CN104530010B - A kind of hydroxyadamantane tetrazotized zole compound, Preparation Method And The Use - Google Patents
A kind of hydroxyadamantane tetrazotized zole compound, Preparation Method And The Use Download PDFInfo
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- CN104530010B CN104530010B CN201510016600.1A CN201510016600A CN104530010B CN 104530010 B CN104530010 B CN 104530010B CN 201510016600 A CN201510016600 A CN 201510016600A CN 104530010 B CN104530010 B CN 104530010B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 title claims description 36
- VLLNJDMHDJRNFK-UHFFFAOYSA-N adamantan-1-ol Chemical compound C1C(C2)CC3CC2CC1(O)C3 VLLNJDMHDJRNFK-UHFFFAOYSA-N 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 16
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims description 9
- 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
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 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 description 2
- 238000000034 method Methods 0.000 claims description 2
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 abstract description 2
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 abstract description 2
- 229960003805 amantadine Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 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
- 230000000452 restraining effect Effects 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000011282 treatment 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
- 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
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 239000003112 inhibitor Substances 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
- 229960000549 4-dimethylaminophenol Drugs 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
- 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
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- AFDNEWRIBNBLKG-UHFFFAOYSA-N adamantan-1-ol 2H-tetrazole Chemical group N1N=NN=C1.OC12CC3CC(CC(C1)C3)C2 AFDNEWRIBNBLKG-UHFFFAOYSA-N 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
- 239000000470 constituent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 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
- 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 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229960004839 potassium iodide Drugs 0.000 description 2
- 235000007715 potassium iodide Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 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
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 1
- JWLNBFIMVNTUKY-HYMJRUIRSA-N CCC(/N=N\C)=N Chemical compound CCC(/N=N\C)=N JWLNBFIMVNTUKY-HYMJRUIRSA-N 0.000 description 1
- OFIKWTNROZGJKW-HSVCZPDLSA-N CCCC/C=C(\C(O)=O)/N=N\CC(NC1(C2)C(CC(C3)C4)C23CC4C1)=O Chemical compound CCCC/C=C(\C(O)=O)/N=N\CC(NC1(C2)C(CC(C3)C4)C23CC4C1)=O OFIKWTNROZGJKW-HSVCZPDLSA-N 0.000 description 1
- XKQADCNWQGTMSL-ZCFIWIBFSA-N C[C@@](CCC1)(N)N1C=O Chemical compound C[C@@](CCC1)(N)N1C=O XKQADCNWQGTMSL-ZCFIWIBFSA-N 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- ALSCEGDXFJIYES-YFKPBYRVSA-N N#C[C@H]1NCCC1 Chemical compound N#C[C@H]1NCCC1 ALSCEGDXFJIYES-YFKPBYRVSA-N 0.000 description 1
- GTZWQXZVYGAJRN-UHFFFAOYSA-N NCC(NC(C1)(C2)CC(C3)C4C2C1CC3C4)=O Chemical compound NCC(NC(C1)(C2)CC(C3)C4C2C1CC3C4)=O GTZWQXZVYGAJRN-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- QQYGSIDXDJLYKH-UHFFFAOYSA-N O=C(CBr)NC(C1)(C2)C3(C4)C1CC4CC2C3 Chemical compound O=C(CBr)NC(C1)(C2)C3(C4)C1CC4CC2C3 QQYGSIDXDJLYKH-UHFFFAOYSA-N 0.000 description 1
- 101710176384 Peptide 1 Proteins 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
- 235000011054 acetic acid Nutrition 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
- 150000001413 amino acids Chemical class 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
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000000593 degrading effect Effects 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
- 230000000857 drug effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000007421 fluorometric assay Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940125396 insulin Drugs 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
- 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
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 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
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- -1 such as Substances 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles 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 pharmaceutical field relevant to diabetes. Specifically, the present invention relates to the dipeptidyl peptidase-iv inhibitor of a kind of hydroxyl amantadine tetrazole structure and its preparation method, and preparing the application in diabetes medicament.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes. Specifically, the present invention relates to the dipeptidyl peptidase-iv inhibitor of a kind of hydroxyadamantane tetrazole structure that diabetes are had therapeutic action and its preparation method, containing their pharmaceutical composition and the medicine in treatment diabetes.
Background technology
According to statistics, global diabetic subject nearly about 2.5 hundred million in 2007, wherein big absolutely number is II type (i.e. non-insulin-depending type) diabetic subject. The current antidiabetic medicine at Clinical practice mainly contains sulfonylurea, N1,N1-Dimethylbiguanide class and trypsin class medicine, and what list in recent years also has medicament of insulin sensitizer and alpha-glucosidase inhibitor etc. These medicines have good therapeutic action, but generally there is the serious side effects such as hypoglycemia, and long-term treatment exists safety issue, such as problems such as liver toxicity and body weight increases.
DPP IV (dipeptidylpeptidaseIV, DPP-IV) can effectively and glucagon peptide 1 (GLP-1) of degrading fast, GLP-1 is one of insulin production and the most effective stimulant of secretion, therefore suppress DPP-IV can strengthen the effect of endogenous property GLP-1, thus improve the level of Regular Insulin in blood. Current medical science has confirmed that DPP-IV inhibitor is a kind of novel antidiabetic treatment medicine, has had multiple medicine list marketing at present. Clinical effectiveness shows such medicine and has good hypoglycemic effect, does not find the untoward reaction thing such as the common body weight increase that other diabetes medicaments produce and hypoglycemia simultaneously.
The major structural types of existing DPP-IV inhibitor has: chemically structure type divides and is mainly divided into piperazine and triazole species, 2-cyano-pyrolidin class, thiazolidines, Pyrimdinone, and other type structure medicines.
The present invention discloses the DPP-IV inhibitor of a kind of hydroxyadamantane tetrazole structure, and these compounds may be used for preparing the medicine for the treatment of 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 pharmacy acceptable salt thereof of formula I structure.
It is a further object to provide preparation and there is the compound of formula I structure and the method for salt thereof.
Now content of the present invention is specifically described by object in conjunction with the present invention.
The compound that the present invention has formula I structure has following structural formula:
Formula I of the present invention is synthesized by following step:
Compound I I and bromoacetyl bromide III is obtained by reacting compound IV in the presence of a base, and the latter and 2H-tetrazole-5-formic acid V are obtained by reacting compound VI in the presence of a base, and compound VI is reacted with VII with under condensing agent existence, obtains Compound I; Above-mentioned condensing agent comprises N, N'-dicyclohexyl carbodiimide (DCC), N-ethyl-N'-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDC) and carbonyl dimidazoles (CDI) etc., these condensing agents can with organic bases conbined usage, such as triethylamine, diisopropyl ethyl amine (DIPEA) and DMAP (DMAP) etc.
The pharmacy acceptable salt of formula I of the present invention comprises, but it is not limited to and various mineral acid, such as, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acid, the pharmacy acceptable salt that such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid etc. generate.
Compound or its salt shown in formula I of the present invention has the restraining effect of DPP-IV, can be used as effective constituent for the preparation of in treatment diabetes medicament; Preferably, described diabetes are non insulin dependent diabetes. The activity of the compounds of this invention is verified by the external restraining effect to DPP-IV enzyme.
Formula I of the present invention or its salt have the restraining effect of DPP-IV, can be used as the medicine of effective constituent for the preparation of diabetes aspect. The activity of formula I of the present invention is by falling sugar modelling verification in body.
The formula I of the present invention is effective in quite wide dosage range. The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times. The actual dosage taking formula I of the present invention can be determined according to relevant situation by doctor. These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated. It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention. Those skilled in the art all should within the protection domain required by the application's claim according to the various changes that the teachings of the present invention is made.
The preparation of embodiment 1 Compound I
1.67g (10mmol) Compound I I and 3.04g (30mmol) triethylamine is dissolved in the methylene dichloride of 20mL drying, ice-water bath cooling is lower stirs, and then slowly drips and adds 2.42g (12mmol) compound III and be dissolved in the methylene dichloride of 5mL drying the solution made. After dropwising, reaction mixture at room temperature continues to stir 1 hour. Reaction mixture is poured in 200mL frozen water, stir, with 50mL �� 3 dichloromethane extraction, merge extraction phase brine It, anhydrous sodium sulfate drying, then steam dry on a rotary evaporator, the resistates column chromatography purification obtained, obtains the sterling of IV, white solid, ESI-MS, m/z=287 and 289 ([M+H]+)��
1.73g (6mmol) compound IV, 0.68g (6mmol) compound V, 1.00g (6mmol) solid potassiumiodide and 4.15g (30mmol) solid carbonic acid potassium stir under 120 DEG C of nitrogen in the DMF of 20mL drying and spend the night. It is poured in 200mL frozen water after reaction mixture is slightly cold, stir, with 50mL �� 3 dichloromethane extraction, merge extraction phase brine It, anhydrous sodium sulfate drying, then steam dry on a rotary evaporator, the resistates column chromatography purification obtained, obtains the sterling of VI, white solid, ESI-MS, m/z=321 ([M+H]+)��
9.63g (3mmol) compound VI, 0.29g (mmol) compound VI I and 0.62g (3mmol) DCC room temperature for overnight in the THF of 6mL drying. Taking out the solid filtering in reaction mixture, filtrate is steamed dry on a rotary evaporator, and resistates column chromatography purification obtains the sterling of product I, white solid, ESI-MS, m/z=399 ([M+H]+)��
The preparation of embodiment 2 reference compound D
For absolutely proving the useful effect of the compounds of this invention, applicant describes in experimentation the following formula: compound D (unexposed) found, as drug effect reference compound.
Its preparation method is as follows:
1.51g (10mmol) Compound I I-1 and 3.04g (30mmol) triethylamine is dissolved in the methylene dichloride of 20mL drying, ice-water bath cooling is lower stirs, and then slowly drips and adds 2.42g (12mmol) compound III and be dissolved in the methylene dichloride of 5mL drying the solution made. After dropwising, reaction mixture at room temperature continues to stir 1 hour. Reaction mixture is poured in 200mL frozen water, stirs, and with 50mL �� 3 dichloromethane extraction, merges extraction phase brine It, anhydrous sodium sulfate drying, then steams dry on a rotary evaporator, and the resistates column chromatography purification obtained, 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 potassiumiodide and 4.15g (30mmol) solid carbonic acid potassium stir under 120 DEG C of nitrogen in the DMF of 20mL drying and spend the night. It is poured in 200mL frozen water after reaction mixture is slightly cold, stirs, with 50mL �� 3 dichloromethane extraction, merge extraction phase brine It, anhydrous sodium sulfate drying, then steam dry on a rotary evaporator, the resistates column chromatography purification obtained, obtains the sterling of VI-1. ESI-MS, m/z=305 ([M+H]+)��
0.92g (3mmol) compound VI-1,0.29g (3mmol) compound VI I and 0.62g (3mmol) DCC room temperature for overnight in the THF of 6mL drying. Taking out the solid filtering in reaction mixture, filtrate is steamed dry on a rotary evaporator, and resistates column chromatography purification obtains the sterling of product D, ESI-MS, m/z=383 ([M+H]+)��
The restraining effect of DPP-IV enzyme is measured by embodiment 3 compound
Using the fluorescence DPP4 Activity determination test kit of BPS Biological Science Co., Ltd, the compound measuring the present invention is to the inhibit activities of DPP-IV enzyme. Being respectively by gradient dilution concentration successively by sample: 5,10,30,100 and 200ng/kg, fluorescent reaction 96 orifice plate, adds sample by following table:
22 DEG C of water-baths, place 10min, SpectraMaxM5 type fluorimetric detector exciting light 350nm, with 450nm fluorometric assay absorption value. IC is calculated according to concentration-fluorescence intensity curves50Value, the results are shown in following table:
Compound is to the IC of the suppression of DPP-IV enzyme50Value
As can be seen from the above table, DPP-IV enzyme is had very strong restraining effect by the compound of the present invention.
Claims (3)
1. formula I or its pharmacy acceptable salt:
2. synthesize the method for compound or its pharmacy acceptable salt described in claim 1, comprise the following steps:
Compound I I and bromoacetyl bromide III is obtained by reacting compound IV in the presence of a base, and compound IV and 2H-tetrazole-5-formic acid V are obtained by reacting compound VI in the presence of a base, and compound VI is reacted with VII under condensing agent exists, and obtains Compound I.
3. compound described in claim 1 or its pharmacy acceptable salt treat the application in diabetes medicament in preparation.
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| WO2006012441A1 (en) * | 2004-07-23 | 2006-02-02 | Susan Marie Royalty | Peptidase inhibitors |
| CN1921856A (en) * | 2004-02-20 | 2007-02-28 | 诺瓦提斯公司 | Dpp-iv inhibitors for treating neurodegeneration and cognitive disorders |
| CN101318922A (en) * | 2007-06-08 | 2008-12-10 | 上海阳帆医药科技有限公司 | Novel dipeptidyl peptidase restrainer, synthesizing process and uses thereof |
| CN101448785A (en) * | 2006-04-03 | 2009-06-03 | 矩阵实验室有限公司 | Novel dipeptidyl peptidase IV inhibitors and processes for their preparation and pharmaceutical compositions containing them |
| EP2318007B1 (en) * | 2008-08-15 | 2013-01-23 | N30 Pharmaceuticals, Inc. | Novel pyrrole inhibitors of s-nitrosoglutathione reductase as therapeutic agents |
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| CN1921856A (en) * | 2004-02-20 | 2007-02-28 | 诺瓦提斯公司 | Dpp-iv inhibitors for treating neurodegeneration and cognitive disorders |
| WO2006012441A1 (en) * | 2004-07-23 | 2006-02-02 | Susan Marie Royalty | Peptidase inhibitors |
| CN101448785A (en) * | 2006-04-03 | 2009-06-03 | 矩阵实验室有限公司 | Novel dipeptidyl peptidase IV inhibitors and processes for their preparation and pharmaceutical compositions containing them |
| CN101318922A (en) * | 2007-06-08 | 2008-12-10 | 上海阳帆医药科技有限公司 | Novel dipeptidyl peptidase restrainer, synthesizing process and uses thereof |
| EP2318007B1 (en) * | 2008-08-15 | 2013-01-23 | N30 Pharmaceuticals, Inc. | Novel pyrrole inhibitors of s-nitrosoglutathione reductase as therapeutic agents |
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