CN104478777B - A kind of containing nitro diamantane (obsolete) with the derivant of amide structure, Preparation Method And The Use - Google Patents
A kind of containing nitro diamantane (obsolete) with the derivant of amide structure, Preparation Method And The Use Download PDFInfo
- Publication number
- CN104478777B CN104478777B CN201510016730.5A CN201510016730A CN104478777B CN 104478777 B CN104478777 B CN 104478777B CN 201510016730 A CN201510016730 A CN 201510016730A CN 104478777 B CN104478777 B CN 104478777B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- present
- acid
- condensing agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- -1 nitro diamantane Chemical compound 0.000 title abstract description 7
- 241001597008 Nomeidae Species 0.000 title description 2
- 125000003368 amide group Chemical group 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 19
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 31
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 9
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 8
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 230000003197 catalytic effect Effects 0.000 claims description 6
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 150000001408 amides Chemical class 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 10
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 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 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 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 2
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 108090000631 Trypsin Chemical class 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000007056 liver toxicity Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical class CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 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(=O)NCC(O)=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 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Chemical class 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The present invention relates to the drug world relevant to diabetes.Specifically, the present invention relates to that there is a kind of containing the isostructural inhibitors of dipeptidyl IV of nitro diamantane (obsolete) and amide, its preparation method and the purposes in preparing diabetes medicament of Formulas I.
Description
Technical field
The present invention relates to the drug world relevant to diabetes.Specifically, the present invention relates to diabetes
Medicative one contains nitro diamantane (obsolete) and the isostructural dipeptidyl peptidase-iv inhibitor of amide and preparation thereof
Method, containing they pharmaceutical composition and treatment diabetes in terms of medicine.
Background technology
According to statistics, global diabetics about about 2.5 hundred million in 2007, wherein the biggest number is II type
(i.e. non-insulin-depending type) diabetics.Antidiabetic medicine at Clinical practice mainly has sulfonylureas at present
Class, metformin class and trypsin class medicine, list in recent years also have medicament of insulin sensitizer and α-
Alpha-glucosidase inhibitors etc..These medicines have good therapeutic effect, but generally there is the serious pairs such as hypoglycemia
Effect, and there is safety issue in long-term treatment, such as problems such as liver toxicity and body weight increases.
DPP IV (dipeptidyl peptidase IV, DPP-IV) can effectively and pancreas of degrading rapidly
Glucagon-like peptide 1 (GLP-1), GLP-1 is insulin production and secretes one of maximally effective stimulant, therefore
Suppression DPP-IV can strengthen the effect of endogenous GLP-1, thus improves the level (CN of insulin in blood
200480017355.6).Medical science it turned out DPP-IV inhibitor at present is a kind of novel antidiabetic treatment
Medicine, has had multiple medicine list marketing.Clinical effectiveness shows that such medicine has good blood sugar lowering effect
Really, do not find the untoward reaction thing such as the increase of common body weight and hypoglycemia produced by other diabetes medicaments simultaneously.
The major structural types of existing DPP-IV inhibitor has: chemically structure type divides and is broadly divided into piperazine
Piperazine triazole type, 2-cyano-pyrolidin class, thiazolidines, Pyrimdinone, and other types structure medicament.
The invention discloses a kind of containing nitro diamantane (obsolete) and the isostructural DPP-IV inhibitor of amide, these are changed
Compound may be used for the medicine of preparation treatment diabetes.
Summary of the invention
It is an object of the present invention to provide one and there is excellent activity, there is compound and the medicine thereof of Formulas I
Acceptable salt on.
It is a further object to provide preparation and there is the compound of Formulas I structure and the method for salt thereof.
It is also another object of the present invention to provide compound the answering in terms for the treatment of diabetes containing Formulas I
With.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has the compound of Formulas I and has a following structural formula:
Compound of formula I of the present invention is synthesized by following steps:
Compound II reacts with III in the presence of condensing agent, obtains compound IV；Compound IV uses
The method of catalytic hydrogenolysis is sloughed Bn protection group and is obtained V；Compound V reacts with VI in the presence of condensing agent,
Obtain compound VII；Compound VII acid treatment is sloughed Boc protection group and is obtained I.
Above-mentioned condensing agent includes N, N '-dicyclohexyl carbodiimide (DCC), N-ethyl-N '-(3-diformazan ammonia
Base propyl group) carbodiimide hydrochloride (EDC) and carbonyl dimidazoles (CDI) etc., these condensing agents can be with organic
Alkali is used in combination, such as triethylamine, diisopropyl ethyl amine (DIPEA) and DMAP (DMAP) etc..
The condition of above-mentioned catalytic hydrogenolysis includes using such as Pd/C and Pd (OH)2Deng catalyst, hydrogen source include hydrogen,
HCO2H、HCO2NH4With cyclohexene etc..Above-mentioned acid include hydrochloric acid, sulphuric acid, methanesulfonic acid, trifluoroacetic acid and
P-methyl benzenesulfonic acid etc..
The pharmaceutically acceptable salt of compound of formula I of the present invention includes, but are not limited to inorganic with various
Acid, such as, hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid etc., or organic acid, such as formic acid, acetic acid, citric acid,
The pharmaceutically acceptable salt that oxalic acid, fumaric acid, maleic acid, aminoacid etc. are generated.
Compound or its salt shown in formula I has the inhibitory action of DPP-IV, can be as effectively
Composition is used for preparing in treatment diabetes medicament；Preferably, described diabetes are non-insulin-dependent diabetes mellitus.
The activity of the compounds of this invention is to be verified by the external inhibitory action to DPP-IV enzyme.
Compound of formula I of the present invention or its salt have the inhibitory action of DPP-IV, can be as effectively becoming
Demultiplexing medicine in terms of preparation diabetes.The activity of compound of formula I of the present invention is by internal fall
Sugar modelling verification.
The compound of formula I of the present invention is effective in comparatively wide dosage range.Such as every day takes
Dosage, about in the range of 1mg-1000mg/ people, is divided into once or is administered for several times.Actual take formula I
The dosage of compound can be determined according to relevant situation by doctor.These situations include: the health of patient
State, route of administration, age, body weight, individual reaction to medicine, the order of severity etc. of symptom.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment
It is only for explanation, and is not intended to limit the present invention.Those skilled in the art are done according to the teachings of the present invention
The various changes gone out all should be within the protection domain required by the application claim.
The preparation of embodiment 1 compound I-1
The round-bottomed flask of one 100mL adds 2.53g (10mmol) compound II, 3.21g (10
Mmol) compound III, 2.06g (10mmol) N, N '-dicyclohexyl carbodiimide (DCC) and 1.22g (10
Mmol) DMAP (DMAP), dissolves with the THF that 20mL is dried, is stirred overnight under room temperature,
TLC display reaction is basically completed.Reactant mixture sucking filtration removes solid, and filtrate is evaporated on a rotary evaporator,
Residue column chromatography purification, obtains compound IV, white solid, ESI-MS, m/z=574 ([M+NH4]+)。
3.34 (6mmol) compound IV is dissolved in 30mL THF, adds 0.10g 10%Pd/C, room
The lower catalytic hydrogenolysis of temperature, reaction completed in 12 hours.Reactant mixture sucking filtration removes catalyst, and filtrate is in rotation
Turn and pour in 200mL water after concentrating on evaporimeter, stirring, extract with 50mL × 3 dichloromethane.Close
And extraction phase, with brine It, anhydrous sodium sulfate is dried, and is evaporated on a rotary evaporator, residue post layer
Analysis purification, obtains V sterling, white solid, ESI-MS, m/z=465 ([M-H]-)。
1.86g (4mmol) compound V-, 0.38g (4mmol) compound VI, 0.82g (4mmol) DCC
It is stirred overnight in the THF that 15mL is dried with 0.49g (10mmol) DMAP (DMAP).
Reactant mixture sucking filtration removes solid, and filtrate is evaporated on a rotary evaporator, residue column chromatography purification, obtains
Compound VII, white solid, ESI-MS, m/z=562 [M+NH4]+)。
1.09g (2mmol) compound VII is dissolved in 1mL dichloromethane and the mixing of 1mL trifluoroacetic acid
In solvent, it is stirred overnight under room temperature.Reactant mixture is poured in 100mL frozen water, stirring, with 50mL ×
3 dichloromethane extractions.Merging extraction phase, with brine It, anhydrous sodium sulfate is dried, at Rotary Evaporators
On be evaporated, residue column chromatography purification, obtain I sterling, white solid, ESI-MS, m/z=462 [M+NH4]+)。
The preparation of embodiment 2 reference compound D1
For absolutely proving the beneficial effect of the compounds of this invention, applicant describes discovery in experimentation
Following formula: compound D1 (is not disclosed), as drug effect reference compound.
Its preparation method is as follows:
The round-bottomed flask of one 100mL adds 2.08g (10mmol) compound II, 3.21g (10
Mmol) compound III, 2.06g (10mmol) N, N '-dicyclohexyl carbodiimide (DCC) and 1.22g (10
Mmol) DMAP (DMAP), dissolves with the THF that 20mL is dried, is stirred overnight under room temperature,
TLC display reaction is basically completed.Reactant mixture sucking filtration removes solid, and filtrate is evaporated on a rotary evaporator,
Residue column chromatography purification, obtains compound IV, white solid, ESI-MS, m/z=529 ([M+NH4]+)。
3.07 (6mmol) compound IV is dissolved in 30mL THF, adds 0.10g 10%Pd/C, room
The lower catalytic hydrogenolysis of temperature, reaction completed in 12 hours.Reactant mixture sucking filtration removes catalyst, and filtrate is in rotation
Turn and pour in 200mL water after concentrating on evaporimeter, stirring, extract with 50mL × 3 dichloromethane.Close
And extraction phase, with brine It, anhydrous sodium sulfate is dried, and is evaporated on a rotary evaporator, residue post layer
Analysis purification, obtains V sterling, white solid, ESI-MS, m/z=420 ([M-H]-)。
1.68g (4mmol) compound V-, 0.38g (4mmol) compound VI, 0.82g (4mmol) DCC
It is stirred overnight in the THF that 15mL is dried with 0.49g (10mmol) DMAP (DMAP).
Reactant mixture sucking filtration removes solid, and filtrate is evaporated on a rotary evaporator, residue column chromatography purification, obtains
Compound VII, white solid, ESI-MS, m/z=517 [M+NH4]+)。
1.00g (2mmol) compound VII is dissolved in 1mL dichloromethane and the mixing of 1mL trifluoroacetic acid
In solvent, it is stirred overnight under room temperature.Reactant mixture is poured in 100mL frozen water, stirring, with 50mL ×
3 dichloromethane extractions.Merging extraction phase, with brine It, anhydrous sodium sulfate is dried, at Rotary Evaporators
On be evaporated, residue column chromatography purification, obtain I sterling, white solid, ESI-MS, m/z=417 [M+NH4]+)。
The inhibitory action of DPP-IV enzyme is measured by embodiment 3 compound
Use the fluorescence DPP4 activity detection kit of BPS Biological Science Co., Ltd, measure the change of the present invention
The compound inhibitory activity to DPP-IV enzyme.
Sample is respectively as follows: 5,10,30,100 and 200ng/kg by gradient dilution concentration successively, glimmering
Photoreaction 96 orifice plate, according to the form below addition sample:
22 DEG C of water-baths, place 10min, Spectra Max M5 type fluorescence detector exciting light 350nm,
With 450nm fluoremetry absorption value.IC is calculated according to concentration-fluorescence intensity curves50Value, result see table.
The compound IC to the suppression of DPP-IV enzyme50Value
As can be seen from the above table, the compound of the present invention has the strongest inhibitory action to DPP-IV enzyme.
Claims (3)
1. there is compound or its pharmaceutically acceptable salt of Formulas I:
2. compound or the method for its pharmaceutically acceptable salt described in synthesis claim 1:
Compound II reacts with III in the presence of condensing agent, obtains compound IV, and wherein, condensing agent is N, N'-bis-
Cyclohexylcarbodiimide；The method of compound IV use catalytic hydrogenolysis is sloughed Bn protection group and is obtained V, its
In, the catalyst of catalytic hydrogenolysis is Pd/C, and hydrogen source is hydrogen；Compound V in the presence of condensing agent with VI
Reaction, obtains compound VII, and wherein, condensing agent is N, N'-dicyclohexyl carbodiimide；Compound VII
Slough Boc protection group with trifluoroacetic acid process and obtain I.
3. compound described in claim 1 or its pharmaceutically acceptable salt are in terms of preparation treatment diabetes medicament
Application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016730.5A CN104478777B (en) | 2015-01-13 | 2015-01-13 | A kind of containing nitro diamantane (obsolete) with the derivant of amide structure, Preparation Method And The Use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016730.5A CN104478777B (en) | 2015-01-13 | 2015-01-13 | A kind of containing nitro diamantane (obsolete) with the derivant of amide structure, Preparation Method And The Use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104478777A CN104478777A (en) | 2015-04-01 |
| CN104478777B true CN104478777B (en) | 2016-08-24 |
Family
ID=52753412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510016730.5A Expired - Fee Related CN104478777B (en) | 2015-01-13 | 2015-01-13 | A kind of containing nitro diamantane (obsolete) with the derivant of amide structure, Preparation Method And The Use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104478777B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000026186A1 (en) * | 1998-11-02 | 2000-05-11 | Welfide Corporation | Pyrrolidine compounds and medicinal utilization thereof |
| WO2005058849A1 (en) * | 2003-12-15 | 2005-06-30 | Glenmark Pharmaceuticals Ltd. | New dipeptidyl peptidase in inhibitors; process for their preparation and compositions containing them |
| WO2005073186A1 (en) * | 2004-01-29 | 2005-08-11 | Ono Pharmaceutical Co., Ltd. | Pyrrolidine derivatives |
| WO2006012441A1 (en) * | 2004-07-23 | 2006-02-02 | Susan Marie Royalty | Peptidase inhibitors |
| CN101050194A (en) * | 2006-04-05 | 2007-10-10 | 上海恒瑞医药有限公司 | Derivative of bicyclo-octanes class, preparation method, and application of medicine |
| CN101090901A (en) * | 2003-06-20 | 2007-12-19 | 霍夫曼-拉罗奇有限公司 | Hexahydropyridoisoqinolines as DPP-IV inhibitors |
-
2015
- 2015-01-13 CN CN201510016730.5A patent/CN104478777B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000026186A1 (en) * | 1998-11-02 | 2000-05-11 | Welfide Corporation | Pyrrolidine compounds and medicinal utilization thereof |
| CN101090901A (en) * | 2003-06-20 | 2007-12-19 | 霍夫曼-拉罗奇有限公司 | Hexahydropyridoisoqinolines as DPP-IV inhibitors |
| WO2005058849A1 (en) * | 2003-12-15 | 2005-06-30 | Glenmark Pharmaceuticals Ltd. | New dipeptidyl peptidase in inhibitors; process for their preparation and compositions containing them |
| WO2005073186A1 (en) * | 2004-01-29 | 2005-08-11 | Ono Pharmaceutical Co., Ltd. | Pyrrolidine derivatives |
| WO2006012441A1 (en) * | 2004-07-23 | 2006-02-02 | Susan Marie Royalty | Peptidase inhibitors |
| CN101050194A (en) * | 2006-04-05 | 2007-10-10 | 上海恒瑞医药有限公司 | Derivative of bicyclo-octanes class, preparation method, and application of medicine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104478777A (en) | 2015-04-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104478777B (en) | A kind of containing nitro diamantane (obsolete) with the derivant of amide structure, Preparation Method And The Use | |
| CN104530009B (en) | Amantadine tetrazole derivant, Preparation Method And The Use | |
| CN104447704B (en) | A kind of itrile group diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use | |
| CN104478861B (en) | A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use | |
| CN104478859B (en) | A kind of hydroxyadamantane tetrazotized zole compound, Preparation Method And The Use | |
| CN104478860B (en) | Diamantane (obsolete) tetrazole derivant, Preparation Method And The Use | |
| CN104530010B (en) | A kind of hydroxyadamantane tetrazotized zole compound, Preparation Method And The Use | |
| CN104529855B (en) | Derivative, the Preparation Method And The Use of a kind of hydroxyl diamantane and amide structure | |
| CN104447703B (en) | A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use | |
| CN104530011B (en) | A kind of itrile group diamantane tetrazotized zole compound, Preparation Method And The Use | |
| CN104529857B (en) | Halo diamantane amide derivatives, Preparation Method And The Use | |
| CN104447478B (en) | Derivative, the Preparation Method And The Use of a kind of nitrile group-containing diamantane and amide structure | |
| CN104356046B (en) | Cyclohexane-carboxylic acid amide derivatives that cycloalkyl replaces and application thereof | |
| CN104496877B (en) | A kind of itrile group diamantane amide derivatives, Preparation Method And The Use | |
| CN104356047B (en) | Substituted cyclohexane-carboxylic acid amide derivatives and its medicinal usage | |
| CN104530012B (en) | Amantadine tetrazole derivative, Preparation Method And The Use | |
| CN104447479B (en) | Containing diamantane and amide derivatives, Preparation Method And The Use | |
| CN104478778B (en) | Diamantane amide derivatives, Preparation Method And The Use | |
| CN104356048B (en) | Cyclohexane-carboxylic acid amide derivatives, Preparation Method And The Use | |
| CN104447501B (en) | Alkyl-substituted benzamidocyclohexanecarboxylic acid derivatives and applications thereof | |
| CN102241644B (en) | Alpha-azyl-3-aryl propionamido thiazole derivative, preparation method and purpose thereof | |
| CN104529856A (en) | Nitro adamantine amide derivative and preparing method and application thereof | |
| CN104447500B (en) | Halogen-substituted benzamidocyclohexanecarboxylic acid derivatives and applications thereof | |
| CN104496968A (en) | Compound with halogen-substituted adamantane tetrazole structure and preparation method and application thereof | |
| CN104496876A (en) | Hydroxyl diamantane amide derivative, preparation method and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Derivative with nitro adamantine structure and amide structure and preparation method and application thereof Effective date of registration: 20170816 Granted publication date: 20160824 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd. Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Registration number: 2017990000756 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20190604 Granted publication date: 20160824 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd. Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Registration number: 2017990000756 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190917 Address after: 064200 Business No. 8 on the East Side of Zunhua City, Tangshan City, Hebei Province Patentee after: Zunhua Yabao Culture Communication Co.,Ltd. Address before: Chancheng district has 528000 Taiwan public in Guangdong province Foshan City No. 32 first floor 1636, shop No. 1637 Patentee before: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201016 Address after: 064200 Huaming Jiayuan Commercial and Residential Building H7, West of Huaming South Road, Zunhua City, Tangshan City, Hebei Province Patentee after: Tangshan Chuangke Jinfu Technology Co.,Ltd. Address before: 064200 Business No. 8 on the East Side of Zunhua City, Tangshan City, Hebei Province Patentee before: Zunhua Yabao Culture Communication Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210107 Address after: No.66 Industrial Park, suyangshan Town, Pizhou City, Xuzhou City, Jiangsu Province Patentee after: XUZHOU HENGHUA PACKAGING TECHNOLOGY Co.,Ltd. Address before: 064200 commercial building H7, Huaming Jiayuan commercial and residential building, west of Huaming South Road, Zunhua City, Tangshan City, Hebei Province Patentee before: Tangshan Chuangke Jinfu Technology Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160824 Termination date: 20220113 |