CN112028875B - Anhydride compounds of PGI2 protein agonist and TXA2 protein inhibitor - Google Patents
Anhydride compounds of PGI2 protein agonist and TXA2 protein inhibitor Download PDFInfo
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Abstract
The invention relates to anhydride compounds of a PGI2 protein agonist and a TXA2 protein inhibitor. The compounds are of formula (I) and pharmaceutically acceptable salts, prodrugs and solvates thereof, pharmaceutical compositions containing said compounds, and methods of synthesizing the same; furthermore, the present invention relates to a protein preparation comprising the compound, which is useful for preventing or treating a disease associated with prostacyclin and thromboxane.
Description
Technical Field
The invention relates to anhydride compounds of a PGI2 protein agonist and a TXA2 protein inhibitor. The compounds are compounds of formula I and pharmaceutically acceptable salts, prodrugs and solvates thereof, and medicaments containing the compounds are useful in the prevention or treatment of diseases associated with prostacyclin and thromboxane proteins.
Background
Prostacyclin (PGI 2) and thromboxane A2 (TXA 2) are both metabolized by arachidonic acid (C20H 32O 2), contain four carbon-carbon double bonds and are high-grade unsaturated fatty acids, and can synthesize different derivatives in different tissue cells, thus having extremely important physiological functions. Prostacyclin (PGI 2) is produced from arachidonic acid by the action of vascular endothelial cell cyclooxygenase and prostacyclin synthase; can relax smooth muscle of blood vessel and inhibit platelet aggregation. Thromboxane A2 (TXA 2) is an important factor for promoting thrombosis, has a strong effect of contracting blood vessels, and can promote platelet aggregation. Under normal physiological conditions, the two components keep a certain proportion relationship to realize balance, and only if the two components are balanced, vasomotor, platelet aggregation, vascular smoothness and the like can be effectively regulated. Otherwise, both are out of balance, which tends to result in serious pathological changes.
PGI2 is an important member of the prostaglandin family, belonging to the endothelial-derived vasodilator. COX is a key enzyme in the PGI2 synthesis pathway, and the effect of different COX subtypes on PGI2 expression may vary depending on the site and stress state of the body. PGI2 is the strongest prostaglandin released in the vascular system against the vasculature, and is 4-8 times stronger than PGE 2. Has effects in inhibiting blood platelet aggregation and dilating blood vessel, and can be used for treating pulmonary arterial hypertension, atherosclerosis, myocardial infarction, etc. PGI2 exerts its regulatory effects on the cardiovascular system by acting on a tissue-specific G protein-coupled receptor on the cell membrane, the prostacyclin receptor (IP 1) and related signaling pathways. Recent studies have found that PGI2/PGI2 analogues can also act on another nuclear receptor peroxisome proliferator-activated receptor (PPAR).
IP1 cloned from human lung tissue comprises 386 amino acids with 7 transmembrane units of G protein coupled receptor. The receptor structure comprises 3 parts: (1) extracellular portion: comprises a short N end and 3 extracellular loops; (2) transmembrane region: including 7 transmembrane segments, the upper half of which is considered the substrate binding pocket. (3) intracellular region: consisting of 4 rings and a relatively long C-terminus. The transmembrane region is closely related to the substrate binding activity, arginine at position 279 is positively charged and is combined with carboxylate ions at position C-1 in PGI2 with negative charges; phenylalanine at position 278 may be bound to the oxalate ring and the α -tail of the ligand; tyrosine at position 75 forms a hydrogen bond with the carboxyl at position C-11 in PGI 2; phenylalanine at position 95 interacts with the omega-tail of PGI2, which rotates freely. In addition, tyrosine in the transmembrane region is also important, and is involved in substrate binding and receptor activation. When PGI2 is combined with IP1, through the activation of adenylate cyclase by G protein, ATP in cytoplasm generates cAMP which plays a role of second messenger, and then cAMP-dependent protein kinase A can be activated, so that PGI2 mediates physiological effects of inhibiting platelet aggregation, dilating blood vessels and the like through a signal transduction mechanism related to cAMP.
Thromboxane A2 (Thromboxane A2, TXA 2) is the product of the isomerisation of prostaglandin endoperoxides (PGH 2) catalyzed by Thromboxane synthase, which binds to its specific TXA2 receptor (TXA 2R), induces platelet aggregation, constricts vascular and respiratory smooth muscle, stimulates vascular smooth muscle mitosis and hypertrophy, and plays an important role in the pathogenesis of acute coronary syndrome, coronary heart disease, pulmonary hypertension. TXA2R is named TP receptor, TXA2 and its precursor PGH2 show similar pharmacological properties in platelets, so both are considered to share the same receptor, and TXA2R is now referred to as TXA2/PGH2 receptor. It is generally found that specific thromboxane synthase inhibitors increase endogenous prostacyclin production in vivo.
Human TXA2R is a G protein-coupled receptor, with an amino terminus extracellular, a carboxy terminus intracellular, 7 transmembrane regions, 3 extracellular loops, and 3 intracellular loops. Encoded by a single gene, the C-terminal is alternatively linked into two variants, which differ only in the amino acid sequence from post arginine 328 to the carboxy-terminal tail of the receptor. Clones originally obtained from placenta encoded a receptor of 343 amino acids (molecular weight 37.4 kD), designated TP alpha; clones obtained from endothelial cells encoded 407 amino acid receptors, designated TP beta. The asparagine amino acid residues at positions 4 and 16 of TXA2R are N-glycosylation sites, and it has been found that simultaneous mutation of Asn-4 and Asn-16 prevents binding of the receptor to the ligand, suggesting that N-glycosylation is critical for ligand binding, which may be that deglycosylation disrupts protein folding and/or expression of the receptor on the cell surface. A critical disulfide bond is formed between cysteine 105 of the first extracellular loop and cysteine 183 of the second extracellular loop of TXA2R to maintain receptor integrity. Mutation of either residue Cys105 or Cys183 completely lost the ability to bind to the ligand, and similar disulfide bonds were found at the corresponding sites in other rhodopsin-type receptors.
When TXA2R binds specifically to a ligand, the G protein coupled to the receptor allosteric triggers a change in a series of information transfer systems within the cell. The information transmission of the TXA2R mediated vascular smooth muscle contraction and proliferation is as follows: after the TXA2R is combined with a ligand, phospholipase Cbeta (PLC beta) is activated through Gq protein, so that phosphodiester bond cleavage of phosphatidylinositol-4, 5-diphosphate (PIP 2) is promoted to generate 1,4, 5-inositol triphosphate (IP 3) and Diacylglycerol (DAG), and the IP3 increases free calcium in cells, and the myosin light chain is phosphorylated to cause vascular smooth muscle contraction. Whereas DAG initiates vascular smooth muscle division proliferation and atherosclerosis formation through Protein Kinase C (PKC) and mitogen-activated protein kinase (MAPK) transduction pathways.
At present, a PGI2 protein agonist and a TXA2 protein inhibitor are in a research stage, and development of new compounds with better drug effect and safety is urgently needed. The novel compounds of the PGI2 protein agonist and the TXA2 protein inhibitor have good biological activity and safety.
Disclosure of Invention
The invention aims at: synthesizing an anhydride compound of a PGI2 protein agonist and a TXA2 protein inhibitor.
The invention also aims to provide a synthesis method of the novel PGI2 protein agonist and TXA2 protein inhibitor compounds.
The invention also aims at the application of the novel compounds of the PGI2 protein agonist and the TXA2 protein inhibitor in treating cardiovascular and cerebrovascular diseases.
The novel compound structure of the PGI2 protein agonist and the TXA2 protein inhibitor is as follows: a novel compound of formula (I):
r is selected from H, halogen, CN, NO 2 、CF 3 、CHO、COOH、COOR 1 、CONR 2 R 2’ 、SONR 3 R 3’ 、COR 4 、R 5 OH、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl group, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups optionally being substituted by one or more R's, identical or different 1 Substitution; c (C) 3-7 Cycloalkyl, C 5-7 Aromatic ring radical, C 5-7 Aromatic heterocyclic group, C 7-11 Aromatic bicyclo group, C 7-11 Aromatic heterobicyclic radicals in which one or more of the radicals R are optionally identical or different 2 And (3) substitution.
A is selected from C 3-7 Cycloalkyl, C 5-7 Aromatic ring radical, C 5-7 Aromatic heterocyclic group, C 7-11 Aromatic bicyclo group, C 7-11 Aromatic heterobicyclic radicals in which one or more of the radicals R are optionally identical or different 1 And (3) substitution.
R 1 Selected from H, halogen, CN, NO 2 、CF 3 、CHO、COOH、COOR 1 、CONR 2 R 2’ 、SONR 3 R 3’ 、COR 4 、R 5 OH、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl group, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups optionally being substituted by one or more R's, identical or different 1 Substitution; c (C) 3-7 Cycloalkyl, C 5-7 Aromatic ring radical, C 5-7 Aromatic heterocyclic group, C 7-11 Aromatic bicyclo group, C 7-11 Aromatic heterobicyclic radicals in which one or more of the radicals R are optionally identical or different 2 And (3) substitution.
R 2 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl group, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 5-7 Aromatic ring radical, C 5-7 Aromatic heterocyclic group, C 7-11 Aromatic bicyclo group, C 7-11 Aromatic heterobicyclic radicals in which one or more of the radicals R are optionally identical or different 1 And (3) substitution.
Within the meaning of the invention, the terms are used as follows:
"halogen" means F, cl, br, I.
“C l-6 Alkyl "refers to an alkyl chain having 1 to 8 carbon atoms, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.
“C 2-6 Alkenyl "refers to alkenyl chains having 2 to 8 carbon atoms, for example: ethylene, propylene, butene, butadiene, pentene, pentadiene, and the like.
“C 2-6 Alkynyl "refers to an alkynyl chain having 2 to 8 carbon atoms, for example: acetylene, propyne, butyne, pentyne, and the like.
“C 3-7 Cycloalkyl "refers to cycloalkyl chains having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and the like.
“C 5-7 The aromatic heterocyclic group "means an aromatic heterocyclic group having 5 to 7 carbon atoms, such as imidazole, thiazole, pyrazole, pyridine, pyrimidine, etc
“C 7-11 An aromatic bicyclic group "means an aromatic bicyclic group having 7 to 11 carbon atoms, such as naphthalene, indene, and the like.
“C 7-11 The aromatic heterobicyclic group "means an aromatic heterobicyclic group having 7 to 11 carbon atoms, such as quinoline, isoquinoline, benzothiazole, and the like. Each hydrogen of the aromatic heterobicyclic group may be replaced by a further specified substituent.
"prodrug" means a derivative which is converted into the compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis or the like each carried out under the catalysis of an enzyme.
"solvate" refers to a form of a compound that is physically bound to a solvent, typically by a solvolysis reaction.
The compound of formula (I) is selected from:
(1) 4- [ (2-chloro-3-formylquinolin-7-yl) methyl ] benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(2) 4- (3-formylquinolin-6-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(3) 4- (2-formylquinolin-6-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(4) 4- (7-formylquinolin-3-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(5) 4- (2-formyl-8-hydroxyquinolin-6-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(6) 4- ((5-bromothiophene-2-carbonyl) oxy) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(7) 4- (5- (5-formylthiophene-2-yl) pyridin-3-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(8) 4- (4-formyl-2-nitrothiophen-3-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(9) 2-oxo-2- (5- (4- ((2- (3, 5, 6-trimethylpyrazin-2-yl) acetoxy) carbonyl) phenyl) thiophen-2-yl) acetate
(10) 4- (3-bromo-2-formylbenzo [ b ] thiophen-5-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(11) 4- (2-chloro-5-formylthiophene-3-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(12) 4- (1- (4-fluorophenyl) -5-formyl-1H-pyrazol-4-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(13) 3'- ((4- (2-formylphenyl) piperazin-1-yl) methyl) - [1,1' -biphenyl ] -4-carboxylic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(14) 4- (5- (3-formylphenyl) pyrazin-2-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
(15) 4- (5-formyl-pyridazin-4-yl) benzoic acid 2- (3, 5, 6-trimethyl-pyrazin-2-yl) acetic anhydride
Pharmaceutically acceptable salts of the compounds of formula (I), comprising one or more basic or acidic groups, are also included in the present invention as are their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically usable salts. Thus, compounds of formula (I) comprising acidic groups can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium, potassium, calcium, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of formula (I) comprising one or more basic groups, i.e. groups that can be protonated, may be present and may be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, benzoic acid, tartaric acid, oxalic acid, p-toluenesulfonic acid and the like, as well as other acids known to those skilled in the art.
The PGI2 protein agonist and TXA2 protein inhibitor related diseases and symptoms in the invention are cardiovascular and cerebrovascular diseases, such as chronic heart failure, ischemic cerebral apoplexy, atherosclerosis, myocardial ischemia reperfusion injury, myocardial hypertrophy, myocardial fibrosis, pulmonary heart disease, pulmonary arterial hypertension and the like.
Detailed Description
Example 1:4- [ (2-chloro-3-formylquinolin-7-yl) methyl ] benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
the synthetic route is as follows:
the synthesis method comprises the following steps:
in a three-necked round bottom flask, the appropriate 4- (chloromethyl) -2-methylbenzoyl chloride (3 mmol), 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic acid (3 mmol) and 1 (25.6 mg,1mol% Co complex) were added to dichloromethane (20 mL). The solution was maintained at 40℃in a water bath for 4 hours and stirred using a slow stream of nitrogen bubbles. After cooling, the polymer-bound catalyst is removed by filtration and the product is purified by recrystallisation, in the case of liquid, by flash chromatography. Into a 10ml reactor was charged Pd/KAP (DCM-TPP), aryl halide (0.5 mmol), (2-chloro-3-formylquinolin-6-yl) boronic acid (0.75 mmol), K3PO4.3H2O (1.5 mmol) and water. The mixture was allowed to react at 100℃for 6 hours. The mixture was rapidly separated by centrifugation. The solid was extracted with a large amount of ethyl acetate and the liquid was concentrated.
1H-NMR(400MHZ，CDCl3，TMS ppm)：
δ7.50(1H)，δ8.73(1H)，δ8.08(1H)，δ7.39(1H)，δ7.79(1H)，δ7.61(1H)，δ8.08(1H)，δ7.39(1H)，δ4.07(2H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)，δ9.73(1-0H)
Example 2:4- (3-formylquinolin-6-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 1
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ8.82(1H)，δ8.38(1H)，δ7.96(1H)，δ8.10(1H)，δ7.85(1H)，δ8.90(1H)，δ8.10(1H)，δ7.85(1H)，δ8.10(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)，δ9.73(1-0H)
Example 3:4- (2-formylquinolin-6-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 1
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ8.41(1H)，δ7.93(1H)，δ8.21(1H)，δ7.85(1H)，δ8.10(1H)，δ7.28(1H)，δ8.89(1H)，δ7.85(1H)，δ8.10(1H)，δ9.71(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)
Example 4:4- (7-formylquinolin-3-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 1
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ8.40(1H)，δ8.25(1H)，δ7.85(1H)，δ9.06(1H)，δ8.10(1H)，δ8.57(1H)，δ7.85(1H)，δ8.10(1H)，δ8.20(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)，δ9.88(1-0H)
Example 5:4- (2-formyl-8-hydroxyquinolin-6-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 1
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ10.01(1H)，δ7.34(1H)，δ7.51(1H)，δ7.85(1H)，δ8.10(1H)，δ7.25(1H)，δ8.84(1H)，δ7.85(1H)，δ8.10(1H)，δ7.91(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)
Example 6:4- ((5-bromothiophene-2-carbonyl) oxy) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
the synthetic route is as follows:
the synthesis method comprises the following steps:
in a three-necked round bottom flask, the appropriate 4-formylbenzoyl chloride (3 mmol), 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic acid (3 mmol) and 1 (25.6 mg,1mol% Co complex) were added to dichloromethane (20 mL). The solution was maintained at 40℃in a water bath for 4 hours and stirred using a slow stream of nitrogen bubbles. After cooling, the polymer-bound catalyst is removed by filtration and the product is purified by recrystallisation, in the case of liquid, by flash chromatography. 4-formyl benzoic acid 2- (3, 5, 6-trimethyl pyrazin-2-yl) acetic anhydride (460 mg), EDC (767 mg) and DMAP (305 mg) were added to a solution of 5-bromothiophene-2-carboxylic acid (518 mg) in THF (15 ml) and stirred for 2 hours. Water and 1N hydrochloric acid were added to the reaction solution, extracted with diethyl ether, and the organic layer was dried over anhydrous Na2SO 4. The solvent was evaporated under reduced pressure. The crude product of 5-bromothiophene-2-carboxylic acid pentafluorophenyl ester (897 mg) was obtained.
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ7.10(1H)，δ7.72(1H)，δ8.33(1H)，δ8.33(1H)，δ7.54(1H)，δ8.07(1H)，δ7.54(1H)，δ8.07(1H)，δ3.67(2H)，δ2.74(3H)
Example 7:4- (5- (5-formylthiophene-2-yl) pyridin-3-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 6
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ7.94(1H)，δ7.80(1H)，δ9.34(1H)，δ8.43(1H)，δ7.85(1H)，δ8.10(1H)，δ7.85(1H)，δ8.10(1H)，δ9.84(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)
Example 8:4- (4-formyl-2-nitrothiophen-3-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 6
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ9.80(1H)，δ7.85(1H)，δ8.10(1H)，δ7.85(1H)，δ8.10(1H)，δ9.73(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)
Example 9: 2-oxo-2- (5- (4- ((2- (3, 5, 6-trimethylpyrazin-2-yl) acetoxy) carbonyl) phenyl) thiophen-2-yl) acetate
Structure of the compound:
synthetic method referring to embodiment 1
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ7.94(1H)，δ7.80(1H)，δ7.98(1H)，δ8.10(1H)，δ7.98(1H)，δ8.10(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)
Example 10:4- (3-bromo-2-formylbenzo [ b ] thiophen-5-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 6
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ7.99(1H)，δ8.12(1H)，δ8.12(1H)，δ7.85(1H)，δ8.10(1H)，δ7.85(1H)，δ8.10(1H)，δ9.84(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)
Example 11:4- (2-chloro-5-formylthiophene-3-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 6
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ8.05(1H)，δδ7.85(1H)，δ8.10(1H)，δ7.85(1H)，δ8.10(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)，δ9.84(1-0H)
Example 12:4- (1- (4-fluorophenyl) -5-formyl-1H-pyrazol-4-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 6
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ9.04(1H)，δ7.20(1H)，δ7.59(1H)，δ7.59(1H)，δ7.85(1H)，δ8.10(1H)，δ7.20(1H)，δ7.59(1H)，δ7.85(1H)，δ8.10(1H)，δ9.75(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)
Example 13:3'- ((4- (2-formylphenyl) piperazin-1-yl) methyl) - [1,1' -biphenyl ] -4-carboxylic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 1
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ3.44(2H)，δ3.44(2H)，δ2.62(2H)，δ2.62(2H)，δ6.92(1H)，δ7.85(1H)，δ7.48(1H)，δ7.90(1H)，δ7.67(1H)，δ8.10(1H)，δ7.85(1H)，δ8.10(1H)，δ7.41(1H)，δ7.57(1H)，δ7.43(1H)，δ6.95(1H)，δ10.36(1H)，δ3.66(2H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)
Example 14:4- (5- (3-formylphenyl) pyrazin-2-yl) benzoic acid 2- (3, 5, 6-trimethylpyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 1
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ8.79(1H)，δ8.79(1H)，δ8.54(1H)，δ8.68(1H)，δ9.02(1H)，δ8.14(1H)，δ8.54(1H)，δ8.14(1H)，δ8.08(1H)，δ7.77(1H)，δ9.88(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)
Example 15:4- (5-formyl-pyridazin-4-yl) benzoic acid 2- (3, 5, 6-trimethyl-pyrazin-2-yl) acetic anhydride
Structure of the compound:
synthetic method referring to embodiment 1
1H-NMR(400MHZ，CDCl3，TMS，ppm)：
δ9.70(1H)，δ9.88(1H)，δ7.85(1H)，δ8.10(1H)，δ7.85(1H)，δ8.10(1H)，δ9.73(1H)，δ3.67(2H)，δ2.74(3H)，δ2.74(3H)，δ2.74(3H)
Example 16: activation of PGI2 proteins
The effect of the compounds on the activity of purified recombinant PGI2 was studied from the enzymatic level for the activation activity of the compounds on PGI 2. The experimental principle is that a luminescence method enzyme detection method is adopted for detecting ADP content generated by the reaction of PGI2 and a substrate Poly (4:1 Glu, tyr) peptide: after ADP is converted into ATP, the ATP can be used as a substrate for the catalytic reaction of Ultra-Glo luciferase to generate optical signals. The luminescence signal is positively correlated with the amount of ADP and enzyme activity. Thus, the activation of the compound on recombinant PGI2 is determined by observing the luminescent signal generated by the reaction of the compound on PGI2 with the substrate.
The experimental method comprises the following steps:
the basic process is as follows: the compound with the lowest concentration of 0.0001 and increasing to 8um and 10 concentration units is incubated with PGI2 for 1 hour at 37 ℃, then the substrate and ATP are added for mixing, the mixture is reacted for 1 hour at 37 ℃, then a certain amount of ADP-Glo is added for mixing for 2 minutes, and the mixture is reacted for 1 hour at room temperature. And adding a detection reagent, incubating for 1 hour at room temperature, and detecting by using a chemiluminescent instrument. The compounds were observed for their activation of PGI2, expressed as IC 50. The results are shown in Table 1.
TABLE 1 experimental results of PGI2 inhibition
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Example 17: inhibition of TXA2 protein
The effect of the compound on the activity of purified recombinant TXA2 was studied from the enzymatic level to investigate the inhibitory activity of the compound on TXA 2. The experimental principle is that a luminescence method enzyme detection method is adopted for detecting ADP content generated by the reaction of TXA2 and a substrate Poly (4:1 Glu, tyr) peptide: after ADP is converted into ATP, the ATP can be used as a substrate for the catalytic reaction of Ultra-Glo luciferase to generate optical signals. The luminescence signal is positively correlated with the amount of ADP and enzyme activity. Thus, the inhibitory effect of the compounds on recombinant TXA2 was determined by observing the luminescent signal generated by the reaction of PGI2 with the substrate.
The experimental method comprises the following steps:
the basic process is as follows: the compound with the lowest concentration of 0.0001 and increasing to 8um and 10 concentration units is incubated with TXA2 for 1 hour at 37 ℃, then the substrate and ATP are added for mixing, the mixture is reacted for 1 hour at 37 ℃, then a certain amount of ADP-Glo is added for mixing for 2 minutes, and the mixture is reacted for 1 hour at room temperature. And adding a detection reagent, incubating for 1 hour at room temperature, and detecting by using a chemiluminescent instrument. The inhibition of TXA2 by the compounds is observed and expressed as IC 50. The results are shown in Table 2.
TABLE 2 experimental results of inhibition of TXA2
/>
Example 18: acute toxicity test in mice
Taking the compound, observing acute toxicity of single oral administration and gastric lavage administration of mice, and calculating LD 50 . The results are shown in Table 3.
TABLE 3 results of acute toxicity experiments with single oral gavage administration in mice
| Compounds of formula (I) | Acute toxicity LD of single oral administration gastric lavage administration of rat 50 (mg/Kg) |
| Inventive example 1 Compound | <450 |
| Inventive example 2 Compounds | <500 |
| Inventive example 3 Compound | <420 |
| Inventive example 4 Compound | <170 |
| Inventive example 5 Compound | <650 |
| Inventive example 6 Compound | <270 |
| Inventive example 7 Compound | <400 |
| Inventive example 8 Compound | <450 |
| Inventive example 9 Compound | <170 |
| Inventive example 10 Compound | <140 |
| Inventive example 11 Compound | <120 |
| Inventive example 12 Compound | <521 |
| Inventive example 13 Compound | <496 |
| Inventive example 14 Compound | <268 |
| Inventive example 15 Compound | <398 |
The foregoing is merely a preferred embodiment of the present invention and it will be apparent to those skilled in the art that numerous modifications and variations can be made without departing from the principles of the invention, and such modifications and variations are to be regarded as being within the scope of the invention.
Claims (2)
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
r is selected from C 1-6 Alkyl, C 5-7 An aromatic heterocyclic group;
a is selected from C 5-7 Aromatic ring radical, C 5-7 Aromatic heterocyclic group, C 7-11 Aromatic bicyclo group, C 7-11 Aromatic heterobicyclic radicals in which one or more of the radicals R are optionally identical or different 1 Substitution;
R 1 selected from H, CHO, halogen, C 1-6 Alkyl, C 2-6 Alkenyl groups.
2. The use of a compound as claimed in claim 1 for the preparation of a medicament for the activation and inhibition of PGI2 protein and TXA2 protein related activity in humans.
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