CN104496877B - A kind of itrile group diamantane amide derivatives, Preparation Method And The Use - Google Patents
A kind of itrile group diamantane amide derivatives, Preparation Method And The Use Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- -1 diamantane amide Chemical class 0.000 title description 4
- 239000003814 drug Substances 0.000 claims abstract description 16
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 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
- 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 6
- 230000003197 catalytic effect Effects 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002560 nitrile group Chemical group 0.000 abstract description 3
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 abstract description 2
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 abstract description 2
- 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 16
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 16
- 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 9
- 238000004440 column chromatography Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000000452 restraining effect Effects 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- 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
- 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
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- 239000002253 acid Substances 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 239000000470 constituent Substances 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
- 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
- 239000012046 mixed solvent 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
- KYARBIJYVGJZLB-UHFFFAOYSA-N 7-amino-4-hydroxy-2-naphthalenesulfonic acid Chemical compound OC1=CC(S(O)(=O)=O)=CC2=CC(N)=CC=C21 KYARBIJYVGJZLB-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
- 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-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
- 238000010306 acid treatment Methods 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
- 230000015572 biosynthetic process 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
- 235000015165 citric acid Nutrition 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 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
- 150000002431 hydrogen Chemical class 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
- 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
- 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
- 238000003786 synthesis reaction Methods 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
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the pharmaceutical field relevant to diabetes. Specifically, the present invention relates to the dipeptidyl peptidase-iv inhibitor of the diamantane amide structure that a kind of nitrile group-containing with formula I structure replaces, its preparation method and in the application preparing 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 the diamantane amide structure that diabetes have a kind of nitrile group-containing of therapeutic action replace 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 (CN200480017355.6) 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 diamantane amides DPP-IV inhibitor that a kind of nitrile group-containing replaces, 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.
It is a further object to provide preparation and there is the compound of formula I and the method for salt thereof.
It is also another object of the present invention to provide the application of the compound of formula I in treatment diabetes.
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 has following structural formula:
The method of compound or its pharmacy acceptable salt described in synthesis claim 1:
Compound I I reacts with III under condensing agent exists, and obtains compound IV; The method of compound IV use catalytic hydrogenolysis is sloughed Bn protecting group and is obtained V; Compound V reacts with VI under condensing agent exists, and obtains compound VI I; Compound VI I acid treatment is sloughed Boc protecting group and is obtained 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 condition of above-mentioned catalytic hydrogenolysis comprises and uses such as Pd/C and Pd (OH)2Deng catalyzer, hydrogen source comprises hydrogen, HCO2H��HCO2NH4With tetrahydrobenzene etc.
Above-mentioned acid comprises hydrochloric acid, sulfuric acid, methylsulfonic acid, trifluoroacetic acid and tosic acid 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
The round-bottomed flask of a 100mL adds 2.19g (10mmol) Compound I I, 3.21g (10mmol) compound III, 2.06g (10mmol) N, N'-dicyclohexyl carbodiimide (DCC) and 1.22g (10mmol) DMAP (DMAP), dissolve with the THF of 20mL drying, room temperature for overnight, TLC display reaction completes substantially. Reaction mixture is taken out and is filtered solid, and filtrate is steamed dry on a rotary evaporator, and resistates column chromatography purification, obtains compound IV, white solid, ESI-MS, m/z=540 ([M+NH4]+)��
3.13g (6mmol) compound IV is dissolved in 30mLTHF, adds 0.10g10%Pd/C, catalytic hydrogenolysis under room temperature, and reaction completed in 12 hours. Reaction mixture is taken out and is filtered catalyzer, and filtrate pours in 200mL water after concentrating on a rotary evaporator, stirs, with 50mL �� 3 dichloromethane extraction. Merging extraction phase, with brine It, anhydrous sodium sulfate drying, steam dry on a rotary evaporator, resistates column chromatography purification, obtains V sterling, white solid, ESI-MS, m/z=431 ([M-H]-)��
1.73g (4mmol) compound V, 0.38g (4mmol) compound VI, 0.82g (4mmol) DCC and 0.49g (10mmol) DMAP (DMAP) stir in the THF of 15mL drying and spend the night. Reaction mixture is taken out and is filtered solid, and filtrate is steamed dry on a rotary evaporator, and resistates column chromatography purification, obtains compound VI I, white solid, ESI-MS, m/z=528 ([M+NH4]+)��
1.02g (2mmol) compound VI I is dissolved in the mixed solvent of 1mL methylene dichloride and 1mL trifluoroacetic acid, room temperature for overnight. Reaction mixture is poured in 100mL frozen water, stirs, with 50mL �� 3 dichloromethane extraction. Merging extraction phase, with brine It, anhydrous sodium sulfate drying, steam dry on a rotary evaporator, resistates column chromatography purification, obtains I sterling, white solid, ESI-MS, m/z=428 ([M+NH4]+)��
The preparation of embodiment 2 reference compound D1
For absolutely proving the useful effect of the compounds of this invention, applicant describes in experimentation the following formula: compound D1 (unexposed) found, as drug effect reference compound.
Its preparation method is as follows:
The round-bottomed flask of a 100mL adds 1.94g (10mmol) Compound I I-1,3.21g (10mmol) compound III, 2.06g (10mmol) N, N'-dicyclohexyl carbodiimide (DCC) and 1.22g (10mmol) DMAP (DMAP), dissolve with the THF of 20mL drying, room temperature for overnight, TLC display reaction completes substantially. Reaction mixture is taken out and is filtered solid, and filtrate is steamed dry on a rotary evaporator, and resistates column chromatography purification, obtains compound IV-1, white solid, ESI-MS, m/z=515 ([M+NH4]+)��
2.99g (6mmol) compound IV-1 is dissolved in 30mLTHF, adds 0.10g10%Pd/C, catalytic hydrogenolysis under room temperature, and reaction completed in 12 hours. Reaction mixture is taken out and is filtered catalyzer, and filtrate pours in 200mL water after concentrating on a rotary evaporator, stirs, with 50mL �� 3 dichloromethane extraction. Merging extraction phase, with brine It, anhydrous sodium sulfate drying, steam dry on a rotary evaporator, resistates column chromatography purification, obtains V-1 sterling, white solid, ESI-MS, m/z=406 ([M-H]-)��
1.63g (4mmol) compound V-1,0.38g (4mmol) compound VI, 0.82g (4mmol) DCC and 0.49g (10mmol) DMAP (DMAP) stir in the THF of 15mL drying and spend the night. Reaction mixture is taken out and is filtered solid, and filtrate is steamed dry on a rotary evaporator, and resistates column chromatography purification, obtains compound VI I-1, white solid, ESI-MS, m/z=503 ([M+NH4]+)��
0.97g (2mmol) compound VI I-1 is dissolved in the mixed solvent of 1mL methylene dichloride and 1mL trifluoroacetic acid, room temperature for overnight. Reaction mixture is poured in 100mL frozen water, stirs, with 50mL �� 3 dichloromethane extraction. Merging extraction phase, with brine It, anhydrous sodium sulfate drying, steam dry on a rotary evaporator, resistates column chromatography purification, obtains D1 sterling, white solid, ESI-MS, m/z=403 ([M+NH4]+)��
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. the compound of formula I or its pharmacy acceptable salt:
2. synthesize the method for compound or its pharmacy acceptable salt described in claim 1:
Compound I I is at condensing agent N, and N'-dicyclohexyl carbodiimide exists lower and III reaction, obtains compound IV; The method of compound IV use catalytic hydrogenolysis is sloughed Bn protecting group and is obtained V, and wherein the catalyzer of catalytic hydrogenolysis is Pd/C, and hydrogen source is H2; Compound V is at condensing agent N, and N'-dicyclohexyl carbodiimide exists lower and VI reaction, obtains compound VI I; The process of compound VI I trifluoroacetic acid is sloughed Boc protecting group and is obtained I.
3. compound described in claim 1 or its pharmacy acceptable salt treat the application in diabetes medicament in preparation.
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