CN113354644B - 一类用作dpp-iv抑制剂的吡唑并嘧啶结构的化合物及应用 - Google Patents
一类用作dpp-iv抑制剂的吡唑并嘧啶结构的化合物及应用 Download PDFInfo
- Publication number
- CN113354644B CN113354644B CN202010141466.9A CN202010141466A CN113354644B CN 113354644 B CN113354644 B CN 113354644B CN 202010141466 A CN202010141466 A CN 202010141466A CN 113354644 B CN113354644 B CN 113354644B
- Authority
- CN
- China
- Prior art keywords
- compound
- dpp
- amino
- pyrazolo
- difluorophenyl
- 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.)
- Active
Links
- -1 Pyrazolopyrimidine compound Chemical class 0.000 title claims abstract description 37
- 239000003112 inhibitor Substances 0.000 title claims abstract description 19
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 title claims abstract 9
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 title claims abstract 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 230000002018 overexpression Effects 0.000 claims abstract description 4
- 201000010099 disease Diseases 0.000 claims abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- 238000011282 treatment Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical group C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 claims 1
- 208000013403 hyperactivity Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 11
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 5
- 206010019280 Heart failures Diseases 0.000 abstract description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 abstract description 2
- 201000001320 Atherosclerosis Diseases 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 25
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 25
- 238000002360 preparation method Methods 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 4
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 3
- WTDFFADXONGQOM-UHFFFAOYSA-N formaldehyde;hydrochloride Chemical compound Cl.O=C WTDFFADXONGQOM-UHFFFAOYSA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- XXPKIDAWGVKUBD-UHFFFAOYSA-N formaldehyde;2,2,2-trifluoroacetic acid Chemical compound O=C.OC(=O)C(F)(F)F XXPKIDAWGVKUBD-UHFFFAOYSA-N 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- DZPAOAZDQHZRGG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-2-carboxylic acid Chemical compound N1=CC=CN2N=C(C(=O)O)C=C21 DZPAOAZDQHZRGG-UHFFFAOYSA-N 0.000 description 2
- YPOXGDJGKBXRFP-UHFFFAOYSA-M pyrimidine-4-carboxylate Chemical compound [O-]C(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-M 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- AHGNLFYXPZBDMS-UHFFFAOYSA-N tert-butyl 3-amino-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC2=C1C(N)=NN2 AHGNLFYXPZBDMS-UHFFFAOYSA-N 0.000 description 2
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 1
- ZZAKLGGGMWORRT-UHFFFAOYSA-N 1-methylsulfonylpiperazine Chemical compound CS(=O)(=O)N1CCNCC1 ZZAKLGGGMWORRT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N 4-Piperidine carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101710167374 Peptidase 1 Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229910052757 nitrogen Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical group C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- FQMZXXRLSOHQSC-UHFFFAOYSA-N piperidine-4-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NC(=O)C1CCNCC1 FQMZXXRLSOHQSC-UHFFFAOYSA-N 0.000 description 1
- GSSYTYYSDFJBFK-UHFFFAOYSA-N piperidine-4-carboxamide;hydrochloride Chemical compound [Cl-].NC(=O)C1CC[NH2+]CC1 GSSYTYYSDFJBFK-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940126532 prescription medicine Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000135 prohibitive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- VPFTZTMJPFIRAN-UHFFFAOYSA-N tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)C(C#N)C1 VPFTZTMJPFIRAN-UHFFFAOYSA-N 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cardiology (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一类用作DPP‑IV抑制剂的吡唑并嘧啶结构的化合物，其结构式如下：
Description
技术领域
本发明涉及一类用作DPP-IV抑制剂的吡唑并嘧啶结构的化合物及应用。
背景技术
近年来，随着经济的高速发展和工业化进程，生活方式的改变和老龄化进程加快，糖尿病已成为21世纪全球最严重的公共卫生问题之一。根据国际糖尿病联合会公布的数据显示，到2017年全球糖尿病患者已经达到4.25亿，预计到2045年，这一数字将增加到6.29亿。
根据2018年Evaluate发布的报告，全球糖尿病市场在2017年达到了创纪录的444亿美元规模，这其中DPP-IV抑制剂及复方的销售额已达到120亿美元，占据了糖尿病用药市场的27％。据预计，到2024年全球糖尿病市场将达到595亿美元，成为仅次于抗肿瘤药物的第二大药物市场。对比国际市场，国内糖尿病治疗药物使用格局大相径庭，根据2017年医院处方用药系统对糖尿病药物的统计，胰岛素约占三分之一，其次双胍类约占百分之二十，是使用最广泛的非胰岛素降糖药，此外传统的α-糖苷酶抑制剂、磺酰脲类、格列奈类、噻唑烷二酮类仍占据较大的处方份额，合计达到45％以上，而新型的DPP-IV抑制剂和GLP-1受体激动剂的占比还极低。这主要是由于前些年DPP-IV抑制剂价格偏高，且不享受医保，令国内很多患者望而却步。随着2017年DPP-IV抑制剂进入医保目录，相信其市场份额将会有显著提升。考虑到DPP-IV抑制剂降糖的有效性及安全性，更低的低血糖风险及其对心脏、血脂等的潜在获益，有理由相信DPP-IV抑制剂在中国糖尿病防治中的地位也会越来越重要，成为糖尿病口服治疗药物中的主力军。
肠降血糖素在维持体内葡萄糖平衡中起着至关重要的作用，研究发现正常饮食后，人体肠道受到刺激，由回肠和结肠的L细胞分泌的胰高血糖素样肽酶-1(GLP-1)及由十二指肠和空肠K细胞分泌的葡萄糖依赖性促胰岛素多肽(GIP)能通过多种途径和机制参与血糖的调控：(1)增加外周肌肉组织对葡萄糖的摄取和利用；(2)抑制肝脏糖异生，减少葡萄糖产生；(3)促进胰岛β细胞增生，增加胰岛素生物合成；(4)根据血糖水平对胰高血糖素的分泌进行调控。二肽基肽酶-IV(DPP-IV)是位于细胞表面的一种丝氨酸蛋白酶，主要表达于胃肠道、肝脏、胰腺、肾脏等，部分以可溶形式存在于循环血液中。GLP-1和GIP极易被DPP-IV分解为无活性形式，并经肝肾清除，这就使得体内GLP-1和GIP的半衰期极短(t1/2＝1～2min)。因此，目前通过开发DPP-IV抑制剂，目的在于延长GLP-1的半衰期，提高内源性GLP-1在血液循环中的浓度，起到调控血糖平衡的作用。通过DPP-IV/GLP-1系统来调控血糖平衡具有其它抗糖尿病药物所不具有的优势：1)GLP-1促进胰岛素分泌的作用具有葡萄糖浓度依赖性，因此其不易引发低血糖；2)长期使用不会导致体重增加；3)保护胰腺细胞，促进胰岛β细胞的增殖再生，抑制β细胞凋亡。
发明内容
本发明针对上述现有技术存在的不足，提供一类用作DPP-IV抑制剂的吡唑并嘧啶结构的化合物及应用。
本发明解决上述技术问题的技术方案如下：一类用作DPP-IV抑制剂的吡唑并嘧啶结构的化合物或其药学上可接受的盐，其结构式如下：
其中，Ar环为被1-5个取代基取代的C6-C10芳基；
R1为氢原子、羟基、-OR3、-NH2、-NHR3、-NR3R4、硫代吗啉-1,1-二氧化物、取代的吡咯、取代的哌啶或取代的哌嗪；
R2为氢原子、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代的C1-C6烷基、C6-C10芳基或C4-C10杂芳基；
R3、R4各自独立地为氢、C1-C6烷基、C2-C6烯基或C2-C6炔基；
酰基-C(O)R1的取代位置为嘧啶环上的4位或6位。
进一步，所述Ar环中的1-5个取代基各自独立地为C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代的C1-C6烷基、卤素、氰基、氨基、羟基、-NHOH、-NH-O-(C1-C6烷基)、-NH-(C1-C6烷基)、-N(C1-C6烷基)2、-C(O)NH2、-C(O)NH-(C1-C6烷基)、-C(O)N(C1-C6烷基)2、-NHC(O)-(C1-C6烷基)、-NHC(O)-(C3-C8环烷基)、-N(C1-C6烷基)C(O)H、-N(C1-C6烷基)C(O)-(C1-C6烷基)或-NHC(O)NH2。
更进一步，Ar环为被1-5个卤素原子取代的苯基。
进一步，所述吡咯的取代基、哌啶的取代基或哌嗪的取代基各自独立地为C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代的C1-C6烷基、卤素、氰基、氨基、羟基、-NHOH、-NH-O-(C1-C6烷基)、-NH-(C1-C6烷基)、-N(C1-C6烷基)2、-C(O)NH2、-C(O)NH-(C1-C6烷基)、-C(O)N(C1-C6烷基)2、-NHC(O)-(C1-C6烷基)、-NHC(O)-(C3-C8环烷基)、-N(C1-C6烷基)C(O)H、-N(C1-C6烷基)C(O)-(C1-C6烷基)、-NHC(O)NH2或-S(O)2-。
进一步，所述化合物或其药学上可接受的盐的结构式如下：
其中，X为碳原子或氮原子；n为0或1；a表示吡咯的取代基、哌啶的取代基或哌嗪的取代基。
更进一步，所述化合物或其药学上可接受的盐的结构式优选如下：
本发明的第二个目的在于提供上述用作DPP-IV抑制剂的吡唑并嘧啶结构的化合物在治疗和/或预防与DPP-IV活性过高或者与DPP-IV过度表达有关疾病的领域的应用，尤其是在治疗糖尿病、非酒精性脂肪肝及心衰领域的应用。
本发明的特点和有益效果在于：
本发明的化合物能够有效治疗和/或预防与DPP-IV活性过高或者与DPP-IV过度表达有关的疾病，对DPP-IV具有良好的抑制作用，具有较好的降血糖活性。
具体实施方式
以下结合实例对本发明的原理和特征进行描述，所举实例只用于解释本发明，并非用于限定本发明的范围。
实施例1
化合物1----9-((3R，5S，6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-羧酸盐酸盐的制备
步骤(1)
向N-Boc-3-氰基-4-哌啶酮(2.24g,10mmol,1.0eq)的乙醇(20mL)溶液中加入水合肼(40mmol，4.0eq)，80℃加热回流反应；TLC检测反应完全，冷却至室温，减压浓缩溶剂，用乙酸乙酯和水萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，减压蒸馏得到粗产品----白色固体化合物3-氨基-6,7-二氢-2H-吡唑并[4,3-c]吡啶-5(4H)-羧酸叔丁酯，未纯化直接用于下一步反应；收率89％。
步骤(2)
向3-氨基-6,7-二氢-2H-吡唑并[4,3-c]吡啶-5(4H)-羧酸叔丁酯(2.38g,10mmol,1.0eq)的乙酸(20mL)溶液中加入乙酰丙酮酸甲酯(12mmol,1.2eq)，80℃加热回流反应；TLC检测反应完全，冷却至室温，减压浓缩溶剂，用乙酸乙酯和水萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，减压蒸馏得到粗产品，柱层析纯化分离得到两个异构体产物----主产物化合物1a和少量的化合物1b；
步骤(3)
将化合物1a(4.6mmol，1.2eq)溶于三氟乙酸(4.6mL)中，室温反应，TLC检测反应完全；降温到0℃，加入DMAc(18.4mL)，再加入三乙胺(3.22mL)，反应10min，调节体系的pH值至碱性；向体系中加入N-[(2R,3S)-2-(2,5-二氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(3.8mmol,1.0eq)，室温反应2h；降温到0℃，分三批加入三乙酰氧基硼氢化钠(5.7mmol,1.5eq)，过夜反应；后处理用乙酸乙酯和水萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，减压蒸馏得到粗产品，柱层析纯化分离得到终产物化合物1c；两步收率67％；
步骤(4)
将化合物1c(3mmol,1.0eq)溶于四氢呋喃：水(4mL:1mL)的混合溶液，加入氢氧化锂(6mmol,2.0eq)，室温过夜反应；TLC检测反应完全，用乙酸乙酯和稀盐酸萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，减压蒸馏得到粗产品，柱层析纯化分离得到终产物化合物1d；收率95％；
步骤(5)
将化合物1d(3mmol,1.0eq)溶于4mmol/L的氯化氢二氧六环溶液中，室温过夜反应；后处理减压蒸馏蒸干溶剂，得到黄色固体即为终产物9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-羧酸盐酸盐；收率90％。
实施例2
化合物2----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-基)(1,1-二氧化硫)甲酮的制备
步骤(1)
将化合物1d(3mmol,1.0eq)溶于DMF(3mL)中，依次加入1,1-二氧化硫代吗啉(3.6mmol,1.2eq)、DIPEA(6mmol,2.0eq)、HATU(4.5mmol,1.5eq)。室温反应，TLC检测反应完全。后处理用用乙酸乙酯和稀盐酸萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，减压蒸馏得到粗产品，柱层析纯化分离得到终产物化合物叔丁基((2R,3S,5R)-2-(2,5-二氟苯基)-5-(2-(1,1-二氧硫代吗啉-4-羰基)-4-甲基-7,8-二氢吡啶基[4”,3′:3,4]吡唑并[1,5-a]嘧啶-9(10H)-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯。产率73％。
步骤(2)
将化合物叔丁基((2R,3S,5R)-2-(2,5-二氟苯基)-5-(2-(1,1-二氧硫代吗啉-4-羰基)-4-甲基-7,8-二氢吡啶基[4”,3′:3,4]吡唑并[1,5-a]嘧啶-9(10H)-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(3mmol,1.0eq)溶于4mmol/L的氯化氢二氧六环溶液中，室温过夜反应，TLC检测反应完全。后处理用乙酸乙酯和饱和碳酸钠溶液萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，减压蒸馏得到粗产品，柱层析纯化分离得到终产物化合物(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-基)(1,1-二氧化硫)甲酮；产率90％。
实施例3
化合物3----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-基)(4-(甲基磺酰基)哌嗪-1-基)甲酮的制备
该化合物的合成方法参考实施例2，将实施例2中步骤(1)中的起始原料1,1-二氧化硫代吗啉换成化合物1-甲磺酰基哌嗪，最终得到化合物(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-基)(4-(甲基磺酰基)哌嗪-1-基)甲酮。
实施例4
化合物4----1-(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-羰基)哌啶-4-甲酰胺的制备
该化合物的合成方法参考实施例2，将实施例2中步骤(1)中的起始原料1,1-二氧化硫代吗啉换成化合物哌啶-4-甲酰胺，最终得到化合物1-(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-羰基)哌啶-4-甲酰胺。
实施例5
化合物5----9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-羧酸盐酸盐的制备
该化合物的合成方法参考实施例1，将实施例1中步骤(3)中的起始原料换成化合物1b，最终得到化合物9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-羧酸盐酸盐。
实施例6
化合物6----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-基)(1,1-二氧化硫)甲酮盐酸盐的制备
该化合物的合成方法参考实施例2，将实施例2中步骤(1)中的起始原料9-((3R,5S,6R)-5-((叔丁氧基羰基)氨基)-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-羧酸换成化合物9-((3R,5S,6R)-5-((叔丁氧基羰基)氨基)-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-羧酸，最终得到化合物(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-基)(1,1-二氧化硫)甲酮盐酸盐。
实施例7
化合物7----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-基)(4-(甲基磺酰基)哌嗪-1-基)甲酮三氟乙酸盐的制备
该化合物的合成方法参考实施例3。
实施例8
化合物8----1-(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-甲基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-羰基)哌啶-4-甲酰胺盐酸盐的制备
该化合物的合成方法参考实施例4。
实施例9
化合物9----9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-苯基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-羧酸盐酸盐的制备
该化合物的合成方法参考实施例1。
实施例10
化合物10----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-苯基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-基)(1,1-二氧化硫)甲酮三氟乙酸盐的制备
该化合物的合成方法参考实施例2。
实施例11
化合物11----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-苯基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-基)(4-(甲基磺酰基)哌嗪-1-基)甲酮三氟乙酸盐的制备
该化合物的合成方法参考实施例3。
实施例12
化合物12----1-(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-苯基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-羰基)哌啶-4-甲酰胺盐酸盐的制备
该化合物的合成方法参考实施例4。
实施例13
化合物13----9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-苯基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-羧酸盐酸盐的制备
该化合物的合成方法参考实施例9。
实施例14
化合物14----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-苯基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-基)(1,1-二氧化硫)甲酮盐酸盐的制备
该化合物的合成方法参考实施例10。
实施例15
化合物15----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-苯基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-基)(4-(甲基磺酰基)哌嗪-1-基)甲酮盐酸盐的制备
该化合物的合成方法参考实施例11。
实施例16
化合物16----1-(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-苯基-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-羰基)哌啶-4-甲酰胺盐酸盐的制备
该化合物的合成方法参考实施例12。
实施例17
化合物17----9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-(噻吩-2-基)-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-羧酸盐酸盐的制备
该化合物的合成方法参考实施例1。
实施例18
化合物18----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-(噻吩-2-基)-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-基)(1,1-二氧化硫)甲酮盐酸盐的制备
该化合物的合成方法参考实施例2。
实施例19
化合物19----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-(噻吩-2-基)-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-基)(4-(甲基磺酰基)哌嗪-1-基)甲酮盐酸盐的制备
该化合物的合成方法参考实施例3。
实施例20
化合物20----1-(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-4-(噻吩-2-基)-7,8,9,10四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-2-羰基)哌啶-4-甲酰胺盐酸盐的制备
该化合物的合成方法参考实施例4。
实施例21
化合物21----9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-(噻吩-2-基)-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-羧酸盐酸盐的制备
该化合物的合成方法参考实施例17。
实施例22
化合物22----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-(噻吩-2-基)-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-基)(1,1-二氧化硫)甲酮三氟乙酸盐的制备
该化合物的合成方法参考实施例18。
实施例23
化合物23----(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-(噻吩-2-基)-7,8,9,10-四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-基)(4-(甲基磺酰基)哌嗪-1-基)甲酮三氟乙酸盐的制备
该化合物的合成方法参考实施例19。
实施例24
化合物24----1-(9-((3R,5S,6R)-5-氨基-6-(2,5-二氟苯基)四氢-2H-吡喃-3-基)-2-(噻吩-2-基)-7,8,9,10四氢吡啶并[4′,3′:3,4]吡唑并[1,5-a]嘧啶-4-羰基)哌啶-4-甲酰胺三氟乙酸盐的制备
该化合物的合成方法参考实施例20。
本发明实施例1-24所得化合物的H-NMR、HRMS的测试结果见表1。
表1
生物学评价
试验1：DPP-IV抑制剂细胞筛选实验
试剂：
试验方法：
取对数生长期Caco-2细胞以1×105个/mL接种细胞于96孔培养板中，每孔200μL，24h待细胞贴壁后，吸出96孔板中Caco-2细胞的培养液，对照组加入新的Caco-2细胞培养液，实验组给予不同浓度的化合物处理，每孔200μL。36h后再次吸净96孔板中的各培养液，并用PBS冲洗一次，按照底物15μL、缓冲液85μL的顺序依次加入96孔板中，使每个孔中的总体积为100μL。各孔的反应温度为37℃，反应时间120min。用酶标仪在405nm处测得吸光度OD值的大小。细胞筛选结果见表2。
表2
由表2中的试验数据可知，上述化合物对DPP-IV均具有良好的抑制作用。
试验2：化合物6的降糖实验
试验方法：选用ICR小鼠进行实验，实验前一天检测小鼠血糖值，分组，每组7只，禁食8小时后再次检测血糖值，随后各组开始给药，西格列汀给药剂量20.8mg/kg，奥格列汀组给药剂量5.2mg/kg，化合物6给药剂量5.2mg/kg，60分钟后腹腔注射葡萄糖溶液(2g/kg)，于注射后15、30、60、90和120分钟检测血糖值。实验结果见表3。实验结果显示化合物6具有与奥格列汀相当的降糖活性。
表3.化合物6的降糖实验结果
注：所有数据为平均值±SEM(n＝7)。*p<0.05vs空白组。
药用片剂的制备
将实施例制备的化合物6(1g)、乳糖(23g)和微晶纤维素(5.7g)用混合机混合。用滚轴压紧机将所得混合物压制成型，制得薄片状压制物料。用锤式粉碎机将所得薄片状压制物料研磨成粉，使所得粉状物料通过20目筛过筛。将轻质二氧化硅(0.3g)和硬脂酸镁(0.3g)加入到已过筛的物料中，并混合。所得混合产物用制片机压片，制备片剂。
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (3)
1.一类用作DPP-IV抑制剂的吡唑并嘧啶结构的化合物或其药学上可接受的盐，其特征在于，其结构通式如下：
Ar环为被1-5个卤素原子取代的苯基。
2.一种用作DPP-IV抑制剂的吡唑并嘧啶结构的化合物或其药学上可接受的盐，其特征在于，选自：
3.一种如权利要求1或2所述用作DPP-IV抑制剂的吡唑并嘧啶结构的化合物在制备治疗和/或预防与DPP-IV活性过高或者与DPP-IV过度表达有关疾病的药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010141466.9A CN113354644B (zh) | 2020-03-04 | 2020-03-04 | 一类用作dpp-iv抑制剂的吡唑并嘧啶结构的化合物及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010141466.9A CN113354644B (zh) | 2020-03-04 | 2020-03-04 | 一类用作dpp-iv抑制剂的吡唑并嘧啶结构的化合物及应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113354644A CN113354644A (zh) | 2021-09-07 |
| CN113354644B true CN113354644B (zh) | 2023-07-04 |
Family
ID=77523191
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010141466.9A Active CN113354644B (zh) | 2020-03-04 | 2020-03-04 | 一类用作dpp-iv抑制剂的吡唑并嘧啶结构的化合物及应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113354644B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113861196B (zh) * | 2021-11-19 | 2023-06-02 | 烟台药物研究所 | 一类4，6-二取代嘧啶结构的dpp-iv抑制剂及其应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1507447A (zh) * | 2001-03-14 | 2004-06-23 | 取代吡唑并嘧啶和噻唑并嘧啶 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE602006003733D1 (de) * | 2005-02-10 | 2009-01-02 | Smithkline Beecham Corp | Pyridopyrazolopyrimidinderivate und ihre anwendung gegen krebs und diabetes |
-
2020
- 2020-03-04 CN CN202010141466.9A patent/CN113354644B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1507447A (zh) * | 2001-03-14 | 2004-06-23 | 取代吡唑并嘧啶和噻唑并嘧啶 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113354644A (zh) | 2021-09-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1661897B1 (en) | Pyrrolopyrimidinone derivative | |
| EP3006445B1 (en) | Bisulfate of janus kinase (jak) inhibitor and preparation method therefor | |
| EP2828259B1 (en) | Substituted pyridopyrimidine compounds and their use as flt3 inhibitors | |
| US20070049590A1 (en) | Compositions comprising zopiclone derivatives and methods of making and using the same | |
| AU776000B2 (en) | Methods of making and using N-desmethylzopiclone | |
| EP2786998B1 (en) | Thienyl [3, 2-d]pyrimidin-4-one compounds, preparation method, pharmaceutical compositions and use thereof | |
| EP3842431B1 (en) | [1,2,4]triazolo[1,5-a]pyridine compound as jak inhibitor and application thereof | |
| US20170217964A1 (en) | Aminotetrahydropyran derivative used as dipeptidyl peptidaseiv inhibitor | |
| CN113354644B (zh) | 一类用作dpp-iv抑制剂的吡唑并嘧啶结构的化合物及应用 | |
| US7557113B2 (en) | Substituted pyrrolo[3,2-d]pyrimidine derivatives | |
| CN116102555A (zh) | 咪唑并芳杂基类衍生物及其应用 | |
| CN113861196B (zh) | 一类4，6-二取代嘧啶结构的dpp-iv抑制剂及其应用 | |
| US20230120294A1 (en) | Antiviral agents for the treatment and prevention of hiv infection | |
| Ran et al. | Scaffold-based design of xanthine as highly potent inhibitors of DPP-IV for improving glucose homeostasis in DIO mice | |
| CN115246816B (zh) | 一种双靶点阿格列汀衍生物 | |
| EP4021452B1 (en) | Substituted (7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino compounds useful as jak1 inhibitors | |
| CN115304604B (zh) | 一种双靶点西格列汀衍生物 | |
| CN109761990B (zh) | 一种嘧啶并嘧啶类衍生物及其制备方法和在医药上的应用 | |
| CN116836154A (zh) | 可用于痛风的化合物 | |
| CN116535361A (zh) | 取代羟基嘧啶类黄嘌呤氧化酶抑制剂及其制法和药物用途 | |
| CN118027016A (zh) | Parg抑制剂及其制备方法和用途 | |
| JPWO2004096812A1 (ja) | 縮合ピリミジン誘導体 | |
| CN113387989A (zh) | 一种氨基吡喃环衍生物及其在医药上的应用 | |
| KR20240136360A (ko) | 다중치환 우라실 유도체 및 이의 제조 방법과 응용 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |