is the integer between 1～6, and Y represents C1～C6 alkyl.

2. compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: described n is 2 or 3.

3. compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: described compound is a kind of in the compound of formula II, formula III, formula IV, formula (V), formula VI, formula (VII) and formula (VIII) expression.

4. but described compound of claim 1 and drug salts thereof are as the purposes of dipeptidyl peptidase-4 inhibitor.

5. described compound of claim 1 and pharmacologically acceptable salt thereof the purposes in preparation diabetes, hyperglycemia, X syndrome, hyperinsulinemia, obesity or atherosclerotic prophylactic agent or medicine.