CN104447703B - A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use - Google Patents
A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use Download PDFInfo
- Publication number
- CN104447703B CN104447703B CN201510016637.4A CN201510016637A CN104447703B CN 104447703 B CN104447703 B CN 104447703B CN 201510016637 A CN201510016637 A CN 201510016637A CN 104447703 B CN104447703 B CN 104447703B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- present
- obsolete
- obtains
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 title claims description 37
- -1 nitro diamantane Chemical compound 0.000 title description 9
- 239000003814 drug Substances 0.000 claims abstract description 18
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 5
- 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 4
- 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 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 claims description 2
- IKNZBNHVVQIRTO-UHFFFAOYSA-N 2h-tetrazole-5-carboxylic acid Chemical compound OC(=O)C=1N=NNN=1 IKNZBNHVVQIRTO-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 229960003805 amantadine Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-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
- 238000000605 extraction Methods 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
- 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
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000006243 chemical reaction Methods 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
- 239000000284 extract Substances 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101800000224 Glucagon-like peptide 1 Proteins 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 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
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 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
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 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
- 206010018473 Glycosuria Diseases 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- 239000002253 acid 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 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
- 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
- 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
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases 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
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 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
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The present invention relates to the drug world relevant to diabetes.Specifically, the present invention relates to a kind of inhibitors of dipeptidyl IV containing nitro amantadine tetrazole structure and preparation method thereof, and the application in terms of preparing diabetes medicament.
Description
Technical field
The present invention relates to the drug world relevant to diabetes.Specifically, the present invention relates to diabetes
The dipeptidyl peptidase-iv inhibitor of medicative a kind of nitro diamantane (obsolete) tetrazole structure and preparation side 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 of insulin in blood.Doctor at present
Learning and it turned out DPP-IV inhibitor is a kind of novel antidiabetic treatment medicine, has had multiple medicine
Thing list marketing.Clinical effectiveness shows that such medicine has good hypoglycemic effect, does not finds other glycosurias simultaneously
The untoward reaction thing such as the increase of common body weight and hypoglycemia produced by medicine.
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 the DPP-IV inhibitor of a kind of nitro diamantane (obsolete) tetrazole structure, these chemical combination
Thing 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, have Formulas I structure compound and
Its pharmaceutically acceptable salt.
It is a further object to provide preparation and there is the compound of Formulas I structure and the method for salt thereof.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has the compound of Formulas I structure and has a following structural formula:
Compound of formula I of the present invention is synthesized by following steps:
Compound II and bromoacetyl bromide III reacts in the presence of a base and obtains compound IV, the latter and 2H-tetra-
Nitrogen azoles-5-formic acid V reacts in the presence of a base and obtains compound VI, compound VI with in the presence of condensing agent with
VII reacts, and obtains compound I；Above-mentioned condensing agent includes N, N'-dicyclohexyl carbodiimide (DCC), N-
Ethyl-N'-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDC) and carbonyl dimidazoles (CDI) etc., these contractings
Mixture can be used in combination with organic base, such as triethylamine, diisopropyl ethyl amine (DIPEA) and 4-dimethylamino
Pyridine (DMAP) 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
1.96g (10mmol) compound II and 3.04g (30mmol) triethylamine is dissolved in two that 20mL is dried
In chloromethanes, the lower stirring of ice-water bath cooling, the most slowly drip 2.42g (12mmol) compound III and be dissolved in 5
The solution made in the dichloromethane that mL is dried.After dropping, reactant mixture at room temperature continues stirring
1 hour.Reactant mixture is poured in 200mL frozen water, stirring, extracts with 50mL × 3 dichloromethane,
Merging extraction phase brine It, anhydrous sodium sulfate is dried, and is evaporated the most on a rotary evaporator, obtains
Residue column chromatography purification, obtains the sterling of IV, white solid, ESI-MS, m/z=316 and
318([M+H]+)。
1.90g (6mmol) compound IV, 0.68g (6mmol) compound V, 1.00g (6mmol) are solid
Body potassium iodide and 4.15g (30mmol) solid carbonic acid potassium stir under 120 DEG C of nitrogen in the DMF that 20mL is dried
Mix overnight.Being poured into after reactant mixture is the coldest in 200mL frozen water, stirring, with 50mL × 3 dichloromethane
Alkane extracts, and merges extraction phase brine It, and anhydrous sodium sulfate is dried, and is evaporated the most on a rotary evaporator,
The residue column chromatography purification obtained, obtains the sterling of VI, white solid, ESI-MS, m/z=
350([M+H]+)。
10.50g (3mmol) compound VI, 0.29g (mmol) compound VII and 0.62g (3mmol)
DCC is stirred overnight under room temperature in the THF that 6mL is dried.Sucking filtration removes the solid in reactant mixture,
Filtrate is evaporated on a rotary evaporator, and residue column chromatography purification obtains the sterling of product I, white solid,
ESI-MS, m/z=428 ([M+H]+)。
The preparation of embodiment 2 reference compound D
For absolutely proving the beneficial effect of the compounds of this invention, applicant describes discovery in experimentation
Following formula: compound D (is not disclosed), as drug effect reference compound.
Its preparation method is as follows:
1.51g (10mmol) compound II-1 and 3.04g (30mmol) triethylamine is dissolved in what 20mL was dried
In dichloromethane, the lower stirring of ice-water bath cooling, the most slowly drip 2.42g (12mmol) compound III and be dissolved in
The solution made in the dichloromethane that 5mL is dried.After dropping, reactant mixture at room temperature continues to stir
Mix 1 hour.Reactant mixture is poured in 200mL frozen water, stirring, extracts with 50mL × 3 dichloromethane
Taking, merge extraction phase brine It, anhydrous sodium sulfate is dried, and is evaporated the most on a rotary evaporator,
The residue column chromatography purification arrived, obtains the sterling of IV-1.ESI-MS, m/z=271 and 273 ([M+H]+)。
1.63g (6mmol) compound IV-1,0.68g (6mmol) compound V, 1.00g (6mmol)
Solid potassium iodide and 4.15g (30mmol) solid carbonic acid potassium are in the DMF that 20mL is dried under 120 DEG C of nitrogen
It is stirred overnight.Being poured into after reactant mixture is the coldest in 200mL frozen water, stirring, with 50mL × 3 dichloro
Methane extracts, and merges extraction phase brine It, and anhydrous sodium sulfate is dried, and steams the most on a rotary evaporator
Dry, the residue column chromatography purification obtained, obtain the sterling of VI-1.ESI-MS, m/z=305 ([M+H]+)。
0.92g (3mmol) compound VI-1,0.29g (3mmol) compound VII and 0.62g (3
Mmol) DCC is stirred overnight under room temperature in the THF that 6mL is dried.Sucking filtration removes in reactant mixture
Solid, filtrate is evaporated on a rotary evaporator, and residue column chromatography purification obtains the sterling of product D, ESI-MS,
M/z=383 ([M+H]+)。
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 by gradient dilution concentration successively, 10,30,
100 and 200ng/kg, fluorescence reaction 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. compound of formula I or its pharmaceutically acceptable salt:
。
2. compound or the method for its pharmaceutically acceptable salt described in synthesis claim 1, comprises the following steps:
Compound II and bromoacetyl bromide III reacts in the presence of a base and obtains compound IV, and compound IV and 2H-tetrazole-5-formic acid V reacts in the presence of a base and obtains compound VI, and compound VI reacts with VII in the presence of condensing agent, obtains compound I.
3. compound described in claim 1 or the application in terms of preparation treatment diabetes medicament of its pharmaceutically acceptable salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016637.4A CN104447703B (en) | 2015-01-13 | 2015-01-13 | A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016637.4A CN104447703B (en) | 2015-01-13 | 2015-01-13 | A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104447703A CN104447703A (en) | 2015-03-25 |
| CN104447703B true CN104447703B (en) | 2016-07-27 |
Family
ID=52894527
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510016637.4A Active CN104447703B (en) | 2015-01-13 | 2015-01-13 | A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104447703B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1310493A1 (en) * | 2001-11-12 | 2003-05-14 | Pfizer Products Inc. | N-adamantylalkyl benzamide derivates as p2x7-receptor antagonists |
| WO2006090244A1 (en) * | 2005-02-22 | 2006-08-31 | Glenmark Pharmaceuticals S.A. | New adamantane derivatives as dipeptidyl, peptidase iv inhibitors, processes for their preparation, and pharmaceutical compositions containing them |
| CN103304501A (en) * | 2013-06-02 | 2013-09-18 | 张远强 | Anti-diabetic compound, as well as preparation method and application thereof |
| CN103304500A (en) * | 2013-06-02 | 2013-09-18 | 张远强 | Novel anti-diabetic compound, as well as preparation method and application thereof |
-
2015
- 2015-01-13 CN CN201510016637.4A patent/CN104447703B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1310493A1 (en) * | 2001-11-12 | 2003-05-14 | Pfizer Products Inc. | N-adamantylalkyl benzamide derivates as p2x7-receptor antagonists |
| WO2006090244A1 (en) * | 2005-02-22 | 2006-08-31 | Glenmark Pharmaceuticals S.A. | New adamantane derivatives as dipeptidyl, peptidase iv inhibitors, processes for their preparation, and pharmaceutical compositions containing them |
| CN103304501A (en) * | 2013-06-02 | 2013-09-18 | 张远强 | Anti-diabetic compound, as well as preparation method and application thereof |
| CN103304500A (en) * | 2013-06-02 | 2013-09-18 | 张远强 | Novel anti-diabetic compound, as well as preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A Potent,Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties;Edwin B. Villhauer,et al.;《J. Med. Chem.》;20030524;2774-2789 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104447703A (en) | 2015-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5968455B2 (en) | Thieno [3,2-d] pyrimidin-4-one compound, method for producing the same, pharmaceutical composition and use | |
| JP2012512186A (en) | Amidothiazole derivatives, process for their production and use | |
| CN104447704B (en) | A kind of itrile group diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use | |
| CN104478859B (en) | A kind of hydroxyadamantane tetrazotized zole compound, Preparation Method And The Use | |
| CN104478861B (en) | A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use | |
| CN104530009B (en) | Amantadine tetrazole derivant, Preparation Method And The Use | |
| CN104478860B (en) | Diamantane (obsolete) tetrazole derivant, Preparation Method And The Use | |
| CN104447703B (en) | A kind of nitro diamantane (obsolete) tetrazotized zole compound, Preparation Method And The Use | |
| CN104530010B (en) | A kind of hydroxyadamantane tetrazotized zole compound, Preparation Method And The Use | |
| CN104530011B (en) | A kind of itrile group diamantane tetrazotized zole compound, Preparation Method And The Use | |
| CN104530012B (en) | Amantadine tetrazole derivative, Preparation Method And The Use | |
| CN104496968A (en) | Compound with halogen-substituted adamantane tetrazole structure and preparation method and application thereof | |
| CN104356046B (en) | Cyclohexane-carboxylic acid amide derivatives that cycloalkyl replaces and application thereof | |
| CN104478777B (en) | A kind of containing nitro diamantane (obsolete) with the derivant of amide structure, Preparation Method And The Use | |
| CN104356047B (en) | Substituted cyclohexane-carboxylic acid amide derivatives and its medicinal usage | |
| CN104447501B (en) | Alkyl-substituted benzamidocyclohexanecarboxylic acid derivatives and applications thereof | |
| CN104356048B (en) | Cyclohexane-carboxylic acid amide derivatives, Preparation Method And The Use | |
| CN104447500B (en) | Halogen-substituted benzamidocyclohexanecarboxylic acid derivatives and applications thereof | |
| CN104529857B (en) | Halo diamantane amide derivatives, Preparation Method And The Use | |
| CN104496877B (en) | A kind of itrile group diamantane amide derivatives, Preparation Method And The Use | |
| CN104529855B (en) | Derivative, the Preparation Method And The Use of a kind of hydroxyl diamantane and amide structure | |
| CN104447479B (en) | Containing diamantane and amide derivatives, Preparation Method And The Use | |
| CN104478778B (en) | 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 | |
| CN102241644B (en) | Alpha-azyl-3-aryl propionamido thiazole derivative, preparation method and purpose thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| 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: Nitro adamantine tetrazole compound and preparation method and application thereof Effective date of registration: 20170816 Granted publication date: 20160727 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: 20160727 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: 20190912 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: 20201015 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: 20210104 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. |