CN102731492B - Cyclohexanes derivant, its preparation method and in application pharmaceutically - Google Patents
Cyclohexanes derivant, its preparation method and in application pharmaceutically Download PDFInfo
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- CN102731492B CN102731492B CN201110083463.5A CN201110083463A CN102731492B CN 102731492 B CN102731492 B CN 102731492B CN 201110083463 A CN201110083463 A CN 201110083463A CN 102731492 B CN102731492 B CN 102731492B
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- formula
- isopropyl
- ring
- diazole
- alkyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 241001597008 Nomeidae Species 0.000 title abstract description 7
- 150000001934 cyclohexanes Chemical class 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 23
- 125000001424 substituent group Chemical group 0.000 claims abstract description 17
- AJJISMLYIMQAKP-OAHLLOKOSA-N 5-[4-[(2r)-4-(3-fluoro-4-methylsulfonylphenoxy)butan-2-yl]piperidin-1-yl]-3-propan-2-yl-1,2,4-oxadiazole Chemical compound CC(C)C1=NOC(N2CCC(CC2)[C@H](C)CCOC=2C=C(F)C(=CC=2)S(C)(=O)=O)=N1 AJJISMLYIMQAKP-OAHLLOKOSA-N 0.000 claims abstract description 13
- 229940100607 GPR119 agonist Drugs 0.000 claims abstract description 13
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 66
- 125000001072 heteroaryl group Chemical group 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 125000004429 atom Chemical group 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 3
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims 1
- 208000030159 metabolic disease Diseases 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- -1 C6-10Aryl Chemical group 0.000 description 70
- 238000006243 chemical reaction Methods 0.000 description 70
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 50
- 239000000047 product Substances 0.000 description 50
- 238000003756 stirring Methods 0.000 description 39
- 125000000753 cycloalkyl group Chemical group 0.000 description 36
- 239000000706 filtrate Substances 0.000 description 34
- 229910052760 oxygen Inorganic materials 0.000 description 34
- 239000001301 oxygen Substances 0.000 description 32
- 239000000243 solution Substances 0.000 description 31
- 239000000376 reactant Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000007787 solid Substances 0.000 description 24
- 229910052799 carbon Inorganic materials 0.000 description 22
- 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 22
- 208000035126 Facies Diseases 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 125000004093 cyano group Chemical group *C#N 0.000 description 18
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 125000004414 alkyl thio group Chemical group 0.000 description 16
- 238000000605 extraction Methods 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 125000000623 heterocyclic group Chemical group 0.000 description 15
- 238000000034 method Methods 0.000 description 15
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 14
- 239000008280 blood Substances 0.000 description 14
- 150000001721 carbon Chemical group 0.000 description 14
- 239000008103 glucose Substances 0.000 description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 14
- ZQWPRMPSCMSAJU-UHFFFAOYSA-N methyl cyclohexanecarboxylate Chemical compound COC(=O)C1CCCCC1 ZQWPRMPSCMSAJU-UHFFFAOYSA-N 0.000 description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 125000003003 spiro group Chemical group 0.000 description 14
- NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Natural products OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000000304 alkynyl group Chemical group 0.000 description 12
- 125000002769 thiazolinyl group Chemical group 0.000 description 12
- 102000004877 Insulin Human genes 0.000 description 11
- 108090001061 Insulin Proteins 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 229940125396 insulin Drugs 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 102100033839 Glucose-dependent insulinotropic receptor Human genes 0.000 description 9
- 101710163236 Glucose-dependent insulinotropic receptor Proteins 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 8
- 125000003282 alkyl amino group Chemical group 0.000 description 8
- 125000000000 cycloalkoxy group Chemical group 0.000 description 8
- 125000005366 cycloalkylthio group Chemical group 0.000 description 8
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 8
- 238000011160 research Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 125000003367 polycyclic group Chemical group 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 0 C*1C=CC(NC)=C(C[N+])C=C1 Chemical compound C*1C=CC(NC)=C(C[N+])C=C1 0.000 description 6
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](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(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 6
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- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
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- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 5
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
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- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 3
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- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- YCIHVFOEJHGEFJ-UHFFFAOYSA-N tributyl-lambda3-chlorane Chemical compound CCCCCl(CCCC)CCCC YCIHVFOEJHGEFJ-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to cyclohexanes derivant, its preparation method and in application pharmaceutically.Specifically, the present invention relates to the new cyclohexanes derivant shown in a kind of formula (I), its preparation method and the pharmaceutical composition containing this derivant and it is as therapeutic agent, especially as the purposes of GPR119 agonist and the medicine in the preparation treatment disease such as diabetes and metabolic disorder, each substituent group of its formula of (I) is identical with the definition in description.
Description
Technical field
The present invention relates to a kind of new cyclohexanes derivant, its preparation method and containing the pharmaceutical composition of this derivant and it is as the therapeutic agent purposes especially as GPR119 agonist and the medicine in the preparation treatment disease such as diabetes and metabolic disorder.
Background technology
The while that one classical symptom of type ii diabetes being to go out insulin resistant with patients, pancreatic beta cell cannot secrete the insulin of q.s.Based on this point, the medicine of clinical treatment type ii diabetes can be divided into two classes, a kind of medicine being used to improve the insulin-resistant conditions of the organ-tissue such as liver, muscle；The second is to act on pancreatic beta cell to promote the medicine of its excreting insulin.At present, have been developed for multiple medicine for realizing this purpose, such as glucagon kind polypeptide-1 analogue (GLP-1mimetics), simultaneously because its mechanism of action is glucose dependency, in clinical treatment use procedure, possibility will not make the symptom of patient from becoming hypoglycemic, thus becomes desirable medicine.To, on GLP-1 Research foundation, have developed again DPP IV (DPPIV) inhibitor, also successfully become novel I type i diabetes medicine for treatment.Along with going deep into further of research, the especially research to pancreatic beta cell excreting insulin process so that a kind of g protein coupled receptor GPR119 becomes the novel targets of a potential type ii diabetes treatment.
G protein coupled receptor 119 (GPR119) is a kind of orphan receptor found through human gene's sequencing analysis, and its gene mapping, in X chromosome, is mainly expressed in the beta Cell of islet in pancreatic tissue and intestinal cell.After further research, it has been found that Oleoyl monoethanolamide (OEA) and derivative of fatty acid oleoyl LYSOLECITHIN SUNLECITHIN A are the endogenic ligands of GPR119.By being combined with GPR119 and exciting GPR119, β intracellular cyclic adenosine monophosphate (cAMP) concentration, the stimulus-secretion coupling in activated cell being improved, promoting flow of calcium ions, thus promoting that insulin vesicle is secreted into outside born of the same parents.
The histiocyte expression characteristic of GPR119 and function are all pointed out, and activate this receptor and can promote GLP-1 and insulin secretion, contribute to glycemic control.This concept has been used in the pharmaceutical research relevant to diabetes.To in the isolated perfusion test separating rat Langerhans islet, GPR119 agonist can stimulate first phase and the secretion of the second phase of insulin, and this promoting insulin secretion has glucose dependency.Additionally, GPR119 agonist may additionally facilitate mouse intestinal L cell line secretes GLP-1.The therapeutical effect of diabetes has been obtained demonstration by GPR119 agonist in zoopery.It is remarkably improved the insulin in blood circulation, GLP-1 and GIP level to Oral Administration in Rats GPR119 agonist, reduces rat blood sugar concentration after accepting carbohydrate tolerance test simultaneously.Give GPR119 agonist continued treatment to be administered orally 4 weeks diabetes rat (ZDFrat) every day, its fasting blood glucose level substantially reduces, the toleration of carbohydrate tolerance test significantly improves, glycated hemoglobin levels significantly improves, dramatically increasing with insulin content, prompting islet function makes moderate progress simultaneously.Above-mentioned result of the test all shows, application GPR119 agonist can improve the diabetic symptom of experimental animal.
As the new formulation for the treatment of type ii diabetes, the main advantage of GPR119 agonist is that secretin's (including GLP-1 and GIP) and islets of langerhans are have multiple secretomotor effect.This is characterized by not available for the resistance to DPP-IV GLP-1 analog degraded and DPP-IV inhibitor.Additionally, animal experiment prompting, GPR119 agonist also has the potential controlling body weight.This novel mechanism of action is likely treating diabetes and brings renewal, higher hypoglycemic effect, thus contributing to increasing the multiformity of diabetes drug treatment, with the demand of satisfied different patients.
Disclose the patent application of a series of GPR119 agonist at present, including WO2005007658 and WO2009012275.
Although the GPR119 agonist of the diseases such as a series for the treatment of diabetes and metabolic disease is had been disclosed at present, but remain a need for the compound with better drug effect that exploitation is new, through being continually striving to, present invention design has the compound of the structure shown in formula (I), and finds that the compound with this class formation shows excellent effect and effect.
Summary of the invention
It is an object of the invention to provide the compound shown in a kind of formula (I) and their tautomer, enantiomer, diastereomer, raceme and pharmaceutically useful salt, and metabolite and metabolic precursor thereof or prodrug.
Wherein:
Ring A is selected from C3-10Cycloalkyl, heterocyclic radical, C6-10Aryl or heteroaryl, wherein said C3-10Cycloalkyl, heterocyclic radical, C6-10Aryl or heteroaryl independently of one another optional further by one or more selected from halogen, cyano group, nitro, C1-6Alkyl, C1-6Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, C3-10Cycloalkyl, heterocyclic radical, C6-10Aryl, heteroaryl ,-OR3、-NR4R5、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-NR4C(O)R5、-NR4SO2R5、-S(O)mR3Or-SO2NR4R5Substituent group replaced；
Ring B is selected from heterocyclic radical or heteroaryl, wherein said heterocyclic radical or heteroaryl independently of one another optional further by one or more selected from halogen, C1-6Alkyl or-OR3Substituent group replaced；
L is selected from a singly-bound or-(CH2)1-4-, one-CH of any of which2-independently of one another optionally by one or more O, N (R6) or S replaced, all the other CH2Optionally it is selected from halogen or C by one or two further1-6The substituent group of alkyl is replaced；
R1Selected from C3-10Cycloalkyl, C6-10Aryl, heterocyclic radical or heteroaryl, wherein said C3-10Cycloalkyl, C6-10Aryl, heterocyclic radical or heteroaryl optional further by one or more selected from halogen, cyano group, nitro, C1-6Alkyl, C2-6Thiazolinyl, C2-6Alkynyl, C3-10Cycloalkyl, heterocyclic radical, C6-10Aryl, heteroaryl ,-OR3、-NR4R5、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-NR4C(O)R5、-NR4SO2R5、-S(O)mR3Or-SO2NR4R5Substituent group replaced；
R2Selected from halogen, cyano group, nitro, C1-6Alkyl ,-OR3Or-NR4R5, wherein said C1-6Alkyl optional further by one or more selected from halogen, cyano group, nitro, hydroxyl, C1-6Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, C3-10Cycloalkyl, heterocyclic radical, C6-10The substituent group of aryl or heteroaryl is replaced；
R3Selected from hydrogen atom, C1-6Alkyl, C3-10Cycloalkyl, heterocyclic radical, C6-10Aryl or heteroaryl, wherein said C1-6Alkyl, C3-10Cycloalkyl, heterocyclic radical, C6-10Aryl or heteroaryl optional further by one or more selected from halogen, cyano group, nitro, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, C3-10Cycloalkyl, heterocyclic radical, C6-10The substituent group of aryl or heteroaryl is replaced；
R4And R5It is each independently selected from hydrogen atom, C1-6Alkyl, C3-10Cycloalkyl, heterocyclic radical, C6-10Aryl or heteroaryl, wherein said C1-6Alkyl, C3-10Cycloalkyl, heterocyclic radical, C6-10Aryl or heteroaryl each individually optional further by one or more selected from halogen, cyano group, nitro, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, C3-10Cycloalkyl, heterocyclic radical, C6-10The substituent group of aryl or heteroaryl is replaced；
Or, R4And R5Collectively form heterocyclic radical with the nitrogen-atoms being connected, wherein said heterocyclic radical is contained within one or more N, O or S (O)mHetero atom, and described heterocyclic radical optional further by one or more selected from halogen, cyano group, nitro, hydroxyl, C1-6Alkyl, C1-6Alkoxyl, C3-10Cycloalkyl, heterocyclic radical, C6-10The substituent group of aryl or heteroaryl is replaced；
R6Selected from hydrogen atom, C1-6Alkyl, C3-10Cycloalkyl, heterocyclic radical, C6-10Aryl or heteroaryl；
M is 0,1 or 2；And
N is 0,1,2 or 3.
The preferred version of the present invention provides the compound shown in a kind of formula (I) or its pharmaceutically useful salt, including the compound shown in formula (II) or its pharmaceutically useful salt:
Wherein:
L、R1Definition with ring A is as described in the appended claim 1；
D, E, F or G are each independently selected from C atom or atom N, and are atom N when adjacent 3 in D, E, F or G or 4 atom differences.
The preferred version of the present invention provides the compound shown in a kind of formula (I) or its pharmaceutically useful salt, including the compound shown in formula (III) or its pharmaceutically useful salt:
Wherein:
L、R1Definition with ring A is as described in the appended claim 1；
E, F or G are each independently selected from C atom or atom N, and are atom N during adjacent 3 atom difference in E, F or G；
R7Selected from C1-6Alkyl, halogen, hydroxyl, cyano group, C1-6Alkoxyl, nitro, C3-10Cycloalkyl or heterocyclic radical, or 2 R7Form carbonyl；
P is 1,2 or 3；
Q is 1,2 or 3.
The preferred version of the present invention provides the compound shown in a kind of formula (I) or its pharmaceutically useful salt, its medium ring AC6-10Aryl, wherein said C6-10Aryl is optional further by one or more halogens or-SO2R3Substituent group replaced.
The preferred version of the present invention provides the compound shown in a kind of formula (I) or its pharmaceutically useful salt, wherein R1For heteroaryl, wherein said heteroaryl is optional further by one or more C1-6Alkyl is replaced.
The preferred version of the present invention provides the compound shown in a kind of formula (I) or its pharmaceutically useful salt, wherein R1For
R8Selected from C1-6Alkyl or C3-10Cycloalkyl.
The preferred version of the present invention provides the compound shown in a kind of formula (I) or its pharmaceutically useful salt, and wherein n is 0.
The preferred version of the present invention provides the compound shown in a kind of formula (I) or its pharmaceutically useful salt, and wherein L is-O-,-O-CH2-or-O-CH (CH3)-。
The typical compound of the present invention includes, but are not limited to:
Or its pharmaceutically useful salt.
The present invention relates to the method that one prepares the compound or pharmaceutically acceptable salt thereof shown in formula (I), the method includes:
Formula (IA) compound is reacted with formula (IB) compound, obtains formula (I) compound；
Wherein:
PG is hydroxyl or leaving group, it is preferred to halogen or-O-S (O)mR9；
R9For C1-6Alkyl or aryl；
Ring A, ring B, m, n, R1、R2Described in definition with L such as formula (I).
The present invention relates to the method that one prepares the compound or pharmaceutically acceptable salt thereof shown in formula (I), the method includes:
Formula (IC) compound is reacted with formula (ID) compound, obtains formula (I) compound；
Wherein:
PG is hydroxyl or leaving group, it is preferred to halogen or-O-S (O)mR9；
R9For C1-6Alkyl or aryl；
Ring A, ring B, m, n, R1、R2Described in definition with L such as formula (I).
The present invention relates to the method that one prepares the compound or pharmaceutically acceptable salt thereof shown in formula (I), the method includes:
The borate of formula (IE) compound with ring A is reacted, obtains formula (I) compound；
Wherein:
X is selected from halogen；
Ring A, ring B, n, R1、R2Described in definition with L such as formula (I).
Another aspect of the present invention relates to the compounds of this invention or its pharmaceutically useful salt purposes in the medicine preparing GPR119 agonist.
Another aspect of the present invention relates to the compounds of this invention or its pharmaceutically useful salt, as the medicine of GPR119 agonist.
The invention still further relates to the compounds of this invention or its pharmaceutically useful salt preparation treatment diabetes and metabolic syndrome disease medicine in purposes.
Further, another aspect of the present invention relates to a kind of pharmaceutical composition, its compounds of this invention containing therapeutically effective dosage or its pharmaceutically useful salt and pharmaceutically useful carrier thereof or excipient.This pharmaceutical composition is used as the medicine of GPR119 agonist.This pharmaceutical composition purposes in the medicine of preparation treatment GPR119 agonist.
Another aspect of the present invention relates to a kind of method of disease treating diabetes and metabolic syndrome, and the method includes the compounds of this invention or its pharmaceutically useful salt that give the effective therapeutic dose of patient of needs treatment.
Another aspect of the present invention relates to the compounds of this invention as treatment diabetes and the medicine of the disease of metabolic syndrome or its pharmaceutically useful salt.
Another aspect of the present invention relates to a kind of method regulating insulin, and the method includes the compounds of this invention or its pharmaceutically useful salt of the effective therapeutic dose of patient of needs treatment.
Another aspect of the present invention relates to the compounds of this invention or its pharmaceutically useful salt of the medicine as regulating insulin.
Detailed description of the invention
Unless stated to the contrary, otherwise following use term in the specification and in the claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, including straight chain and the branched group of 1 to 20 carbon atom.Preferably comprise the alkyl of 1 to 10 carbon atom, more preferably contain the alkyl of 1 to 6 carbon atom.Non-limiting example includes methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyls, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-thmethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyls, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyls, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethyl amyl groups, 2,4-dimethyl amyl groups, 2,2-dimethyl amyl groups, 3,3-dimethyl amyl groups, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 2,2-dimethylhexanyl, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethyl amyl groups, positive decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers etc..More preferably contain the low alkyl group of 1 to 6 carbon atom, non-limiting example includes methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 2, 2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1, 1, 2-thmethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2, 3-dimethylbutyl etc..Alkyl can be replace or unsubstituted, when substituted, substituent group can be replaced on any spendable junction point, it is preferably one or more following groups, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo ,-OR3、-NR4R5、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-NR4C(O)R5、-NR4SO2R5、-S(O)mR3Or-SO2NR4R4。
" cycloalkyl " refers to the unsaturated monocycle of saturated or part or multi-ring cyclic hydrocarbon substituent, and it includes 3 to 20 carbon atoms, it is preferable that include 3 to 12 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 10 carbon atoms.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc..Polycyclic naphthene base includes the cycloalkyl of volution, condensed ring and bridged ring.
" spiro cycloalkyl group " refers to 5 to 20 yuan, shares the polycyclic moiety of a carbon atom (title spiro-atom) between monocycle, and these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double; two spiro cycloalkyl group base or many spiro cycloalkyl group by the number according to spiro-atom shared between ring and ring, it is preferred to single spiro cycloalkyl group and double; two spiro cycloalkyl group.It is more preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
" cycloalkyl " refers to 5 to 20 yuan, each ring in system shares the full carbon polycyclic moiety of a pair carbon atom adjoined with other rings in system, wherein one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl, it is preferred to dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyls.The non-limiting example of cycloalkyl comprises
" bridge ring alkyl " refers to 5 to 20 yuan, and any two ring shares the full carbon polycyclic moiety of two carbon atoms not being directly connected to, and these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or multi-ring bridge ring alkyl, it is preferred to dicyclo, three rings or Fourth Ring, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises
Described cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and the ring wherein linked together with precursor structure is cycloalkyl, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Cycloalkyl can be optionally substituted or unsubstituted, when substituted, substituent group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo ,-OR3、-NR4R5、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-NR4C(O)R5、-NR4SO2R5、-S(O)mR3Or-SO2NR4R5。
" thiazolinyl " refers to the alkyl as defined above being made up of at least two carbon atom and at least one carbon-to-carbon double bond.Preferably comprise the thiazolinyl of 1 to 10 carbon atom, more preferably contain the thiazolinyl of 1 to 6 carbon atom.Such as vinyl, 1-acrylic, 2-acrylic, 1-, 2-or 3-cyclobutenyl etc..Thiazolinyl can be replace or unsubstituted, when substituted, substituent group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-OR3、-NR4R5、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-NR4C(O)R5、-NR4SO2R5、-S(O)mR3Or-SO2NR4R5。
" alkynyl " refers at least two carbon atom and the alkyl as defined above of at least one carbon-to-carbon triple bond composition.Preferably comprise the alkynyl of 1 to 10 carbon atom, more preferably contain the alkynyl of 1 to 6 carbon atom.Such as acetenyl, 1-propinyl, 2-propynyl, 1-, 2-or 3-butynyl etc..Alkynyl can be replace or unsubstituted, when substituted, substituent group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-OR3、-NR4R5、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-NR4C(O)R5、-NR4SO2R5、-S(O)mR3Or-SO2NR4R5。
" heterocyclic radical " refers to the unsaturated monocycle of saturated or part or multi-ring cyclic hydrocarbon substituent, and it includes 3 to 20 annular atomses, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not include the loop section of-O-O-,-O-S-or-S-S-, all the other annular atomses are carbon.Preferably including 3 to 12 annular atomses, wherein 1～4 is hetero atom, and more preferably cycloalkyl ring comprises 3 to 10 annular atomses.The non-limiting example of monocyclic cycloalkyl comprises pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc..Polycyclic naphthene base includes the heterocyclic radical of volution, condensed ring and bridged ring." spiro heterocyclic radical " refers to 5 to 20 yuan, shares the polycyclic heterocyclic group of an atom (title spiro-atom) between monocycle, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)pThe hetero atom of (wherein p is integer 0 to 2), all the other annular atomses are carbon.These can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro heterocyclic radical, double; two spiro heterocyclic radical or many spiro heterocyclic radicals by the number according to spiro-atom shared between ring and ring, it is preferred to single spiro cycloalkyl group and double; two spiro cycloalkyl group.It is more preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
" condensed hetero ring base " refers to 5 to 20 yuan, each ring in system shares the polycyclic heterocyclic group of a pair atom adjoined with other rings in system, one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)pThe hetero atom of (wherein p is integer 0 to 2), all the other annular atomses are carbon.It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or multi-ring fused heterocycloalkyl, it is preferred to dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.The non-limiting example of condensed hetero ring base comprises
" bridge heterocyclic radical " refers to 5 to 14 yuan, any two ring shares the polycyclic heterocyclic group of two atoms not being directly connected to, these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), all the other annular atomses are carbon.It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or multi-ring bridge ring alkyl, it is preferred to dicyclo, three rings or Fourth Ring, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises:
Described heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and the ring wherein linked together with precursor structure is heterocyclic radical, and non-limiting example comprises:
Deng.Heterocyclic radical can be optionally substituted or unsubstituted, when substituted, substituent group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo ,-OR3、-NR4R5、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-NR4C(O)R5、-NR4SO2R5、-S(O)mR3Or-SO2NR4R5。
" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (namely sharing the ring of adjacent carbon atoms pair) group, there is multi-ring (namely it is with the ring of phase adjacency pair carbon atom) group of the pi-electron system of conjugation, it is preferably 6 to 10 yuan, for instance phenyl and naphthyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is aryl rings, and non-limiting example comprises:
Aryl can be replace or unsubstituted, when substituted, substituent group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-OR3、-NR4R5、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-NR4C(O)R5、-NR4SO2R5、-S(O)mR3Or-SO2NR4R5。
" heteroaryl " refers to comprise 1 to 4 hetero atom, the heteroaromatic system of 5 to 14 annular atomses, and wherein hetero atom includes oxygen, sulfur and nitrogen.It is preferably 5 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl is preferably, for instance furyl, thienyl, pyridine radicals, pyrrole radicals, N-alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is heteroaryl ring, and non-limiting example comprises:
Heteroaryl can be optionally substituted or unsubstituted, when substituted, substituent group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-OR3、-NR4R5、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-NR4C(O)R5、-NR4SO2R5、-S(O)mR3Or-SO2NR4R5。
" alkoxyl " refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), and wherein alkyl is as defined above.Non-limiting example comprises methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..Alkoxyl can be optionally substituted or unsubstituted, when substituted, substituent group is preferably one or more following group, independently selected from for alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-OR3、-NR4R5、-C(O)R3、-C(O)OR3、-C(O)NR4R5、-NR4C(O)R5、-NR4SO2R5、-S(O)mR3Or-SO2NR4R5。
" haloalkyl " refers to that alkyl is by one or more halogen substiuted.
" hydroxyl " refers to-OH group.
" hydroxyalkyl " refers to that alkyl is optionally substituted by a hydroxyl group.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH2。
" cyano group " refers to-CN.
" nitro " refers to-NO2。
" benzyl " refers to-CH2-phenyl.
" oxo " refers to=O.
" carboxylic acid " refers to-C (O) OH.
" carboxylate " refers to-C (O) O (alkyl) or (cycloalkyl).
" optionally " or " optionally " mean ground described later event or environment can but need not occur, this explanation includes this event or environment occurs or not spot occasion.Such as, " heterocyclic group optionally replaced by alkyl " mean alkyl can but necessarily exist, this explanation includes situation that heterocyclic group replaced by alkyl and the situation that heterocyclic group is not replaced by alkyl.
" replacement " refers to the one or more hydrogen atoms in group, it is preferred to maximum 5, more preferably 1～3 hydrogen atom is replaced by the substituent group of respective number independently of one another.Self-evident, substituent group is only in their possible chemical position, and those skilled in the art can determine (by experiment or theoretical) possible or impossible replacement when not paying and too much making great efforts.Such as, have the amino of free hydrogen or hydroxyl with have the carbon atom of unsaturated (such as olefinic) key in conjunction with time be probably instability.
" pharmaceutical composition " represent containing one or more compounds described herein or its physiology upper/mixture of pharmaceutically useful salt or prodrug and other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.The purpose of pharmaceutical composition is to promote the administration to organism, is beneficial to the absorption of active component and then plays biological activity.
M and R3～R5Definition such as formula (I) compound described in.
The synthetic method of the compounds of this invention
In order to complete the purpose of the present invention, the present invention adopts the following technical scheme that
The preparation method of the compound or its salt described in formula of the present invention (I), comprises the following steps:
Formula (IA) compound is reacted with formula (IB) compound, obtains formula (I) compound；
The preferred version of this synthetic method:
By formula (IA) compound and formula (IB) compound when triphenylphosphine with condensation reagent, it is preferred to diisopropyl azodiformate, obtain formula (I) compound；
Or, by formula (IA) compound with formula (IB) compound in the basic conditions, it is preferred to carbonate or sodium hydride, obtain formula (I) compound；
Wherein:
PG is hydroxyl or leaving group, it is preferred to halogen or-O-S (O)mR9；
R9For C1-6Alkyl or aryl；
Ring A, ring B, m, n, R1、R2Described in definition with L such as formula (I).
The preparation method of the compound or its salt described in formula of the present invention (I), comprises the following steps:
Formula (IC) compound is reacted with formula (ID) compound, obtains formula (I) compound；
The preferred version of this synthetic method:
By formula (IA) compound and formula (IB) compound when triphenylphosphine with condensation reagent, it is preferred to diisopropyl azodiformate, obtain formula (I) compound；
Or, by formula (IA) compound with formula (IB) compound in the basic conditions, it is preferred to carbonate or sodium hydride, obtain formula (I) compound；
Wherein:
PG is hydroxyl or leaving group, it is preferred to halogen or-O-S (O)mR9；
R9For C1-6Alkyl or aryl；
Ring A, ring B, m, n, R1、R2Described in definition with L such as formula (I).
The preparation method of the compound or its salt described in formula of the present invention (I), comprises the following steps:
By the borate of formula (IE) compound Yu ring A, under the existence of palladium catalyst, it is preferred to two (triphenylphosphine) palladium chloride reacts, and obtains formula (I) compound；
Wherein:
X is selected from halogen；
Ring A, ring B, n, R1、R2Described in definition with L such as formula (I).
Detailed description of the invention
It is used for further describing the present invention below in conjunction with embodiment, but these embodiments not limit the scope of the present invention.
Embodiment
The structure of compound by nuclear magnetic resonance, NMR (NMR) or/and mass spectrum (MS) is determined.NMR displacement (δ) is with 10-6(ppm) unit provides.The mensuration of NMR is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), tetramethylsilane (TMS) inside it is designated as.
The mensuration of MS is with FINNIGANLCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: FinniganLCQadvantageMAX).
The mensuration of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (SunfireC18150 × 4.6mm chromatographic column) and Waters2695-2996 high pressure liquid chromatograph (GiminiC18150 × 4.6mm chromatographic column).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that the silica gel plate that thin layer chromatography (TLC) uses adopts is 0.15mm～0.2mm, and the specification that thin layer chromatography separation purified product adopts is 0.4mm～0.5mm.
It is carrier that column chromatography generally uses Yantai Huanghai Sea silica gel 200～300 order silica gel.
The known initiation material of the present invention can adopt or synthesize according to methods known in the art, or it is commercially available from ABCRGmbH&Co.KG, AcrosOrganics, AldrichChemicalCompany, splendid remote chemistry science and technology (AccelaChemBioInc), reach the companies such as auspicious chemicals.
Argon atmospher or blanket of nitrogen refer to that reaction bulb connects argon or the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction uses Parr3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.
The usual evacuation of hydrogenation, is filled with hydrogen, repeatable operation 3 times.
Microwave reaction uses CEMDiscover-S908860 type microwave reactor.
Without specified otherwise in embodiment, reaction carries out under blanket of nitrogen or argon atmospher.
Without specified otherwise in embodiment, solution refers to aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is optimum reaction temperature, is 20 DEG C～30 DEG C.
The monitoring of the reaction process in embodiment adopts thin layer chromatography (TLC), the system of the developing solvent that reaction uses has: dichloromethane and methanol system, normal hexane and ethyl acetate system, the volume ratio of solvent is adjusted according to the polarity difference of compound.
The system of eluant and the developing solvent system of thin layer chromatography of the column chromatography that purifying compounds adopts include: A: dichloromethane and methanol system, B: normal hexane and ethyl acetate system, the volume ratio of solvent is adjusted according to the polarity difference of compound, it is also possible to add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent is adjusted.
Embodiment 1
3-isopropyl-5-[trans-4-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl] cyclohexyl]-1,2,4-diazole
The first step
Trans-4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexane carboxylic acid ethyl ester
By N '-hydroxy-2-methyl-propylamine 1a (153mg, 1.50mmol) it is dissolved in 15mL oxolane, it is sequentially added into (1R, 4R)-4-ethoxy carbonyl cyclohexane carboxylic acid (301mg, 1.50mmol), triethylamine (455mg, 4.50mmol), 1-hydroxy benzo triazole (223mg, 1.65mmol) with 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (317mg, 1.65mmol), stirring reaction 12 hours.Concentrating under reduced pressure reactant liquor, adds 20mL toluene, and heating is backflow extremely, stirring reaction 2 hours.Reactant liquor concentrating under reduced pressure, adding 30mL ethyl acetate, wash (30mL × 2) with water, anhydrous magnesium sulfate dries, filter, filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product trans-4-(3-isopropyl-1,2,4-diazole-5-base) cyclohexane carboxylic acid ethyl ester 1b (260mg, colorless oil), productivity: 65.2%.
MSm/z (ESI): 267.2 [M+1]
Second step
Trans-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] methanol
By (1R, 4R)-4-(3-isopropyl-1,2,4-diazole-5-base) cyclohexane carboxylic acid ethyl ester 1b (260mg, 1mmol) is dissolved in 20mL oxolane, adds Li-Al hydrogen (74mg, 2mmol), stirring reaction 1 hour.It is slowly dropped into 0.2mL saturated ammonium chloride solution, filter, with washed with dichloromethane (5mL), filtrate dries with anhydrous magnesium sulfate, filters, filtrate reduced in volume, obtain crude title product trans-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] methanol 1c (240mg, colorless oil), product is not purified is made directly next step reaction.
MSm/z (ESI): 225.1 [M+1]
3rd step
5-bromo-pyrazine-2-amine
Under ice bath, pyrazine-2-amine 1d (11.87g, 12.50mmol) is dissolved in 300mL dichloromethane, is dividedly in some parts N-bromo-succinimide (22.20g, 125mmol), stirring reaction 2 hours.Add 100mL saturated sodium carbonate solution cancellation reaction, separatory, organic facies uses saturated sodium carbonate solution (50mL × 1), water washing (50mL × 2) successively, and anhydrous sodium sulfate dries, filter, filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 5-bromo-pyrazine-2-amine 1e (13g, yellow solid), productivity: 60.0%.
MSm/z (ESI): 173.9 [M+1]
4th step
5-(4-methanesulfonylphenYl) pyrazine-2-amine
By 5-bromo-pyrazine-2-amine 1e (0.50g; 2.79mmol); (4-methanesulfonylphenYl) boric acid (0.57g; 2.79mmol); two (triphen phosphino-) palladium chloride (65mg; 0.06mmol) it is dissolved in the mixed solvent (V/V=5: 2) of 14mL1,4-dioxane and methanol with 4mL2M sodium carbonate liquor, rises to 100 DEG C of stirring reactions 3 hours.Add 100mL water; sucking filtration; filter cake washes (50mL × 2) with water; filter cake 50mL ethyl acetate is pulled an oar; stir 20 minutes, sucking filtration, obtain crude title product 5-(4-methanesulfonylphenYl) pyrazine-2-amine 1f (570mg; yellow solid), crude product is not purified is made directly next step reaction.
MSm/z (ESI): 250.1 [M+1]
5th step
5-(4-methanesulfonylphenYl) pyrazine-2-alcohol
Under cryosel bath; sodium nitrite (230mg, 3mmol) is dividedly in some parts 1.5mL concentrated sulphuric acid, rises to 50 DEG C of stirrings; make solid entirely molten; it is down to 0 DEG C again, the concentrated sulfuric acid solution of dropping 4.5mL5-(4-methanesulfonylphenYl) pyrazine-2-amine 1f (560mg, 2.20mmol); in keeping, temperature is at 0 DEG C-5 DEG C; finish, reaction 15 minute, 45 DEG C stirring reaction 45 minute are stirred at room temperature.Reactant liquor is poured into 50mL frozen water; stirring; it is 4 that dropping 12.5M sodium hydroxide solution regulates reactant liquor pH; filter; collect solid, purify gained residue with silica gel column chromatography with eluant system A, obtain title product 5-(4-methanesulfonylphenYl) pyrazine-2-alcohol 1g (330mg; faint yellow solid), productivity: 60.0%.
MSm/z (ESI): 251.1 [M+1]
6th step
3-isopropyl-5-[trans-4-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl] cyclohexyl]-1,2,4-diazole
By crude product trans-[4-(3-isopropyl-1; 2; 4-diazole-5-base) cyclohexyl] methanol 1c (240mg; 1mmol) it is dissolved in 20mL toluene, adds 5-(4-methanesulfonylphenYl) pyrazine-2-alcohol 1g (250mg, 1mmol) and triphenylphosphine (394mg; 1.50mmol); slowly instill diisopropyl azodiformate (242mg, 1.20mmol), stirring reaction 2 hours.Reactant liquor concentrating under reduced pressure; gained residue is purified with eluant system B with silica gel column chromatography; obtain title product 3-isopropyl-5-[trans-4-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl] cyclohexyl]-1; 2; 4-diazole 1 (60mg; white solid), productivity: 13.3%.
MSm/z (ESI): 467.2 [M+1]
1HNMR (400MHz, CDCl3) δ 8.58 (d, 1H), 8.34 (d, 1H), 8.12-8.16 (m, 2H), 8.03-8.07 (m, 2H), 4.26 (d, 2H), 3.10 (s, 3H), 3.05-3.13 (m, 1H), 2.89-2.98 (m, 1H), 2.21-2.29 (m, 2H), 2.05-2.13 (m, 2H), 1.65-1.76 (m, 2H), 1.35 (d, 6H), 1.25-1.31 (m, 3H).
Embodiment 2
3-isopropyl-5-[trans-4-[[6-(4-methanesulfonylphenYl)-3-pyridine] oxygen methyl] cyclohexyl]-1,2,4-diazole
The first step
Trans-4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexane carboxylic acid methyl ester
By N '-hydroxy-2-methyl-propylamine 1a (817mg, 8mmol) it is dissolved in 60mL oxolane, add trans-4-methoxycarbonyl cyclohexane carboxylic acid (1.49g, 8mmol), triethylamine (3.3mL, 24mmol) is sequentially added, 1-hydroxy benzo triazole (1.19g, 8.80mmol) with 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.68g, 8.80mmol), stirring reaction 12 hours.Concentrating under reduced pressure reactant liquor, adds 60mL toluene, and heating is backflow extremely, stirring reaction 4 hours.Reactant liquor concentrating under reduced pressure, add 100mL ethyl acetate, washing (50mL × 2) with water, anhydrous magnesium sulfate dries, and filters, filtrate reduced in volume, obtain crude title product trans-4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexane carboxylic acid methyl ester 2a (1.95g, brown oil), product is not purified is made directly next step reaction.
MSm/z (ESI): 253.1 [M+1]
Second step
Trans-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] methanol
Crude product trans-4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexane carboxylic acid methyl ester 2a (252mg, 1mmol) is dissolved in 20mL oxolane, adds Li-Al hydrogen (74mg, 2mmol), stirring reaction 1 hour.It is slowly dropped into 0.2mL saturated ammonium chloride solution, filters, wash solid (10mL × 2) with oxolane, merging filtrate, dry with anhydrous magnesium sulfate, filter, filtrate reduced in volume, gained residue is purified with eluant system B with silica gel column chromatography, obtain title product trans-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] methanol 2b (120mg, colorless oil), productivity: 54.0%.
MSm/z (ESI): 225.2 [M+1]
3rd step
Trans-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] methyl methylsulfonate
By trans-[4-(3-isopropyl-1,2,4-diazole-5-base) cyclohexyl] methanol 2b (200mg, 0.90mmol) it is dissolved in 10mL dichloromethane, add triethylamine (0.4mL, 2.70mmol), add mesyl chloride (154mg, 1.35mmol), stirring reaction 1 hour.Reactant liquor concentrating under reduced pressure, adds 20mL water, with dichloromethane extraction (40mL × 2), merge organic facies, washing (20mL × 1) with water, anhydrous magnesium sulfate dries, and filters, filtrate reduced in volume, obtain crude title product trans-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] methyl methylsulfonate 2c (250mg, colorless oil), product is not purified is made directly next step reaction.
MSm/z (ESI): 303.0 [M+1]
4th step
6-(4-methanesulfonylphenYl) pyridine-3-alcohol
By 6-chloropyridine-3-alcohol 2d (0.65g; 5mmol) with (4-methanesulfonylphenYl) boric acid (1g; 5mmol) it is dissolved in 30mL dimethyl ether; add tetrakis triphenylphosphine palladium (288mg; 0.25mmol) with 7.5mL2M sodium carbonate liquor, 100 DEG C of stirring reactions of microwave 30 minutes.Reactant liquor concentrating under reduced pressure; adding 150mL water, regulating reactant liquor pH with dilute hydrochloric acid is 5～6, is extracted with ethyl acetate (150mL × 3); merge organic facies; anhydrous magnesium sulfate dries, and filters, filtrate reduced in volume; gained residue is purified with eluant system B with silica gel column chromatography; obtain title product 6-(4-methanesulfonylphenYl) pyridine-3-alcohol 2e (420mg, white solid), productivity: 37.5%.
MSm/z (ESI): 249.6 [M+1]
5th step
3-isopropyl-5-[trans-4-[[6-(4-methanesulfonylphenYl)-3-pyridine] oxygen methyl] cyclohexyl]-1,2,4-diazole
By crude product trans-[4-(3-isopropyl-1; 2; 4-diazole-5-base) cyclohexyl] methyl methylsulfonate 2c (242mg; 0.80mmol) it is dissolved in 10mLN, in N '-dimethyl Methanamide, adds 6-(4-methanesulfonylphenYl) pyridine-3-alcohol 2e (199mg; 0.80mmol) with potassium carbonate (221mg; 1.60mmol), heat to 80 DEG C, stirring reaction 1.5 hours.Cooling; add 60mL water; it is extracted with ethyl acetate (60mL × 3), merges organic facies, wash (30mL × 1) with water; gained residue is purified with developing solvent system A with thin layer chromatography chromatography; obtain title product 3-isopropyl-5-[trans-4-[[6-(4-methanesulfonylphenYl)-3-pyridine] oxygen methyl] cyclohexyl]-1,2,4-diazole 2 (80mg; white solid), productivity: 30.0%.
MSm/z (ESI): 456.0 [M+1]
1HNMR (400MHz, CDCl3) δ 8.42 (d, 1H), 8.15 (d, 2H), 8.02 (d, 2H), 7.75 (d, 1H), 7.31-7.34 (m, 1H), 5.30 (s, 1H), 3.93 (d, 2H), 3.04-3.11 (m, 3H), 2.90-2.94 (m, 1H), 2.25 (d, 2H), 2.10 (d, 2H), 1.65-1.67 (m, 2H), 1.33-1.35 (m, 9H).
Embodiment 3
3-isopropyl-5-[cis-4-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl] cyclohexyl]-1,2,4-diazole
The first step
5-bromo-pyrazine-2-alcohol
Under ice bath, by 5-bromo-pyrazine-2-amine 1e (2g, 11.50mmol) be dissolved in 6rnL concentrated sulphuric acid, heat to 45 DEG C of hydrotropies, 8mL sodium nitrite (1.07g is dripped under ice bath, 15.50mmol) concentrated sulfuric acid solution, be stirred at room temperature reaction 15 minutes, then be warming up to 45 DEG C react 1 hour.Reactant liquor is added in 20mL frozen water, dropping 12.50M sodium hydroxide solution is 4～5 to reactant liquor pH, and extraction into ethyl acetate (50mL × 3) merges organic facies, (50mL × 2) are washed with saturated nacl aqueous solution, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, gained residue is purified with eluant system B with silica gel column chromatography, obtain title product 5-bromo-pyrazine-2-alcohol 3a (1.30g, yellow solid), productivity: 65.0%.
MSm/z (ESI): 176.9 [M+1]
Second step
Cis-hexamethylene-Isosorbide-5-Nitrae-carboxylic acid dimethyl ester
Cis-hexamethylene-Isosorbide-5-Nitrae-dicarboxylic acids 3b (10g, 5.80mmol) is dissolved in 80mL methanol, adds 0.4mL concentrated sulphuric acid, heat to back flow reaction 5 hours.Reactant liquor concentrating under reduced pressure, add 50mL ethyl acetate, successively with saturated sodium bicarbonate solution (50mL × 1), water (50mL × 1), saturated nacl aqueous solution washing (50mL × 1), anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, obtain crude title product cis-hexamethylene-1,4-carboxylic acid dimethyl ester 3c (12.40g, colorless oil), product is not purified is made directly next step reaction.
MSm/z (ESI): 218.1 [M+18]
3rd step
(1S, 4S)-4-methoxycarbonyl cyclohexane carboxylic acid
Being dissolved in 100mL methanol by crude product cis-hexamethylene-Isosorbide-5-Nitrae-carboxylic acid dimethyl ester 3c (11.60g, 57.90mmol), heating, to backflow, is slowly added into the methanol solution of 30mL potassium hydroxide (3.25g, 57.90mmol), back flow reaction 5 hours.Reactant liquor concentrating under reduced pressure, adds 100mL water, and ether extracts (40mL × 3), remove raw material, dropping 1M hydrogen chloride solution is 5～6 to aqueous phase pH, and extraction into ethyl acetate (30mL × 3) washs (50mL × 1) with saturated nacl aqueous solution, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, obtain crude title product cis-4-methoxycarbonyl cyclohexane carboxylic acid 3d (5.60g, white solid), product is not purified is made directly next step reaction.
MSm/z (ESI): 187.1 [M+1]
4th step
Cis-4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexane carboxylic acid methyl ester
By N '-hydroxy-2-methyl-propylamine 1a (3.07g, 30mmol) it is dissolved in 60mL oxolane, add crude product (1S, 4S)-4-methoxycarbonyl cyclohexane carboxylic acid 3d (5.60g, 30mmol), sequentially add triethylamine (12.5mL, 90mmol), 1-hydroxy benzo triazole (4.46g, 33mmol) with 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (6.33g, 33mmol), stirring reaction 5 hours.Concentrating under reduced pressure reactant liquor, adds 80mL toluene, and heating is backflow extremely, stirring reaction 12 hours.Reactant liquor concentrating under reduced pressure, add 100mL water, extraction into ethyl acetate (50mL × 3), wash (50mL × 2) with saturated nacl aqueous solution, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, obtain crude title product cis-4-(3-isopropyl-1,2,4-diazole-5-base) cyclohexane carboxylic acid methyl ester 3e (6.70g, yellow oily), product is not purified is made directly next step reaction.
MSm/z (ESI): 253.1 [M+1]
5th step
Cis-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] methanol
Under ice bath, by Li-Al hydrogen (630mg, 16.60mmol) be dissolved in 50mL oxolane, dropping 20mL crude product (1S, 4S)-4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexane carboxylic acid methyl ester 3e (2g, tetrahydrofuran solution 8.30mmol), is stirred at room temperature reaction 5 hours.It is slowly dropped into 1.3mL saturated ammonium chloride solution, filter, with oxolane washing leaching cake (10mL × 2), merging filtrate, dry with anhydrous magnesium sulfate, filter, filtrate reduced in volume, add 50mL ethyl acetate, washing (50mL × 2) with saturated nacl aqueous solution, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, obtain crude title product cis-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] methanol 3f (1.6g, yellow oil), product is not purified is made directly next step reaction.
MSm/z (ESI): 225.1 [M+1]
6th step
Cis-5-[4-[(5-bromo-pyrazine-2-base) oxygen methyl] cyclohexyl]-3-isopropyl-1,2,4-diazole
Under ice bath, by (1S, 4S)-[4-(and 3-isopropyl-1,2,4-diazole-5-base) cyclohexyl] methanol 3f (224mg, 1mmol) it is dissolved in 10mL oxolane with 5-bromo-pyrazine-2-alcohol 3a (175mg, 1mmol), adds triphenylphosphine (524mg, 2mmol), within ultrasonic 1 minute, dissolve, drip 297 μ L diisopropyl azodiformates, ultrasonic reaction 20 minutes.Add 20mL dichloromethane, concentrating under reduced pressure reactant liquor, gained residue is purified with eluant system B with silica gel column chromatography, obtain title product cis-5-[4-[(5-bromo-pyrazine-2-base) oxygen methyl] cyclohexyl]-3-isopropyl-1,2,4-diazole 3g (250mg, colorless oil), productivity: 65.6%.
MSm/z (ESI): 383.0 [M+1]
7th step
Cis-3-isopropyl-5-[4-[[5-(4-methylsulfanylphenyl) pyrazine-2-base] oxygen methyl] cyclohexyl]-1,2,4-diazole
By cis-5-[4-[(5-bromo-pyrazine-2-base) oxygen methyl] cyclohexyl]-3-isopropyl-1,2,4-diazole 3g (250mg, 0.65mmol), (4-methylsulfanylphenyl) boric acid (110mg, 0.65mmol), two (triphen phosphino-) palladium chloride (9.20mg, 0.01mmol) it is dissolved in 3.5mL1 with 1mL2M sodium carbonate liquor, in the mixed solvent (V/V=5: 2) of 4-dioxane and methanol, rise to 95 DEG C of stirring reactions 12 hours.Add 5mL water, extraction into ethyl acetate (30mL × 3), merges organic facies, washs (50mL × 2) with saturated nacl aqueous solution, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, obtain crude title product cis-3-isopropyl-5-[4-[[5-(4-methylsulfanylphenyl) pyrazine-2-base] oxygen methyl] cyclohexyl]-1,2,4-diazole 3h (220mg, yellow solid), product is not purified is made directly next step reaction.
MSm/z (ESI): 425.1 [M+1]
8th step
3-isopropyl-5-[cis-4-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl] cyclohexyl]-1,2,4-diazole
By crude product cis-3-isopropyl-5-[4-[[5-(4-methylsulfanylphenyl) pyrazine-2-base] oxygen methyl] cyclohexyl]-1,2,4-diazole 3h (220mg, 0.52mmol) it is dissolved in the mixed solvent (V/V=2: 1) of 15mL acetone and water, add potassium hydrogen persulfate composite salts (955mg, 1.55mmol), stirring reaction 12 hours.Dropping saturated sodium bicarbonate solution is 7 to reactant liquor pH; concentrating under reduced pressure reactant liquor; add 30mL water; it is extracted with ethyl acetate (50mL × 2); merge organic facies; anhydrous sodium sulfate dries; filter; filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system B, obtains title product 3-isopropyl-5-[cis-4-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl] cyclohexyl]-1; 2; 4-diazole 3 (80mg, white solid), productivity: 33.7%.
MSm/z (ESI): [M+1]
1HNMR (400MHz, CDCl3) δ 8.60 (s, 1H), 8.34 (s, 1H), 8.17 (d, 2H), 8.08 (d, 2H), 4.32 (d, 2H), 3.32-3.22 (m, 1H), 3.20-3.07 (m, 4H), 2.33-2.20 (m, 2H), 2.18-2.05 (m, 1H), 1.98-1.80 (m, 4H), 1.64-1.51 (m, 2H), 1.39 (d, 6H).
Embodiment 4
3-isopropyl-5-[trans-4-[1-[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen ethyl] cyclohexyl]-1,2,4-diazole
The first step
Trans-4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexane carboxylic acid
By crude product trans-4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexane carboxylic acid methyl ester 2a (440mg, 1.74mmol) it is dissolved in 5mL methanol, add sodium hydroxide (139mg, 3.50mmol), be warming up to 30 DEG C of stirring reactions 16 hours.Reactant liquor concentrating under reduced pressure, add 10mL water, extraction into ethyl acetate (10mL × 2), dropping 2M hydrogen chloride solution is 3 to aqueous phase pH, it is extracted with ethyl acetate (20mL × 4), merge organic facies, washing (20mL × 2) with saturated nacl aqueous solution, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, obtain crude title product trans-4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexane carboxylic acid 4a (400mg, white solid), product is not purified is made directly next step reaction.
MSm/z (ESI): 237.1 [M-1]
Second step
Trans-4-(3-isopropyl-1,2,4-diazole-5-bases)-N-methoxy-. N-methyl-cyclohexyl Methanamide
By crude product (1R, 4R)-4-(3-isopropyl-1,2,4-diazole-5-base) cyclohexane carboxylic acid 4a (200mg, 0.84mmol), 1-hydroxy benzo triazole (113mg, 0.84mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (177mg, 0.92mmol), N-methoxymethylamine hydrochloride (123mg, 1.26mmol) and triethylamine (254mg, 2.50mmol) it is dissolved in 15mL dichloromethane, stirring reaction 16 hours.Add 20mL water, dichloromethane extraction (30mL × 3), merges organic facies, washs (20mL × 1) with saturated nacl aqueous solution, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, obtain crude title product trans-4-(3-isopropyl-1,2,4-diazole-5-base)-N-methoxy-. N-methyl-cyclohexyl Methanamide 4b (200mg, colorless oil), product is not purified is made directly next step reaction.
3rd step
Trans-1-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] ethyl ketone
By crude product (1R, 4R)-4-(3-isopropyl-1,2,4-diazole-5-base)-N-methoxy-. N-methyl-cyclohexyl Methanamide 4b (200mg, 0.71mmol) it is dissolved in 10mL ether, is slowly added dropwise into 0.5mL3M methyl-magnesium-bromide, stirring reaction 2 hours.It is added dropwise to 20mL saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate (30mL × 3), merge organic facies, (20mL × 1) is washed with saturated nacl aqueous solution, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, gained residue is purified with eluant system B with silica gel column chromatography, obtain title product trans-1-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] ethyl ketone 4c (140mg, colorless oil), productivity: 83.8%.
4th step
Trans-1-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] ethanol
Trans-1-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] ethyl ketone 4c (140mg, 0.59mmol) is dissolved in 5mL methanol, adds sodium borohydride (45mg, 1.18mmol), stirring reaction 1 hour.Add 5mL saturated ammonium chloride solution cancellation reaction, it is extracted with ethyl acetate (20mL × 3), merges organic facies, wash (20mL × 1) with saturated nacl aqueous solution, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, obtain crude title product trans-1-[4-(3-isopropyl-1,2,4-diazole-5-base) cyclohexyl] ethanol 4d (140mg, colorless oil), product is not purified is made directly next step reaction.
MSm/z (ESI): 239.1 [M+1]
5th step
Trans-1-[4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl] ethyl methane sulfonate
By crude product trans-1-[4-(3-isopropyl-1,2,4-diazole-5-base) cyclohexyl] ethanol 4d (140mg, 0.59mmol) it is dissolved in 5mL dichloromethane, add triethylamine (0.3mL, 1.76mmol), add mesyl chloride (0.1mL, 0.88mmol), stirring reaction 1 hour.Add 10mL water, with dichloromethane extraction (20mL × 3), merge organic facies, wash (20mL × 1) with saturated nacl aqueous solution, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, obtain crude title product trans-1-[4-(3-isopropyl-1,2,4-diazole-5-base) cyclohexyl] ethyl methane sulfonate 4e (160mg, white solid), product is not purified is made directly next step reaction.
6th step
3-isopropyl-5-[trans-4-[1-[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen ethyl] cyclohexyl]-1,2,4-diazole
By crude product trans-1-[4-(3-isopropyl-1; 2; 4-diazole-5-base) cyclohexyl] ethyl methane sulfonate 4e (160mg; 0.51mmol) it is dissolved in 5mLN; in N '-dimethyl Methanamide, add 5-(4-methanesulfonylphenYl) pyrazine-2-alcohol 1g (140mg, 0.56mmol) and cesium carbonate (332mg; 1.02mmol), 90 DEG C of stirring reactions it are warming up to 5 hours.Add 15mL water; it is extracted with ethyl acetate (30mL × 3); merge organic facies; (20mL × 2) are washed with saturated nacl aqueous solution; anhydrous sodium sulfate dries; filter; filtrate reduced in volume; gained residue is purified with developing solvent system B with thin layer chromatography chromatography; obtain title product 3-isopropyl-5-[trans-4-[1-[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen ethyl] cyclohexyl]-1,2,4-diazole 4 (35mg; white solid), productivity: 14.6%.
MSm/z (ESI): 471.1 [M+1]
1HNMR (400MHz, CDCl3) δ 8.60 (s, 1H), 8.32 (s, 1H), 8.17 (d, 2H), 8.08 (d, 2H), 5.25-5.14 (m, 1H), 3.72-3.59 (m, 1H), 3.18-3.06 (m, 5H), 2.91 (dd, 2H), 2.31-2.20 (m, 4H), 2.10 (dd, 2H), 2.04 (s, 1H), 1.90 (d, 1H), 1.70 (d, 1H), 1.40 (d, 6H).
Embodiment 5,6
Trans-5-[4-[[7-(the fluoro-4-Metlianesulfonyl-phenyl of 2-)-5,6-pyrrolin [2,3-d] pyrimidine-4-yls] oxygen base] cyclohexyl]-3-isopropyl-1,2,4-diazole
Cis-5-[4-[[7-(the fluoro-4-Metlianesulfonyl-phenyl of 2-)-5,6-pyrrolin [2,3-d] pyrimidine-4-yls] oxygen base] cyclohexyl]-3-isopropyl-1,2,4-diazole
The first step
The silica-based cyclohexane carboxylic acid of 4-triethyl group
4-hydroxy cyclohexylphenyl yl carboxylic acid 5a (2.90g, 20mmol) is dissolved in 50mL oxolane, adds imidazoles (1.43g, 21mmol) and tert-butyl chloro-silicane (3.02g, 20mmol), stirring reaction 3 hours.Add 200mL ethyl acetate, wash (150mL × 2) with water, anhydrous magnesium sulfate dries, filter, filtrate reduced in volume, obtaining the crude title product silica-based cyclohexane carboxylic acid 5b of 4-tert-butyldimethylsilyl chloride (4.80g, colourless liquid), product is not purified is made directly next step reaction.
MSm/z (ESI): 259.1 [M+1]
Second step
Trans-4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl alcohol
Cis-4-(3-isopropyl-1,2,4-diazole-5-bases) cyclohexyl alcohol
By N '-hydroxy-2-methyl-propylamine 1a (1.90g, 18.50mmol) be dissolved in 150mL oxolane, add the silica-based cyclohexane carboxylic acid 5b (4.80g of 4-tert-butyldimethylsilyl chloride, 18.50mmol), add triethylamine (5.62g, 55.50mmol), 1-hydroxy benzo triazole (3g, 22.20mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (4.26g, 22.20mmol), stirring reaction 12 hours.Concentrating under reduced pressure reactant liquor, adds 150mL toluene, and heating is backflow extremely, stirring reaction 5 hours.Reactant liquor concentrating under reduced pressure, gained residue is purified with eluant system B with silica gel column chromatography, obtain a pair diastereomer product, be respectively trans-4-(3-isopropyl-1,2,4-diazole-5-base) cyclohexyl alcohol 5c (800mg, pale yellowish oil), and cis-4-(3-isopropyl-1,2,4-diazole-5-base) cyclohexyl alcohol 5d (1.50g, pale yellowish oil).
3rd step
5-pi-allyl pyrimidine-4,6-glycol
Under ice bath, 50% Feldalat NM (1.20g, 22mmol) is dissolved in 30mL methanol, add formamidine hydrochloride (885mg, 11mmol), then drip 10mL2-pi-allyl propyl group diethylester 5e (2g, methanol solution 1mmol), stirring reaction 12 hours.Reactant liquor concentrating under reduced pressure, adds 60mL water, and dropping 6M hydrogen chloride solution is 3 to reactant liquor pH, precipitates out a large amount of solid, filter, wash (30mL × 2), vacuum drying, obtain title product 5-pi-allyl pyrimidine-4,6-glycol 5f (880mg, white solid), productivity: 58.0%.
MSm/z (ESI): 151.1 [M-1]
4th step
5-pi-allyl-4,6-Dichloro-pyrimidin
By 5-pi-allyl pyrimidine-4,6-glycol 5f (4.30g, 28mmol) is placed in reaction bulb, is slowly added to 30mL phosphorus oxychloride, heats to return stirring reaction 2 hours.Reactant liquor is poured in 200g ice, under ice bath, is 7 with 4M sodium hydroxide solution to reacting liquid pH value, extraction into ethyl acetate (150mL × 3), merge organic facies, saturated nacl aqueous solution washing (200mL × 2), anhydrous magnesium sulfate dries, filter, filtrate reduced in volume, obtains crude title product 5-pi-allyl-4,6-Dichloro-pyrimidin 5g (5g, brown liquid), productivity: 93.6%.
MSm/z (ESI): 190.9 [M+1]
5th step
2-(4,6-dichloro pyrimidine-5-base) acetaldehyde
By crude product 5-pi-allyl-4,6-Dichloro-pyrimidin 5g (5g, 26mmol) it is dissolved in the mixed solvent (V/V=1: 1) of 100mL acetone and water, under ice bath, add Osmic acid. (500mg, 1.90mmol), it is dividedly in some parts sodium metaperiodate (7.20g again, 33.80mmol), it is ensured that temperature, lower than 40 DEG C, finishes and reaction 1 hour is stirred at room temperature.Filter, filter cake is quickly poured in saturated sodium thiosulfate solution, filtrate is with saturated sodium thiosulfate solution washing (30mL × 2), concentrating under reduced pressure, aqueous phase is with dichloromethane extraction (20mL × 5), merge organic facies, saturated nacl aqueous solution washing (20mL × 2), anhydrous magnesium sulfate dries, and filters, filtrate reduced in volume, obtain crude title product 2-(4,6-dichloro pyrimidine-5-base) acetaldehyde 5h (2.60g, brown solid), productivity: 51.7%.
6th step
The chloro-7-of 4-(the fluoro-4-Metlianesulfonyl-phenyl of 2-)-5,6-pyrrolin [2,3-d] pyrimidines
10mL trifluoroacetic acid is placed in there-necked flask; it is cooled to-10 DEG C, adds the fluoro-4-mesyl of 2--aniline (446mg, 2.40mmol); at-15 DEG C; add Sodium triacetoxyborohydride (763mg, 3.60mmol), stir 10 minutes; add 10mL crude product 2-(4; 6-dichloro pyrimidine-5-base) dichloromethane solution of acetaldehyde 5h (500mg, 2.60mmol), reaction 12 hour is stirred at room temperature.Add 50mL dichloromethane; dropping saturated sodium carbonate solution is 8 to reactant liquor pH; extract separatory; aqueous phase is with dichloromethane extraction (20mL × 3); merge organic facies; saturated nacl aqueous solution washing (40mL); anhydrous magnesium sulfate dries, and filters, filtrate reduced in volume; gained residue is purified with eluant system B with silica gel column chromatography; obtain the chloro-7-of title product 4-(the fluoro-4-Metlianesulfonyl-phenyl of 2-)-5,6-pyrrolin [2,3-d] pyrimidine 5i (100mg; white solid), productivity: 13.0%.
MSm/z (ESI): 328.0 [M+1]
7th step
Trans-5-[4-[[7-(the fluoro-4-Metlianesulfonyl-phenyl of 2-)-5,6-pyrrolin [2,3-d] pyrimidine-4-yls] oxygen base] cyclohexyl]-3-isopropyl-1,2,4-diazole
Cis-5-[4-[[7-(the fluoro-4-Metlianesulfonyl-phenyl of 2-)-5,6-pyrrolin [2,3-d] pyrimidine-4-yls] oxygen base] cyclohexyl]-3-isopropyl-1,2,4-diazole
By 60% sodium hydride (90mg; 2.34mmol) it is dissolved in 10mL oxolane; add (1R; 4R)-4-(3-isopropyl-1; 2; 4-diazole-5-base) cyclohexyl alcohol 5c (55mg; 0.26mmol), it is heated to reflux 1.5 hours, is cooled to room temperature; add the chloro-7-of 4-(the fluoro-4-Metlianesulfonyl-phenyl of 2-)-5; 6-pyrrolin [2,3-d] pyrimidine 5i (85mg, 0.26mmol); return stirring reacts 4 hours, then 60 DEG C are reacted 16 hours.Add 50mL shrend to go out reaction, dropping 2M hydrogen chloride solution is 8 to reactant liquor pH, with dichloromethane extraction (30mL × 3), merge organic facies, anhydrous magnesium sulfate dries, filter, filtrate reduced in volume, gained residue is purified with developing solvent system B with thin layer chromatography chromatography, obtain a pair diastereomer product, it is trans-5-[4-[[7-(the fluoro-4-Metlianesulfonyl-phenyl of 2-)-5 respectively, 6-pyrrolin [2, 3-d] pyrimidine-4-yl] oxygen base] cyclohexyl]-3-isopropyl-1, 2, 4-diazole 5 (45mg, white solid), productivity: 34.6%；Cis-5-[4-[[7-(the fluoro-4-Metlianesulfonyl-phenyl of 2-)-5,6-pyrrolin [2,3-d] pyrimidine-4-yls] oxygen base] cyclohexyl]-3-isopropyl-1; 2; 4-diazole 6 (30mg, white solid), productivity: 23.1%.
MSm/z (ESI): 502.1 [M+1]
5:1HNMR (400MHz, CDCl3) δ 8.29 (s, 1H), 8.02-8.08 (m, 1H), 7.68-7.77 (m, 2H), 5.16-5.26 (m, 1H), 4.21 (t, 2H), 3.13 (t, 2H), 3.04-3.10 (m, 1H), 3.06 (s, 3H), 2.93-3.02 (m, 1H), 2.21-2.33 (m, 4H), 1.79-1.92 (m, 2H), 1.48-1.58 (m, 2H), 1.34 (d, 6H).
6:1HNMR (400MHz, CDCl3) δ 8.30 (s, 1H), 8.03-8.09 (m, 1H), 7.69-7.76 (m, 2H), 5.41-5.47 (m, 1H), 4.21 (t, 2H), 3.15 (t, 2H), 3.02-3.11 (m, 2H), 3.05 (s, 3H), 2.06-2.16 (m, 4H), 1.97-2.05 (m, 2H), 1.75-1.87 (m, 2H), 1.35 (d, 6H).
Embodiment 7
Cis-5-[4-[[6-(the fluoro-4-pyridine of 3-)-3-pyridine] oxygen methyl] cyclohexyl]-3-isopropyl-1,2,4-diazole
The first step
Tributyl-(the fluoro-4-pyridine of 3-) stannum
Under the dry ice bath, diisopropylamine 1e (0.7mL, 5.25mmol) is dissolved in 20mL oxolane, add the n-BuLi (2mL of 1M, hexane solution 5.00mmol), stirring reaction 30 minutes, add 10mL3-fluorine pyridine 7a (0.51g, tetrahydrofuran solution 5.25mmol), stirring reaction 90 minutes, adds tributyl chlorine stannum (1.63g, 5.00mmol), rise to room temperature, stirring reaction 2 hours.Add 50mL water, ether extracts (40mL × 3), merge organic facies, washing (50mL × 2) with saturated nacl aqueous solution, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, obtaining crude title product tributyl-(the fluoro-4-pyridine of 3-) stannum 7b (1.93g, colourless liquid), product is not purified is made directly next step reaction.
Second step
6-(the fluoro-4-pyridine of 3-) pyridine-3-alcohol
By tributyl-(the fluoro-4-pyridine of 3-) stannum 7b (1.93g, 5.00mmol) it is dissolved in 10mLN, in dinethylformamide, add 6-bromopyridine-3-alcohol 7c (0.87g, 5.00mmol), triphenyl phosphorus palladium chloride (175mg, 0.25mmol) with iodate Asia ketone (95mg, 0.50mmol), heat to 150 DEG C, stirring reaction 5 hours.Reactant liquor concentrating under reduced pressure, add 50mL water, extraction into ethyl acetate (40mL × 3), merge organic facies, (50mL × 2) are washed with saturated nacl aqueous solution, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, gained residue is purified with eluant system B with silica gel column chromatography, obtain title product 6-(the fluoro-4-pyridine of 3-) pyridine-3-alcohol 7d (0.50g, light yellow solid), productivity: 65.6%.
MSm/z (ESI): 191.0 [M+1]
3rd step
Cis-[4-(3-isopropyl-1,2,4-diazole-5-bases) hexamethylene] methylmethanesulfonate ester
By cis-[4-(3-isopropyl-1,2,4-diazole-5-base) cyclohexyl] methanol 3f (0.80g, 3.57mmol) it is dissolved in 20mL dichloromethane, add triethylamine (1.5mL, 10.71mmol) and mesyl chloride (0.6mL, 7.13mmol), stirring reaction 5 hours.Reactant liquor concentrating under reduced pressure, adds 50mL water, extraction into ethyl acetate (30mL × 3), merge organic facies, washing (50mL × 2) with saturated nacl aqueous solution, anhydrous sodium sulfate dries, and filters, filtrate reduced in volume, obtain title product cis-[4-(3-isopropyl-1,2,4-diazole-5-bases) hexamethylene] methylmethanesulfonate ester 7e (1.00g, yellow liquid), productivity: 93.45%.
MSm/z (ESI): 303.1 [M+1]
4th step
Cis-5-[4-[[6-(the fluoro-4-pyridine of 3-)-3-pyridine] oxygen methyl] cyclohexyl]-3-isopropyl-1,2,4-diazole
By 6-(the fluoro-4-pyridine of 3-) pyridine-3-alcohol 7d (0.10g, 0.526mmol) it is dissolved in 5mLN, in N-dimethyl formyl, add (1S, 4S)-[4-(3-isopropyl-1,2,4-diazole-5-base) hexamethylene] methylmethanesulfonate ester 7e (0.16g, 0.526mmol) and potassium carbonate (0.22g, 1.58mmol), heat to 85 DEG C, stirring reaction 5 hours.Reactant liquor concentrating under reduced pressure, add 50mL water, extraction into ethyl acetate (30mL × 3), merge organic facies, (50mL × 2) are washed with saturated nacl aqueous solution, anhydrous sodium sulfate dries, filter, filtrate reduced in volume, purifies gained residue with silica gel column chromatography with eluant system A, obtains title product cis-5-[4-[[6-(the fluoro-4-pyridine of 3-)-3-pyridine] oxygen methyl] cyclohexyl]-3-isopropyl-1,2,4-diazole 7 (0.08g, white solid), productivity: 38.5%.
MSm/z (ESI): 397.1 [M+1]
1HNMR (400MHz, CDCl3) δ 8.53 (d, 1H), 8.49 (d, 1H), 8.43 (dd, 1H), 8.00 (m, 1H), 7.88 (m, 1H), 3.93 (d, 2H), 3.07 (m, 1H), 2.93 (m, 1H), 2.24 (m, 2H), 2.09 (m, 2H), 1.86 (m, 2H), 1.70 (m, 2H), 1.52 (m, 1H), 1.35 (d, 6H).
Test case:
Biological assessment
Following methods is used for measuring the compounds of this invention agonist activity to GPR119.Experimental technique is summarized as follows:
Inoculating hamster beta islet cells (HIT-T15) (being purchased from ATCC, article No. CRL-1777) in 96 orifice plates, inoculating cell density is 2x104.Cell at 37 DEG C, 5%CO2Cultivating after 48 hours under condition, remove culture fluid, adding 100 μ L stimulates buffer (Hanks, 5mMHEPES, 0.5mMIBMX, 0.1%BSA, pH7.4), and in incubated at room 15 minutes.Hole adds variable concentrations medicine, after hatching 30 minutes, removes buffer, add the lysate of 75 μ L pre-coolings, and hatch on ice 20 minutes, suitably vibrate.Lysate is transferred in 1.5mL centrifuge tube, is centrifuged 10 minutes with the rotating speed of 13000rpm.Take 50 μ L sample supernatants, detect cAMP content, the EC of compound according to cAMPELISA test kit (CellBiolabs, Inc.) standard step50Value can be drawn by cAMP cubage.
The EC of test-compound50It is worth as shown in the table:
| Compound number | EC50(HIT-T15)/(μM) |
| Embodiment 1 | 0.047 |
| Embodiment 2 | 0.035 |
| Embodiment 3 | 0.075 |
| Embodiment 5 | 0.036 |
Conclusion: 1,2,3 and 5 couples of GPR119 of embodiment of the present invention compound have obvious agonist activity.
Pharmacokinetic Evaluation
The pharmacokinetics test of test case 1 the compounds of this invention
1, summary
The not drug level in blood plasma in the same time after the oral embodiment of the present invention 5 compound of research.Research the compounds of this invention pharmacokinetics behavior in rat body, evaluates its characteristics of pharmacokinetics.
2, testing program
2.1 test drugs
Embodiment 5 compound
2.2 experimental animals
Healthy adult SD rat 4, male and female half and half, purchased from Shanghai western pul-Bi Kai laboratory animal company limited, animal productiong credit number: SCXK (Shanghai) 2008-0016.
2.3 medicine preparations
Weigh a certain amount of medicine, add 0.5%CMC-Na, ultrasonic make 1.0mg/ml suspension.
2.4 administration and sample collectings
Fasting one distinguishes gastric infusion after night, and dosage is 10.0mg/kg, is administered volume 10ml/kg.Before administration and be administered in latter 24 hours each moment and take a blood sample, anticoagulant heparin, separated plasma is in-20 DEG C of preservations.It is administered feed in latter 2 hours.
3. analyze method
Establishing LC/MS/MS method and measure embodiment 5 compound, the range of linearity of method is 1.00～2000ng/ml, and plasma sample is analyzed after protein precipitation processes.
4, pharmacokinetic parameter result
The pharmacokinetic parameter of the compounds of this invention such as following table:
Conclusion: in embodiment 5 compound rat body after oral administration, blood drug level and exposure level are all higher, have good medicine dynamic characteristic.
Pharmacodynamics is tested
1. research purpose
With ICR mice for animal subject, observe the impact on glucose load mouse blood sugar value of the embodiment 5 compound single multiple dose administration.
2. test-compound
Embodiment 1 and embodiment 5 compound
3. experimental animal
Healthy ICR mice (about body weight 20-24g) 40, male and female half and half, purchased from Shanghai western pul-Bi Kai laboratory animal company limited, animal productiong credit number: SCXK (Shanghai) 2008-0016.
4. medicine preparation
Weighing appropriate compound and become the suspension of 1 and 3mg/ml with 0.5% Carboxymethyl cellulose sodium solution, positive compound is configured to the suspension of 3mg/ml, ultrasonic suspending before administration.
5. test method
5.1 packets
Male and female Mus totally 40, overnight fast 16 hours.Basal plasma glucose value is measured, according to the 30mg/kg group (5 female 5 is male) that blood glucose height random packet is Blank group (5 female 5 is male), embodiment 1 compound, 10 and the 30mg/kg group (5 female 5 is male respectively) of embodiment 5 compound after weighing.
5.2 dosage are arranged
Dosage be 10 and 30mg/kg, Blank group give 0.5% Carboxymethyl cellulose sodium aqueous solution.
5.3 medications
Gastric infusion, gives the glucose solution (every mice gives 0.4ml) of 20% by 4g/kg after being administered 15 minutes.
The mensuration of 5.4 blood glucose values
According to dosage it is administered, measures blood glucose value (-15 minutes).
Give the glucose solution of 20% after being administered 15 minutes by 4g/kg, and use when 0,15,30,45,60 and 120 minutes the full Instrument for Measuring Blood Sugar of Roche Luo Kang to measure the blood glucose value of each mice.
5.5 data statisticss
Use Excel statistical software: meansigma methods calculates with avg；SD value calculates with STDEV；Group difference P value calculates with TTEST.
AUC computing formula:
AUC=(t15min+t0min)x0.25/2+(t30min+t15min)x0.25/2+(t45min+t30min)x0.25/2+(t60min+t45min)x0.25/2+(t120min+t60min)x1/2
Wherein t0min, t15min, t30min, t45min, t60min, t120minFor the blood glucose value that different time points records.
6. result of the test
Giving 30 minutes interior blood glucose rates of descent to area under the drug-time curve (AUC) after embodiment 1 compound of 30mg/kg (P=0.011) is 12.16%；Giving after the embodiment compound of 10mg/kg and 30mg/kg (P=0.031) 30 minutes interior blood glucose rates of descent to area under the drug-time curve (AUC) respectively 12.27% and 15.91%, result shows that embodiment 1 and 5 compound all has and significantly reduces the effect that mouse blood sugar raises.
Claims (7)
1. the compound shown in a formula (II) or (III) or its pharmaceutically useful salt:
Wherein:
D, E, F or G are each independently selected from CH or atom N, and are atom N during adjacent 3 atom difference in D, E, F or G；
Ring A is selected from-C6-10Aryl or heteroaryl, wherein said-C6-10Aryl or heteroaryl independently of one another optional further by one or more selected from halogen ,-S (O)mR3Substituent group replaced；
L is selected from a singly-bound or-(CH2)1-4-, one-CH of any of which2-optionally replaced by one or more O, all the other CH2Optionally it is selected from halogen or-C by one or two further1-6The substituent group of alkyl is replaced；
R1It is selected from
R3Selected from hydrogen atom ,-C1-6Alkyl；
R7Optional from-C1-6Alkyl or halogen；
R8Selected from isopropyl；
Described heteroaryl is comprise 1 to 4 optionally for the hetero atom of N or O, the heteroaromatic group of 5 to 10 annular atomses；
M is 0,1 or 2；
P is 1,2 or 3；And
Q is 1,2 or 3.
2. the compound shown in formula according to claim 1 (II) or (III) or its pharmaceutically useful salt, its medium ring A is-C6-10Aryl, wherein said-C6-10Aryl is optional further by one or more halogens or-SO2R3Substituent group replaced.
3. the compound shown in formula according to claim 1 (II) or (III) or its pharmaceutically useful salt, wherein L is-O-,-O-CH2-or-O-CH (CH3)-。
4. the compound shown in formula according to claim 1 (II) or (III) or its pharmaceutically useful salt, wherein this compound is:
5. a pharmaceutical composition, described pharmaceutical composition is made up of the formula (II) in any of the one of Claims 1 to 4 of therapeutically effective dosage or the compound shown in (III) or its pharmaceutically useful salt and pharmaceutically useful carrier.
6. formula (II) in any of the one of Claims 1 to 4 or the compound shown in (III) or its pharmaceutically useful salt or the pharmaceutical composition according to claim 5 purposes in preparing GPR119 agonist.
7. formula (II) in any of the one of Claims 1 to 4 or the compound shown in (III) or its pharmaceutically useful salt or the pharmaceutical composition according to claim 5 purposes in the medicine of preparation treatment diabetes and the disease of metabolic syndrome.
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| US9527847B2 (en) | 2012-06-25 | 2016-12-27 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
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