WO2019007140A1 - Dérivé de 4-aminopyrimidine utilisé en tant qu'antagoniste du récepteur a2a de l'adénosine et son application - Google Patents

Dérivé de 4-aminopyrimidine utilisé en tant qu'antagoniste du récepteur a2a de l'adénosine et son application Download PDF

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WO2019007140A1
WO2019007140A1 PCT/CN2018/085021 CN2018085021W WO2019007140A1 WO 2019007140 A1 WO2019007140 A1 WO 2019007140A1 CN 2018085021 W CN2018085021 W CN 2018085021W WO 2019007140 A1 WO2019007140 A1 WO 2019007140A1
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adenosine
compound
cancer
receptor
aminopyrimidine derivative
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PCT/CN2018/085021
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Chinese (zh)
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钟燕
曹西蓉
王永临
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上海肇钰医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to the field of pharmaceuticals and organic chemistry, and in particular to a 4-aminopyrimidine derivative as an adenosine A 2A receptor antagonist and uses thereof.
  • adenosine As an endogenous regulator of most physiological functions in the central (CNS) and peripheral nervous system, adenosine is widely distributed in multiple tissues and organs such as the nervous system, cardiovascular system, digestive system, and respiratory system. The role of physiological processes. It exerts its biological effects through a class of membrane-specific receptors belonging to the G-protein coupled receptor superfamily.
  • adenosine receptor subtypes Four adenosine receptor subtypes have been identified, respectively: A 1 , A 2A , A 2B and A 3 .
  • a 1 and A 2A are high expression receptors, which can produce a low level of adenosine concentration under physiological conditions, while A 2B and A 3 have low expression levels, and only a large amount of adenosine increases under pathological conditions.
  • the A 1 and A 3 receptors regulate the level of cells down by their coupling to the G protein that inhibits adenylate cyclase; in contrast, the A 2A and A 2B receptors and the Gs protein that activates adenylate cyclase Coupling and increasing intracellular levels. Through the action of these receptors, adenosine can achieve a wide range of physiological function regulation.
  • a 2A receptors are mostly found in areas rich in dopamine, such as basal ganglion elements, various mammals including human striatum and globus pallidus.
  • the basal ganglia and striatum act as central components involved in the integration of information in the cortex, thalamus and marginal lobes to produce motor behavior. It has been found in the striatum that the A 2A receptor and the dopamine D2 receptor are closely concentrated in the striatum globus gamma-aminobutyric acid neuron, forming a so-called indirect export pathway from the striatum, which is motility Inhibition related.
  • the A 2A receptor regulates the neurotransmission of gamma-aminobutyric acid, dopamine, acetylcholine, and glutamate through various pathways to promote the control of motor behavior.
  • the interaction of A2A with the D2 receptor, particularly A2A as an antagonist is of great benefit in the treatment of Parkinson's disease, which can result in a decrease in dopamine levels.
  • the A2A receptor interacts closely and antagonistically with the D2 receptor, causing a decrease in dopamine affinity when the D2 receptor is stimulated.
  • A2A receptor antagonists can potentiate the effects of endogenous dopamine and clinically applied dopamine receptor agonists and increase the drug response time of dopaminergic agents.
  • A2A receptor agonists and antagonists have been extensively described in the pharmacological, behavioral, and neuroprotective experiments of rodent and non-human primates.
  • D2 receptor antagonist and agonist-induced A 2A receptor can be clearly exemplified in close D2 and A 2A receptor interaction catalepsy model, which is A 2A receptor antagonist and D2 receptor agonist reaction.
  • a 2A receptor antagonist and D2 receptor agonist reaction are A 2A receptor antagonist and D2 receptor agonist reaction.
  • many researchers have reported the potential of A 2A receptor antagonists to resist tremor paralysis.
  • the adenosine A 2A receptor antagonists SCH58261 and KW-6002 both enhanced bilateral rotation caused by subdomain dose of levodopa in unilateral 6-hydroxydopamine (6-OHDA) injured mice and rats. .
  • a 2A receptor antagonist KW-6002 significantly improves long-term treatment with non-human primates by dopamine receptor agonist levodopa from 1-methyl-4-phenyl-1 , 2,3,6-tetrahydropyridine (MPTP)-induced motor injury that does not cause dyskinesia. Therefore, A 2A receptor antagonists have shown great potential as future drugs for long-term use in patients with Parkinson's disease, as they not only reverse motor damage and can slow or stop disease progression by prolonging cell life.
  • MPTP 2,3,6-tetrahydropyridine
  • A2A receptor antagonists are effective in treating neurodegenerative diseases such as Parkinson's disease, Huntington's disease or Alzheimer's disease. It has been reported that A2A receptor antagonists have neuroprotective effects in both in vivo and in vitro models of different neurodegenerative diseases. In summary, A2A receptor antagonists are effective in protecting different neurons from various forms of damage-induced neurodegenerative diseases.
  • a 2A receptor knockout mice are less sensitive to "inhibitory drugs” than their wild type counterparts. Consistent with this study, the A 2A receptor antagonists SCH58261 and KW6002 reduced the total immobility time in the mouse tail suspension assay. It was also found that the antagonists SCH8261 and ZM241385 reduced immobility when administered to mice that had been screened for high immobility time, whereas in this model SCH58261 reduced their selective selection for "helpless" feeding. The immobility of the mouse. Mouse studies with A 2A knockouts showed that these animals were unresponsive to psychostimulants such as amphetamines and cocaine.
  • adenosine A 2A receptor antagonists may have antidepressant and/or antipsychotic functions by regulating the dopaminergic pathway of the striatum or the middle adrenocortical.
  • a 2A receptor activation can help to improve a range of neuropsychiatric disorders and disorders such as depression, excessive daytime sleep, leg hyperactivity syndrome (RLS), attention deficit hyperactivity disorder, and cognitive fatigue.
  • RLS leg hyperactivity syndrome
  • Extrapyramidal syndrome is a generic term for a series of adverse neurological reactions associated with the use of antipsychotics.
  • EPS-related neurological syndromes 4 of which are dystonia, sedation, pseudo Parkinson's disease (Parkinson's syndrome) and delayed dyskinesia in patients taking antipsychotic medications.
  • Tension disorder is the pain of the muscles, especially the neck, jaw, back, pharynx and throat. It is most commonly found in young men treated with antipsychotics, but can also be associated with the use of cocaine, tricyclic antidepressants, lithium salt anticonvulsants (such as phenytoin and carbamazepine).
  • Pseudo Parkinson's disease manifests itself as an inability to exercise (tonic, stiff and slow voluntary movement, hunchback, walking) and tremors, as well as these symptoms that occur within weeks or months after the start of therapy.
  • meditation can not manifest itself as hyperactivity, subjective feelings of distress or discomfort, often misunderstood as agitation or anxiety, this common syndrome is often not diagnosed and has minimal response to treatment.
  • Delayed dyskinesia is a late-onset syndrome associated with long-term use of neuroleptic drugs. It occurs more often in older patients and is characterized by stereotyped, repetitive, involuntary, and rapid dance-like movements of the face, eyelids, mouth, tongue, limbs, and body.
  • Sedation can also be a feature of RLS and PLMS (periodic limb movement during sleep) and PLMD (periodic leg (or limb) dyskinesia).
  • RLS is a general disorder that causes the patient to have an unbearable and unpleasant desire to move their legs; it often appears at rest and/or at night and may disturb sleep. Patients who do not have typical RLS symptoms but who exhibit intermittent leg movements that adversely affect sleep are diagnosed with PLMS.
  • Treatment of RLS and PLMS has included levodopa/carbidopa, levodopa/benserazide, dopamine agonists (such as pramipexole and ropinirole), benzodiazepines Drugs, opioids, anticonvulsants and iron (ferrous sulfate).
  • dopamine agonists such as pramipexole and ropinirole
  • benzodiazepines Drugs
  • opioids opioids
  • anticonvulsants anticonvulsants
  • iron iron
  • A2A receptor is present in the basal ganglia at high density, which is important in controlling good exercise.
  • selective antagonists of the A 2A receptor are pharmacologically important because they exhibit reduced efficacy for motor impairment, thereby improving neurodegenerative diseases such as Parkinson's disease and related dyskinesias (eg Huntington's disease).
  • a 2A antagonists appear to exhibit a tendency to reduce side effects (eg, no dyskinesia) as compared to current dopaminergic treatments that result in an increased therapeutic index.
  • a 2A antagonists also have antidepressant properties and stimulate cognitive function.
  • a 2A receptor antagonists are not only expected to treat neurodegenerative diseases such as Parkinson's disease, Huntington's disease or Alzheim It is also a disease, and can also be used to treat other CNS-related diseases such as depression, hyperactivity syndrome, sleep disorders and anxiety.
  • adenosine A 2A receptor is also closely related to immune regulation. Immune regulation is an important means for the body to maintain a stable internal environment and resist external harmful stimuli. As an important transmitter and temperament of the body, adenosine is greatly increased in metabolic disorders and cell damage, activates adenosine receptors and exerts biological effects, and participates in the immune regulation of the body. Recent studies have shown that activation of adenosine A 2A receptors may play an important immunomodulatory role in many pathological processes such as ischemia, hypoxia, inflammation, trauma, transplantation, etc., which may be related to A 2A receptors in T cells, B cells, mononuclear macrophages, neutrophils and other immune cells have higher expression levels.
  • a 2A receptors are closely related to tumors. Under normal circumstances, the body can rely on the complete immune mechanism to effectively monitor and reject cancerous cells, such as: in cellular immunity, T lymphocytes, antibody-dependent cytotoxic cells (K cells), NK cells and macrophages to tumors The cells have a killing effect. However, if the cancerous cells themselves or the functions of the above-mentioned immune cells are changed, the immune system of the off-line is cleared, and the malignant hyperplasia forms a tumor. Studies have shown that the activation of A 2A receptor can promote the body to produce immune tolerance, and closely participate in the formation of "immune escape” or "immunosuppression" of tumor cells, which creates favorable conditions for the occurrence and development of tumors.
  • a 2A receptor activation can promote angiogenesis in a dose-dependent manner by inhibiting the expression of thrombospondin in vascular endothelial cells, creating a favorable environment for the growth of vascular-dependent tumors; activation of A 2A receptors can also be achieved by increasing cAMP.
  • Activation of PKA inhibits the killing of tumor cells by natural killer cells; it can promote the proliferation of tumor cells such as melanoma A375 cells, fibroblast NIH3T3 cells and pheochromocytoma PC12 cells.
  • a 2A receptor antagonists can be used to treat various tumors such as lung cancer, especially non-small cell lung cancer.
  • Candidates for A 2A receptor antagonists need to bind strongly to the A 2A receptor but not to other adenosine receptors, ie, require a higher A 2A receptor subtype selectivity, so Helps reduce potential side effects.
  • a number of small-molecule adenosine A 2A receptor antagonists have been introduced into clinical phase I studies for the treatment of tumors. Corvus companies such as CPI-444, show a binding affinity A 2A receptor (Ki) of 3.5nm, A 1 receptor affinity (Ki) of 192nm, the selectivity to the A 1 receptor subtype of 54 times. Based on these results, the investigators believe that CPI-444 has sufficient safety and potential efficacy in a reasonable dose range at the current expected dose level.
  • CPI-444 was tested in three mouse models of different tumors, namely the EL-4 lymphoma model, the MC38 colon tumor model, and the CT26 colon tumor model, and the results showed that the number of lymph nodes at the cancer cells was significantly reduced, or The tumor volume at the primary site was significantly reduced, or the tumor volume was stable or resolved, and even some mice showed complete cure.
  • Heptares' AZD4635 also entered the clinical phase I treatment of advanced solid tumors.
  • a 2A receptors are also closely related to wound healing or atrial fibrillation. Many studies have shown that A 2A receptor antagonists can also be used to treat diabetes.
  • the Chinese invention patent (CN102892761) provides a 4-aminopyrimidine derivative as an adenosine A 2A receptor antagonist:
  • R 1 represents a pyrazole, thiazole or triazole ring optionally substituted by one or two halogen atoms or substituted by one or two methyl or trifluoromethyl groups.
  • This compound has a better antagonistic effect on the adenosine A 2A receptor, showing its affinity for A 2A , but its selectivity for A 1 is also low, resulting in the presence of the A 1 receptor. The selectivity of the A 2A receptor is low.
  • the pyrazole compounds of the invention have poor pharmacokinetic characteristics, high plasma clearance, and a short half-life in rats.
  • the present invention provides a 4-aminopyrimidine derivative as an adenosine A 2A receptor antagonist, which has the following structural formula (I):
  • R 1 is selected from halogen, cyano or trifluoromethyl
  • R 2 is selected from pyrazolyl, pyrrolidinyl, or pyrazolyl or pyrrolidinyl substituted by one or more halogen or C 1-3 alkyl;
  • R 3 is selected from oxazolyl, oxadiazolyl, triazolyl, or oxazolyl substituted with one or more halogen or C 1-3 alkyl.
  • the above 4-aminopyrimidine derivative as an adenosine A 2A receptor antagonist, wherein R 2 is selected from pyrazolyl or pyrrolidinyl; and R 3 is selected from oxazolyl, oxadiazolyl, and tri A oxazolyl group or an oxazolyl group substituted with a C 1-3 alkyl group.
  • the above 4-aminopyrimidine derivative as an adenosine A 2A receptor antagonist, wherein the 4-aminopyrimidine derivative is selected from the group consisting of:
  • the 4-aminopyrimidine derivative is selected from the group consisting of (1), (5), (8), (10), (13), (14), (17) or (18).
  • the invention also provides the use of a 4-aminopyrimidine derivative as described above for the manufacture of a medicament for the treatment of a disease or condition responsive to A2A antagonism.
  • the disease or condition comprises any one or more of a neurodegenerative disease, an extrapyramidal syndrome, depression, hyperactivity syndrome, sleep disorder, anxiety, diabetes or a tumor.
  • the tumor is lung cancer, ovarian cancer, pancreatic cancer, gastric cancer, breast cancer, glioblastoma, melanoma, renal cell carcinoma, triple negative breast cancer, colorectal cancer, head and neck cancer, bladder cancer, Prostate cancer, hepatocellular carcinoma or cholangiocarcinoma.
  • the lung cancer is non-small cell lung cancer.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described 4-aminopyrimidine derivative as an adenosine A 2A receptor antagonist, and a pharmaceutically acceptable excipient thereof.
  • the present invention also provides a compound drug comprising the above 4-aminopyrimidine derivative and a drug capable of being used therewith.
  • the combination drug is a compound for treating a disease or a condition: a neurodegenerative disease, an extrapyramidal syndrome, depression, hyperactivity syndrome, sleep disorder, anxiety, diabetes, or tumor.
  • the 4-aminopyrimidine derivative provided by the invention has obvious selective antagonism to the adenosine A 2A receptor, has good pharmacokinetic characteristics, and can be applied to the treatment of A 2A
  • a composition or combination of diseases or conditions in which a response is responsive particularly for the treatment of diseases such as neurodegenerative diseases, extrapyramidal syndrome, depression, hyperactivity syndrome, sleep disorders, anxiety disorders, diabetes or tumors or Illness.
  • the present invention provides a 4-aminopyrimidine derivative as an adenosine A 2A receptor antagonist, which has the following structural formula (I):
  • R 1 is selected from halogen, cyano or trifluoromethyl
  • R 2 is selected from pyrazolyl, pyrrolidinyl, or pyrazolyl or pyrrolidinyl substituted by one or more halogen or C 1-3 alkyl;
  • R 3 is selected from oxazolyl, oxadiazolyl, triazolyl, or oxazolyl substituted with one or more halogen or C 1-3 alkyl.
  • the above 4-aminopyrimidine derivative as an adenosine A 2A receptor antagonist, wherein R 2 is selected from pyrazolyl or pyrrolidinyl; and R 3 is selected from oxazolyl, oxadiazolyl, and tri A oxazolyl group or an oxazolyl group substituted with a C 1-3 alkyl group.
  • the above 4-aminopyrimidine derivative as an adenosine A 2A receptor antagonist, wherein the 4-aminopyrimidine derivative is selected from the group consisting of:
  • the 4-aminopyrimidine derivative is selected from the group consisting of (1), (5), (8), (10), (13), (14), (17) or (18).
  • the invention also provides the use of a 4-aminopyrimidine derivative as described above for the manufacture of a medicament for the treatment of a disease or condition responsive to A2A antagonism.
  • the disease or condition comprises any one or more of a neurodegenerative disease, an extrapyramidal syndrome, depression, hyperactivity syndrome, sleep disorder, anxiety, diabetes or a tumor.
  • the tumor is lung cancer, ovarian cancer, pancreatic cancer, gastric cancer, breast cancer, glioblastoma, melanoma, renal cell carcinoma, triple negative breast cancer, colorectal cancer, head and neck cancer, bladder cancer, Prostate cancer, hepatocellular carcinoma or cholangiocarcinoma.
  • the lung cancer is non-small cell lung cancer.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described 4-aminopyrimidine derivative as an adenosine A 2A receptor antagonist, and a pharmaceutically acceptable excipient thereof.
  • the present invention also provides a compound drug comprising the above 4-aminopyrimidine derivative and a drug capable of being used therewith.
  • the combination drug is a compound for treating a disease or a condition: a neurodegenerative disease, an extrapyramidal syndrome, depression, hyperactivity syndrome, sleep disorder, anxiety, diabetes, or tumor.
  • the 4-aminopyrimidine derivatives provided by the present invention as adenosine A 2A receptor antagonists can be synthesized by one of the following synthetic routes:
  • Reagents and conditions (a), acetic anhydride, reflux; (b), pyrazole, cesium carbonate, dimethylformamide (DMF), 80 ° C; (c), trans- ⁇ -styrene boronic acid, sodium carbonate, Dioxane, room temperature; tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), 90 ° C; (d), ozone, methanol (MeOH) / dichloromethane (CH 2 Cl 2 ), -78 °C; (e), p-toluenesulfonylmethyl isocyanide (TOSMIC), potassium carbonate (K 2 CO 3 ), MeOH, 80 ° C; (f), N-bromosuccinimide, DMF.
  • Reagents and conditions (a), m-chloroperbenzoic acid, dichloromethane, room temperature; (b), N-bromosuccinimide (NBS), DMF, room temperature; (c), 1. oxazole, Butyllithium (n-BuLi), tetrahydrofuran (THF), -78 ° C ⁇ -20 ° C, 2. Pd (PPh 3 ) 4 , 80 ° C; (d), 1H-pyrazole, cesium carbonate, DMF, 90 ° C (e), pyrrolidine, cesium carbonate, DMF, 90 ° C.
  • DMF dimethyl methacrylate
  • a base such as cesium carbonate or butyl lithium
  • a sulfoxide of formula (G) with a different commercially available five-membered heterocyclic ring (eg, pyrazole, oxazole, oxadiazole or tri
  • the azole derivative is reacted at room temperature or at a low temperature to form two derivatives substituted with a five-membered heterocyclic ring.
  • an intermediate of formula (G) is reacted with an oxazole under these conditions to provide a derivative of formula (H).
  • the 6-position chlorine atom of the pyrimidine derivative is further substituted by a five-membered heterocyclic derivative (for example, pyrazole or pyrrolidine) using DMF as a solvent in the presence of a base such as cesium carbonate or sodium methoxide.
  • a five-membered heterocyclic derivative for example, pyrazole or pyrrolidine
  • DMF dimethyl methoxide
  • a base such as cesium carbonate or sodium methoxide.
  • the compound (19) and (23) can be obtained by reacting the derivative (H) with a pyrazole or pyrrolidine under these conditions.
  • Reagents and conditions (a), cuprous cyanide, pyridine, microwave (MW), and the reaction was carried out at 250 ° C for 20 minutes. (b) potassium fluoride (KF), bis(dibenzylideneacetone)palladium (Pd(dba) 2 ), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4 ',6'-Triisopropyl-1,1'-biphenyl, trimethyl(trifluoromethyl)silane, dioxane, 20 h, 140 °C.
  • KF potassium fluoride
  • Pd(dba) 2 bis(dibenzylideneacetone)palladium
  • Pd(dba) 2 bis(dibenzylideneacetone)palladium
  • a similar precursor compound as shown in the compound (1) may be employed, as described in the synthesis scheme 3. The methods were prepared separately.
  • the preparation of the compound (1) has the following structural formula:
  • the third step is to prepare the intermediate (C)
  • the intermediate (C) (0.4 g, 1.6 mmol) was dissolved in a mixture of methanol/dichloromethane (4/1, 20 ml), cooled to -78 ° C After completion of the reaction, nitrogen gas was introduced for 20 minutes, methyl ether was added, and the reaction liquid was heated to room temperature, and then nitrogen gas was introduced to completely evaporate the solvent to obtain a crude product (D). MS m/z (ESI): 2321. [M+1] + .
  • Compound (6) is obtained according to the synthesis scheme 1, wherein the compound obtained by the step 5 is prepared by replacing methyl p-toluenesulfonylmethyl isocyanide (Me-TOSMIC) with p-toluenesulfonylmethyl isocyanide (TOSMIC) to obtain a compound ( An analog of E).
  • the third step preparation of the intermediate 5-bromo-6-chloro-2-(oxazol-2-yl)pyrimidine-4-amine (H):
  • Example 15 Prepared according to the above synthetic route 2, and the specific method is shown in Example 15.
  • the intermediate (G) and 1H-triazole are replaced by a reaction of cesium carbonate in a DMF solution at room temperature for several hours to prepare a corresponding intermediate (H) analog.
  • the compound (25) was obtained by substituting a pyrazole at the 6-position of the pyrimidine with a similar method of Example 15.
  • the binding affinity of the compounds of the invention to the human adenosine A 2A receptor in vitro was determined by determining the conversion of the human adenosine A 2A receptor selective radioligand [ 3 H]CGS-21680 using standard techniques. In Table 1.
  • NECA adenosine-5'-N-ethylcarboxyamide
  • the concentration-response binding competition curve was determined by analyzing a plurality of different concentrations. IC 50 values were calculated using a nonlinear fitting program. The inhibition constant (Ki) of the compound was calculated by Cheng-Prusoff equation (II).
  • Ki IC 50 /(1+[L]/KD) (II)
  • IC 50 is the concentration of the compound when 50% of the radioligand is converted
  • [L] is the free concentration of the radioligand
  • KD is the dissociation constant of the radioligand.
  • the IC 50 value was obtained by fitting the data by nonlinear regression using Prism software. The smaller the Ki value, the more obvious the antagonism of the compound to the human adenosine A 2A receptor.
  • the binding affinity of a compound of the invention to a human adenosine A 1 receptor in vitro is determined by determining the conversion of the human adenosine A 1 receptor selective radioligand [ 3 H]DPCPX using standard techniques to determine the present invention. The selective strength of the compound to the A 2A receptor. The results are summarized in Table 1.
  • CGS-21680 is a high adenosine A 2A receptor agonist activity, can function to promote platelet aggregation adenosine A 2A receptor.
  • the antagonistic activity of the compounds of the invention on the adenosine A 2A receptor at the cellular level can be obtained by testing the compound to inhibit CGS-21680-induced platelet aggregation. The results are summarized in Table 1.
  • the test compound When no significant agonistic activity was observed at a certain test substance concentration, which reduced CGS-21680 (1 ⁇ M)-induced inhibition by 50% or more ( ⁇ 50%), the test compound had adenosine A 2A Receptor antagonistic activity.
  • the inhibition constant (Ki) of the compound was calculated as described above, and the smaller the Ki value, the more obvious the antagonistic effect of the compound on the human adenosine A 2A receptor.
  • the compound prepared by the present invention has a significant antagonistic effect on the human adenosine A 2A receptor at the nM concentration level. And when the hydrogen absorption property of the R 1 group is enhanced, such as a halogen atom changing from bromine to chlorine, or from a halogen atom to a cyano group, the antagonistic activity of the compound of the present invention on the human adenosine A 2A receptor is markedly improved. .
  • Example 1 is a compound of Example 1 in CN102892761, which is a pyrazole compound, and has the following structural formula:
  • a 1 and A 2A are highly expressed receptors, low levels of adenosine concentration can be produced under physiological conditions, while A 2B and A 3 are expressed at lower levels. Only in the pathological situation, a large increase in adenosine can activate the pathological effect.
  • the oxazole compound of the present invention has a markedly high selectivity to the A 2A receptor relative to the A 1 receptor (the selectivity coefficient is the inhibition constant and the pair of compounds in Table 1 for the affinity of the human adenosine A 1 receptor)
  • the ratio of the inhibition constant of human adenosine A 2A receptor affinity), and the selectivity coefficient of some compounds 3-4 times the selectivity coefficient of the reported compound VI in CN102892761, can be considered significant in the art. progress.
  • the antagonistic and functional activity of the oxazole compound of the present invention against the human adenosine A 2A receptor is comparable or superior to that of the pyrazole compound VI described in CN102892761, and is directed to the human gland.
  • the affinity of the glycoside A 1 receptor is significantly reduced, exhibiting a high selectivity for the A 2A receptor.
  • SD rats were used as test animals according to a conventional method, and the rats were intravenously administered with the compounds of the present invention (1), (5), (8), (10), and (13) by LC/MS/MS method.
  • the drug concentration in the plasma at the time of the study, the pharmacokinetic behavior of the compound of the present invention in rats was investigated, and its pharmacokinetic characteristics were evaluated.
  • Compound VI reported in the patent CN102892761 is now used as a positive control and tested simultaneously by the above method. The results are summarized in Table 2.
  • the oxazole compound of the present invention has better pharmacokinetic characteristics and has a significantly lower plasma clearance than the pyrazole compound VI described in CN102892761, thereby maintaining high The blood concentration and the longer effective time; the half-life of the oxazole compound of the present invention in rats is more than three times the half life of the compound VI, and the half-life is extended by 20% to 40% in the technical field. It can be considered that it is better, and it is considered to have a significant improvement by more than one time; therefore, the compound of the present invention maintains a higher blood concentration and a longer effective treatment time than the pyrazole compound VI described in CN102892761. Significant progress.
  • the 4-aminopyrimidine derivative provided by the present invention has a significant antagonistic effect on the human adenosine A 2A receptor and exhibits high A 2A receptor selectivity and metabolism in rats.
  • Good absorption can be applied to compositions or combination products for treating diseases or conditions responsive to A 2A antagonism, especially for treating neurodegenerative diseases, extrapyramidal syndrome, depression, hyperactivity syndrome, sleep disorders A disease or condition such as anxiety, diabetes or cancer.

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Abstract

L'invention concerne un dérivé de 4-aminopyrimidine utilisé en tant qu'antagoniste du récepteur A2A de l'adénosine, ayant la formule générale structurale (I). R1 est choisi parmi un atome d'halogène, groupe cyano ou groupe trifluorométhyle ; R2 est choisi parmi le pyrazolyle, pyrrolidyle, ou pyrazolyle ou pyrrolidyle substitué par un ou plusieurs halogènes ou groupes alkyle en C1-3 ; R3 est choisi parmi un groupe oxazolyle, groupe oxadiazole, groupe triazole ou oxazolyle substitué par un ou plusieurs halogènes ou des groupes alkyle en C1-3. Le dérivé de 4-aminopyrimidine fourni par la présente invention présente une action antagoniste évidente sur un récepteur A2A de l'adénosine d'origine humaine, et peut être appliqué à des compositions ou des combinaisons de produits pour le traitement de maladies ou de symptômes pathologiques ayant des réponses à l'action antagoniste de A2A, en particulier pour le traitement de maladies neurodégénératives, du syndrome extrapyramidal, de la dépression, du syndrome hypercinétique, du trouble du sommeil, du trouble de l'anxiété, du diabète, de tumeurs et d'autres maladies.
PCT/CN2018/085021 2017-07-05 2018-04-28 Dérivé de 4-aminopyrimidine utilisé en tant qu'antagoniste du récepteur a2a de l'adénosine et son application WO2019007140A1 (fr)

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CN201710542349.1 2017-07-05
CN201710542349.1A CN107286146B (zh) 2017-07-05 2017-07-05 作为腺苷a2a受体拮抗剂的4-氨基嘧啶衍生物及其用途

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CN109662966A (zh) * 2017-10-16 2019-04-23 北京莱科金基因科技有限责任公司 伊曲茶碱在制备用于肿瘤治疗的药物中的用途
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