WO2017088755A1 - Composé aminopyrimidine hétérocyclique présentant une activité antagoniste du récepteur de l'adénosine - Google Patents
Composé aminopyrimidine hétérocyclique présentant une activité antagoniste du récepteur de l'adénosine Download PDFInfo
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- WO2017088755A1 WO2017088755A1 PCT/CN2016/106906 CN2016106906W WO2017088755A1 WO 2017088755 A1 WO2017088755 A1 WO 2017088755A1 CN 2016106906 W CN2016106906 W CN 2016106906W WO 2017088755 A1 WO2017088755 A1 WO 2017088755A1
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- 0 */C(/C(*)=N)=C(/*)\[N+]I Chemical compound */C(/C(*)=N)=C(/*)\[N+]I 0.000 description 5
- SIBZHUFSEIKYOK-UHFFFAOYSA-N Cc1cc(C)n[n]1-c(nc1N)nc(-c2cccc(N3CCN(CCO)CC3)n2)c1C#N Chemical compound Cc1cc(C)n[n]1-c(nc1N)nc(-c2cccc(N3CCN(CCO)CC3)n2)c1C#N SIBZHUFSEIKYOK-UHFFFAOYSA-N 0.000 description 2
- APCBTRDHCDOPNY-SSDOTTSWSA-N CC(C)(C)OC(N(CC1)C[C@@H]1O)=O Chemical compound CC(C)(C)OC(N(CC1)C[C@@H]1O)=O APCBTRDHCDOPNY-SSDOTTSWSA-N 0.000 description 1
- APCBTRDHCDOPNY-ZETCQYMHSA-N CC(C)(C)OC(N(CC1)C[C@H]1O)=O Chemical compound CC(C)(C)OC(N(CC1)C[C@H]1O)=O APCBTRDHCDOPNY-ZETCQYMHSA-N 0.000 description 1
- JDQRSSIMVTUYLJ-UHFFFAOYSA-O CC([NH2+]I)=CC(C(F)(F)F)=N Chemical compound CC([NH2+]I)=CC(C(F)(F)F)=N JDQRSSIMVTUYLJ-UHFFFAOYSA-O 0.000 description 1
- MKAGQKICEHJCIJ-UHFFFAOYSA-N CCCNc1nc(-c(nc(nc2N)S(C)(=C)=C)c2C#N)ccc1 Chemical compound CCCNc1nc(-c(nc(nc2N)S(C)(=C)=C)c2C#N)ccc1 MKAGQKICEHJCIJ-UHFFFAOYSA-N 0.000 description 1
- WGIJOXAHSXYCDI-UHFFFAOYSA-N CCCNc1nc(-c2nc(-[n]3nc(C)cc3C)nc(N)c2C#N)ccc1 Chemical compound CCCNc1nc(-c2nc(-[n]3nc(C)cc3C)nc(N)c2C#N)ccc1 WGIJOXAHSXYCDI-UHFFFAOYSA-N 0.000 description 1
- PENINBLXMANRTE-UHFFFAOYSA-N CS(c(nc1Cl)nc(N)c1F)(=O)=O Chemical compound CS(c(nc1Cl)nc(N)c1F)(=O)=O PENINBLXMANRTE-UHFFFAOYSA-N 0.000 description 1
- MYWFFRQHPJCVNE-UHFFFAOYSA-N CSc(nc1N)nc(-c2cccc(Br)n2)c1C#N Chemical compound CSc(nc1N)nc(-c2cccc(Br)n2)c1C#N MYWFFRQHPJCVNE-UHFFFAOYSA-N 0.000 description 1
- FNOCMLDBRRASGU-UHFFFAOYSA-N Cc([n](nc1C)I)c1F Chemical compound Cc([n](nc1C)I)c1F FNOCMLDBRRASGU-UHFFFAOYSA-N 0.000 description 1
- VFKSBCYOXIJXAN-UHFFFAOYSA-N Cc(cc1C(F)(F)F)n[n]1I Chemical compound Cc(cc1C(F)(F)F)n[n]1I VFKSBCYOXIJXAN-UHFFFAOYSA-N 0.000 description 1
- DZKLEICJWIZWGU-UHFFFAOYSA-N Cc1c[n](C)nc1I Chemical compound Cc1c[n](C)nc1I DZKLEICJWIZWGU-UHFFFAOYSA-N 0.000 description 1
- USMHBSFETLMCEQ-UHFFFAOYSA-N Cc1cc(C)n[n]1-c(nc1-c(nc(cc2)N(CC3)CCC3OC)c2Cl)nc(N)c1C#N Chemical compound Cc1cc(C)n[n]1-c(nc1-c(nc(cc2)N(CC3)CCC3OC)c2Cl)nc(N)c1C#N USMHBSFETLMCEQ-UHFFFAOYSA-N 0.000 description 1
- LCYZHFJXASAOOM-UHFFFAOYSA-N Cc1cc(C)n[n]1-c(nc1-c2cccc(Br)n2)nc(N)c1C#N Chemical compound Cc1cc(C)n[n]1-c(nc1-c2cccc(Br)n2)nc(N)c1C#N LCYZHFJXASAOOM-UHFFFAOYSA-N 0.000 description 1
- UNUPJXYGLDBNFA-UHFFFAOYSA-N Cc1cc(C)n[n]1I Chemical compound Cc1cc(C)n[n]1I UNUPJXYGLDBNFA-UHFFFAOYSA-N 0.000 description 1
- LBTIQTFUCOVWKY-UHFFFAOYSA-N Cc1n[n](C)cc1I Chemical compound Cc1n[n](C)cc1I LBTIQTFUCOVWKY-UHFFFAOYSA-N 0.000 description 1
- XKTBNBFQKGBXHL-UHFFFAOYSA-N Cc1n[n](C)nc1I Chemical compound Cc1n[n](C)nc1I XKTBNBFQKGBXHL-UHFFFAOYSA-N 0.000 description 1
- HGTFGUSXBAVSDO-UHFFFAOYSA-N FC(c1cc(C(F)(F)F)n[n]1I)(F)F Chemical compound FC(c1cc(C(F)(F)F)n[n]1I)(F)F HGTFGUSXBAVSDO-UHFFFAOYSA-N 0.000 description 1
- IYWQCCHIVFXZML-UHFFFAOYSA-N I[n]1nccc1 Chemical compound I[n]1nccc1 IYWQCCHIVFXZML-UHFFFAOYSA-N 0.000 description 1
- FNOJZTQYFHKDPQ-UHFFFAOYSA-N I[n]1ncnc1 Chemical compound I[n]1ncnc1 FNOJZTQYFHKDPQ-UHFFFAOYSA-N 0.000 description 1
- LSYJAEKSDPYVEQ-UHFFFAOYSA-N Ic1cc(-c2cccc(I)n2)cnc1 Chemical compound Ic1cc(-c2cccc(I)n2)cnc1 LSYJAEKSDPYVEQ-UHFFFAOYSA-N 0.000 description 1
- NNXBSBHTRNCQQS-UHFFFAOYSA-N Ic1cccnn1 Chemical compound Ic1cccnn1 NNXBSBHTRNCQQS-UHFFFAOYSA-N 0.000 description 1
- USYVBQLOSZDDBE-UHFFFAOYSA-N Ic1ccncn1 Chemical compound Ic1ccncn1 USYVBQLOSZDDBE-UHFFFAOYSA-N 0.000 description 1
- OYWPFIUVDKHHGQ-UHFFFAOYSA-N Ic1cnccn1 Chemical compound Ic1cnccn1 OYWPFIUVDKHHGQ-UHFFFAOYSA-N 0.000 description 1
- VAQSRTGFMKWNIH-UHFFFAOYSA-N Ic1ncc[s]1 Chemical compound Ic1ncc[s]1 VAQSRTGFMKWNIH-UHFFFAOYSA-N 0.000 description 1
- AXDGIPMYJALRKV-UHFFFAOYSA-N Ic1ncccn1 Chemical compound Ic1ncccn1 AXDGIPMYJALRKV-UHFFFAOYSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N OCCN1CCNCC1 Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- Disclosed herein relates to the field of pharmaceutical technology, and particularly relates toan aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity.
- Adenosine is a ubiquitous modulator of a number of physiological activities, particularly within the cardiovascular and nervous systems, and regulates a wide range of physiological functionsby interacting with specific cell surface receptors.
- Known adenosine receptors (ARs) are classified as receptors A1, A2A, A2Band A3, and belong to the G protein-coupled receptor family.
- the A1and A3receptors down-regulate cellular cAMP levels through their coupling to G proteins to inhibit adenylate cyclase.
- the A2Aand A2Breceptors up-regulate cellular cAMP levels through their coupling to G proteins to activate adenylate cyclase.
- A1 ARs Under normal physiological conditions, A1 ARs are quiescent. However, A1 ARs are upregulated in conditions of stress, such as ischaemia, and in conditions of inflammation. A1 ARs are upregulated and activated in airway epithelium and bronchial smooth muscle in human asthmatics. Activation of A1 ARs induces the release of mediators and cytokines that lead to airway hyperreactivity, inflammation and airway remodeling, produces bronchoconstriction in human asthmatic bronchial tissue. Thus, the A1 AR antagonists can play potential therapeutic role in inflammatory diseases and asthma. In addition, A1 antagonists have also been shown to have therapeutic potential in diseases such as hypertension, congestive heart failure.
- the A2B adenosine receptor subtype (see Feoktistov, I., Biaggioni, I., Pharmacol. Rev. 1997, 49, 381-402) has been identified in a variety of human and murine tissues and is involved in the regulation of various physiological activities. For example, the binding of adenosine to A2B receptorsstimulates angiogenesis by promoting the growth ofendothelialcells. However, the hyperproliferation ofendothelialcellspromotesdiabeticretinopathy, and an undesirable increase in blood vessels occurs in neoplasia.
- A2B adenosine receptor subtypes appear to be associated with regulation of hepatic glucose production, modulation of intestinal motility and intestinal secretion. Therefore, A2B antagonists may be helpful for the treatment of type II diabetes and obesity.
- type I hypersensitivity disorders suchasasthma, hayfever, andatopiceczema, are stimulated by binding to A2B-receptorsof mast cells. Therefore, blocking these adenosinereceptorswould provide a therapeutic benefit againstsuchdisorders.
- A3 receptor antagonists have been recommended for development as anti-asthma drugs (Fishman and Bar-Yehuda, 2003; Nadeem and Mustafa, 2006) .
- A3 receptor antagonists have also been shown to play therapeutic role in various diseases including cardio-protection (Vasc. Pharmacol., 2005, 42, 271; J. Pharm. Exp. Ther., 2006, 319, 1200) and cancer (WO200010391) .
- Adenosine A2A receptors mainly distribute in striatum, modulate the release of GABA in the striatum, which possibly regulates the function of medium spiny neurons.
- CNS central nervous system
- ADHD attention deficit hyperactivity disorders
- stroke stroke
- ADHD attention deficit hyperactivity disorders
- Alzheimer's disease Feterholm et al., Annu. Rev. Pharmacol. Toxicol. 2005 45: 385-412; Higgins et al., Behav. Brain Res. 2007 185: 32-42; Dall'Igna et al., Exp Neurol.
- A2Areceptor antagonists may be a useful treatment for neurodegenerative movement disorders such as Parkinson and Huntington's disease (Tuite P, et al., J. Expert Opin Investig Drugs. 2003, 12: 1335-52; Popoli P. et al., J. Neurosci. 2002, 22: 1967-75) , restless leg syndrome (Happe S, et al., Neuropsychobiology.
- A2A antagonists may have therapeutic potential that be used as neuroprotective agents (Stone TW, Drug Dev. Res. 2001, 52: 323-330) , and for the treatment of sleep disorders (Dunwiddie TV., Ann. Rev. Neurosci. 2001, 24: 31-55) .
- the immune system is not only responsible for defending its host against microbial invasion, but also can remove the changed host component from organism, where anti-tumor immune mechanism exists.
- immune surveillance function is weakened due to immune system per se or tumor cells, favorable conditions are provided for the development and progression of tumors. It is demonstrated that the hypoxia in tumor tissue would induce the release of higher concentrations of adenosine, and activate T-cell surface A2A adenosine receptor-mediated A2A receptor binding dependent signaling pathway, thereby reduce the release of IFN- ⁇ and overexpress PD-1, CTLA-4, COX2, IL-10 and TGF- ⁇ , ultimately lettingtumor cells escape from the attack of the immune system and achieving immune escape (Sitkovsky M. V. et.
- A2A adenosine receptor antagonists are used for inhibiting A2A adenosine receptors on lymphocyte surface, the anti-tumor immunity in tumor microenvironment would be enhanced, thereby controlling and killing tumor cells.
- the A2A adenosine receptor antagonists in combination with other cancer immunotherapy, such as immune checkpoint monoclonal antibody, can enhance the killing effect on tumor cells (Comput. Struct. Biotechnol. J., 2015, 13: 265-2672) .
- an aminopyrimidine heterocyclic compound which can be used as an effective adenosine receptor antagonist, and can be used for the treatment or prevention of disorders caused by abnormal level of adenosine.
- An aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity comprising the compound of the general formula (I) ,
- a 1 , A 2 , A 3 , and A 4 are each independently selected from the group consisting of N and CR 6 ;
- R 1 is aryl or 5-6 membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O and S, wherein said aryl or 5-6 membered heteroaryl is unsubstituted or substituted by 1-3 R 7 groups;
- R 2 is independently selected from the group consisting of cyano and halo
- R 3 is independently selected from the group consisting of halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 ureido, C 2-6 oxoureido, C 1-6 alkoxy, C 1-6 acyl, NR 4 R 5 and CONR 4 R 5 ;
- R 4 andR 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 acyl, wherein said alkyl, cycloalkyl, and acyl may be substituted by 1-3 R 8 groups; or R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a saturated heterocycle comprising 1-3 heteroatoms independently selected from the group consisting of N, O and S, and said saturated heterocycle may be substituted by 1-3 R 9 groups, and two R 9 substituents may, together with the atom to which they are attached, also form a ring;
- R 6 and R 7 are each independently selected from the group consisting of hydrogen, deuterium, halo, hydroxy, cyano, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl unsubstituted or substituted by halo or deuterium;
- R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium, halo, hydroxy, cyano, morpholino, piperazin-1-yl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl unsubstituted or substituted by halo or deuterium;
- aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity preferably, it is the compound of the general formula (II) ,
- a 1 , A 2 , A 3 , and A 4 are each independently selected from the group consisting of N and CR 6 ;
- R 1 is aryl or 5-6 membered heteroaryl comprising 1-3 heteroatoms independently selected from N, O and S, wherein said aryl or 5-6 membered heteroaryl is unsubstituted or substituted by 1-3 R 7 groups;
- R 3 is independently selected from the group consisting of halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 ureido, C 2-6 oxoureido, C 1-6 alkoxy, C 1-6 acyl, NR 4 R 5 and CONR 4 R 5 ;
- R 4 andR 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 acyl, wherein said alkyl, cycloalkyl, and acyl may be substituted by 1-3 R 8 groups; or R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a saturated heterocycle comprising 1-3 heteroatoms independently selected from the group consisting of N, O and S, and said saturated heterocycle may be substituted by 1-3 R 9 groups, and two R 9 substituents may, together with the atom to which they are attached, also form a ring;
- R 6 and R 7 are each independently selected from the group consisting of hydrogen, deuterium, halo, hydroxy, cyano, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl unsubstituted or substituted by halo or deuterium;
- R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium, halo, hydroxy, cyano, morpholino, piperazin-1-yl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl unsubstituted or substituted by halo or deuterium;
- R 1 includes:
- aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity preferably, it is the compound of the general formula (IIA) ,
- R 1 is independently selected from
- a 1 , A 2 , A 3 , and A 4 are each independently selected from the group consisting of N and CR 6 ; wherein A 1 , A 2 , A 3 , and A 4 are each CR 6 ; alternatively, one of A 1 , A 2 , A 3 , and A 4 is N, the others are each CR 6 ;
- R 3 is independently selected from the group consisting of halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 ureido, C 2-6 oxoureido, C 1-6 alkoxy, C 1-6 acyl, NR 4 R 5 and CONR 4 R 5 ;
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 acyl, wherein said alkyl, cycloalkyl, and acyl may be substituted by 1-3 R 8 groups; or R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a saturated heterocycle comprising 1-3 heteroatoms independently selected from the group consisting of N, O and S, and said saturated heterocycle may be substituted by 1-3 R 9 groups, and two R 9 substituents may, together with the atom to which they are attached, also form a ring;
- R 6 and R 7 are each independently selected from the group consisting of hydrogen, deuterium, halo, hydroxy, cyano, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl unsubstituted or substituted by halo or deuterium;
- R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium, halo, hydroxy, cyano, morpholino, piperazin-1-yl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl unsubstituted or substituted by halo or deuterium;
- R 10 , R 11 , and R 12 are each independently selected from the group consisting of hydrogen, deuterium, halo, cyano, C 3-6 cycloalkyl, and C 1-6 alkyl unsubstituted or substituted by halo or deuterium; or a pharmaceutically acceptable salt thereof.
- aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity preferably, it is the compound of the general formula (IIB) ,
- R 1 is independently selected from
- a 1 , A 2 , A 3 , and A 4 are each independently selected from the group consisting of N and CR 6 ; wherein A 1 , A 2 , A 3 , and A 4 are each CR 6 ; alternatively, one of A 1 , A 2 , A 3 , and A 4 is N, the others are each CR 6 ;
- R 3 is NR 4 R 5 ;
- R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 acyl, wherein said alkyl, cycloalkyl, and acyl may be substituted by 1-3 R 8 groups; or R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a saturated heterocycle comprising 1-3 heteroatoms independently selected from the group consisting of N, O and S, and said saturated heterocycle may be substituted by 1-3 R 9 groups, and two R 9 substituents may, together with the atom to which they are attached, also form a ring;
- R 6 and R 7 are each independently selected from the group consisting of hydrogen, deuterium, halo, hydroxy, cyano, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl unsubstituted or substituted by halo or deuterium;
- R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium, halo, hydroxy, cyano, morpholino, piperazin-1-yl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 alkyl unsubstituted or substituted by halo or deuterium;
- R 10 , R 11 , and R 12 are each independently selected from the group consisting of hydrogen, deuterium, halo, cyano, C 3-6 cycloalkyl, and C 1-6 alkyl unsubstituted or substituted by halo or deuterium;
- R 3 includes:
- aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity described above preferably, it includes the following Example shown in Table 1 and possible enantiomers,
- the present invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising, an aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or diluent.
- the present invention further provides a combination comprising an aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity, the combination is a combination of an aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activitydisclosed herein with one or more of L-DOPA, dopamine agonists, dopamine decarboxylase inhibitors, catechol-O-methyltransferase inhibitors and monoamine oxidase inhibitors, cancer immunotherapy such as cancer vaccines, immune checkpoint inhibitors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) .
- CTLA-4 cytotoxic T-lymphocyte-associated protein 4
- PD-1 programmed cell death protein 1
- the present invention further provides use of an aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity or a combination comprising aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity in the manufacture of a medicament for antagonising an adenosine receptor.
- the aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activity disclosed herein is useful in the treatment of pathological conditions or diseases susceptible of being improved by antagonism of an adenosine receptor, in particular by antagonism of the A2Aadenosine receptor.
- the diseases or conditions susceptible of being improved by antagonism of an adenosine receptor include, but not limited to, tumor, Alzheimer's disease, Parkinson's disease, neuroprotection, schizophrenia, anxiety, pain, respiratory deficiency, depression, asthma, allergy, and psychoactive substance abuse.
- the present invention has the following prominent advantages:
- aminopyrimidine heterocyclic compound with adenosine receptor antagonistic activitydisclosed herein can be used as an effective adenosine receptor antagonist, and can be used for the treatment or prevention of disorders caused by abnormal level of adenosine.
- FIG. 1 depicts the inhibition curve of compound B10 of the present invention in the binding assay
- FIG. 2 depicts the inhibition curve of compound B16 of the present invention in the binding assay
- FIG. 3 depicts the inhibition histogram of compound Bl of the present invention in the function assay
- FIG. 4 depicts the inhibition histogram of compound Bl5 of the present invention in the function assay.
- Step A 4-amino-6- (6-bromopyridin-2-yl) -2- (methylthio) pyrimidine-5-carbonitrile
- Step B 4-amino-6- (6-bromopyridin-2-yl) -2- (methylsulfonyl) pyrimidine -5-carbonitrile
- Step C 4-amino-6- (6-bromopyridin-2-yl) -2- (3, 5-dimethyl-1H-pyrazol -1-yl) pyrimidine-5-carbonitrile
- Step D 4-amino-2- (3, 5-dimethyl-1H-pyrazol-1-yl) -6- (6- (4-methoxypiperidin -1-yl) pyridin-2-yl) pyrimidine-5-carbonitrile
- Step A 4-amino-6- (3, 6-dichloropyridin-2-yl) -2- (methylthio) pyrimidine -5-carbonitrile
- Step B 4-amino-6- (3, 6-dichl o ropyridin-2-yl) -2- (methylsulfonyl) pyrimidine-5-carbonitrile
- step A To a suspension of the product from step A (600 mg, 1.92 mmol) in a mixed solvent (THF/H 2 O, 10: 1, 7 mL) was added oxone ( 1.45 g, 4.84 mmol) . The mixture w as stirred at rt for 4 hs. 70 mL of H 2 O was added. A gray solid was precipi t ated and was filtered. The filte r cake was dried under lamp to give the title product (650 mg, crude) as a white solid.
- a mixed solvent THF/H 2 O, 10: 1, 7 mL
- oxone 1.45 g, 4.84 mmol
- Step C 4-amino-6- (3, 6-dichloropyridin-2-yl) -2- (3, 5-dimethyl-1H-pyrazol-1-yl) pyrimidine-5-carbonitrile
- Step D 4-amino-6- (3-chloro-6- (4-methoxypiperidin-1-yl) pyridin-2-yl) -2- (3, 5-dimethyl-1H-pyrazol-1-yl) pyrimidine-5-carbonitrile
- Step A tert-butyl (S) -3-hydroxypyrrolidine-1-carboxylate
- Step B tert-butyl (S) -3-methoxypyrrolidine-1-carboxylate
- step B To a solution of the product from step B (1.69 g, 8.41 mmol) in EA (5 mL) was added HCl/EA (10 mL) . The mixture was stirred at rt for 6 h. The solvent was removed to give the title product (1.24 g) as a brown oil which was used directly in the next step.
- Step D (S) -4-amino-2- (3, 5-dimethyl-1H-pyrazol-1-yl) -6- (6- (3-methoxy pyrrolidin-1-yl) pyridin-2-yl) pyrimidine-5-carbonitrile
- Step A tert-butyl (R) -3-hydroxypyrrolidine-1-carboxylate
- Step B tert-butyl (R) -3-methoxypyrrolidine-1-carboxylate
- step B To a solution of the product from step B (1.65 g, 8.21 mmol) in EA (5 mL) was added HCl/EA (10 mL) . The mixture was stirred at rt for 6 h. The solvent was removed to give the title product (1.14 g) as a brown oil which was used directly in the next step.
- Step D (R) -4-amino-2- (3, 5-dimethyl-1H-pyrazol-1-yl) -6- (6- (3-methoxy pyrrolidin-1-yl) pyridin-2-yl) pyrimidine-5-carbonitrile
- Step B
- Step C
- Step A tert-butyl 4-cyclopropylpiperazine-1-carboxylate
- Step A 4-amino-6- (3-methoxyphenyl) -2- (methylthio) pyrimidine-5-carbonitrile
- Step B 4-amino-6- (3-methoxyphenyl) -2- (methylsulfonyl) pyrimidine-5-carbonitrile
- Step B 4-amino-6- (3-methoxyphenyl) -2- (methylsulfonyl) pyrimidine-5-carbonitrile
- Step B 4-amino-6- (5-methoxypyridin-3-yl) -2-phenylpyrimidine-5-carbonitrile
- Step A 4-amino-6- (5-methoxypyridin-3-yl) -2- (methylthio) pyrimidine-5-carbonitrile
- Step B 4-amino-6- (5-methoxypyridin-3-yl) -2- (methylsulfonyl) pyrimidine
- Step A 6-chloro-5-fluoro-2- (methylthio) pyrimidin-4-amine
- Step B 6-chloro-5-fluoro-2- (methylsulfonyl) pyrimidin-4-amine
- Step C 6-chloro-2- (3, 5-dimethyl-1H-pyrazol-1-yl) -5-fluoropyrimidin-4-amine
- Step D potassium trifluoro (5-methoxypyridin-3-yl) borate
- Step A (R) -3- (2-methylpiperazin-1-yl) propanenitrile
- Step A (S) -3- (2-methylpiperazin-1-yl) propanenitrile (3-1)
- HEK293 (G418 resistant) cells stably expressing adenosine A2A were collected and dissolvedinto lysis buffer (5 mM Tris base, pH 7.4, EDTA ⁇ Na 25 mM, EGTA 5 mM, PMSF 1: 1000) , and then lysed on ice for 30 min. The lysate was passed through needle (1 mL needle) on ice bath for 15 times, and then high speed centrifugation (40000 r/min, 4°C, 20 min) to give crude HEK293/A2A cell membrane.
- lysis buffer 5 mM Tris base, pH 7.4, EDTA ⁇ Na 25 mM, EGTA 5 mM, PMSF 1: 1000
- reaction buffer 50mM Tris, pH 7.4, 2mM MgCl2
- reaction buffer 50mM Tris, pH 7.4, 2mM MgCl2
- high speed centrifugation 40000 r/min, 4°C, 20 min
- the membrane protein was dissolved in 500 ⁇ L reaction buffer and passed through needle (1 mL needle) on ice bath for 10 times. Protein concentration was measured by BCA assay, and the protein was stored in a refrigerator at -80°C.
- membrane protein 50 ⁇ g
- 0.1 nM [3H] ZM241385 50.00 Ci/mmol
- the bound ligands and free ligands were separated by GF/B glass fiber filter papers through vacuum filtration on a 12-well Millipore cell sample collector, and then were washed with ice cold 50 mM Tris-HCl for 3 times.
- the membrane was oven-dried and placed in EP tube, to which 540 ⁇ L scintillation solutions were added.
- the binding of the radioactive ligands was measured by Beckman LS-6500 Liquid Scintillation Counter.
- the percentage competitive inhibition rate of each Examplegainst the binding of isotope with the protein receptor was calculated according to the following formula, where cpm is the reading value of the radioactive ligand measured by the assay:
- Inhibition rate (I%) (Total binding tube cpm-compound cpm) / (Total binding tube cpm-non-specific binding tube cpm) ⁇ 100%
- the Ki value of a test compound was calculatedfrom a plot of the concentration of the Examples X-axis versus the competitive inhibition rate of each Examplegainst the binding of isotope with the protein receptor as Y-axis. The smaller the Ki value, the better the binding ability of the compound to A2A adenosine receptor.
- the aminopyrimidine heterocyclic compounds of the Examples areeffective adenosine receptor antagonists, have a strong binging to the receptor, and effectively block adenosine receptor.
- the aminopyrimidine heterocyclic compounds disclosed herein can be used for the treatment or prevention of disorders caused by abnormal level of adenosine.
- Lymphocytes isolated from the spleen of C57/BL6 mice were placed in 96-well plate with 5 ⁇ 10 5 cells each well.
- Mouse spleen cells would produce IFN- ⁇ under the induction of 0.1 ⁇ g/mL CD3 monoclonal antibody (mAb) .
- mAb monoclonal antibody
- the addition of 100 nM A2A receptor agonist CGS21680 could inhibit the production of IFN- ⁇ .
- different concentrations of test compounds taken together with 100 nM A2A receptor agonist CGS21680 were added to mouse spleen cells to which CD3 mAb had been added.
- the supernatant was collected to perform enzyme-linked immunosorbent assay (ELISA assay) by using a kit from eBioscience (Cat: #887314) , and determine the concentration of IFN- ⁇ in the supernatant.
- ELISA assay enzyme-linked immunosorbent assay
- the EC50 value of a test compound was calculatedfrom a histogram of the concentration of the Examples X-axis versus the concentration of IFN- ⁇ in the supernatant as Y-axis. The smaller the EC50 value, the better the inhibitory ability of T-cell surface A2A adenosine receptor-mediated A2A receptor binding dependent signaling pathway.
- the aminopyrimidine heterocyclic compounds of the Examples are effective adenosine receptor antagonists, are able to effectively block the adenosine receptor on lymphocyte surface such that the cancer cells fail to escape from immune surveillance.
- the aminopyrimidine heterocyclic compounds disclosed herein can thusbe used for the treatment or prevention of cancer.
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Abstract
La présente invention concerne un composé aminopyrimidine hétérocyclique avec une activité antagoniste du récepteur de l'adénosine, comprenant un composé de formule générale (I), ou un sel pharmaceutiquement acceptable de celui-ci. Le composé aminopyrimidine hétérocyclique avec une activité antagoniste du récepteur de l'adénosine de la présente invention peut être utilisé en tant qu'antagoniste efficace du récepteur de l'adénosine, et peut être utilisé pour le traitement ou la prévention de troubles causés par un niveau anormal d'adénosine.
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