WO2021018023A1 - Small molecule glp-1 receptor modulator - Google Patents
Small molecule glp-1 receptor modulator Download PDFInfo
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- WO2021018023A1 WO2021018023A1 PCT/CN2020/104059 CN2020104059W WO2021018023A1 WO 2021018023 A1 WO2021018023 A1 WO 2021018023A1 CN 2020104059 W CN2020104059 W CN 2020104059W WO 2021018023 A1 WO2021018023 A1 WO 2021018023A1
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- 0 Cc1nc(ccc2c3ccnc2)c3[n]1* Chemical compound Cc1nc(ccc2c3ccnc2)c3[n]1* 0.000 description 5
- BGHNWJOTRMAJGU-LBPRGKRZSA-N CC(C)(C)OC(c1ccc2nc(CCl)[n](C[C@H]3OCC3)c2c1)=O Chemical compound CC(C)(C)OC(c1ccc2nc(CCl)[n](C[C@H]3OCC3)c2c1)=O BGHNWJOTRMAJGU-LBPRGKRZSA-N 0.000 description 2
- HZCMEMLSGCCCBR-UHFFFAOYSA-N C=C(CC(C#N)O)F Chemical compound C=C(CC(C#N)O)F HZCMEMLSGCCCBR-UHFFFAOYSA-N 0.000 description 1
- OOEWWXWSBJSJOY-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC=C1c1cc(S(=C)=C)cc(N)n1)=O Chemical compound CC(C)(C)OC(N(CC1)CC=C1c1cc(S(=C)=C)cc(N)n1)=O OOEWWXWSBJSJOY-UHFFFAOYSA-N 0.000 description 1
- NUNYMJODUBHUGO-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCC1c1nc(C)ccc1)=O Chemical compound CC(C)(C)OC(N(CC1)CCC1c1nc(C)ccc1)=O NUNYMJODUBHUGO-UHFFFAOYSA-N 0.000 description 1
- XCBQLDHJEOBMQZ-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCC1c1nc(NC(c(c(F)c2)ccc2C#N)=O)ccc1)=O Chemical compound CC(C)(C)OC(N(CC1)CCC1c1nc(NC(c(c(F)c2)ccc2C#N)=O)ccc1)=O XCBQLDHJEOBMQZ-UHFFFAOYSA-N 0.000 description 1
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- FXDNQVGXRTZQPD-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1c1nc(NS(c(cccc2)c2F)(=O)=O)ccc1)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1c1nc(NS(c(cccc2)c2F)(=O)=O)ccc1)=O FXDNQVGXRTZQPD-UHFFFAOYSA-N 0.000 description 1
- VVDCRJGWILREQH-UHFFFAOYSA-N CC(C)(C)OC(N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1)=O Chemical compound CC(C)(C)OC(N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1)=O VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 1
- SJTBAUMUVAGWLC-NDEPHWFRSA-N CC(C)(C)OC(c(cc1)cc2c1nc(CN(C)Cc(cc1)cc3c1ccc(OCc(ccc(C#N)c1)c1F)n3)[n]2C[C@H]1OCC1)=O Chemical compound CC(C)(C)OC(c(cc1)cc2c1nc(CN(C)Cc(cc1)cc3c1ccc(OCc(ccc(C#N)c1)c1F)n3)[n]2C[C@H]1OCC1)=O SJTBAUMUVAGWLC-NDEPHWFRSA-N 0.000 description 1
- MSXYAMLAEHUEOE-FQEVSTJZSA-N CC(C)(C)OC(c(cc1)cc2c1nc(CN(CC1)CCC1c1nc(N)ccc1)[n]2C[C@H]1OCC1)=O Chemical compound CC(C)(C)OC(c(cc1)cc2c1nc(CN(CC1)CCC1c1nc(N)ccc1)[n]2C[C@H]1OCC1)=O MSXYAMLAEHUEOE-FQEVSTJZSA-N 0.000 description 1
- MRKPYNOHPOGSEH-VWLOTQADSA-N CC(C)(C)OC(c(cc1)cc2c1nc(CN(CC1)CCN1c1nc(NC(c(c(F)c3)ccc3C#N)=O)ccc1)[n]2C[C@H]1OCCC1)=O Chemical compound CC(C)(C)OC(c(cc1)cc2c1nc(CN(CC1)CCN1c1nc(NC(c(c(F)c3)ccc3C#N)=O)ccc1)[n]2C[C@H]1OCCC1)=O MRKPYNOHPOGSEH-VWLOTQADSA-N 0.000 description 1
- IXZXLIYQZAUULN-UHFFFAOYSA-N CC(C)(C)OC(c1ccc2nc(CN(C)Cc(cc3)cc4c3ccc(OCC(C(C3)F)=CC=C3C#N)n4)[n](CC3OCC3)c2c1)=O Chemical compound CC(C)(C)OC(c1ccc2nc(CN(C)Cc(cc3)cc4c3ccc(OCC(C(C3)F)=CC=C3C#N)n4)[n](CC3OCC3)c2c1)=O IXZXLIYQZAUULN-UHFFFAOYSA-N 0.000 description 1
- ZGFDEAQSASQRPH-SANMLTNESA-N CC(C)(C)OC(c1ccc2nc(CN(CC3)CCC3c3nc(OCc(c(F)c4)ccc4C#N)ccn3)[n](C[C@H]3OCC3)c2c1)=O Chemical compound CC(C)(C)OC(c1ccc2nc(CN(CC3)CCC3c3nc(OCc(c(F)c4)ccc4C#N)ccn3)[n](C[C@H]3OCC3)c2c1)=O ZGFDEAQSASQRPH-SANMLTNESA-N 0.000 description 1
- LCZIBVFSBLOUOG-LYGNXSNRSA-N CC(C)(C)OC1N=C(CN(CC2)CCN2c2nc(N)ccc2)N(C[C@H]2OCC2)C1C=C Chemical compound CC(C)(C)OC1N=C(CN(CC2)CCN2c2nc(N)ccc2)N(C[C@H]2OCC2)C1C=C LCZIBVFSBLOUOG-LYGNXSNRSA-N 0.000 description 1
- YRGICZBLQYBNSH-UHFFFAOYSA-N CCCNc1nc(O)ccc1 Chemical compound CCCNc1nc(O)ccc1 YRGICZBLQYBNSH-UHFFFAOYSA-N 0.000 description 1
- HPIWOQRFWJDAKZ-LJAQVGFWSA-N CCN(Cc1nc(ccc(C(OC(C)(C)C)=O)c2)c2[n]1C[C@H]1OCC1)Cc(cc1)cc2c1ccc(OCc(ccc(C#N)c1)c1F)n2 Chemical compound CCN(Cc1nc(ccc(C(OC(C)(C)C)=O)c2)c2[n]1C[C@H]1OCC1)Cc(cc1)cc2c1ccc(OCc(ccc(C#N)c1)c1F)n2 HPIWOQRFWJDAKZ-LJAQVGFWSA-N 0.000 description 1
- HWKZWNNYJMGBFG-UHFFFAOYSA-N CCNCc1cc2nc(OCc(ccc(C#N)c3)c3F)ccc2cc1 Chemical compound CCNCc1cc2nc(OCc(ccc(C#N)c3)c3F)ccc2cc1 HWKZWNNYJMGBFG-UHFFFAOYSA-N 0.000 description 1
- QASRKYJPWKYDRR-UHFFFAOYSA-N CCc([n](CC1OCCC1)c1c2)nc1ccc2C(OC(C)(C)C)=O Chemical compound CCc([n](CC1OCCC1)c1c2)nc1ccc2C(OC(C)(C)C)=O QASRKYJPWKYDRR-UHFFFAOYSA-N 0.000 description 1
- SNDNIVHXQFGRJE-VWLOTQADSA-N CN(Cc1nc(ccc(C(O)=O)c2)c2[n]1C[C@H]1OCC1)Cc(cc1)cc2c1ccc(OCc(c(F)c1)ccc1C#N)n2 Chemical compound CN(Cc1nc(ccc(C(O)=O)c2)c2[n]1C[C@H]1OCC1)Cc(cc1)cc2c1ccc(OCc(c(F)c1)ccc1C#N)n2 SNDNIVHXQFGRJE-VWLOTQADSA-N 0.000 description 1
- GVLBOIITNFMQEZ-VIFPVBQESA-N CNc(ccc(C(O)=O)c1)c1NC[C@H]1OCC1 Chemical compound CNc(ccc(C(O)=O)c1)c1NC[C@H]1OCC1 GVLBOIITNFMQEZ-VIFPVBQESA-N 0.000 description 1
- DRQGZMZPKOYPKW-UHFFFAOYSA-N CS(c(cccc1)c1F)(=O)=O Chemical compound CS(c(cccc1)c1F)(=O)=O DRQGZMZPKOYPKW-UHFFFAOYSA-N 0.000 description 1
- NXMBFOCQLZWIHS-INIZCTEOSA-N Cc1cccc(N2CCC(C/C(/NC[C@H]3OCC3)=N/C)CC2)n1 Chemical compound Cc1cccc(N2CCC(C/C(/NC[C@H]3OCC3)=N/C)CC2)n1 NXMBFOCQLZWIHS-INIZCTEOSA-N 0.000 description 1
- WVKIEEVFGCAMFO-UHFFFAOYSA-N N#Cc1cc(F)c(COc2cccc(N3CCNCC3)n2)cc1 Chemical compound N#Cc1cc(F)c(COc2cccc(N3CCNCC3)n2)cc1 WVKIEEVFGCAMFO-UHFFFAOYSA-N 0.000 description 1
- SEGSJKKKGDWWOK-UHFFFAOYSA-N N#Cc1ccc(C(Nc2cccc(N3CCNCC3)n2)=O)c(F)c1 Chemical compound N#Cc1ccc(C(Nc2cccc(N3CCNCC3)n2)=O)c(F)c1 SEGSJKKKGDWWOK-UHFFFAOYSA-N 0.000 description 1
- RLKLLWWCWOXFNA-NRFANRHFSA-N N#Cc1ccc(C(Nc2nc(N3CCN(Cc4nc(ccc(C(O)=O)c5)c5[n]4C[C@H]4OCC4)CC3)ccc2)=O)c(F)c1 Chemical compound N#Cc1ccc(C(Nc2nc(N3CCN(Cc4nc(ccc(C(O)=O)c5)c5[n]4C[C@H]4OCC4)CC3)ccc2)=O)c(F)c1 RLKLLWWCWOXFNA-NRFANRHFSA-N 0.000 description 1
- PHNZXQRIDUETFL-QHCPKHFHSA-N N#Cc1ccc(COc2ccnc(C3CCN(Cc4nc(ccc(C(O)=O)c5)c5[n]4C[C@H]4OCC4)CC3)n2)c(F)c1 Chemical compound N#Cc1ccc(COc2ccnc(C3CCN(Cc4nc(ccc(C(O)=O)c5)c5[n]4C[C@H]4OCC4)CC3)n2)c(F)c1 PHNZXQRIDUETFL-QHCPKHFHSA-N 0.000 description 1
- CAACQLNHRTYCGE-UHFFFAOYSA-N N#Cc1ccc(COc2ccnc(C3CCNCC3)n2)c(F)c1 Chemical compound N#Cc1ccc(COc2ccnc(C3CCNCC3)n2)c(F)c1 CAACQLNHRTYCGE-UHFFFAOYSA-N 0.000 description 1
- HYBAKUMPISVZQP-DEOSSOPVSA-N N#Cc1ccc(COc2nc(C3CCN(Cc4nc(ccc(C(O)=O)c5)c5[n]4C[C@H]4OCC4)CC3)ccc2)c(F)c1 Chemical compound N#Cc1ccc(COc2nc(C3CCN(Cc4nc(ccc(C(O)=O)c5)c5[n]4C[C@H]4OCC4)CC3)ccc2)c(F)c1 HYBAKUMPISVZQP-DEOSSOPVSA-N 0.000 description 1
- DUEDRJQDBMKSBA-UHFFFAOYSA-N NC(c(c(F)c1)ccc1C#N)=O Chemical compound NC(c(c(F)c1)ccc1C#N)=O DUEDRJQDBMKSBA-UHFFFAOYSA-N 0.000 description 1
- HRXCKBDBXBOQGY-DEOSSOPVSA-N NC(c(cc1)cc2c1nc(CN(CC1)CCC1c1nc(OCc(c(F)c3)ccc3C#N)ccc1)[n]2C[C@H]1OCC1)=O Chemical compound NC(c(cc1)cc2c1nc(CN(CC1)CCC1c1nc(OCc(c(F)c3)ccc3C#N)ccc1)[n]2C[C@H]1OCC1)=O HRXCKBDBXBOQGY-DEOSSOPVSA-N 0.000 description 1
- UMHDTYLVLFDAMT-QHCPKHFHSA-N NC(c(cc1)cc2c1nc(CN(CC1)CCC1c1nc(OCc(c(F)c3)ccc3C#N)ccn1)[n]2C[C@H]1OCC1)=O Chemical compound NC(c(cc1)cc2c1nc(CN(CC1)CCC1c1nc(OCc(c(F)c3)ccc3C#N)ccn1)[n]2C[C@H]1OCC1)=O UMHDTYLVLFDAMT-QHCPKHFHSA-N 0.000 description 1
- XIORRBJRRZDMFV-KRWDZBQOSA-N Nc1cccc(C2CCN(Cc3nc(ccc(C(O)=O)c4)c4[n]3C[C@H]3OCC3)CC2)n1 Chemical compound Nc1cccc(C2CCN(Cc3nc(ccc(C(O)=O)c4)c4[n]3C[C@H]3OCC3)CC2)n1 XIORRBJRRZDMFV-KRWDZBQOSA-N 0.000 description 1
- BKLJUYPLUWUEOQ-UHFFFAOYSA-N Nc1nc(Br)ccc1 Chemical compound Nc1nc(Br)ccc1 BKLJUYPLUWUEOQ-UHFFFAOYSA-N 0.000 description 1
- RIFCANWNINVTTN-UHFFFAOYSA-N O=Cc([n](CC1OCC1)c1c2)cc1ccc2Br Chemical compound O=Cc([n](CC1OCC1)c1c2)cc1ccc2Br RIFCANWNINVTTN-UHFFFAOYSA-N 0.000 description 1
- DJXZBHFMCZAWLR-SFHVURJKSA-N O=Cc([n](C[C@H]1OCC1)c1c2)cc1ccc2C(Oc1ccccc1)=O Chemical compound O=Cc([n](C[C@H]1OCC1)c1c2)cc1ccc2C(Oc1ccccc1)=O DJXZBHFMCZAWLR-SFHVURJKSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the invention belongs to the technical field of medicine, and specifically relates to a small molecule GLP-1 receptor modulator with a new structure, a preparation method and a pharmaceutical application thereof.
- Diabetes is a metabolic disease characterized by high blood sugar. Due to factors such as insulin secretion defects or decreased physiological function of pancreatic islet B cells, it leads to a long-term high blood sugar state in the body, which in turn leads to chronic diseases of the eyes, kidneys, heart, blood vessels, nerves and other organs and tissues. Damage or dysfunction. According to different pathogenesis, diabetes can be divided into type I diabetes and type II diabetes. Type II diabetes is caused by the decline of pancreatic islet B cell function and insulin resistance, which is the main type of diabetes.
- Glucagon-like peptide-1 receptor (GLP-1 receptor) is one of the effective targets for the treatment of type II diabetes.
- the GLP-1 receptor belongs to the B family of G protein-coupled receptors, with seven transmembrane domains, and its natural agonist ligand is glucagon-like peptide-1 (ie GLP-1).
- GLP-1 receptor When the GLP-1 receptor is activated, it can further activate downstream signal pathways such as PKA, PI3K, MAPK, and promote the release of insulin and reduce the release of glucagon, thereby reducing blood sugar levels.
- GLP-1 receptor agonists developed in the early stage are GLP-1 analogues, which are all peptides, including liraglutide, semaglutide, etc., through genetic engineering methods and preparation improvements, etc., long-term effects have been developed Polypeptide drugs that can be taken orally, but oral polypeptides are still subject to many disadvantages such as administration time, dosage, and gastrointestinal disturbances.
- small molecule compounds can also be used to regulate the function of GLP-1 receptors, and then develop small molecule GLP-1 receptor agonists (Document 1), including some low molecular weight flavonoids and containing Nitrogen heterocyclic compounds and compounds Boc-4 and S4P that mimic the structure of polypeptides, etc.
- the existing small molecule agonists have limited structure types, and the specificity and safety of GLP-1 receptors are not strong, so it is necessary to develop New structure type and specific agonist for GLP-1 receptor.
- Literature 1 Willard FS, et al. Small molecule drug discovery at the glucagon-like peptide-1 receptor, Journal of Diabetes Research, 2012, 2012: 344-350.
- the purpose of the present invention is to provide a new structure of small molecule GLP-1 receptor modulator, its preparation method and pharmaceutical application.
- the present invention provides a small molecule GLP-1 receptor modulator with the following structure, and a pharmaceutically acceptable salt, ester, stereoisomer, ether, prodrug or solvate thereof:
- A is a substituted or unsubstituted aromatic ring, aromatic heterocyclic ring, C 2 -C 8 alkenyl group, the substitution is one or more than two, and the substituents may be the same or different;
- L is a link chain, selected from -(CH 2 ) m -, -CONR 7 -, -SO 2 NR 7 -, -NR 7 CO-, -NR 7 SO 2 -, -(CH 2 ) m O-,- O(CH 2 ) m -, -(CH 2 ) m S-, -S(CH 2 ) m -, -(CH 2 ) m NR 7 -, -NR 7 (CH 2 ) m -; said R 7 It is selected from hydrogen, a C 1-8 straight or branched chain alkyl group or a C 3-8 cycloalkyl group, and the alkyl group is optionally further substituted with one or more halogen, cyano, amino or hydroxy; preferably , R 7 is selected from hydrogen, C 1-3 linear alkyl; more preferably, said L is selected from -CH 2 O-, -CONH-, -CH 2 NH- or -CH 2 N
- B is a combined structure of two or more saturated or unsaturated carbocyclic rings, and the carbocyclic ring optionally contains one or more heteroatoms;
- n are independently selected from 1, 2 or 3;
- Z may be the same or different, selected from CH, CR 9 or N; said R 9 is halogen, selected from F, Cl, Br, I;
- R 4 is selected from C 1-4 alkyl or C 1-4 alkoxy.
- the C 1-4 alkyl or C 1-4 alkoxy is optionally further substituted by one or more halogen or cyano groups,
- the hydroxyl group is substituted or further substituted by a saturated or unsaturated carbocyclic ring or a heteroatom-containing carbocyclic ring; the saturated or unsaturated carbocyclic ring or a heteroatom-containing carbocyclic ring is optionally further substituted by one or more halogens , Cyano, amino or hydroxyl; preferably, the saturated or unsaturated carbocyclic ring or heteroatom-containing carbocyclic ring is a four-membered ring, a five-membered ring, or a six-membered ring; more preferably, the saturated or The unsaturated carbocyclic ring or the heteroatom-containing carbocyclic ring is a butylene oxide substituent, a pentylene oxide substituent or
- R 5 is one or more than two, selected from hydrogen, hydroxy, amino, halogen, cyano, carboxy, tetrazolyl, amide; and the hydroxy, amino, carboxy, tetrazolyl or amide group is optional Is further substituted by one or more hydroxy, hydroxyalkyl, carboxyalkyl, aminoalkyl, and the alkyl is selected from C 1-4 alkyl; preferably, R 5 is selected from carboxy, amide, or A hydroxy, hydroxyalkyl, carboxyalkyl, or aminoalkyl substituted amide group; the amide group substituted by a hydroxy, hydroxyalkyl, carboxyalkyl, or aminoalkyl group is, for example, hydroxy, hydroxymethyl, Amido groups substituted by hydroxyethyl, carboxymethyl, and carboxyethyl;
- R 5 may form a ring system structure, the ring system structure may further contain one or more nitrogen atoms and/or one or more intra-ring carbonyl groups, and the ring system structure is optionally surrounded by one or more R 6 substitution, said R 6 is selected from hydrogen, hydroxy, amino, halogen, cyano, carboxy, tetrazolyl, amide; and said hydroxy, amino, carboxy, tetrazolyl or amide optionally further Is substituted by one or two or more hydroxy, hydroxyalkyl, carboxyalkyl, aminoalkyl, the alkyl is selected from C 1-4 alkyl; preferably, R 5 is connected to Form a ring structure or The ring system structure is optionally substituted with one or more R 6 .
- L is selected from -(CH 2 ) m O-, -SO 2 NR 7 -, -(CH 2 ) m NR 7 -, and m is 1; more preferably, R 7 is selected from H or methyl;
- A is one or two or more R 1 substituted aromatic rings or aromatic heterocycles or C 2 -C 8 alkenyl groups
- R 1 is selected from hydrogen, hydroxyl, amino, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl or C 1-4 alkoxy substituted by one or more halogens; preferably, A is substituted with one or more R 1 Phenyl i is selected from an integer of 1-5, such as 1,2,3,4,5; preferably, i is 1 or 2, preferably, R 1 is selected from cyano, F, Cl, Br, I, more preferably , A is The X is halogen, selected from F, Cl, Br, I; preferably, A is Preferably, R 1 is selected from F, Cl, Br, I; in some embodiments, B is selected from the following exemplary structures:
- Y can be the same or different, and is selected from CH or N; Z is defined as above, R 2 , R 3 , R 8 can be one or more than two, independently selected from hydrogen, hydroxyl, amino, halogen, cyanide Group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl or C 1-4 alkoxy substituted with one or more halogens.
- B is selected from the following exemplary structures:
- R 2 and R 3 are the same as before;
- B is selected from the following exemplary structures:
- R 2 and R 3 are the same as before;
- the compound of the present invention has the following structure:
- Y can be the same or different, and is selected from CH or N;
- Z, R 2 , R 3 , R 4 , R 5 have the same definitions as before, (R 1 ) i represents that i can be the same or different on the phenyl group substituted by R 1, the same as R 1 defined before, I is an integer selected from 1-5, for example, 1,2,3,4,5, preferably, i is 1 or 2.
- the compound of the present invention has the following structure:
- the compound of the present invention has the following structure:
- the compound of the present invention has the following structure:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and i have the same definitions as before, X is selected from -CH 2 -, -CO- or -SO 2 -, Y may be the same or different, and From CH or N, Z may be the same or different, and are selected from CH, CR 9 or N.
- the R 9 is halogen, selected from F, Cl, Br, and I.
- the compound of the present invention has the following structure:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and i have the same definitions as before, X is selected from -CH 2 -, -CO- or -SO 2 -, Y may be the same or different, and From CH or N.
- the compound of the present invention has the following structure:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and i have the same definitions as before, X is selected from -CH 2 -, -CO- or -SO 2 -, Y may be the same or different, and From CH or N.
- the compound of the present invention has the following structure:
- R 1 , R 3 , R 4 , R 5 , and i are as defined above, Z may be the same or different, and are selected from CH, CR 9 or N, and R 9 is halogen, selected from F, Cl, Br, I.
- the compound of the present invention has the following structure:
- R 1 , R 2 , R 3 , R 4 , and i are as defined above
- Y may be the same or different, and are selected from CH or N
- R 6 is one or more than two, and are selected from hydrogen, hydroxyl, amino, halogen, A cyano group, a carboxyl group, a tetrazolium group, an amide group, and the hydroxyl group, an amino group, a carboxyl group, a tetrazolium group or an amide group is optionally further substituted with one or more hydroxyalkyl groups, carboxyalkyl groups,
- the alkyl group is selected from C 1-4 alkyl groups;
- the compound of the present invention has the following structure:
- R 1 , R 2 , R 3 , R 4 , R 5 and i are as defined above, X is selected from -CH 2 -, -CO- or -SO 2 -, Y may be the same or different, and is selected from CH or N , Z may be the same or different, and are selected from CH, CR 9 or N.
- the R 9 is halogen, selected from F, Cl, Br, and I.
- the compound of the present invention has the following structure:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and i are as defined above, X is selected from -CH 2 -, -CO- or -SO 2 -, Y may be the same or different, and are selected from CH or N, Z may be the same or different, and are selected from CH, CR 9 or N, and R 9 is halogen, selected from F, Cl, Br, and I.
- the compound of the present invention has the following structure:
- R 1 , R 2 , R 3 , R 4 , R 5 , and i are as defined above, Y may be the same or different, selected from CH or N, Z may be the same or different, selected from CH, CR 9 or N, so Said R 9 is halogen, selected from F, Cl, Br, I.
- the compound of the present invention has the following structure:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and i are as defined above, X is selected from -CH 2 -, -CO- or -SO 2 -, Y can be the same or different , Selected from CH or N, Z may be the same or different, selected from CH, CR 9 or N, said R 9 is halogen, selected from F, Cl, Br, I.
- the compound of the present invention has the following structure:
- R 1 , R 4 , R 5 , R 7 , and i are as defined above, X is selected from -CH 2 -, -CO- or -SO 2 -, Y can be the same or different, and can be selected from CH or N, Z can Same or different, selected from CH, CR 9 or N, said R 9 is halogen, selected from F, Cl, Br, I; preferably, R 1 is selected from hydrogen, halogen, cyano, C 1-4 alkane Group, C 1-4 alkoxy, C 1-4 alkyl or C 1-4 alkoxy substituted with one or more halogens.
- the compound of the present invention has the following structure:
- the present invention also provides a compound with the following structure, which serves as an intermediate in the preparation of the compound of the present invention:
- R 1 , R 2 , R 3 , R 7 , Z, Y, and i are as defined above, Y'is selected from CR 10 or NR 10 , and R 10 is selected from H, C1-C8 alkyl, C1 -C4 alkyl carboxyl, C1-C4 alkyl hydroxy; preferably, the R 10 is selected from H, methyl, carboxy, carboxymethyl, carboxyethyl.
- the intermediate has the following structure:
- the intermediate described in the present invention has the following structure:
- the GLP-1 receptor modulator provided by the present invention has the function of activating, enhancing or agonizing the GLP-1 receptor.
- the present invention provides a medicament comprising a compound of the present invention, a pharmaceutically acceptable salt, hydrolyzable ester, stereoisomer, ether, prodrug, or solvate thereof, and at least one pharmaceutically acceptable carrier combination.
- the GLP-1 receptor modulator compound of the present invention can be combined with a pharmaceutically acceptable carrier to provide suitable for lactation
- a pharmaceutically acceptable carrier for diseases of animals, preferably humans.
- the specific carriers used in these pharmaceutical compositions can vary depending on the type of administration required (for example, intravenous, oral, topical, suppository, or parenteral administration type).
- conventional pharmaceutical media such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. can be used for formulation.
- carriers such as diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used.
- Embodiments of the present invention also include prodrugs of the compounds of the present invention, which are converted into the compounds of the present invention with pharmacological activity through enzymatic and chemical reactions in vivo.
- prodrugs are functional derivatives of the compounds of the present invention, and conventional methods for selecting and preparing suitable prodrug derivatives are known in the art.
- the compounds of the present invention provide methods for treating malignant conditions in subjects that medically require activation, enhancement, or agonism of GLP-1 receptors by following a frequency or duration sufficient to provide a beneficial effect to the patient An effective amount of the compound of the invention is administered to the subject for treatment.
- the treatment method provided by the present invention includes administering the compound of the present invention alone or in combination with another pharmacologically active agent to a subject or patient suffering from a malignant condition that medically requires the activation, enhancement or agonism of the glucagon-like peptide 1 receptor Or the second drug is to administer the compound of the present invention, the malignant conditions such as type I diabetes, type II diabetes, gestational diabetes, obesity, excessive appetite, insufficient satiety or metabolic disorders.
- the invention provides a pharmaceutical composition comprising a compound of the invention and a second drug.
- the second drug is a polypeptide GLP-1 agonist or other type II diabetes treatment drugs, such as DPP-IV inhibitors.
- the second drug is Exenatide, Semaglutide, Liraglutide, Tasglutide, Albiglutide, Lixisenatide, and/or other insulin modulating peptides.
- the second drug is a DPPIV inhibitor, such as sitagliptin.
- the second drug is a sodium-glucose co-transporter SGLT1 and/or SGLT2 inhibitor; or the second drug is a biguanide hypoglycemic drug, such as metformin; or the second drug is a sulfonylurea hypoglycemic drug , Such as glibenclamide, glipizide, gliclazide and/or glimepiride; or the second drug is a thiazolidinedione hypoglycemic agent, pioglitazone and/or rosiglitazone; or the second drug
- the drugs are diabetes treatment or adjuvant treatment drugs such as acarbose, miglitol, colesevelam and/or bromocriptine.
- the present invention provides a new compound that modulates glucagon-like peptide-1 (GLP-1) receptor, its synthesis method, and its pharmaceutical use.
- GLP-1 glucagon-like peptide-1
- the provided new compound has obvious agonistic effect on GLP-1 receptor, and its EC 50 value reaches the nm level.
- the active compound has no obvious binding effect on hERG, indicating that it has a lower risk of cardiotoxicity.
- the compound of the present invention can be used alone as a diabetes treatment drug, or combined with a polypeptide GLP-1 receptor agonist such as liraglutide, or combined with drugs for the treatment of type II diabetes with other mechanisms.
- the agonistic activity of the compound on the GLP-1 receptor was characterized by the changes in the cAMP content of HEK293 cells that highly expressed the GLP-1 receptor.
- Use the cAMP detection kit (Cisbio Cat#62AM4PEJ).
- Cisbio CAMP-GS DYNAMIC KIT manual please refer to the Cisbio CAMP-GS DYNAMIC KIT manual.
- HTRF cAMP determination of agonist Use an electronic multi-channel pipette to add 10 ⁇ L of cell suspension to the test plate, mix at 1000 rpm for 60 sec, incubate at room temperature for 30 minutes, add 5 ⁇ L of detection reagent to each well; cover with a sealing film, Incubate at room temperature for 60 minutes; remove the sealing film, use EnVision (PerkinElmer) to read, calculate the EC 50 value, where +++++ means between 1-2nm, ++++ means between 2-5nm, +++ means Between 5-20nm, ++ means 20-1000nm, + means 1-10 ⁇ M. As shown in Table 1.
- Compound number Activity (EC 50 ) Compound number Activity (EC 50 ) A + 1T ++++ B + 2T + C + 3T ++++ D + 4T ++ E + 5T ++++ F + 6T +++ G + 7T ++++ H + 8T +++++ I + 9T + J + 10T + K ++ 11T +++ L ++ 12T + M ++ 13T + N ++ 14T + O + To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To To
- hERG gene Human Ether-a-go-go Related Gene encodes myocardial delayed rectifier potassium channel current. Studies have found that some drugs have an inhibitory effect on hERG potassium channels, which leads to prolonged cardiac QT interval and induces arrhythmia. By detecting the binding capacity of the compound to hERG, the potential risk of cardiotoxicity of the compound can be initially assessed.
- the starting concentration of the test compound was 2 mM, the starting concentration of the control compound was 0.2 mM, and DMSO was the solvent, respectively, with 4-fold gradient dilutions, each taking 8 data points.
- Transfer 1 ⁇ L of the compound to the test plate add 100 ⁇ L of hERG/CHO cells, add 100 ⁇ L of [ 3 H]Dofetilide, seal the plate, and incubate at room temperature for 1 h.
- the reaction mixture was filtered, washed, and the test plate was dried at 50°C for 1 hour.
Abstract
Description
化合物编号Compound number | 活性(EC 50) Activity (EC 50 ) | 化合物编号Compound number | 活性(EC 50) Activity (EC 50 ) |
AA | ++ | 1T1T | ++++++++ |
BB | ++ | 2T2T | ++ |
CC | ++ | 3T3T | ++++++++ |
DD | ++ | 4T4T | ++++ |
EE | ++ | 5T5T | ++++++++ |
FF | ++ | 6T6T | ++++++ |
GG | ++ | 7T7T | ++++++++ |
HH | ++ | 8T8T | ++++++++++ |
II | ++ | 9T9T | ++ |
JJ | ++ | 10T10T | ++ |
KK | ++++ | 11T11T | ++++++ |
LL | ++++ | 12T12T | ++ |
MM | ++++ | 13T13T | ++ |
NN | ++++ | 14T14T | ++ |
OO | ++ | To | To |
化合物编号Compound number | 活性(IC 50,nm) Activity (IC 50 ,nm) |
3T3T | 59225922 |
5T5T | >100000>100000 |
7T7T | 10621062 |
8T8T | 4994549945 |
dofetilidedofetilide | 3.233.23 |
Claims (18)
- 一种具有如下结构的小分子GLP-1受体调节剂,其药学上可接受的盐、酯、立体异构体、醚、前药或溶剂化物:A small molecule GLP-1 receptor modulator with the following structure, and its pharmaceutically acceptable salt, ester, stereoisomer, ether, prodrug or solvate:其中,among them,A为取代或未取代的芳环、芳杂环、C 2-C 8的烯基,所述的取代为一个或两个以上,取代基可以相同或不同; A is a substituted or unsubstituted aromatic ring, aromatic heterocyclic ring, C 2 -C 8 alkenyl group, the substitution is one or more than two, and the substituents may be the same or different;L为连接链,选自-(CH 2) m-,-CONR 7-,-SO 2NR 7-,-NR 7CO-,-NR 7SO 2-,-(CH 2) mO-,-O(CH 2) m-,-(CH 2) mS-,-S(CH 2) m-,-(CH 2) mNR 7-,-NR 7(CH 2) m-;所述R 7选自氢,C 1-8直链或支链烷基或C 3-8环烷基,且所述烷基任选的进一步被一个或两个以上卤素,氰基,氨基或羟基取代; L is a link chain, selected from -(CH 2 ) m -, -CONR 7 -, -SO 2 NR 7 -, -NR 7 CO-, -NR 7 SO 2 -, -(CH 2 ) m O-,- O(CH 2 ) m -, -(CH 2 ) m S-, -S(CH 2 ) m -, -(CH 2 ) m NR 7 -, -NR 7 (CH 2 ) m -; said R 7 Selected from hydrogen, C 1-8 straight or branched chain alkyl or C 3-8 cycloalkyl, and the alkyl is optionally further substituted with one or more halogen, cyano, amino or hydroxy;m,n独立地选自1,2或3;m, n are independently selected from 1, 2 or 3;优选的,所述的L选自-CH 2O-,-CONH-,-CH 2NH-或者-CH 2N(CH 3)-; Preferably, said L is selected from -CH 2 O-, -CONH-, -CH 2 NH- or -CH 2 N(CH 3 )-;B为两个或两个以上的饱和或不饱和的碳环的组合结构,所述碳环上任选的包含一个或两个以上杂原子;B is a combined structure of two or more saturated or unsaturated carbocyclic rings, and the carbocyclic ring optionally contains one or more heteroatoms;Z可以相同或不同,选自C-H,C-R 9或N;所述的R 9为卤素,选自F,Cl,Br,I; Z may be the same or different, selected from CH, CR 9 or N; said R 9 is halogen, selected from F, Cl, Br, I;R 4选自C 1-4烷基或C 1-4烷氧基,所述的C 1-4烷基或C 1-4烷氧基任选的进一步被一个或多个卤素、氰基,羟基取代,或进一步被饱和或不饱和的碳环或含杂原子的碳环取代;所述的饱和或不饱和的碳环或含杂原子的碳环任选的进一步被一个或两个以上卤素,氰基,氨基或羟基取代;优选的,所述饱和或不饱和的碳环或含杂原子的碳环为四元环、五元环,或六元环;更优选的,所述饱和或不饱和的碳环或含杂原子的碳环为环氧丁烷取代基、环氧戊烷取代基或噁唑取代基;优选的,R 4选自被环氧丁烷取代基、环氧戊烷取代基或噁唑取代基取代的甲基、乙基或丙基;更优选的,R 4选自被环氧丁烷取代基、环氧戊烷取代基或噁唑取代基取代的甲基; R 4 is selected from C 1-4 alkyl or C 1-4 alkoxy. The C 1-4 alkyl or C 1-4 alkoxy is optionally further substituted by one or more halogen or cyano groups, The hydroxyl group is substituted or further substituted by a saturated or unsaturated carbocyclic ring or a heteroatom-containing carbocyclic ring; the saturated or unsaturated carbocyclic ring or a heteroatom-containing carbocyclic ring is optionally further substituted by one or more halogens , Cyano, amino or hydroxyl; preferably, the saturated or unsaturated carbocyclic ring or heteroatom-containing carbocyclic ring is a four-membered ring, a five-membered ring, or a six-membered ring; more preferably, the saturated or The unsaturated carbocyclic ring or the heteroatom-containing carbocyclic ring is a butylene oxide substituent, a pentylene oxide substituent or an oxazole substituent; preferably, R 4 is selected from the group consisting of a butylene oxide substituent, pentylene oxide Methyl, ethyl or propyl substituted with alkyl substituents or oxazole substituents; more preferably, R 4 is selected from methyl substituted with butylene oxide substituents, epoxypentane substituents or oxazole substituents ;R 5为一个或两个以上,选自氢,羟基,氨基,卤素,氰基,羧基,四氮唑基,酰胺基;且所述羟基,氨基,羧基,四氮唑基或酰胺基任选的进一步被一个或两个以上羟基,羟基烷基,羧基烷基,氨基烷基取代,所述烷基选自C 1-4烷基;优选的,R 5选自羧基、酰胺基、或者被一个羟基,羟基烷基,羧基烷基,氨基烷基取代的酰胺基;所述的被一个羟基,羟基烷基,羧基烷基,氨基烷基取代的酰胺基例如是被羟基、羟甲基、羟乙基、羧甲基、羧乙基取代的酰胺基; R 5 is one or more than two, selected from hydrogen, hydroxy, amino, halogen, cyano, carboxy, tetrazolyl, amide; and the hydroxy, amino, carboxy, tetrazolyl or amide group is optional Is further substituted by one or more hydroxy, hydroxyalkyl, carboxyalkyl, aminoalkyl, and the alkyl is selected from C 1-4 alkyl; preferably, R 5 is selected from carboxy, amide, or A hydroxy, hydroxyalkyl, carboxyalkyl, or aminoalkyl substituted amide group; the amide group substituted by a hydroxy, hydroxyalkyl, carboxyalkyl, or aminoalkyl group is, for example, hydroxy, hydroxymethyl, Amido groups substituted by hydroxyethyl, carboxymethyl, and carboxyethyl;或R 5可形成环系结构,所述环系结构上可进一步含有一个或多个氮原子和/或一个或多个环内羰基,所述环系结构任选的被一个或两个以上R 6取代,所述R 6选自氢,羟基,氨基,卤素,氰基,羧基或四氮唑基,酰胺基;且所述羟基,氨基,羧基,四氮唑基或酰胺基任选的进一步被一个或两个以上羟基,羟基烷基,羧基烷基,氨基烷基取代,所述烷基选自C 1-4烷基;优选的,R5与连接的 形成环系结构 或者 所述环系结构任选的被一个或两个以上R 6取代。 Or R 5 may form a ring system structure, the ring system structure may further contain one or more nitrogen atoms and/or one or more intra-ring carbonyl groups, and the ring system structure is optionally surrounded by one or more R 6 substitution, said R 6 is selected from hydrogen, hydroxy, amino, halogen, cyano, carboxy or tetrazolyl, amide; and said hydroxy, amino, carboxy, tetrazolyl or amide optionally further Is substituted by one or two or more hydroxy, hydroxyalkyl, carboxyalkyl, aminoalkyl, the alkyl is selected from C 1-4 alkyl; preferably, R5 is connected to Form a ring structure or The ring system structure is optionally substituted with one or more R 6 .
- 根据权利要求1所述的GLP-1受体调节剂,其药学上可接受的盐、酯、立体异构体、醚、前药或溶剂化物,其特征在于:The GLP-1 receptor modulator according to claim 1, its pharmaceutically acceptable salt, ester, stereoisomer, ether, prodrug or solvate, characterized in that:A为一个或两个以上R 1取代的芳环或芳杂环或C 2-C 8的烯基,R 1选自氢,羟基,氨基,卤素,氰基,C 1-4烷基,C 1-4烷氧基,由一个或多个卤素取代的C 1-4烷基或C 1-4烷氧基;优选的,A为一个或两个以上R 1取代的苯基 i选自1-5的整数,例如是1,2,3,4,5;优选的,i为1或2,优选的,R 1选自氰基,F,Cl,Br,I,更优选的,A为 所述的X为卤素,选自F,Cl,Br,I;优选的,A为 优选的,R 1选自F,Cl,Br,I; A is an aromatic ring or aromatic heterocyclic ring substituted by one or more R 1 or a C 2 -C 8 alkenyl group, R 1 is selected from hydrogen, hydroxyl, amino, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl or C 1-4 alkoxy substituted by one or more halogens; preferably, A is phenyl substituted with one or more R 1 i is selected from an integer of 1-5, such as 1,2,3,4,5; preferably, i is 1 or 2, preferably, R 1 is selected from cyano, F, Cl, Br, I, more preferably , A is The X is halogen, selected from F, Cl, Br, I; preferably, A is Preferably, R 1 is selected from F, Cl, Br, I;B具有如下结构:B has the following structure:其中,Y可以相同也可以不同,选自为C-H或N;R 2,R 3,R 8为一个或两个以上,选自氢,羟基,氨基,卤素,氰基,C 1-4烷基,C 1-4烷氧基,由一个或多个卤素取代的C 1-4烷基或C 1-4烷氧基。 Among them, Y may be the same or different, and are selected from CH or N; R 2 , R 3 , and R 8 are one or more than two, and are selected from hydrogen, hydroxyl, amino, halogen, cyano, C 1-4 alkyl , C 1-4 alkoxy, C 1-4 alkyl or C 1-4 alkoxy substituted by one or more halogens.
- 根据权利要求1所述的GLP-1受体调节剂,其药学上可接受的盐、酯、立体异构体、醚、 前药或溶剂化物,其特征在于,具有如下结构:The GLP-1 receptor modulator according to claim 1, wherein a pharmaceutically acceptable salt, ester, stereoisomer, ether, prodrug or solvate thereof is characterized in that it has the following structure:其中,Y可以相同也可以不同,选自C-H或N;(R 1) i代表苯基上可以为i个相同或不同的R 1所取代,i选自1-5的整数。 Wherein, Y may be the same or different, and is selected from CH or N; (R 1 ) i represents that the phenyl group may be substituted with i same or different R 1 , and i is selected from an integer of 1-5.
- 根据权利要求5所述的GLP-1受体调节剂,其药学上可接受的盐、酯、立体异构体、醚、前药或溶剂化物,其特征在于,具有如下的结构:The GLP-1 receptor modulator according to claim 5, its pharmaceutically acceptable salt, ester, stereoisomer, ether, prodrug or solvate, characterized in that it has the following structure:其中,X选自-CH 2-,-CO-或-SO 2-,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-R 9或N; Wherein, X is selected from -CH 2 -, -CO- or -SO 2 -, Y can be the same or different, selected from CH or N, Z can be the same or different, selected from CH, CR 9 or N;或具有如下的结构:Or have the following structure:其中,Z可以相同或不同,选自C-H,C-R 9或N; Among them, Z can be the same or different, and are selected from CH, CR 9 or N;或具有如下的结构:Or have the following structure:其中,Y可以相同或不同,选自C-H或N,R 6取代基为一个或两个以上,选自氢,羟基,氨基,卤素,氰基,羧基,四氮唑基,酰胺基,且所述羟基,氨基,羧基,四氮唑基或酰胺基任选的进一步被一个或两个以上羟基烷基、羧基烷基取代,所述烷基选自C 1-4烷基; Wherein, Y can be the same or different, selected from CH or N, R 6 substituent is one or more, selected from hydrogen, hydroxyl, amino, halogen, cyano, carboxyl, tetrazolyl, amide, and so The hydroxyl group, amino group, carboxyl group, tetrazolium group or amide group is optionally further substituted with one or more hydroxyalkyl groups and carboxyalkyl groups, and the alkyl group is selected from C 1-4 alkyl groups;或具有如下的结构:Or have the following structure:其中,X选自-CH 2-,-CO-或-SO 2-,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-R 9或N; Wherein, X is selected from -CH 2 -, -CO- or -SO 2 -, Y can be the same or different, selected from CH or N, Z can be the same or different, selected from CH, CR 9 or N;或具有如下的结构:Or have the following structure:其中,X选自-CH 2-,-CO-或-SO 2-,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-R 9或N; Wherein, X is selected from -CH 2 -, -CO- or -SO 2 -, Y can be the same or different, selected from CH or N, Z can be the same or different, selected from CH, CR 9 or N;或具有如下的结构:Or have the following structure:其中,R 1,R 2,R 3,R 4,R 5定义同前,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-F或N; Wherein, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined above, Y may be the same or different, selected from CH or N, and Z may be the same or different, selected from CH, CF or N;或具有如下的结构:Or have the following structure:其中,X选自-CH 2-,-CO-或-SO 2-,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-R 9或N; Wherein, X is selected from -CH 2 -, -CO- or -SO 2 -, Y can be the same or different, selected from CH or N, Z can be the same or different, selected from CH, CR 9 or N;或具有如下的结构:Or have the following structure:其中,X选自-CH 2-,-CO-或-SO 2-,Y可以相同或不同,选自C-H或N,Z可以相同或不同,选自C-H,C-R 9或N。 Wherein, X is selected from -CH 2 -, -CO- or -SO 2 -, Y may be the same or different, selected from CH or N, and Z may be the same or different, selected from CH, CR 9 or N.
- 一种药物组合物,其特征在于,包含权利要求1-10任一项所述的GLP-1受体调节剂,其药学上可接受的盐、酯、立体异构体、醚、前药或溶剂化物和至少一种药物可接受的载体。A pharmaceutical composition, characterized by comprising the GLP-1 receptor modulator according to any one of claims 1-10, and a pharmaceutically acceptable salt, ester, stereoisomer, ether, prodrug or Solvate and at least one pharmaceutically acceptable carrier.
- 一种药物组合物,其特征在于,包含权利要求1-10任一项所述的GLP-1受体调节剂,其药学上可接受的盐,酯、立体异构体、醚、前药或溶剂化物,和第二药物,所述第二药物为多肽类GLP-1受体激动剂或其他II型糖尿病治疗药物。A pharmaceutical composition, characterized by comprising the GLP-1 receptor modulator according to any one of claims 1-10, a pharmaceutically acceptable salt, ester, stereoisomer, ether, prodrug or Solvate, and a second drug, the second drug is a polypeptide GLP-1 receptor agonist or other type II diabetes treatment drugs.
- 根据权利要求12所述的药物组合物,其特征在于,所述的多肽类GLP-1受体激动剂选 自艾塞那肽、索马鲁肽、利拉鲁肽、他司鲁肽、阿必鲁肽、利西拉肽或其他胰岛素调节肽;所述的其他II型糖尿病治疗药物的第二药物为DPPIV抑制剂,例如西格列汀;或第二药物为钠-葡萄糖共转运载体SGLT1和/或SGLT2抑制剂;或第二药物为双胍类降糖药物,例如二甲双胍;或第二药物为磺酰脲类降糖药物,例如格列本脲、格列吡嗪、格列齐特和/或格列美脲;或第二药物为噻唑烷二酮类降糖药,吡格列酮和/或罗格列酮;或第二药物为阿卡波糖、米格列醇、考来维仑和/或溴隐亭等糖尿病治疗或辅助治疗药物。The pharmaceutical composition according to claim 12, wherein the polypeptide GLP-1 receptor agonist is selected from the group consisting of exenatide, semaglutide, liraglutide, tasglutide, a Biglutide, lixisenatide or other insulin-regulating peptides; the second drug of the other type II diabetes treatment drugs is a DPPIV inhibitor, such as sitagliptin; or the second drug is sodium-glucose co-transporter SGLT1 And/or SGLT2 inhibitor; or the second drug is a biguanide hypoglycemic drug, such as metformin; or the second drug is a sulfonylurea hypoglycemic drug, such as glibenclamide, glipizide, gliclazide and / Or glimepiride; or the second drug is a thiazolidinedione hypoglycemic agent, pioglitazone and/or rosiglitazone; or the second drug is acarbose, miglitol, colesevelam and / Or bromocriptine and other diabetes treatment or adjuvant therapy drugs.
- 根据权利要求1-10任一项所述的GLP-1受体调节剂,其药学上可接受的盐、酯、立体异构体、醚、前药或溶剂化物或根据权利要求11-13任一项所述的药物组合物用于制备治疗在医学上需要GLP-1受体的激活、增强或激动的对象的恶性病况的药物的应用,其特征在于,通过按照足以为患者提供有益作用的频率或持续时间向对象施用有效量的所述调节剂来进行治疗。The GLP-1 receptor modulator according to any one of claims 1-10, its pharmaceutically acceptable salt, ester, stereoisomer, ether, prodrug or solvate or any one of claims 11-13 An application of the pharmaceutical composition for the preparation of a medicament for the treatment of malignant conditions of a subject that medically requires the activation, enhancement, or stimulus of GLP-1 receptors, characterized in that it is characterized in that the drug An effective amount of the modulator is administered to the subject for treatment at a frequency or duration.
- 根据权利要求14所述的应用,其特征在于,所述的恶性病况选自I型糖尿病、II型糖尿病、妊娠期糖尿病、肥胖症、食欲过盛、饱腹感不足或代谢紊乱。The use according to claim 14, wherein the malignant condition is selected from the group consisting of type I diabetes, type II diabetes, gestational diabetes, obesity, excessive appetite, insufficient satiety or metabolic disorders.
- 具有如下结构的化合物:Compounds with the following structure:其中,L为连接链,选自-(CH 2) m-,-CONR 7-,-SO 2NR 7-,-NR 7CO-,-NR 7SO 2-,-(CH 2) mO-,-O(CH 2) m-,-(CH 2) mS-,-S(CH 2) m-,-(CH 2) mNR 7-,-NR 7(CH 2) m-;所述R 7选自氢,C 1-8直链或支链烷基或C 3-8环烷基,且所述烷基任选的进一步被一个或两个以上卤素,氰基,氨基或羟基取代;优选的,所述的L选自-CH 2O-,-CONH-,-CH 2NH-或者-CH 2N(CH 3)-; Among them, L is a link chain, selected from -(CH 2 ) m -, -CONR 7 -, -SO 2 NR 7 -, -NR 7 CO-, -NR 7 SO 2 -, -(CH 2 ) m O- , -O(CH 2 ) m -, -(CH 2 ) m S-, -S(CH 2 ) m -, -(CH 2 ) m NR 7 -, -NR 7 (CH 2 ) m -; R 7 is selected from hydrogen, C 1-8 linear or branched alkyl or C 3-8 cycloalkyl, and the alkyl is optionally further substituted with one or more halogen, cyano, amino or hydroxy ; Preferably, said L is selected from -CH 2 O-, -CONH-, -CH 2 NH- or -CH 2 N(CH 3 )-;R 1选自氢,羟基,氨基,卤素,氰基,C 1-4烷基,C 1-4烷氧基,由一个或多个卤素取代的C 1-4烷基或C 1-4烷氧基;i选自1-5的整数;优选的,i为1或2; R 1 is selected from hydrogen, hydroxy, amino, halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted by one or more C 1-4 alkyl or C 1-4 alkoxy Oxy; i is selected from an integer of 1-5; preferably, i is 1 or 2;m选自1,2或3;m is selected from 1, 2 or 3;Z可以相同或不同,选自C-H,C-R 9或N;所述的R 9为卤素,选自F,Cl,Br,I; Z may be the same or different, selected from CH, CR 9 or N; said R 9 is halogen, selected from F, Cl, Br, I;Y可以相同也可以不同,选自为C-H或N;R 2,R 3为一个或两个以上,选自氢,羟基,氨基,卤素,氰基,C 1-4烷基,C 1-4烷氧基,由一个或多个卤素取代的C 1-4烷基或C 1-4烷氧基; Y can be the same or different, selected from CH or N; R 2 and R 3 are one or more than two, selected from hydrogen, hydroxyl, amino, halogen, cyano, C 1-4 alkyl, C 1-4 Alkoxy, C 1-4 alkyl or C 1-4 alkoxy substituted by one or more halogens;Y’选自C-R 10或N-R 10,所述的R 10选自H,C1-C8的烷基,C1-C4的烷基羧基,C1-C4的烷基羟基;优选的,所述的R 10选自H,甲基、羧基、羧甲基、羧乙基。 Y'is selected from CR 10 or NR 10 , said R 10 is selected from H, C1-C8 alkyl, C1-C4 alkyl carboxyl, C1-C4 alkyl hydroxy; preferably, said R 10 Selected from H, methyl, carboxyl, carboxymethyl, carboxyethyl.
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