CN115087643B - Condensed heterocyclic compound, preparation method and medical application thereof - Google Patents

Condensed heterocyclic compound, preparation method and medical application thereof Download PDF

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CN115087643B
CN115087643B CN202280002344.9A CN202280002344A CN115087643B CN 115087643 B CN115087643 B CN 115087643B CN 202280002344 A CN202280002344 A CN 202280002344A CN 115087643 B CN115087643 B CN 115087643B
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殷惠军
闫旭
史记周
刘国标
李斌
费腾
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Abstract

Relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in treating type II diabetes, pre-diabetes, obesity, non-alcoholic fatty liver, non-alcoholic steatohepatitis, cardiovascular diseases and the like. Wherein each substituent in the general formula (I) is defined as the specification.

Description

Condensed heterocyclic compound, preparation method and medical application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a condensed heterocyclic compound, a preparation method thereof, a pharmaceutical composition containing the same and application of the condensed heterocyclic compound in treating type II diabetes, pre-diabetes, obesity, non-alcoholic fatty liver, non-alcoholic steatohepatitis and cardiovascular diseases.
Background
The prevalence of diabetes increases rapidly worldwide and is associated with a number of health risks. Diabetes is caused by defective insulin production or insulin resistance, or both, resulting in elevated blood glucose levels. Diabetes mellitus can be divided into two main types, type I and type II. Type I diabetes (T1D) is caused by destruction of pancreatic cells by the human immune system. Since pancreatic cells are the only cells in the human body that produce insulin that regulates blood glucose, type I diabetics can only improve blood glucose by exogenous insulin. Type II diabetes mellitus (T2 DM) generally fails to maintain normal blood glucose levels due to insulin resistance or insufficient insulin secretion.
Currently, there are a variety of drugs used to treat T2DM. These drugs can be divided into six main classes, each of which acts through a different mechanism of action (Hampp et al Use of Antidiabetic Drugs in the u.s.,2003-2012,Diabetes Care 37:1367-1374, 2014). Insulin secretion agonists, including sulfonylureas (e.g., glipizide, glimepiride, glibenclamide), glinides (e.g., repaglinide, nateglinide), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin phosphate, saxagliptin, linagliptin, and vildagliptin), and glucagon-like peptide-1 receptor (GLP-1R) agonists (e.g., liraglutide, aprlutide, ai Saina peptide, lixiletide, du Latang peptide, cord Ma Lutai), which enhance insulin secretion by acting on pancreatic islet beta cells. However, sulfonylurea drugs and glinide drugs have limited therapeutic effects and tolerance, are prone to weight gain and often cause hypoglycemia. DPP-IV inhibitors have limited therapeutic efficacy. GLP-1R agonists are mostly subcutaneous polypeptides. Biguanides (e.g. metformin) are thought to act primarily by reducing hepatic glucose production, but biguanides often cause gastrointestinal disturbances and lactic acidosis, limiting their use. Glycosidase inhibitors (e.g., acarbose) reduce intestinal glucose absorption, but these formulations also often cause gastrointestinal disorders. Thiazolidinediones (e.g. pioglitazone, rosiglitazone) act on specific receptors (gamma type receptors for peroxisome proliferator-activated factor activators) in liver, muscle and adipose tissue, they modulate lipid metabolism, and subsequently enhance the response of these tissues to insulin action, and frequent use of these drugs may lead to weight gain and may cause oedema and anaemia. Insulin is used in more severe cases, alone or in combination with the above drugs, but frequent use may also lead to weight gain and risk of hypoglycemia. Sodium-glucose co-transporter 2 (SGLT 2) inhibitors (e.g., dapagliflozin, engagliflozin, canagliflozin, elagliflozin) inhibit the reabsorption of glucose by the tubules, thereby reducing glucose levels in the blood, but such drugs may be associated with ketoacidosis and urinary tract infections.
Diabetes patients often suffer from insulin resistance, increased hepatic glucose production, impaired islet cell function, and oxidative stress. These drugs all exert hypoglycemic activity from a relatively single mechanism, and researchers have also demanded to develop compounds that improve homeostasis in the blood glucose from multiple perspectives in order to select better compounds for the treatment of diabetes and related diseases.
Increased liver glucose production is the leading cause of elevated fasting blood glucose in diabetics (A R Saltiel et al, cell 104:517-529, 2001). Liver gluconeogenesis is regulated by a variety of enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6 Pase), and metformin can activate adenylate-activated protein kinase (AMPK) to inhibit transcription of these genes (Max C Petersen et al, nat Rev Endocrinol, 2017; he, L et al, cell 137:635-646, 2009). In addition, several studies suggest that gluconeogenesis is associated with mitochondrial electron respiratory chain complex I, and that inhibition of mitochondrial complex I activity alters the energy charge of adenine nucleotides, increasing the AMP/ATP ratio, which in turn activates AMPK, inhibits the activity of fructose-1, 6-bisphosphatase, which is also a key gluconeogenic enzyme, affecting gluconeogenesis (El-Mir, M.Y. et al, J.biol. Chem.275:223-228, 2000). However, one study showed that AMPK activation was not dependent on a change in AMP/ATP ratio. Recent studies have shown that metformin inhibits a metabolic shuttle involved in balancing cytoplasmic and mitochondrial redox states, can non-competitively inhibit granoglycepin-3-phosphate dehydrogenase (mGP), and reduces gluconeogenesis of lactic acid and glycerol (Madiraju, A.K. et al, nature 510:542-546, 2014).
Insulin is secreted by islet beta cells, and is circulated to target organs through blood, and the expression and translocation of glucose transporter proteins to cell membranes are regulated on target tissue cells, so that the utilization of glucose by an organism is improved, and the blood sugar is reduced. Insulin activates two major signaling pathways within the cell: mitogen Activated Protein Kinase (MAPK) and 3-phosphoinositide kinase (PI 3K) pathways (Ho, C.K. et al Molecular Genetics and Metabolism 3:288-292, 2016; copps, K.D. et al diabetes 10:2565-2582, 2012). After insulin binds to its receptor, insulin Receptor Substrates (IRSs), SHC-transforming proteins (SHC proteins) and scaffold proteins with PH and SH2 domains (APS proteins) are recruited, which creates a suitable binding site for IRS-1, which is then activated by differential insulin-induced kinase phosphorylation (Kiselyov, et al Molecular Systems Biology 5:243, 2009). Activated IRS-1 binds and activates PI3K, which phosphorylates phosphatidylinositol diphosphate (PIP 2) to produce PIP3, which activates pyruvate dehydrogenase kinase 1 (PDK 1) and PDK2 as second messengers in cells, and then recruits protein kinase B (Akt) to the cell membrane, phosphorylating Akt and activating its protein kinase activity. Akt phosphorylates a number of downstream signaling molecules, including phosphorylating Glycogen Synthase Kinase (GSK) -3 beta, and causes transfer of glucose transporter-2 (GLUT-2) and GLUT-4 from the cytoplasm to the plasma membrane, promoting cellular glucose uptake, inhibiting glycogen synthesis, and thus achieving a reduction in blood glucose (Okada T et al, J Biol Chem 269:3568-3573, 1994).
Insulin resistance is a metabolic state of reduced sensitivity and responsiveness of peripheral tissues or target organs to insulin, is a central link in type II diabetes, and inhibits glucose from entering insulin-dependent cells such as adipocytes, skeletal muscle cells, and cardiac muscle cells, etc. Phosphorylation of serine sites on IRS-1 may be a key cause of insulin receptor/IRS-1 and/or IRS-1/PI3K separation, inhibiting PI3K activation or increased IRS-1 degradation, leading to the development of insulin resistance (MorinoK et al, diabetes 55, 2006).
Free radicals are constantly produced during normal metabolic processes and play an important role in cell signaling. However, when the cell function is overloaded, oxidative stress occurs, which is closely related to insulin resistance. Oxidative stress can induce insulin resistance by compromising insulin signaling, causing deregulation of adipokines. Such as Reactive Oxygen Species (ROS), activate the IKKKβ/NF-. Kappa.B and c-Jun amino terminal kinase (JNK) signaling pathways, phosphorylate IRS proteins, leading to degradation of IRS (Kiritoshi S et al, diabetes 52:2570-2577, 2003). Too much ROS can also inhibit membrane translocation of GLUT-4 and impair insulin signaling.
Mitochondria are the major metabolic organelles in insulin-dependent tissues and play an important role in insulin signal transduction. Mitochondria are involved in many physiological processes including energy metabolism, calcium homeostasis, and programmed cell death. Mitochondrial dysfunction is common in diabetes and compromises the response of insulin dependent cells (adipocytes, cardiomyocytes and myocytes) to insulin. Mitochondrial capacity is considered a criterion for insulin sensitivity, hyperglycemia induces intracellular glucose oxidation to produce reduced Nicotinamide Adenine Dinucleotide (NADH) and pyruvate, and increases pyruvate flow into mitochondria, and under high glucose conditions ROS are produced at the interface of mitochondrial respiratory chain complex I and ubiquinone with complex III if the potential difference is too great (Dugan LL et al, J Clin Invest 123:4888-4899, 2013). Mitochondrial dysfunction also affects pancreatic cell function, reduces insulin production and release, and in response to excessive glucose exposure or nutritional stress, mitochondrial superoxide, oxidative phosphorylation and mitochondrial ATP production are reduced, a series of evidence suggests that activation of AMPK, sirtuin 1/3 (SIRT 1/3) and peroxisome proliferator-activated receptor gamma-assisted activator 1 (PGC-1α) can increase mitochondrial oxidative phosphorylation capacity, restore mitochondrial superoxide production, these favoring pancreatic beta-cell insulin secretion, and restore skeletal muscle and liver insulin sensitivity (Shalma K et al, diabetes 64:663-672, 2015). Thus, maintaining normal mitochondrial function is also an important aspect of treating diabetes.
In view of the role of biguanides in the field of diabetes, and the ubiquitous hypersonic production of liver sugar, inadequate insulin secretion and insulin resistance in diabetics. Imegelimin developed by Poxel is already in phase III clinical studies and can act on liver, pancreas islet and muscle simultaneously to improve the blood glucose homeostasis of patients. There is also a need for developing more molecules that enable patients to benefit from a variety of aspects to select better compounds for supplementing existing oral hypoglycemic agents against insulin resistance and/or insulin hyposecretion.
Disclosure of Invention
Through intensive research, the inventor designs and synthesizes a series of condensed heterocyclic compounds, and performs relevant characterization on the condensed heterocyclic compounds. The compounds can be used for treating type II diabetes, pre-diabetes, obesity, non-alcoholic fatty liver, non-alcoholic steatohepatitis, cardiovascular diseases, etc.
The present invention is therefore directed to a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
X 1 and X 2 Each independently selected from the group consisting of carbon atoms and nitrogen atoms;
ring a is selected from saturated or partially saturated heterocyclyl;
R 1 And R is 2 Each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR a 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、NR a R b 、-NHC(O)R a 、-S(O) n R a 、-S(O) n NR a R b and-NHS (O) n R a Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or alternatively
R 1 And R is 2 Together with the carbon atom to which it is attached, form a cycloalkyl or heterocyclyl group, which cycloalkyl or heterocyclyl group is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
R 3 selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR a 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、NR a R b 、-NHC(O)R a 、-S(O) n R a 、-S(O) n NR a R b and-NHS (O) n R a Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
R 4 selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR a 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、NR a R b 、-NHC(O)R a 、-S(O) n R a 、-S(O) n NR a R b and-NHS (O) n R a Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
R 5 each independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, cyano, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each independently is optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R a And R is b Each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroarylWherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,
R a and R is b Together with the nitrogen atom to which it is attached, form a heterocyclic group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
m is an integer from 0 to 4;
n is 0, 1 or 2.
According to one embodiment of the present invention, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the invention, wherein X 1 Is N.
According to another embodiment of the present invention, the compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the invention, wherein X 2 Is N.
In a preferred embodiment of the present invention, the compound of formula (I) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein the ring A, R 1 ～R 5 M is defined as in formula (I).
According to one embodiment of the present invention, the compound of formula (I) or formula (II) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, 5-to 6-membered heterocyclyl, C 6 -C 10 Aryl, 5-to 10-membered heteroaryl, -OR a 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NR a R b 、-NHC(O)R a 、-S(O) n R a 、-S(O) n NR a R b and-NHS (O) n R a Wherein said C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, 5-to 6-membered heterocyclyl, C 6 -C 10 Aryl and 5 to 10 membered heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably R 4 is-NR a R b ；
R a 、R b And n is as defined in formula (I).
In another preferred embodiment of the present invention, the compound of formula (I) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein,,
R a and R is b Each independently selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 5-to 6-membered heterocyclyl, C 6 -C 10 Aryl and 5 to 10 membered heteroaryl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 5-to 6-membered heterocyclyl, C 6 -C 10 Aryl and 5 to 10 membered heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,
R a and R is b Together with the nitrogen atom to which it is attached, form a 4-to 7-membered heterocyclic group, preferably a 5-to 6-membered heterocyclic group, said heterocyclic group being optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;
ring A, R 1 ～R 3 、R 5 M is defined as the general formula (I).
According to one embodiment of the present invention, the compounds of formula (I), formula (II) or formula (III) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein a is a saturated or partially saturated monocyclic heterocyclyl, preferably a 5 to 7 membered monocyclic heterocyclyl, more preferably a 5 to 6 membered monocyclic heterocyclyl.
In another preferred embodiment of the present invention, the compound of formula (I) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein,,
t is 0, 1 or 2; preferably t is 0 or 1;
R a and R is b Each independently selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 5-to 6-membered heterocyclyl, C 6 -C 10 Aryl and 5 to 10 membered heteroaryl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 5-to 6-membered heterocyclyl, C 6 -C 10 Aryl and 5 to 10 membered heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,
R a and R is b Together with the nitrogen atom to which it is attached, form a 4-to 7-membered heterocyclic group, preferably a 5-to 6-membered heterocyclic group, said heterocyclic group being optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;
R 1 、R 2 、R 3 、R 5 M is defined as the general formula (I).
According to one embodiment of the invention, the invention isA compound of the general formula (I), the general formula (II), the general formula (III) or the general formula (IV) or a tautomer, a meso, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R a And R is b Each independently selected from hydrogen and C 1 -C 6 An alkyl group.
According to one embodiment of the present invention, the compounds of formula (I), formula (II), formula (III) or formula (IV) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Each independently selected from hydrogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 5-to 6-membered heterocyclyl, C 6 -C 10 Aryl and 5 to 10 membered heteroaryl; wherein said C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 5-to 6-membered heterocyclyl, C 6 -C 10 Aryl and 5 to 10 membered heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R 1 And R is 2 Each independently selected from hydrogen and C 1 -C 6 An alkyl group.
According to one embodiment of the present invention, the compounds of formula (I), formula (II), formula (III) or formula (IV) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Together with the carbon atoms to which they are attached form C 3 -C 6 Cycloalkyl or 5-to 6-membered heterocyclyl, said C 3 -C 6 Cycloalkyl or 5-to 6-membered heterocyclyl is optionally further substituted with one or more substituents selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, arylOne or more groups of heteroaryl groups.
According to one embodiment of the present invention, the compounds of formula (I), formula (II), formula (III) or formula (IV) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl; wherein said C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 5-to 6-membered heterocyclyl, C 6 -C 10 Aryl and 5 to 10 membered heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R 3 Selected from hydrogen and C 1 -C 6 An alkyl group.
According to one embodiment of the present invention, the compounds of formula (I), formula (II), formula (III) or formula (IV) according to the present invention or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from hydrogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl; wherein said C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 5-to 6-membered heterocyclyl, C 6 -C 10 Aryl and 5 to 10 membered heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
m is 0, 1 or 2.
Typical compounds of the invention include, but are not limited to:
The present invention further provides a process for preparing a compound of formula (III) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
step 1: reacting compounds Ia and Ib in a solvent to give compound Ic, wherein the solvent is preferably dichloromethane;
step 2: the compound Ic and Id hydrochloride react in a solvent at high temperature to obtain a compound Ie; wherein the solvent is preferably isobutanol, and the temperature is preferably 100-120 ℃;
step 3: reacting compound Ie with a ketone, aldehyde or acetal, ketal in the presence of an acidic or basic catalyst to give a compound of formula (III), wherein an acidic catalyst is preferred, and p-toluene sulphonic acid is more preferred; the ketone, aldehyde or acetal, ketal is preferably an alkyl ketone, alkyl aldehyde or acetal, alkyl ketal, more preferably acetaldehyde or acetal;
wherein the ring A, R 1 ～R 3 、R 5 、m、R a 、R b As defined by formula (III).
The present invention further provides a process for preparing a compound of formula (IV) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
Step 1: reacting compounds Ia and IVb in a solvent to obtain compound IVc, wherein the solvent is preferably dichloromethane;
step 2: carrying out high-temperature reaction on the compound IVc and Id hydrochloride in a solvent to obtain a compound IVe; wherein the solvent is preferably isobutanol, and the temperature is preferably 100-120 ℃;
step 3: reacting compound IVe with a ketone, aldehyde or acetal, ketal in the presence of an acidic or basic catalyst to give a compound of formula (IV), wherein an acidic catalyst is preferred, and p-toluene sulphonic acid is more preferred; the ketone, aldehyde or acetal, ketal is preferably an alkyl ketone, alkyl aldehyde or acetal, alkyl ketal, more preferably acetaldehyde or acetal;
wherein R is 1 ～R 3 、R 5 、t、m、R a 、R b As defined by formula (IV).
The invention further provides a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III) or formula (IV) according to the invention or an isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention further provides the use of a compound of formula (I), formula (II), formula (III) or formula (IV) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a medicament for the treatment of a pathological condition associated with insulin resistance syndrome.
The invention further provides the use of a compound of formula (I), formula (II), formula (III) or formula (IV) according to the invention, or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a medicament for the treatment of diabetes, such as type I or type II diabetes, preferably type II diabetes.
The invention further provides the use of a compound of formula (I), formula (II), formula (III) or formula (IV) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a medicament for the treatment of a pathological condition caused by hyperglycosylation.
The invention further provides the use of a compound of formula (I), formula (II), formula (III) or formula (IV) according to the invention, or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a medicament for the treatment of a pathological condition selected from the group consisting of renal complications, atherosclerosis, cardiovascular diseases, alzheimer's disease, neurodegenerative diseases and aging.
The invention further provides the use of a compound of formula (I), formula (II), formula (III) or formula (IV) according to the invention, or a meso-, racemate-, enantiomer-, diastereomer-, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the manufacture of a medicament for the treatment of a pathological condition selected from dyslipidemia, non-alcoholic fatty liver, non-alcoholic steatohepatitis, obesity, hypertension, retinopathy and neuropathy.
The invention further provides a compound of formula (I), formula (II), formula (III) or formula (IV) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use as a medicament. The medicament may be used for the treatment of pathological conditions associated with insulin resistance syndrome, diabetes such as type I or type II diabetes, pathological conditions due to hyperglycosylation, pathological conditions selected from renal complications, atherosclerosis, cardiovascular disease, alzheimer's disease, neurodegenerative diseases and aging, or pathological conditions selected from dyslipidemia, non-alcoholic fatty liver, non-alcoholic steatohepatitis, obesity, hypertension, retinopathy and neuropathy.
The present invention further provides a method for treating a disease or pathological condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) or formula (IV) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. The disease or pathological condition may be a pathological condition associated with insulin resistance syndrome, diabetes, such as type I or type II diabetes, a pathological condition resulting from hyperglycosylation, a pathological condition selected from the group consisting of renal complications, atherosclerosis, cardiovascular disease, alzheimer's disease, neurodegenerative diseases and aging, or a pathological condition selected from the group consisting of dyslipidemia, non-alcoholic fatty liver, non-alcoholic steatohepatitis, obesity, hypertension, retinopathy and neuropathy.
The compounds of the general formula (I), general formula (II), general formula (III) or general formula (IV) of the present invention may form pharmaceutically acceptable acid addition salts with acids according to conventional methods in the art to which the present invention pertains. The acid includes inorganic acids and organic acids, and hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid and the like are particularly preferable.
The compounds of the general formula (I), general formula (II), general formula (III) or general formula (IV) of the present invention may form pharmaceutically acceptable base addition salts with bases according to methods conventional in the art to which the present invention pertains. The base includes inorganic bases and organic bases, acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like, and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
In addition, the present invention also includes prodrugs of the compounds of the present invention represented by general formula (I), general formula (II), general formula (III) or general formula (IV). The prodrugs of the present invention are derivatives of the compounds of formula (I), formula (II), formula (III) or formula (IV), which may themselves have a relatively weak or even no activity, but are converted to the corresponding biologically active form after administration under physiological conditions, e.g. by metabolism, solvolysis or otherwise.
Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water-soluble taste masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethylcellulose, cellulose acetate butyrate may be used.
Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier, for example polyethylene glycol or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and acacia; the dispersing or wetting agent may be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid, such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecaethyleneoxycetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or Jin Zhengbing esters of nipagin, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
Dispersible powders and granules suitable for use in the preparation of an aqueous suspension by the addition of water provide the active ingredient in combination with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are as described above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding it to a mixture of water and glycerol. The injection or microemulsion may be injected into the patient's blood stream by local bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend stock oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
It is well known to those skilled in the art that the amount of drug administered depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of the drugs, etc. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
The invention can contain the compound shown in the general formula (I), the general formula (II), the general formula (III) or the general formula (IV) and pharmaceutically acceptable salts, hydrates or solvates thereof as active ingredients, and can be mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and be prepared into clinically acceptable dosage forms. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not exert other adverse effects such as allergic reactions and the like. The compounds of the present invention may be used as the sole active ingredient, and may also be used in combination with other drugs for the treatment of diabetes-related disorders. Combination therapy is achieved by simultaneous, separate or sequential administration of the individual therapeutic components.
Detailed description of the invention
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer of O to 2), but does not include-O-; a ring moiety of O-S-or-S-S-, the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably from 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and,Pyranyl and the like, preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having a single ring of 5 to 20 members sharing one atom (referred to as the spiro atom) between them, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered.
The term "fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon.
The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to-NH 2 。
The term "cyano" refers to-CN.
The term "nitro" refers to-NO 2 。
The term "oxo" refers to = O.
The term "carboxy" refers to-C (O) OH.
The term "mercapto" refers to-SH.
The term "ester group" refers to a-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
The term "acyl" refers to compounds containing a-C (O) R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "sulfonic acid group" means-S (O) 2 OH。
The term "sulfonate esterThe radical "means-S (O) 2 O (alkyl) or-S (O) 2 O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
The term "sulfonyl" refers to-S (O) 2 A compound of R groups, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "aminoacyl" refers to-C (O) -NRR ', wherein R, R' are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "sulfamoyl" or "sulfamido" refers to-S (O) 2 -NRR ', wherein R, R' are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
Synthesis method of compound of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme.
The compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof of the present invention can be prepared by the following scheme 1:
scheme 1
Step 1: reacting compounds Ia and Ib in a suitable solvent and temperature to give compound Ic; the solvent used in the reaction may be methylene chloride, tetrahydrofuran, preferably methylene chloride;
step 2: reflux reaction of the hydrochloride of the compound Ic and Id in a solvent to obtain a compound Ie; the solvent used in the reaction may be isobutanol, 1, 4-dioxane, preferably isobutanol;
step 3: reacting a compound Ie with ketone, aldehyde or acetal or ketal in the presence of an acidic or basic catalyst to obtain a compound shown in a general formula (III), wherein the acidic catalyst used in the reaction can be p-toluenesulfonic acid or hydrochloric acid, and preferably p-toluenesulfonic acid; the alkaline catalyst can be sodium hydroxide and potassium hydroxide; among them, an acidic catalyst is preferable, and p-toluenesulfonic acid is more preferable;
Wherein the ring A, R 1 ～R 3 、R 5 、m、R a 、R b As defined by formula (III).
The process for preparing a compound of the general formula (IV) or a pharmaceutically acceptable salt thereof according to the present invention can be carried out as follows scheme 2:
scheme 2
Step 1: reacting the compounds Ia and IVb in a solvent to obtain a compound IVc; the solvent used in the reaction may be methylene chloride, tetrahydrofuran, preferably methylene chloride;
step 2: carrying out high-temperature reaction on the compound IVc and Id hydrochloride in a solvent to obtain a compound IVe; the solvent used in the reaction may be isobutanol, 1, 4-dioxane, preferably isobutanol;
step 3: reacting compound IVe with ketone, aldehyde or acetal, ketal in the presence of an acidic or basic catalyst to give a compound of formula (IV); the acid catalyst used in the reaction can be p-toluenesulfonic acid or hydrochloric acid; the alkaline catalyst is sodium hydroxide and potassium hydroxide; among them, an acidic catalyst is preferable, and p-toluenesulfonic acid is more preferable;
wherein R is 1 ～R 3 、R 5 、t、m、R a 、R b As defined by formula (IV).
The ketone, aldehyde or acetal, ketal used in the above reaction is generally referred to as an alkyl ketone, alkyl aldehyde or acetal, alkyl ketal, such as acetaldehyde or acetal.
Detailed Description
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift at 10 -6 Units of (ppm) are given. NMR was performed using Bruker dps300 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS).
MS was measured using a 1100Series LC/MSD Trap (ESI) mass spectrometer (manufacturer: agilent).
The examples are not specifically described, and the liquid phase was prepared using an lc3000 high performance liquid chromatograph and an lc6000 high performance liquid chromatograph (manufacturer: innovative). The column was Daisogel C18 10 μm 60A (20 mm. Times.250 mm). Mobile phase: acetonitrile, water (0.05 formic acid%).
HPLC was performed using a Shimadzu LC-20AD high pressure liquid chromatograph (Agilent TC-C18X14.6mm5um liquid chromatography column) and a Shimadzu LC-2010AHT high pressure liquid chromatograph (Phenomnex C18X14.6mm5um liquid chromatography column).
The thin layer chromatography silica gel plate uses Qingdao ocean chemical GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses Qingdao ocean silica gel of 100-200 meshes and 200-300 meshes as a carrier.
The known starting materials of the present invention may be synthesized using or according to methods known in the art or may be purchased from commercial establishments, beijing couplings, sigma, carbofuran, yi Shiming, shanghai book, inoki, nanjing, an Naiji chemistry, and the like.
The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The microwave reaction used was a CEM Discover SP type microwave reactor.
The examples are not specifically described, and the solution refers to an aqueous solution.
The temperature of the reaction is room temperature, in particular 20℃to 30℃unless otherwise specified in the examples.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using the following system of developing agents: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound.
The eluent system for column chromatography and the developing agent system for thin layer chromatography used for purifying the compound include: a: dichloromethane and methanol system, B: petroleum ether, ethyl acetate and dichloromethane system, C: petroleum ether and ethyl acetate system, the volume ratio of the solvent is regulated according to the polarity of the compound, and small amount of alkaline or acidic reagent such as triethylamine and acetic acid can be added for regulation.
Examples
Example 1: preparation of N, N, 4-trimethyl-6, 7,8, 9-tetrahydro-4H-pyrimidine [1,2-a ] [1,3,5] triazin-2-amine hydrochloride (1)
Step 1: synthesis of N- (tetrahydropyrimidin-2 (1H) -ylidene) cyanamide (1 c)
A solution of N-cyanoimino-S, S-dithiocarbonate (3.00 g,20.52 mmol) in methylene chloride (30 mL) was added to a solution of propane-1, 3-diamine (3.03 g,41.04 mmol) in methylene chloride (60 mL) at 0deg.C, stirred at 0deg.C for 30 min, warmed naturally to room temperature, and stirred for 3 h. The reaction solution was concentrated under reduced pressure, a white solid was precipitated, filtered, and the cake was rinsed with methyl tert-butyl ether (30 mL) and dried to give 2.50g of the crude title compound as a white solid, yield: 98.1%.
LC-MS：m/z 125[M+H] + 。
Step 2: synthesis of 1, 1-dimethyl-3- (tetrahydropyrimidine-2 (1H) -ylidene) guanidine (1 e)
N- (tetrahydropyrimidine-2 (1H) -ylidene) cyanamide (2.50 g,20.14 mmol) and dimethylamine hydrochloride (1.64 g,20.14 mmol) were dissolved with toluene (90 mL) at room temperature, reacted overnight at 110 ℃, concentrated under reduced pressure, and the residue was recrystallized from isopropanol to give crude title compound as a white solid, 1.57g, yield: 46.1%. It was used in the next step without purification.
LC-MS：m/z 170[M+H] + 。
Step 3: synthesis of N, N, 4-trimethyl-6, 7,8, 9-tetrahydro-4H-pyrimido [1,2-a ] [1,3,5] triazin-2-amine hydrochloride (1)
To a solution of 1, 1-dimethyl-3- (tetrahydropyrimidine-2 (1H) -ylidene) guanidine (1.50 g,8.86 mmol) and 1, 1-diethoxyethane (1.26 g,10.64 mmol) in isopropanol (6 mL) was added at room temperature, and the mixture was stirred overnight at 110 ℃. The reaction solution was concentrated under reduced pressure to obtain 2.46g of a white solid. The crude product was slurried with acetonitrile, filtered, the filter cake rinsed with acetonitrile and dried to yield 337mg of the title compound as a white solid in 22.2% yield.
LC-MS：m/z 196[M+H] + 。
1 H NMR(300MHz，DMSO-d 6 )：δppm 8.74-8.73(m，1H)，8.21(s，1H)，4.79-4.76(m，1H)，3.39-3.29(m，2H)，3.22-3.20(m，2H)，2.99(s，6H)，1.90-1.85(m，2H)，1.29(d，J＝6.0Hz，3H)。
Example 2: preparation of N, N, 4-trimethyl-4, 6,7, 8-tetrahydroimidazo [1,2-a ] [1,3,5] triazin-2-amine hydrochloride (2)
The title compound 2 was obtained in the same manner as in the preparation method of example 1 except that ethane-1, 2-diamine was used instead of propane-1, 3-diamine (1 b).
LC-MS：m/z 182[M+H] + 。
1 H NMR(400MHz，DMSO-d 6 )：δppm 8.77(s，1H)，8.46(s，1H)，4.79-4.74(m，1H)，3.69-3.39(m，4H)，3.06(s，6H)，1.41(d，J＝6Hz，3H)。
Example 3: preparation of N, 4-dimethyl-6, 7,8, 9-tetrahydro-4H-pyrimido [1,2-a ] [1,3,5] triazin-2-amine hydrochloride (3)
Step 1: synthesis of 1- (2, 4-dimethoxybenzyl) -1-methyl-3- (tetrahydropyrimidine-2 (1H) -alkylene) guanidine hydrochloride (3 b)
Hydrochloric acid-dioxane (12 mL, 4M) was added to a solution of N- (tetrahydropyrimidine-2 (1H) -ylidene) cyanamide (1 c) (5.00 g,40.3 mmol) and 1- (2, 4-dimethoxyphenyl) -N-methylmethylamine (8.76 g,48.3 mmol) in isobutanol (50 mL) at room temperature, reacted overnight at 105℃and concentrated under reduced pressure to give 17.3g of the crude title compound as a yellow oil. It was used in the next step without purification.
LC-MS：m/z 306[M+H] + 。
Step 2: synthesis of N- (2, 4-dimethoxybenzyl) -N, 4-dimethyl-6, 7,8, 9-tetrahydro-4H-pyrimido [1,2-a ] [1,3,5] triazin-2-amine (3 c)
To a solution of 1- (2, 4-dimethoxybenzyl) -1-methyl-3- (tetrahydropyrimidine-2 (1H) -alkylene) guanidine hydrochloride (17.3 g, crude) and 1, 1-diethoxyethane (5.66 g,48.0 mmol) in isobutanol (50 mL) at room temperature was added p-toluenesulfonic acid (344 mg,2.00 mmol) and stirred overnight at 105 ℃. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (mobile phase: DCM/meoh=100:1-10:1) to give the title compound as a white solid 1.54g, two-step yield: 11.6%.
LC-MS：m/z 332[M+H] + 。
Step 3: synthesis of N, 4-dimethyl-6, 7,8, 9-tetrahydro-4H-pyrimido [1,2-a ] [1,3,5] triazin-2-amine hydrochloride (3)
Hydrochloric acid-dioxane (60.0 ml,4 m) was added to N- (2, 4-dimethoxybenzyl) -N, 4-dimethyl-6, 7,8, 9-tetrahydro-4H-pyrimido [1,2-a ] [1,3,5] triazin-2-amine (1.20 g,3.62 mmol) at room temperature and stirred overnight at 50 ℃. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid chromatography (column: 30 mm. Times.250 mm; filler: C18, 10 μm; method: 2-22min, acetonitrile 5-10%, wavelength: 220nm, flow rate: 45mL/min; mobile phase: acetonitrile/water) to give 325mg of the title compound as colorless oily liquid in a yield of 41.2%.
LC-MS：m/z 182[M+H] + 。
1 H NMR(400MHz，DMSO-d 6 )：δppm 8.61-8.00(m，2H)，7.64-7.46(m，1H)，4.78-4.74(m，1H)，3.39-3.26(m，2H)，3.24-3.17(m，2H)，2.72(s，3H)，1.92-1.86(m，2H)，1.30-1.26(m，3H)。
Example 4: preparation of 4-methyl-6, 7,8, 9-tetrahydro-4H-pyrimido [1,2-a ] [1,3,5] triazin 2-amine hydrochloride (4)
The title compound 4 was obtained in the same manner as in the preparation method of example 1 except that (2, 4-dimethoxyphenyl) methylamine hydrochloride was used instead of dimethylamine hydrochloride (1 d) in step 2.
LC-MS：m/z 168[M+H] + 。
1 H NMR(300MHz，DMSO-d 6 )：δppm 8.47-8.43(m，1H)，8.03-8.02(m，1H)，7.18-7.16(m，2H)，4.74-4.72(m，1H)，3.30-3.24(m，2H)，3.22-3.17(m，2H)，1.93-1.85(m，2H)，1.28-1.26(m，3H)。
Example 5: preparation of N, N,4, 9-tetramethyl-6, 7,8, 9-tetrahydro-4H-pyrimido [1,2-a ] [1,3,5] triazin-2-amine hydrochloride (5)
The same preparation as in example 1 is carried out, except that N 1 Methyl propane-1, 3-diamine instead of propane-1, 3-diamine (1 b), the title compound 5 was prepared.
LC-MS：m/z 210[M+H] + 。
1 H NMR(300MHz，DMSO-d 6 )：δppm 8.96(s，1H)，4.81-4.76(m，1H)，3.43-3.28(m，4H)，3.07(s，6H)，3.03(s，3H)，2.03-1.89(m，2H)，1.27(d，J＝4.2Hz，3H)。
Example 6: preparation of N,4, 9-trimethyl-6, 7,8, 9-tetrahydro-4H-pyrimido [1,2-a ] [1,3,5] triazin-2-amine hydrochloride (6)
The same preparation as in example 1 is carried out, except that N 1 The title compound 6 was obtained by substituting propane-1, 3-diamine (1 b) in step 1 with methyl propane-1, 3-diamine and dimethylamine hydrochloride (1 d) in step 2 with 1- (2, 4-dimethoxyphenyl) -N-methyl methylamine hydrochloride.
LC-MS：m/z 196[M+H] + 。
1 H NMR(300MHz，DMSO-d 6 )：δppm 8.51(s，1H)，7.65(s，1H)，4.76-4.74(m，1H)，3.41-3.38(m，4H)，3.09-3.04(m，3H)，2.53-2.50(m，3H)，2.03-1.87(m，2H)，1.29-1.24(m，3H)。
Example 7: preparation of 4, 9-dimethyl-6, 7,8, 9-tetrahydro-4H-pyrimido [1,2-a ] [1,3,5] triazin-2-amine hydrochloride (7)
The same preparation as in example 1 is carried out, except that N 1 The title compound 7 was obtained by substituting propane-1, 3-diamine (1 b) in step 1 with-methylpropane-1, 3-diamine and dimethylamine hydrochloride (1 d) in step 2 with 1- (2, 4-dimethoxyphenyl) -N-methylamine hydrochloride.
LC-MS：m/z 182[M+H] + 。
1 H NMR(300MHz，DMSO-d 6 )：δppm 8.57(s，1H)，7.47-7.22(m，2H)，4.78-4.73(m，1H)，3.38-3.29(m，4H)，3.05(s，3H)，1.97-1.91(m，2H)，1.25(d，J＝2Hz，3H)。
Examples 7-a and 7-b: preparation of (S) -4, 9-dimethyl-6, 7,8, 9-tetrahydro-4H-pyrimido [1,2-a ] [1,3,5] triazin-2-amine hydrochloride and (R) -4, 9-dimethyl-6, 7,8, 9-tetrahydro-4H-pyrimido [1,2-a ] [1,3,5] triazin-2-amine hydrochloride
Compounds 7-a and 7-b were isolated from compound 7 by Supercritical Fluid Chromatography (SFC).
SFC separation conditions:
chromatographic column model: pak-as-H4.6 mm x 250mm,5 μm, mobile phase: etOH (0.2% NH) 3 ·H 2 O)/CO 2 Flow rate =60:40: 40g/min.
Compound 7-a:
retention time: 2.03min.
LC-MS：m/z 182[M+H] + 。
1 H NMR(400MHz，DMSO-d 6 )：δppm 8.68(s，1H)，7.56-7.30(m，3H)，4.78-4.75(m，1H)，3.36-3.29(m，4H)，3.04(s，3H)，1.96-1.88(m，2H)，1.25(d，J＝5.6Hz，3H)。
Compound 7-b:
retention time: 3.09min.
LC-MS：m/z 182[M+H] + 。
1 H NMR(400MHz，DMSO-d 6 )：δppm 8.54(s，1H)，7.32(s，2H)，4.78-4.73(m，1H)，3.36-3.27(m，4H)，3.04(s，3H)，1.96-1.89(m，2H)，1.25(d，J＝6.0Hz，3H)。
Biological experiments
Test example 1: analysis of in vitro inhibition of primary hepatocyte gluconeogenesis Activity of rats by the Compounds of the invention
Hepatocytes are the primary site for gluconeogenesis, converting a variety of non-sugar substances into glucose or glycogen. The test uses Amplex to test the ability of the compounds of the invention to inhibit the conversion of lactate/pyruvate to glucose in rat primary hepatocytes under sugarless culture conditions TM The Red Glucose/Glucose Oxidase Assay kit (a 22189, invitrogen) detects the concentration of Glucose converted in the medium.
The test method comprises the following steps:
a. rat primary hepatocytes (Bioreclamation IVT) were cultured in William E medium (12551032, gibco) supplemented with 10% fetal bovine serum (10099141, gibco), 50U or ug/ml double antibody (15140122, invitrogen), 6ug/ml insulin (11070-73-8, sigma), and cell culture plates were used 10ug/cm in advance 2 Is coated at 37℃for 1h, and cells are plated at 20 ten thousand per well in 24-well cell culture plates (3524, corning).
b. 400mM stock solutions of the compounds of the invention (stock solutions of the compounds of the invention in 400mM in sterile water) were used as starting concentrations and diluted to 400mM, 200mM, 100mM, 50mM, 25mM, 0mM in sterile water in a 2-fold ratio.
c. 100mM dexamethasone (BCP 09055, BIOchemartner) stock (stock of dexamethasone 100mM in DMSO) was diluted 10-fold to 10mM with 100% DMSO, followed by 200-fold to 50. Mu.M with William E medium. 50mM cAMP (C3912-10 MG, sigma) stock (cAMP in sterile water to make 50mM stock) is diluted 10-fold to 5mM with William E medium. The above 50. Mu.M dexamethasone and 5mM cAMP were mixed in a ratio of 1:1 to prepare a Mix.
d. 390. Mu.L of William E medium was added to each well of 24-well plate cells, followed by 2. Mu.L of each concentration of the compound of the present invention, and simultaneously 8. Mu.L of the Mix mixture prepared in c above was added thereto, and the final reaction system was 400. Mu.L, so that the final concentration of dexamethasone in the cells was 0.5. Mu.M, the final concentration of cAMP was 50. Mu.M, and the final concentrations of the compound of the present invention were 2mM, 1mM, 0.5mM, 0.25mM, 0.125mM, and 0mM.
e. The cell culture plates were placed in a cell incubator for pretreatment for 16h.
f. 100mM dexamethasone stock (dexamethasone in DMSO to make 100mM stock) was diluted 10-fold to 10mM with 100% DMSO, followed by 200-fold to 50. Mu.M dilution with sugar-free phenol red-free DMEM medium (A1443001, gibco). 50mM cAMP stock (cAMP in sterile water to make 50mM stock) is diluted 10-fold to 5mM in sugar-free phenol red-free DMEM medium. Lactate (L1750-10G, sigma) and pyruvate (P5280-25G, sigma) stock solutions were 1M, and the pyruvate stock solution was diluted to 100mM with sugar-free phenol red-free DMEM. The above 50. Mu.M dexamethasone, 5mM cAMP, 1M lactate and 100mM pyruvate were mixed in a ratio of 1:1:1:1 to prepare a Mix.
g. After 16h of pretreatment of the cells, the medium was discarded and washed 1 time with PBS.
h. 286.5. Mu.L of sugar-free phenol red-free DMEM medium was added to each well of the 24-well plate cells, and 1.5. Mu.L of each concentration of the compound of the present invention was added so that the final concentration of the compound of the present invention was 2mM, 1mM, 0.5mM, 0.25mM, 0.125mM, 0mM. Then, 12. Mu.L of the Mix mixture containing the substrate prepared in f above was added thereto, and the final reaction system was 300. Mu.L, so that dexamethasone in the cells had a final concentration of 0.5. Mu.M and cAMP had a final concentration of 50. Mu.M.
i. The cell culture plates were placed in a cell incubator for 4h incubation.
j. The cell culture plates were removed from the incubator, and the supernatant was collected using amplix TM The Red Glucose/Glucose Oxidase Assay kit (A22189, invitrogen) detects the concentration of Glucose in the medium.
k. After harvesting the supernatant, the cells were added CellTiter-Glo in equal amounts of the remaining medium volume TM (Promega) reagents, mixed well, incubated at room temperature for 10 min. The chemiluminescent signal is detected by a Cystation 3 enzyme label instrument.
And I, simultaneously arranging a control compound hole, wherein the operation flow is the same as a-i, when the operation flow is finished, discarding the compound to replace the cell culture medium without the compound, culturing for 24 hours, and adding CellTiter-Glo with the same volume of the residual culture medium into the cells TM (Promega) reagents, mixed well, incubated at room temperature for 10 min. The chemiluminescent signal is detected by a Cystation 3 enzyme label instrument.
Gluconeogenesis inhibition rate= (OD cpd -OD ctrl )/OD ctrl
Wherein OD cpd OD value, OD, for glucose detection in cell culture supernatants incubated at various concentrations of compound ctrl The OD value of the glucose assay in the cell culture supernatant under negative control conditions.
The activity of the compounds of the present invention in vitro to inhibit gluconeogenesis of primary hepatocytes in rats is shown in Table 1 below.
TABLE 1 inhibition of the Glycomogenesis of Primary hepatocytes in rats by the Compounds of the invention
Conclusion: the compound can obviously inhibit gluconeogenesis of primary hepatocytes of rats.
Test example 2: analysis of MIN6 cell insulin secretion promoting Activity of Compounds of the invention in vitro
For insulin secretion studies, glucose-dependent insulin secretion experiments (GSIS) were commonly used to perform stimulation of low sugar (2.8 mM glucose) and high sugar (16.7 mM glucose), respectively, and the insulin secretion amounts under the low sugar stimulation and the high sugar stimulation were examined. The activity of the compounds of the present invention was confirmed by testing the promotion of insulin secretion by MIN6 cells. Insulin secretion was measured using an Insulin Ultra-Sensitive kit (62IN2 PEG, cisbio).
The test method comprises the following steps:
a. mouse islet tumor cells MIN6 cells (Kang Long) were cultured in DMEM medium (10567-014, gibco) supplemented with 15% fetal bovine serum (10099-141, gibco) and 50. Mu.M beta. -mercaptoethanol (21985-023, invitrogen) and the cells were assayed at a concentration of 2X 10 6 cells/mL were seeded in 96-well cell culture plates (3599, corning) with 100uL of cells per well. Placing the cell culture plate into an incubator at 37deg.C with 5% CO 2 Culturing for 24 hours.
b. The next day, cells starved, old medium was removed, cells were rinsed twice with PBS (10010-031, gibco), then 100uL serum-free DMEM medium was added to each well, the plates were returned to the incubator at 37℃with 5% CO 2 The culture was carried out overnight under the conditions.
c. KRB buffer was prepared containing 118mM sodium chloride (S7653, sigma), 4.4mM potassium chloride (P9333, sigma), 1.2mM magnesium chloride (M8266, sigma), 1.5mM dipotassium hydrogen phosphate (1.37010, sigma), 1.3mM calcium chloride (C1016, sigma), 5mM sodium bicarbonate (S6297, sigma), 10mM HEPES (PHG 0001, sigma) and 0.2% BSA (A1933, sigma), pH 7.2-7.4, and the prepared solution was filtered through a 0.22 μm pore size filter.
d. Old medium was removed, cells were rinsed twice with PBS, and glucose was diluted from 1M to 2.8mM working solution with KRB buffer. KRB buffer containing 2.8mM glucose was added to each well and the plates were returned to the incubator at 37℃with 5% CO 2 Incubate for 30 minutes under conditions.
e. By H 2 O the compounds according to the invention were diluted in a 1:3 gradient, respectively, for a total of 4 concentrations.
f. The compounds of different concentrations from the previous dilution were diluted with KRB buffer containing 2.8mM glucose and 16.7mM glucose, respectively, to give working solutions (initial concentration of 2mM, 3-fold dilution, 4 gradients).
g. After diluting the positive control Exendin-4 (HY-13443, MCE) from 5mM to 2uM with DMSO, 10nM working solution was prepared with KRB buffer containing 2.8mM glucose and 16.7mM glucose, respectively.
h. Adding 100 uL/hole of working solution into the corresponding drug treatment hole; the negative control was KRB buffer containing 2.8mM glucose and 16.7mM glucose, respectively.
i. The plates were returned to the incubator at 37℃with 5% CO 2 Culturing for 3 hours under the condition.
After j.3 hours, the cell culture plates were centrifuged at 2000rpm for 10 minutes, the cell culture plates were placed on ice, 80uL of cell supernatant was transferred to a new 96 well clear plate and labeled.
k. Insulin content in cell supernatants was measured using an ins Ultra-Sensitive kit. Specifically, 1mM insulin standard (62IN2 PEG, cisbio) was diluted to 20ng/mL with KRB buffer. 20ng/mL insulin standard was diluted in 2.5-fold gradients on 96-well cell culture plates, for a total of 9 gradients, with the final gradient being KRB buffer. 10uL of each gradient standard was applied to the assay plate. After 50/100 times dilution of the test sample with KRB buffer, 10uL was applied to 384-well assay plates. 10uL of Anti-Injulin-Eu was added to each of the Insulin standard well and the sample well 3+ Working fluid was mixed with Crypate antibody and Anti-ins-XL 665 antibody. After sealing plate films are attached, the materials are evenly mixed on a plate vibrator for 15 seconds and then centrifuged for 1 minute at 1000 rmp. After overnight incubation at 25℃in an incubator, the Envision 2104 was used to read at Em665/Em 620.
Insulin sample concentration (ng/mL) =b×dilution, B being the insulin concentration of the sample wells derived from the standard curve.
The in vitro MIN6 cell insulin secretion promoting activity of the compounds of the present invention is shown in tables 2-1 and 2-2 below.
TABLE 2-1 Compounds of the invention stimulate MIN6 cell insulin secretion rate under low sugar conditions
TABLE 2-2 stimulation of MIN6 cell insulin secretion rates by the inventive compounds under high sugar conditions
* Insulin secretagogues are the percentage of insulin secretion under the incubation conditions of the compound relative to the insulin secretion under the negative control conditions.
Conclusion: the compound of the invention can obviously promote the secretion of MIN6 cell insulin under the conditions of low sugar (2.8 mM glucose) and high sugar (16.7 mM glucose).
Test example 3: analysis of the glucose uptake Activity of the Compounds of the invention in vitro on C2C12 cells
The ability of a compound to promote glucose uptake by a cell is indirectly reflected by the assay of the residual glucose content of the cell culture medium.
The test method comprises the following steps:
a. mouse myoblasts C2C12 cells (Nanjac Bai) were cultured in DMEM medium (8120039, gibco) containing 10% fetal bovine serum (10099141, gibco) and, when assayed, the cells were cultured at 5X 10 4 Each cell/mL was seeded in 96-well plates (3599, corning) at 200. Mu.L per well, i.e., 10000 cells/well.
b. When the cell density was as high as 90% confluence, cell differentiation was induced by changing DMEM medium containing 2% hs (16050130, gibco).
c. Cells were replaced daily with DMEM medium containing 2% hs, differentiated continuously for 5 days, and induced to pool into myotubes.
d. Stock solutions of the compounds of the present invention (stock solutions of the compounds of the present invention in sterile water to prepare 400 mM) were used as starting concentrations and diluted to 400mM, 200mM, 100mM, 50mM, 25mM, 0mM in a 2-fold ratio with sterile water.
e. After cell differentiation 199. Mu.L of DMEM and 1. Mu.L of each of the above concentrations of the compound solution were added to each well at 37℃with 5% CO 2 Culturing for 48h under the condition.
f. Cell culture supernatant was taken and assayed for residual glucose content in the medium using an AU480 biochemical analyzer.
The activity of the compounds of the invention in promoting glucose uptake in C2C12 cells in vitro is shown in table 3 below.
TABLE 3 in vitro promoting the glucose uptake Activity of the compounds of the invention in C2C12 cells
* Glucose uptake is the percentage of the amount of glucose in the cell utilization medium under the compound incubation conditions relative to the amount of glucose in the cell utilization medium under the negative control conditions.
Conclusion: the compound can obviously promote glucose uptake of C2C12 cells.
Test example 4: in vivo pharmacokinetic evaluation in wistar rats
Oral administration of the invention to Male 6 week old wistar rats (Vitrehua Experimental animal technologies Co., beijing city)Compounds of formula (I)(the compound was dissolved in physiological saline to prepare a 15mg/mL solution). Blood was collected from the canthus venous plexus at 0.25, 0.50, 1.00, 2.00, 4.00, 7.00, 10.00 and 24.00 hours before and after administration, respectively. Blood was anticoagulated with heparin sodium, centrifuged at 3500rpm at 4℃for 10 minutes, and plasma was obtained and stored at-20℃until tested. 50. Mu.L of plasma sample was taken in a 1.5mL EP tube, 400. Mu.L of acetonitrile working solution containing 5ng/mL verapamil hydrochloride (internal standard) (100223-200102, china medicine biologicals detection institute) was added, vortexed for 1 min to mix well, and centrifuged at 10000rpm for 10 min. After removing 0.2mL of the supernatant, filtering with 0.22. Mu.M organic film (AS 081320-T, agela Technologies), adding into a sample injection vial, analyzing to obtain bleeding drug concentration by LC/MS (Waters UPLC I Class/LC 30AD, waters), and analyzing pharmacokinetic parameters by DAS software 3.3.0.
TABLE 4 pharmacokinetic parameters of Compounds of the invention administered orally to Male wistar rats in a single pass
Conclusion: the compound of the invention has good drug substitution parameters and is suitable for developing oral administration.
Test example 5: research on pharmacodynamics of mice
Experimental materials: streptozotocin (S0130-1G, sigma)
The experimental method comprises the following steps: male 6 week old C57BL/6 mice (Vitolihua laboratory animal technologies Co., beijing) were given a continuous intraperitoneal injection of streptozotocin-induced diabetes model, once daily for 5 days. After two weeks of molding, animals with fasting blood glucose greater than 11.1mmol/L were selected for grouping. The animals were dosed individually according to the protocol, the design of the experiment being shown in Table 5-1 below. The compound was dissolved in 0.5% sodium carboxymethylcellulose (C104984, aladin) to prepare 5mg/mL, 15mg/mL and 30mg/mL solutions, and each experimental group was administered once daily for 4 weeks continuously
TABLE 5-1 pharmacodynamic protocol of the Compounds of the invention in a model of streptozotocin-induced mouse diabetes
After 2h from the last administration, the fasting blood glucose level of the tail vein was measured by a rapid blood glucose meter (20190829A 5, happy, etc.), and the fasting blood glucose decrease ratio was the ratio of the change in fasting blood glucose after 4 weeks of administration to the fasting blood glucose before administration of each experimental group. The results of the compound detection are shown in Table 5-2 below.
TABLE 5-2 results of diabetic mice pharmacodynamic experiments with the Compounds of the invention
From the experimental results, the compounds 4 and 7 can obviously reduce the fasting blood glucose level of the diabetic mice, and have good drug effect on the streptozotocin-induced mouse diabetes model.

Claims (15)

1. A compound of formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein,,
R 1 and R is 2 Each independently selected from hydrogen and C 1 -C 6 An alkyl group;
R 3 selected from hydrogen and C 1 -C 6 An alkyl group;
R 5 selected from hydrogen;
m is 1;
t is 0, 1 or 2;
R a and R is b Each independently selected from hydrogen and C 1 -C 6 An alkyl group.
2. A compound of formula (IV) according to claim 1, wherein t is 0 or 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
3. A compound of formula (IV) according to claim 1 or 2, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
4. a compound of formula (IV) according to claim 1 or 2, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
5. A process for preparing a compound of formula (IV) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
step 1: reacting compounds Ia and Ib in a solvent to obtain a compound Ic;
step 2: the compound Ic and Id hydrochloride react in a solvent at high temperature to obtain a compound Ie;
step 3: reacting compound Ie with ketone, aldehyde or acetal, ketal in the presence of an acidic or basic catalyst to give a compound of formula (IV);
wherein R is 1 ～R 3 、R 5 、m、R a 、R b T is as defined in claim 1.
6. The process of claim 5, wherein the solvent in step 1 is methylene chloride.
7. The process according to claim 5, wherein the solvent in step 2 is isobutanol at a temperature of 100 to 120 ℃.
8. The process of claim 5, wherein step 3 is performed in the presence of an acidic catalyst, the acidic catalyst being p-toluene sulfonic acid.
9. A pharmaceutical composition comprising a compound of the general formula (IV) according to any one of claims 1 to 4 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable carrier.
10. Use of a compound of general formula (IV) according to any one of claims 1 to 4 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the preparation of a medicament for the treatment of a pathological condition associated with insulin resistance syndrome.
11. Use of a compound of general formula (IV) according to any one of claims 1 to 4 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the preparation of a medicament for the treatment of diabetes.
12. The use of claim 11, wherein the diabetes is type I or type II diabetes.
13. Use of a compound of general formula (IV) according to any one of claims 1 to 4 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the preparation of a medicament for the treatment of a pathological condition resulting from hyperglycosylated formation.
14. Use of a compound of general formula (IV) according to any one of claims 1 to 4 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment of a pathological condition selected from renal complications, atherosclerosis, cardiovascular diseases, alzheimer's disease, neurodegenerative diseases and aging.
15. Use of a compound of general formula (IV) according to any one of claims 1 to 4 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment of a pathological condition selected from dyslipidemia, non-alcoholic fatty liver, non-alcoholic steatohepatitis, obesity, hypertension, retinopathy and neuropathy.
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