CN111116592A - Pyrimidotriazole compounds and medical application thereof - Google Patents
Pyrimidotriazole compounds and medical application thereof Download PDFInfo
- Publication number
- CN111116592A CN111116592A CN201911179457.2A CN201911179457A CN111116592A CN 111116592 A CN111116592 A CN 111116592A CN 201911179457 A CN201911179457 A CN 201911179457A CN 111116592 A CN111116592 A CN 111116592A
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- China
- Prior art keywords
- alkyl
- unsubstituted
- substituted
- compound
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- GIIGHSIIKVOWKZ-UHFFFAOYSA-N 2h-triazolo[4,5-d]pyrimidine Chemical class N1=CN=CC2=NNN=C21 GIIGHSIIKVOWKZ-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 9
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 125000004035 thiopropyl group Chemical group [H]SC([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 27
- 239000003146 anticoagulant agent Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 16
- 230000000702 anti-platelet effect Effects 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 11
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 10
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 9
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- QHCCDDQKNUYGNC-UHFFFAOYSA-N n-ethylbutan-1-amine Chemical compound CCCCNCC QHCCDDQKNUYGNC-UHFFFAOYSA-N 0.000 claims description 4
- 230000002785 anti-thrombosis Effects 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000001336 alkenes Chemical group 0.000 claims description 2
- 150000001345 alkine derivatives Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 22
- 239000000203 mixture Substances 0.000 abstract description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 68
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 29
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- 239000000243 solution Substances 0.000 description 27
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 239000003208 petroleum Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 8
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 8
- 210000004623 platelet-rich plasma Anatomy 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- -1 cyclopentyl pyrimidotriazole compound Chemical class 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- CDLOITPKGGWOCP-UHFFFAOYSA-N 1-aminocyclopent-2-ene-1-carboxylic acid Chemical compound OC(=O)C1(N)CCC=C1 CDLOITPKGGWOCP-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
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- DDEDQHVHVPJFAC-UHFFFAOYSA-N 4,6-dichloro-5-nitro-2-propylsulfanylpyrimidine Chemical compound CCCSC1=NC(Cl)=C([N+]([O-])=O)C(Cl)=N1 DDEDQHVHVPJFAC-UHFFFAOYSA-N 0.000 description 4
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 4
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- DDUFYKNOXPZZIW-UHNVWZDZSA-N (1s,4r)-3-azabicyclo[2.2.1]hept-5-en-2-one Chemical compound C1[C@@H]2C(=O)N[C@H]1C=C2 DDUFYKNOXPZZIW-UHNVWZDZSA-N 0.000 description 3
- BQMUXHINUCSTAQ-UHFFFAOYSA-N 1-amino-2,3-dihydroxycyclopentane-1-carboxylic acid Chemical compound OC(=O)C1(N)CCC(O)C1O BQMUXHINUCSTAQ-UHFFFAOYSA-N 0.000 description 3
- CJJLJBFJNXMANZ-UHFFFAOYSA-N 4,6-dichloro-2-propylsulfanylpyrimidin-5-amine Chemical compound CCCSC1=NC(Cl)=C(N)C(Cl)=N1 CJJLJBFJNXMANZ-UHFFFAOYSA-N 0.000 description 3
- JNDANYQUROGPBP-UHFFFAOYSA-N 4-hydroxy-2-propylsulfanyl-1h-pyrimidin-6-one Chemical compound CCCSC1=NC(O)=CC(=O)N1 JNDANYQUROGPBP-UHFFFAOYSA-N 0.000 description 3
- PHMVMACIFWKESN-UHFFFAOYSA-N 4-hydroxy-5-nitro-2-propylsulfanyl-1h-pyrimidin-6-one Chemical compound CCCSC1=NC(O)=C([N+]([O-])=O)C(O)=N1 PHMVMACIFWKESN-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 229940127218 antiplatelet drug Drugs 0.000 description 3
- 229940127217 antithrombotic drug Drugs 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 3
- 229960003009 clopidogrel Drugs 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- ANVYHALMQXHQSG-RITPCOANSA-N methyl (1s,4r)-4-aminocyclopent-2-ene-1-carboxylate Chemical compound COC(=O)[C@H]1C[C@@H](N)C=C1 ANVYHALMQXHQSG-RITPCOANSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
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- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 3
- 229960002528 ticagrelor Drugs 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
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- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 2
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000003715 nutritional status Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention relates to a compound of a general formula (I) or an isomer, a hydrate or a pharmaceutically acceptable salt thereof. The invention also relates to a preparation method of the compound or the isomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof, a medicinal composition containing the compound and application thereof in preparing medicaments for resisting platelet aggregation and treating related diseases such as thrombosis.
Description
Technical Field
The present invention relates to novel pyrimidotriazoles and their use for the inhibition of platelet aggregation. The invention also relates to a preparation method of the compound or the isomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof, a medicinal composition containing the compound and application of the compound or the isomer thereof, the hydrate thereof or the pharmaceutically acceptable salt thereof in preparing anti-platelet aggregation or anti-thrombosis medicaments for treating related diseases such as thrombosis.
Background
The thrombus disease causes the dysfunction of human body, leads to the death of a large number of patients every year, becomes the first killer threatening the human health, and the market needs safe and effective medicine for preventing and treating the thrombus disease urgently.
Antithrombotic drugs mainly include antiplatelet drugs, anticoagulant drugs and thrombolytics, and the antiplatelet drugs are the main drugs. The P2Y12 receptor plays a central role in the platelet activation and aggregation process and becomes an important target for antiplatelet drug therapy. Clopidogrel, an antiplatelet anti-thrombotic drug, is a P2Y12 receptor irreversible antagonist.
However, clopidogrel limits its therapeutic effect by irreversibly inhibiting platelets, presenting a series of side reactions. The newly-appeared ticagrelor and other drugs reversibly inhibit the action mechanism of the P2Y12 receptor, and show safer and more effective treatment effects. Therefore, the research of the novel P2Y12 receptor antagonist for resisting platelet aggregation is of great significance.
Ticagrelor (Ticagrelor) is a representative cyclopentyl pyrimidotriazole compound, and is a novel selective small molecule anticoagulant developed by the american company AstraZeneca (AstraZeneca). The medicine can act on P2Y12 receptor reversibly, has obvious inhibition effect on platelet aggregation caused by ADP, and has quick effect after oral administration, thereby effectively improving symptoms of patients with acute coronary heart disease. Has stronger effect on preventing new heart attack and reducing heart disease death than clopidogrel. And approved by FDA as a new anti-platelet aggregation medicine in 7 months in 2011.
There remains a need in the art for new effective anti-platelet aggregation and treatment-related diseases such as antithrombotic agents.
Disclosure of Invention
The invention provides a novel pyrimidotriazole compound which is discovered and provided unexpectedly, has good anti-platelet aggregation activity in vitro activity research, and can be used for anti-platelet aggregation and treatment of related diseases such as antithrombotic drugs.
Specifically, the invention provides a compound of a general formula (I) or an isomer, a hydrate or a pharmaceutically acceptable salt thereof,
wherein
R, R' independently represents hydrogen, unsubstituted or substituted alkyl, cycloalkyl, alkoxyalkyl, aminoalkyl, phenylalkyl, heterocyclylalkyl or phenyl,
R1represents hydrogen, unsubstituted or substituted alkyl, alkene, alkyne, cycloalkyl, alkoxyalkyl, aminoalkyl, phenylalkyl, heterocyclylalkyl, benzeneThe base group is a group of a compound,
R2represents hydrogen, unsubstituted or substituted alkyl, alkoxyalkyl, aminoalkyl, phenylalkyl, heterocyclylalkyl, phenyl, heterocyclylalkyl, heteroaromatic,
R3、R4independently represent hydrogen, unsubstituted or substituted alkyl, cycloalkyl, alkoxyalkyl, aminoalkyl, phenylalkyl, heterocyclylalkyl, phenyl, heterocyclyl, or R4And R5May form a ring together with the adjacent carbon atom.
Among them, the alkyl group is preferably a 1-8C alkyl group, particularly a 1-4C alkyl group, including straight-chain and branched alkyl groups such as methyl, ethyl, propyl, isopropyl, tert-butyl and the like.
Wherein the cycloalkyl group includes (3-8C) cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
Among them, the alkoxy group includes 1-8C alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.
Wherein the substituent in the aforementioned substituted or substituted alkyl, cycloalkyl, alkoxyalkyl, aminoalkyl, phenylalkyl, heterocyclylalkyl or phenyl group may be a hydroxyl group, a 1-3C alkyl group unsubstituted or substituted with a 1-3C alkyl group, a 1-3C alkoxy group unsubstituted or substituted with a 1-3C alkyl group, a phenyl group unsubstituted or substituted with a 1-3C alkyl group, or a benzyl group unsubstituted or substituted with a 1-3C alkyl group.
In one aspect of the present invention, R, R' in the compound of formula (I) independently represents hydrogen, alkyl which is unsubstituted or substituted by a substituent, phenylalkyl which is unsubstituted or substituted by a substituent. In yet another aspect of the present invention, the substituent is hydroxy, 1-3C alkyl unsubstituted or substituted with 1-3C alkyl, 1-3C alkoxy unsubstituted or substituted with 1-3C alkyl, phenyl unsubstituted or substituted with 1-3C alkyl, benzyl unsubstituted or substituted with 1-3C alkyl.
In one aspect of the invention, R in the compound of formula (I)1Represents hydrogen, unsubstituted or substituted alkyl, said substitutionThe radical is a 1-3C alkyl radical which is unsubstituted or substituted by a 1-3C alkyl radical, or a 1-3C alkoxy radical which is unsubstituted or substituted by a 1-3C alkyl radical.
In one aspect of the invention, R in the compound of formula (I)2Represents hydrogen, unsubstituted or substituted alkyl, which is unsubstituted or substituted by 1-3C alkyl, 1-3C alkoxy which is unsubstituted or substituted by 1-3C alkyl.
In one aspect of the invention, R in the compound of formula (I)3、R4Independently represent hydrogen, alkyl which is unsubstituted or substituted by a substituent which is 1-3C alkyl which is unsubstituted or substituted by 1-3C alkyl, 1-3C alkoxy which is unsubstituted or substituted by 1-3C alkyl.
As used herein, the term "pharmaceutically acceptable" generally means that it is useful in the pharmaceutical or medical arts, or that it is not directly useful in the pharmaceutical or medical arts, but is useful as an intermediate in the manufacture of pharmaceutical or medical products and is removed by a suitable method prior to its ultimate use in the pharmaceutical or medical arts. For example, pharmaceutically acceptable salts include not only pharmaceutically acceptable salts that are clinically useful, but also salts that are not directly clinically useful but which may be used in the preparation of the compounds of the invention and removed during subsequent processing.
Suitable pharmaceutically acceptable salts of the compounds of general formula (I) according to the invention are, for example, acid addition salts of the compounds of formula I, for example with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid or maleic acid; or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.
In one aspect of the invention, the compound of formula (I) is selected from:
(3R,4S,6R,6S) -6- [ 7-amino-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide;
(3R,4S,6R,6S) -6- [ 7-N-butylamine-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide;
(3R,4S,6R,6S) -6- [ 7-isopentylamine-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide;
(3R,4S,6R,6S) -6- [ 7-phenethylamine-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide;
(3R,4S,6R,6S) -6- [7- (3, 4-dimethoxyphenethylamine) -5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide;
(3R,4S,6R,6S) -6- [7- (N-ethylbutylamine) -5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide.
The compounds of the invention are particularly suitable for use in the inhibition of platelet aggregation.
Suitable hydrates of the compounds of general formula (I) according to the invention are, for example, hemihydrate, monohydrate, dihydrate or trihydrate or alternatively combinations thereof.
The inventors have unexpectedly found that the compound of the general formula (I) or an isomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof has an anti-platelet aggregation effect. Thus, the general formula (I) of the present invention
The compounds of general formula (I) useful in the present invention can be prepared by the following method (synthesis of compound 14b in the scheme):
in one aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined or an isomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient, for example a diluent or carrier. The medicinal composition is used for resisting platelet aggregation or treating platelet aggregation related diseases.
The pharmaceutical compositions of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. For example, compositions intended for oral use may contain excipients which are one or more coloring, sweetening, flavoring and/or preservative agents and the like. As used herein, the term "pharmaceutically acceptable carrier, diluent or excipient" refers to a pharmaceutically acceptable excipient commonly used in the formulation industry, such as those listed in Romingshen et al, pharmaceutical excipients university, Sichuan scientific and technical Press, 1995.
The pharmaceutical compositions of the invention may take a form suitable for oral administration (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., finely divided powders or liquid aerosols), for administration by insufflation (e.g., finely divided powders), or for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intraperitoneal or intramuscular administration or suppositories for rectal administration).
The dosage and method of administration of the compounds of the present invention will depend upon a variety of factors including the age, weight, sex, physical condition, nutritional status, the strength of the activity of the compound, time of administration, metabolic rate, the severity of the condition, and the subjective judgment of the treating physician. Preferably, the dosage is from 0.001 to 100mg/kg body weight/day, more preferably from 0.01mg/kg to 50mg/kg body weight/day, even more preferably from 0.1mg/kg to 25mg/kg body weight/day, and most preferably from 1mg/kg to 10mg/kg body weight/day. If desired, effective daily doses may be divided into multiple doses for administration purposes; thus, a single dose composition may contain such an amount, or a sub-dose thereof, to constitute a daily dose. The frequency of administration of the above-described compound of formula I may be determined according to the experience of a clinician and factors such as the age, body weight, sex, general health of the patient, and the type and severity of the disease, for example, 1,2,3, 4, 5 times daily, etc., or once every 2 days, 1 every 3 days, 1 every 1 week, 1 every 2 weeks, etc.
According to a further aspect of the present invention, there is provided a use of a compound of the general formula (I) as described above, or an isomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the anti-platelet aggregation or treatment of a platelet aggregation-related disease such as antithrombotic.
Detailed Description
The following examples are provided to further illustrate the spirit and advantages of the present invention. The examples are given solely for the purpose of illustration and are not intended to be limiting.
EXAMPLE 1 preparation of (3R,4S,6R,6S) -6- [ 7-amino-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide
Preparation of methyl (1S,4R) -4-aminocyclopent-2-enecarboxylate (2)
Adding 10g (0.092mol) of (1R,4S) -2-azabicyclo [2.2.1] hept-5-en-3-one (1) into a 150mL three-necked flask, dissolving in 9.43g of methanol, adding a drying tube, stirring at room temperature for 15min, then slowly dropwise adding 5.72g (0.048mol) of thionyl chloride, controlling the acceleration, increasing the temperature during dropwise adding, controlling the temperature to be 25-30 ℃, continuing stirring and reacting for 1.5h, then adding a solution of 6.88g (0.046mol) of L-tartaric acid dissolved in 20mL of water, continuing stirring and reacting for 8h, removing insoluble sludge-like solids by suction filtration, then dropwise adding 5.17g of triethylamine, slowing stirring when the solution is half, controlling the dropwise adding speed, controlling the reaction temperature to be lower than 50 ℃, continuing stirring and reacting for 2 dL, then standing at room temperature, and adding a trace amount of seed crystals for natural crystallization, thus obtaining white-like square crystals 3.85g (24-8652 ℃.: 862.32 ℃.: C/169).
Preparation of methyl (1S,4R) -4-phthalimide aminocyclopent-2-enecarboxylate (3)
2.91g (1.00mmol) of methyl (1S,4R) -4-aminocyclopent-2-enoate and 2.22g (1.50mmol) of phthalic anhydride are introduced into a 100mL three-necked flask and dissolved in 25mL of toluene with stirring. 2.5mL of triethylamine was added dropwise over about 10 min. Under the protection of nitrogen, heating to 65 ℃ is started, and the reaction solution becomes clear from suspension. The reaction was maintained at this temperature and progress of the reaction was monitored by TLC until no apparent change in product point was observed. The reaction was carried out for about 17 h. Then, 20mL of a saturated sodium bicarbonate solution was added for liquid separation, 20mL of water was washed three times, and 20mL of saturated chloride was washed three times. Under reduced pressure, toluene was distilled off. The residue was allowed to stand for 3 to 4 hours to obtain light brown square transparent crystals (2.3 g, 85% yield). After separation by a silica gel column, 2.05g of a compound having the desired optical purity was obtained.
Rf (EtOAc/petroleum:2D/2mL):0.25, MSm/z: 271, peak 212, 1H-NMR (400MHz, DMSO-D6) δ: 7.84 to 7.81(m,4H, Ar-H), 6.02 to 6.01(m,1H, ═ CH), 5.87 to 5.85(m,1H, ═ CH),5.21 to 5.20(m,1H, N-CH),3.71 to 3.67(m,1H, CO-CH),3.66(s,3H, CO2-CH3), 2.52 to 2.51(m,1H, -CH2),2.34(m,1H, -CH2), [ α ] D20 ℃ -146.98, C ═ 1g/dL, 1% methanol solution.
Preparation of methyl (1S,2R,3S,4R) -4-phthalimide amino-2, 3-dihydroxycyclopentylcarboxylate (4)
To a 150mL three-necked flask, 1.71g (7.5mmol) of methyl (1S,4R) -4-phthalimide aminocyclopent-2-enecarboxylate, 3.3mL of N-methylmorpholine oxynitride NMO (50% in water, 14mmol) and a catalytic amount of 60mg of aqueous OSO4 solution were added, dissolved in 20mL of acetone with stirring, and reacted at room temperature for about 2.5 h. After 2h, without half an hour, TCL monitored the progress of the reaction until the reaction was essentially complete with methyl (1S,4R) -4-phthalimide aminocyclopent-2-enecarboxylate. Then, 100mL of saturated sodium hydrogensulfite was added to quench the reaction, and the mixture was stirred for 30 min. Adding dilute sulfuric acid to acidify until the pH value is 3. And (3) removing black insoluble substances by suction filtration, removing acetone by rotary evaporation, extracting with 80mL ethyl acetate for three times, washing an ester layer with 150mL saturated sodium chloride for three times, adding anhydrous sodium sulfate for drying, then carrying out rotary drying to obtain yellow liquid, standing for 2-3h, precipitating white-like solid 2.06g, and obtaining the yield of 90%. After EtOAc/petroleum ═ 2: 1 silica gel column separation gave 1.98g of a white solid.
Rf (EtOAc/petroleum:2mL/1mL) 0.42, MS m/z 305, 1H-NMR (400MHz, DMSO-D6) delta 7.86-7.85(m,4H, Ar-H), 5.04-4.99(m,2H, 2X-OH), 4.42-4.32(m,2H, 2X O-CH), 4.21-4.9(m,1H, N-CH),3.66(s,3H, CO2-CH3),2.79-2.77(m,1H, CO-CH),2.17-2.12(m,2H, -CH2) [ α ] D25 ℃ - — 12.8, C ═ 1g/dL, 1% methanol solution.
Preparation of methyl (3R,4S,6R,6S) -6-phthalimidylamino-2, 2-dimethylcyclopenta- [1,3] -diketal-4-carboxylate (5)
To a 50mL three-necked flask, 2.5mL of 2, 2-dimethoxypropane and a catalytic amount of 10mg of p-toluenesulfonic acid were added dissolved in 10mL of anhydrous acetone, and after stirring for 10min, a solution of 1g (3.28mmol) of methyl (1S,2R,3S,4R) -4-phthalimide amino-2, 3-dihydroxycyclopentanecarboxylate in 10mL of anhydrous acetone was added dropwise over 30 min. The reaction was stirred at room temperature for about 6h under nitrogen. TLC monitored the progress of the reaction until (1S,2R,3S,4R) -4-phthalimido-amino-2, 3-dihydroxycyclopentanecarboxylic acid methyl ester was essentially completely reacted. Acetone was removed by rotary evaporation, diluted with 20mL of water, extracted three times with 15mL of ethyl acetate and washed three times with 40mL of saturated sodium chloride. After drying over anhydrous sodium sulfate, 1.10g of crude off-white solid was obtained. After EtOAc/petroleum ═ 1: silica gel column 2 to obtain 1.08g of white solid.
Rf(EtOAc/petroleum:1mL/2mL):0.26；MS m/z：345；1H-NMR(400 MHz,DMSO-d6)δ：7.87-7.86(m,4H,Ar-H),4.95-4.91(m,2H, 2×O-CH)，4.55-4.54(m,1H,N-CH),3.65(s,3H,CO2-CH3),3.02-3.00 (m,1H,CO-CH),2.43-2.33(m,2H,-CH2),1.47(s,3H,O-CH3),1.23(s,3H,O-CH3)
Preparation of (3R,4S,6R,6S) -6-phthalimidylamino-N, 2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide (6)
1.5g (4.34mmol) of methyl (3R,4S,6R,6S) -6-phthalimide amino-2, 2-dimethylcyclopenta- [1,3] -diketal-4-enoate is added into a 50mL three-necked bottle, stirred and dissolved in 15mL of absolute ethyl alcohol, heated to 40 ℃ until the mixture is completely dissolved, then naturally cooled to room temperature, and 5mL of 30% methylamine alcohol solution is slowly dropped into the bottle until the dropping is finished within about 20 min. TCL monitors the progress of the reaction until (3R,4S,6R,6S) -6-phthalimido-amino-2, 2-dimethylcyclopenta- [1,3] -diketal-4-enecarboxylic acid methyl ester has reacted substantially to completion. Then slowly adding 15mL of 30% methylamine alcohol solution dropwise, adding a condensing tube and a drying tube, heating to 70 ℃ and reacting for about 12 hours under micro reflux, and monitoring the progress of the reaction by TLC until the (3R,4S,6R,6S) -6-phthalimide amino-N, 2, 2-trimethylcyclopenta- [1,3] -ketene dimer-4-ene formamide is basically completely reacted. And (4) carrying out suction filtration to remove insoluble substances, and carrying out spin drying to remove the solvent and obtain the reacted methylamine. Adding 15mL of ethanol for three times, and evaporating to dryness to obtain 0.47g of light yellow solid with the yield of 51%. The mixture is placed in an open air hood for 24 hours and dried in vacuum at 40 ℃ for 12 hours until methylamine is basically removed.
Rf(CH2Cl2/CH3OH:5mL/0.5mL):0.31。
Preparation of 4, 6-dihydroxy-2- (propylsulfanyl) pyrimidine (8)
To a 100mL three-necked flask, 15mL of water was added to 5g (34.69mmol) of 2-thiobarbituric acid (7) at room temperature. The resulting mixture was stirred and a saturated aqueous sodium hydroxide solution (3.2g sodium hydroxide solution 7.2mL water) was added dropwise over 20min at PH 12. Then, 6.2g (36.32mmol) of iodopropane and 10mL of methyl pyrrolidone solution were added dropwise, and the reaction solution became turbid from clear after the addition. The reaction was carried out for 22h at room temperature under a water bath. Then, 1M hydrochloric acid was added dropwise to a PH of 6.5, and about 20mL was used, and 6M hydrochloric acid was added dropwise to a PH of 2.5, and about 5mL was used. Stirring and reacting for 18h after dripping, precipitating solid, filtering to obtain white powdery solid, and washing with 40mL of water, 20mL of ethanol and 40mL of water in sequence. The product was dried under vacuum at 50 ℃ overnight to give 3.75g of a white powder in 97.1% yield.
Rf(CH2Cl2/CH3OH:2mL/1mL):0.43；MS m/z：186；1H-NMR(400MHz, DMSO-d6)δ：11.57(s，2H,2-OH),5.12(s,1H,Ar-H),3.09～3.05 (t,2H,S-CH2),1.69～1.62(m,2H,-CH2)，0.98～0.94(t,3H,-CH3)。
Preparation of 5-nitro-4, 6-dihydroxy-2- (propylsulfanyl) pyrimidine (9)
To a 50mL three-necked flask, 0.93g (5mmol) of 4, 6-dihydroxy-2- (propylsulfanyl) pyrimidine was dissolved in 10mL of glacial acetic acid, and the mixture was stirred at room temperature for 20 min. Then, 1.9g (20.5mmol) of 68% concentrated nitric acid was slowly added dropwise thereto, and the reaction was stirred at room temperature for 12 hours. The solid in the bottle is separated out and generates reddish brown gas, nitrogen is increased to be discharged, and the gas is absorbed by alkali liquor. Thereafter, 20mL of water was added to the reaction flask and stirred for 1 hour. Suction filtration gave 0.612g of a pale yellow powdery solid in 53% yield.
1H-NMR(400MHz,DMSO-d6)δ：11.80(s,2-OH),3.18-3.14(t, 2H,S-CH2),1.70～1.65(m,2H,-CH2),0.98～0.95(t,3H,-CH3)。
Preparation of 5-nitro-4, 6-dichloro-2- (propylsulfanyl) pyrimidine (10)
300mg (1.30mmol) of 5-nitro-4, 6-dihydroxy-2- (propylsulfanyl) pyrimidine are introduced into a 25mL three-necked flask, 10mL (107.2mmol) of phosphorus oxychloride are added dropwise, and the addition is completed in about 10 min. Stirring and heating to 100 ℃, adding a drying tube, and carrying out reflux reaction for 6 hours to obtain red reaction liquid. After the reaction, the phosphorus oxychloride is distilled off under reduced pressure. The residue was slowly sucked up, added dropwise to 20mL of ice water, and stirred for 10 min. The mixture was extracted three times with 15mL of ethyl acetate, washed three times with 20mL of saturated sodium chloride, and spin-dried to give 166.6mg of a red oily liquid with a yield of 48. 3 percent.
Rf (EtOAc/petroleum:1d/3mL) 0.35; MS m/z: 267, base peak 225, major fragment peaks 252, 239.
5-amino-4, 6-dichloro-2- (propylsulfanyl) pyrimidine (11)
To a 100mL three-necked flask, 1g (3.74mmol) of 5-nitro-4, 6-dichloro-2- (propylsulfanyl) pyrimidine was added, dissolved in 25mL of ethanol with stirring, and mechanically stirred. 4mL of a solution of 37% hydrochloric acid diluted in 25mL of water at room temperature was added dropwise, and the reaction solution became turbid and gradually cleared with stirring. Heating to 65 ℃ was then started. 2g of iron powder were added in three portions, each time at 1h intervals. The reaction was carried out with mechanical stirring and the progress of the reaction was monitored by TLC until 5-nitro-4, 6-dichloro-2- (propylsulfanyl) pyrimidine was essentially completely reacted. Filtering to remove iron mud, spin-drying the filtrate, adding 30mL ethyl acetate, and stirring for 30 min. Then, the layers were separated, and the ethyl acetate layer was washed three times with 30mL of water and three times with 30mL of saturated sodium chloride. Spin-dry to give 0.762g of red oil, 85.7% yield. Separation over a silica gel column (EtOAc/petroleum ═ 1: 20) afforded 0.72g of red crystals.
Rf(EtOAc/petroleum:2d/2mL):0.25；1H-NMR(400MHz,DMSO-d6) δ：5.89(s,2H,-NH2),3.03-.99(t,2H,S-CH2),1.66-1.62(m,2H, -CH2),0.98-0.95(t,3H,-CH3)。
(3R,4S,6R,6S) -6- { [ 5-amino-6-chloro-2- (thiopropyl) pyrimidin-4-yl ] amino
Preparation of yl } -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide (12)
To a 50mL three-necked flask was added (3R,4S,6R,6S) -6-amino-N, 2, 2-trimethylcyclopenta- [1,3] -diketal-4-ene carboxamide, 0.47g (2.21mmol) of the crude product, which was dissolved in 10mL of ethanol, and 0.5mL of triethylamine was slowly added dropwise, followed by stirring for 10 min. Then a solution of 0.59g (2.5mmol) of 5-amino-4, 6-dichloro-2- (propylsulfanyl) pyrimidine in 10mL of ethanol was added dropwise over 25 min. After the addition, the mixture is heated to 70 ℃ and stirred for reaction. TLC monitored the progress of the reaction until no apparent change in product point. Stopping heating, naturally cooling to room temperature, and removing the solvent by rotary evaporation. Diluting with 15mL of water, extracting with 15mL of ethyl acetate for three times, washing with 30mL of saturated sodium chloride for three times, drying with anhydrous sodium sulfate, and spin-drying to obtain 0.93g of red oily liquid with more impurity points. After EtOAc/petroleum ═ 1.5: silica gel column 1 column separation gave 0.65g of red crystals, 76% yield.
Rf(EtOAc/petroleum:1.5mL/1mL):0.18；MS m/z：418；1H-NMR(400 MHz,DMSO-d6)δ：8.16-8.15(d,1H,N-H,J＝4.8Hz),7.39-7.37(d, 1H,N-H,J＝7.3Hz),4.69-4.67(m,1H,O-CH),4.64(s,2H,NH2), 4.46-4.45(m,1H,O-CH),4.38(m,1H,N-CH),2.99-2.97(t,2H,S-CH2), 2.79-2.78(m,1H,CO-CH),2.61-2.60(d,3H,NH-CH3,J＝4.8Hz),2.35 (m,1H,-CH2),1.81(m,1H,-CH2),1.67-1.62(m,2H,-CH2),1.43(s, 3H,O-CH3),1.22(s,3H,O-CH3),0.98-0.94(t,3H,-CH3)。
Preparation of (3R,4S,6R,6S) -6- [ 7-chloro-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide (13)
To a 25mL three-necked flask, 100mg (0.241mmol) of (3R,4S,6R,6S) -6- { [ 5-amino-6-chloro-2- (thiopropyl) pyrimidin-4-yl ] amino } -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-enecarboxamide is added, dissolved with stirring in 1mL of glacial acetic acid and 1mL of water, and cooled to 0 ℃; while stirring 16mg (0.241mmol) of sodium nitrite in 1.5mL of water, it was cooled to 0 ℃. Then the obtained acetic acid solution of (3R,4S,6R,6S) -6- { [ 5-amino-6-chloro-2- (thiopropyl) pyrimidin-4-yl ] amino } -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-ene carboxamide is added dropwise into the aqueous solution of sodium nitrite, the dropping speed is controlled, the reaction temperature is kept at 0-5 ℃, and the reaction is stirred for 3 hours. 10mL of ethyl acetate, 37% aqueous potassium carbonate solution was added dropwise to a pH of 7. The ethyl acetate layer was washed with 21% potassium carbonate and 10mL saturated sodium chloride, and spin-dried to give 89.31mg of a red solid with a yield of 87%. After EtOAc/petroleum ═ 1: 1, separating by a silica gel column to obtain a pure product of 87 mg.
Rf(EtOAc/petroleum:1.5mL/1mL):0.34；MS m/z：429；1H-NMR(400 MHz，DMSO-d6)δ：8.05-8.03(d,1H,N-H,J＝4.5Hz),5.28-5.22(m, 1H,N-CH),5.11-5.08(m,1H,O-CH),4.94-4.92(m,1H,O-CH), 3.22-3.21(t,2H,S-CH2,J＝2.0Hz),2.95-2.91(m,1H,CO-CH),2.82-2.74(m,1H,-CH2),2.62-2.60(m,1H,-CH2),2.60-2.59(d,3H, NH-CH3,J＝4.5Hz),1.78-1.74(m,2H,-CH2),1.52(s,3H,O-CH3),1.25 (s,3H,O-CH3),1.04-1.00(t,3H,-CH3)。
Preparation of (3R,4S,6R,6S) -6- [ 7-amino-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide (14a)
100mg (0.23mmol) of (3R,4S,6R,6S) -6- [ 7-chloro-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide was charged into a 25mL eggplant-shaped bottle, and the mixture was dissolved in 5mL of a saturated aqueous ethanol solution of ammonia with stirring, heated to 75 ℃ in a sealed system, and reacted for about 3 hours. TCL monitors the progress of the reaction until (3R,4S,6R,6S) -6- [ 7-chloro-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide is essentially reacted to completion. The solvent and ammonia gas were removed by rotary evaporation, diluted with 10mL of water, and extracted three times with 10mL of ethyl acetate. Concentration gave 89.9mg of crude product in 97% yield. After EtOAc/petroleum ═ 1: separating with silica gel column to obtain 86mg red crystal
Rf(EtOAc/petroleum:1.5mL/1mL):0.15；MS m/z：410；1H-NMR(400 MHz，DMSO-d6)δ：8.49,8.14(2×s,2H,N-H),8.05-8.04(d,1H,N-H, J＝4.5Hz),5.11-5.09(m,1H,N-CH),5.06-5.03(m,1H,O-CH), 4.92-4.89(m,1H,O-CH),3.09-3.07(t,2H,S-CH2,J＝1.7Hz),2.92-2.87(m,1H,CO-CH),2.76-2.67(m,1H,-CH2),2.62-2.61(d,3H, NH-CH3,J＝4.5Hz),2.51-2.50(m,1H,-CH2),1.74-1.68(m,2H,-CH2), 1.51(s,3H,O-CH3),1.25(s,3H,O-CH3),1.02-0.98(t,3H,-CH3)。
Wherein the melting point of the compound is determined by a RY-1 melting point apparatus. Mass spectra were determined on a Micromass Zabspec high resolution mass spectrometer (resolution 1000).1H NMR was measured by JNM-ECA-400 superconducting NMR instrument, working frequency 1H NMR 400MHz,13C NMR 100MHz。
EXAMPLE 2 preparation of (3R,4S,6R,6S) -6- [ 7-N-butylamine-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide (14b)
The method of example 1 was used to replace the ammonia ethanol solution with n-butylamine in the last amino substitution step. To a 25mL eggplant-shaped bottle, 100mg (0.23mmol) of (3R,4S,6R,6S) -6- [ 7-chloro-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide was added, and the mixture was dissolved in 5mL of an anhydrous ethanol solution under stirring, and 20.2mg (2.76mmol) of N-butylamine was slowly added dropwise to dilute the solution in 5mL of ethanol. Heating to 75 ℃ under a sealed system, and reacting for about 3 h. TCL monitors the progress of the reaction until (3R,4S,6R,6S) -6- [ 7-chloro-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide is essentially reacted to completion. The solvent and methylamine were removed by rotary evaporation, diluted with 10mL of water, and extracted three times with 10mL of ethyl acetate. Concentration gave 101.0mg of crude product in 97.8% yield. After 1/1 of EtoAc/petroleum: silica gel column 1 gave 97mg of a white solid.
Rf(EtOAc/petroleum:1.5mL/1mL):0.30；MS m/z：463；1H-NMR(400 MHz，DMSO-d6)δ：9.08-9.05(t,1H，N-H),8.05-8.04(d,1H,N-H, J＝4.8Hz),5.04-5.03(m,1H,N-CH),5.03-5.02(m,1H,O-CH), 4.92-4.90(m,1H,O-CH),3.52-3.47(m,2H,N-CH2),3.11-3.07(t,2H, S-CH2),3.09-3.07(t,2H,S-CH2),2.91-2.88(m,1H,-CH2),2.68-2.65 (m,1H,CO-CH),2.51-2.50(m,1H,-CH2),2.61-2.60(d,3H,NH-CH3, J＝4.8Hz),2.51-2.50(m,1H,-CH2),1.74-1.69(m,2H,-CH2), 1.63-1.58(m,2H,-CH2),1.50(s,3H,O-CH3),1.37-1.32(m,2H,-CH2), 1.24(s,3H,O-CH3),1.01-0.98(t,3H,-CH3),0.93-0.89(t,3H,-CH3), EA：δ：4.06-4.00(q,3H)，2.00(s,4H),1.20-1.16(t,5H)。
EXAMPLE 3 preparation of (3R,4S,6R,6S) -6- [ 7-isopentylamine-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide (14c)
By using the method of example 2, the n-butylamine in the reaction solution was changed to isopentylamine to give 106mg of a target product as a white solid in a yield of 96.5%
Rf(EtOAc/petroleum:1.5mL/1mL):0.32；MS m/z：477；1H-NMR(400 MHz，DMSO-d6)δ：9.06-9.03(m,1H,N-H),8.05-8.03(d,1H,N-H, J＝4.8Hz),5.10-5.04(m,1H,N-CH),5.03-5.02(m,1H,O-CH), 4.91-4.88(m,1H,O-CH),3.54-3.49(m,2H,N-CH2),3.10-3.08(t,2H, S-CH2),2.91-2.88(m,1H,-CH2),2.68-2.61(m,1H,CO-CH),2.51-2.50 (m,1H,-CH2),2.61-2.60(d,3H,NH-CH3,J＝4.8Hz),2.51-2.50(m, 1H,-CH2),1.74-1.69(m,2H,-CH2),1.69-1.55(m,1H,-CH), 1.53-1.50(m,2H,-CH2),1.51(s,3H,O-CH3),1.22(s,3H,O-CH3),1.01-0.97(t,3H,-CH3),0.92-0.90(d,6H,2×-CH3)。
EXAMPLE 4 preparation of (3R,4S,6R,6S) -6- [ 7-phenethylamine-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide (14d)
Using the method of example 2, the n-butylamine contained in the reaction solution was changed to phenethylamine, whereby 106.1mg of a target product was obtained as a yellow solid in a yield of 92%.
Rf(EtOAc/petroleum:1.5mL/1mL):0.10；MS m/z：511；1H-NMR(400 MHz，DMSO-d6)δ：9.17-9.14(m,1H,N-H),8.05-8.04(d,1H,N-H, J＝4.8Hz),7.32-7.27(m,5H,Ar-H),5.05-5.04(m,1H,N-CH), 5.02-5.01(m,1H,O-CH),4.91-4.90(m,1H,O-CH),3.75-3.70(m,2H, N-CH2),3.11-3.09(t,2H,S-CH2),2.96-2.93(m,2H,-CH2),2.90-2.88 (m,1H,CO-CH),2.70-2.66(m,1H,-CH2),2.61-2.60(d,3H,NH-CH3, J＝4.8Hz),2.51-2.48(m,1H,-CH2),1.75-1.69(m,2H,-CH2),1.51(s, 3H,O-CH3),1.24(s,3H,O-CH3),1.00-0.97(t,3H,-CH3)。
EXAMPLE 5 preparation of (3R,4S,6R,6S) -6- [7- (3, 4-Dimethoxyphenylethylamine) -5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide (14e)
The method of example 2 was used to change n-butylamine to 3, 4-dimethoxyphenethylamine to give the desired product as a white solid (123.5 mg, 93.7% yield)
Rf(EtOAc/petroleum:1.5mL/1mL):0.10；MS m/z：571；1H-NMR(400 MHz，DMSO-d6)δ：9.13-9.11(m,1H,N-H),8.05-8.03(d,1H,N-H, J＝4.8Hz),6.86-6.77(ABX,3H,Ar-H),5.10-5.04(m,1H，N-CH), 5.04-5.03(m,1H,O-CH),4.90-4.88(m,1H,O-CH),3.72-3.70(s,6H, 2×O-CH3),3.71-3.70(m,2H,N-CH2),3.11-3.09(t,2H,S-CH2), 2.89-2.87(m,2H,-CH2),2.89-2.87(m,1H,CO-CH),2.70-2.66(m, 1H,-CH2),2.61-2.60(d,3H,NH-CH3,J＝4.8Hz),2.51-2.49(m,1H, -CH2),1.75-1.71(m,2H,-CH2),1.51(s,3H,O-CH3),1.24(s,3H,O-CH3),1.00-0.97(t,3H,-CH3)。
EXAMPLE 6 preparation of (3R,4S,6R,6S) -6- [7- (N-ethylbutylamine) -5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide (14f)
Using the method of example 2 in which N-butylamine was changed to N-ethylbutylamine, the desired product was obtained as a white solid (81.7 mg) in a yield of 72.2%.
Rf(EtOAc/petroleum:1.5mL/1mL):0.10；MS m/z：571；1H-NMR(400 MHz，DMSO-d6)δ：8.05-8.04(d,1H,N-H,J＝4.5Hz),5.10-5.04(m, 1H,N-CH),5.04-5.02(m,1H,O-CH),4.92-4.89(m,1H,O-CH), 4.20-4.10(m,2H,N-CH2),3.75-3.71(m,2H,N-CH2),3.11-3.07(t,2H, S-CH2),2.91-2.88(m,1H,CO-CH),2.67-2.64(m,1H,-CH2),2.61-2.60 (d,3H,NH-CH3,J＝4.5Hz),2.51-2.49(m,1H,-CH2),1.73-1.68(m,2H, -CH2),1.68-1.62(m,2H,-CH2),1.51(s,3H,O-CH3),1.40-1.32(m, 2H,-CH2),1.24(s,3H,O-CH3),1.20-1.16(t,3H,-CH3),1.02-0.98 (t,3H,-CH3),0.95-0.93(m,3H,-CH3)。
Example 7 detection of anti-platelet aggregation Activity
The anti-platelet aggregation effect of the compounds was determined as described below.
The anti-platelet aggregation test of the compounds was performed using a platelet aggregation meter (Beijing prisheng LBY-NJ2 four-channel blood aggregation meter). Adenosine diphosphate (adenosine diphosphonate, ADP, sigma, usa), sodium citrate (beijing chemical reagent company), 0.9% physiological saline (yus pharmaceutical industry, kunming), centrifuge LXJ-ii (shanghai medical analytical instrument factory), glass microsampler 0-50 μ L (shanghai medical laser instrument factory), siliconized capped test tube 10mL (pentazhou medical plastics factory), turbidized tube (beijing prisheng), small magnetic rod (beijing prisheng).
Collecting a blood sample: pentobarbital-anesthetized inbred Sprague-Dawley male rats 10 with a body weight of 200 + -10 g. Rats were fasted for 12 hours before surgery without water deprivation. The 2.5% sodium pentobarbital solution is administered intraperitoneally at a dose of 0.1ml per 100g body weight. And (3) taking 9mL of blood for celiac artery puncture, adding 3.8% of sodium citrate as anticoagulant according to the volume ratio of 1:9, and mixing.
Plasma preparation: centrifuging at the rotation speed of 800r/min for 10min at room temperature, taking the upper layer plasma, namely Platelet Rich Plasma (PRP), controlling the time to be 10 minutes in principle, taking out the PRP after the centrifuge naturally stops, sucking the centrifuged PRP into another test tube by using a pipette, and sucking out the PRP completely. The PRP-aspirated blood was recentrifuged at 3000r/min for 10 minutes, and the supernatant was Platelet Poor Plasma (PPP). Platelet counts in PRP were adjusted to 250 × 109/l with PPP. Platelet aggregation assay was started 30 minutes after PRP preparation and the whole activity assay was completed within 3 hours.
The experimental process comprises the following steps: performing platelet aggregation experiments according to the Born turbidimetric method; mu.l of PPP was added to the blank tube, and the tube was incubated at 37 ℃ with setting the light transmittance to 100%. 300 mul PRP is added into the measuring tube, 30 mul of each sample to be measured is respectively added, the final concentration of the corresponding sample is calculated, and the light transmittance is set to be 0%. The samples were incubated at 7 ℃ for 3 minutes, 10. mu.l of platelet aggregation inducer ADP (final concentration of 5. mu. mol/L) was added, the assay was started for a total of 5 minutes, the platelet aggregation Rate (MAR) was recorded within 5 minutes, and the platelet Aggregation Inhibition Rate (AIR) was calculated using physiological saline (NS) as a control. Concentration inhibition curves were plotted from sample concentration and dose dependent curves were made using origin6.0 statistical software. The half inhibitory concentration of the maximum inhibition rate (IC50) was found by a linear regression equation.
The results of determining the anti-platelet aggregation activity of the example compounds are as follows:
the foregoing is illustrative of the present invention and is not to be construed as limiting thereof. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of organic chemistry, polymer chemistry, biotechnology and the like, and it will be apparent that the invention may be practiced otherwise than as specifically described in the foregoing description and examples. Other aspects and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains. Many modifications and variations are possible in light of the above teaching and are therefore within the scope of the invention.
Claims (10)
1. A compound of the general formula (I) or an isomer, a hydrate or a pharmaceutically acceptable salt thereof,
wherein
R, R' independently represents hydrogen, unsubstituted or substituted alkyl, cycloalkyl, alkoxyalkyl, aminoalkyl, phenylalkyl, heterocyclylalkyl or phenyl,
R1represents hydrogen, alkyl which is unsubstituted or substituted by substituents, alkene, alkyne, cycloalkyl, alkoxyalkyl, aminoalkyl, phenylalkyl, heterocyclylalkyl, phenyl,
R2represents hydrogen, unsubstituted or substituted alkyl, alkoxyalkyl, aminoalkyl, phenylalkyl, heterocyclylalkyl, phenyl, heterocyclylalkyl, heteroaromatic,
R3、R4independently represent hydrogen, unsubstituted or substituted alkyl, cycloalkyl, alkoxyalkyl, aminoalkyl, phenylalkyl, heterocyclylalkyl, phenylHeterocyclic group, or R4And R5May form a ring together with the adjacent carbon atom.
2. The compound of claim 1, or an isomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, wherein R, R' independently represents hydrogen, alkyl which is unsubstituted or substituted with a substituent, phenylalkyl which is unsubstituted or substituted with a substituent.
3. The compound according to claim 2, wherein the substituent is a hydroxyl group, a 1-3C alkyl group unsubstituted or substituted with a 1-3C alkyl group, a 1-3C alkoxy group unsubstituted or substituted with a 1-3C alkyl group, a phenyl group unsubstituted or substituted with a 1-3C alkyl group, or a benzyl group unsubstituted or substituted with a 1-3C alkyl group, or an isomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1, or an isomer, hydrate or pharmaceutically acceptable salt thereof, wherein R1Represents hydrogen, alkyl which is unsubstituted or substituted by a substituent which is 1-3C alkyl which is unsubstituted or substituted by 1-3C alkyl, 1-3C alkoxy which is unsubstituted or substituted by 1-3C alkyl.
5. The compound of claim 1, or an isomer, hydrate or pharmaceutically acceptable salt thereof, wherein R2Represents hydrogen, alkyl which is unsubstituted or substituted by a substituent which is 1-3C alkyl which is unsubstituted or substituted by 1-3C alkyl, 1-3C alkoxy which is unsubstituted or substituted by 1-3C alkyl.
6. The compound of claim 1, or an isomer, hydrate or pharmaceutically acceptable salt thereof, wherein R3、R4Independently represent hydrogen, alkyl which is unsubstituted or substituted by a substituent which is 1-3C alkyl which is unsubstituted or substituted by 1-3C alkyl, 1-3C alkoxy which is unsubstituted or substituted by 1-3C alkyl.
7. The compound of claim 1, or an isomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is:
(1) (3R,4S,6R,6S) -6- [ 7-amino-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide
(2) (3R,4S,6R,6S) -6- [ 7-N-butylamine-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide
(3) (3R,4S,6R,6S) -6- [ 7-isopentylamine-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide
(4) (3R,4S,6R,6S) -6- [ 7-phenethylamine-5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide
(5) (3R,4S,6R,6S) -6- [7- (3, 4-dimethoxyphenethylamine) -5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide; or
(6) (3R,4S,6R,6S) -6- [7- (N-ethylbutylamine) -5- (thiopropyl) - [1,2,3] triazolopyrimidin-3-yl ] -N,2, 2-trimethylcyclopenta- [1,3] -diketal-4-carboxamide.
8. A pharmaceutical composition comprising a compound of any one of claims 1-7, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
9. The pharmaceutical composition according to claim 8, which is a pharmaceutical composition for anti-platelet aggregation or treatment of related diseases such as antithrombotic.
10. Use of a compound according to any one of claims 1 to 7, or an isomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for anti-platelet aggregation or treatment of a related disease such as thrombosis.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1271359A (en) * | 1997-07-22 | 2000-10-25 | 英国阿斯特拉药品有限公司 | Novel compounds |
| CN1291193A (en) * | 1998-02-17 | 2001-04-11 | 阿斯特拉曾尼卡英国有限公司 | Novel triazolo (4.5-d) pyrimidine compounds |
| US6297232B1 (en) * | 1996-12-20 | 2001-10-02 | Astrazeneca Ab | Triazolo[4,5-D]pyrimidinyl derivatives and their use as medicaments |
| EP1097153B1 (en) * | 1998-07-17 | 2003-10-01 | AstraZeneca AB | Novel triazolo[4,5-d]pyrimidine compounds |
-
2019
- 2019-11-27 CN CN201911179457.2A patent/CN111116592A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6297232B1 (en) * | 1996-12-20 | 2001-10-02 | Astrazeneca Ab | Triazolo[4,5-D]pyrimidinyl derivatives and their use as medicaments |
| CN1271359A (en) * | 1997-07-22 | 2000-10-25 | 英国阿斯特拉药品有限公司 | Novel compounds |
| CN1291193A (en) * | 1998-02-17 | 2001-04-11 | 阿斯特拉曾尼卡英国有限公司 | Novel triazolo (4.5-d) pyrimidine compounds |
| EP1097153B1 (en) * | 1998-07-17 | 2003-10-01 | AstraZeneca AB | Novel triazolo[4,5-d]pyrimidine compounds |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112341350A (en) * | 2020-10-19 | 2021-02-09 | 江苏威奇达药业有限公司 | Method for treating by-product after enzymatic resolution of gamma-lactam |
| CN112876485A (en) * | 2021-01-25 | 2021-06-01 | 郭丽伟 | Compound for treating uterine smooth muscle high-frequency tonic contraction related diseases |
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