CN104478777A - Derivative with nitro adamantine structure and amide structure and preparation method and application thereof - Google Patents
Derivative with nitro adamantine structure and amide structure and preparation method and application thereof Download PDFInfo
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- CN104478777A CN104478777A CN201510016730.5A CN201510016730A CN104478777A CN 104478777 A CN104478777 A CN 104478777A CN 201510016730 A CN201510016730 A CN 201510016730A CN 104478777 A CN104478777 A CN 104478777A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 125000003368 amide group Chemical group 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 17
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 33
- 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 8
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 5
- 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
- 238000000034 method Methods 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 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 claims description 2
- 238000010306 acid treatment Methods 0.000 claims description 2
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 abstract description 4
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 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
- 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
- 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000452 restraining effect Effects 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
- 230000002218 hypoglycaemic effect Effects 0.000 description 4
- -1 nitro diamantane Chemical compound 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical group 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
- 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
- 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
- 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
- 102100040918 Pro-glucagon Human genes 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
- 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
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen 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
- 239000012046 mixed solvent Substances 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
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 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
- 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
- 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
- 235000015165 citric acid Nutrition 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 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
- 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
- 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
- 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
- 230000028327 secretion Effects 0.000 description 1
- 238000001228 spectrum Methods 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
- 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
- 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
- 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 invention relates to the field of drugs relevant to diabetes, in particular to a dipeptidyl peptidase-IV inhibitor with a nitro adamantine structure, an amide structure and the like shown in the formula I, a preparation method of the dipeptidyl peptidase-IV inhibitor, and the application of the dipeptidyl peptidase-IV inhibitor in diabetes drug preparation.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes.Specifically, the present invention relates to diabetes medicative a kind of containing nitro diamantane and the isostructural dipeptidyl peptidase-iv inhibitor of acid amides and preparation method thereof, containing they pharmaceutical composition and treatment diabetes in medicine.
Background technology
According to statistics, global diabetic subject nearly about 2.5 hundred million in 2007, wherein large absolutely number is II type (i.e. non-insulin-depending type) diabetic subject.Mainly contain sulfonylurea, N1,N1-Dimethylbiguanide class and trypsin class medicine at the antidiabetic medicine of Clinical practice at present, what go on the market in recent years also has medicament of insulin sensitizer and alpha-glucosidase inhibitor etc.These medicines have good therapeutic action, but the serious side effects such as ubiquity hypoglycemia, and there is safety issue in long-term treatment, as problems such as liver toxicity and body weight increases.
DPP IV (dipeptidyl peptidase IV, DPP-IV) can effectively and to degrade rapidly glucagon-like peptide 1 (GLP-1), GLP-1 is one of insulin production and the most effective stimulant of secretion, therefore suppress DPP-IV can strengthen the effect of endogenous 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 types structure medicament.
The invention discloses a kind of containing nitro diamantane and the isostructural DPP-IV inhibitor of acid amides, these compounds may be used for the medicine preparing treatment diabetes.
Summary of the invention
An object of the present invention is to provide one and there is excellent activity, there is compound and the pharmacy acceptable salt thereof of formula I.
Another object of the present invention is to provide preparation and has the compound of formula I structure and the method for salt thereof.
Another object of the present invention is to provide the application of compound in treatment diabetes containing formula I.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has formula I has following structural formula:
Formula I of the present invention is synthesized by following steps:
Compound II per reacts with III under condensing agent exists, and obtains compound IV; Compound IV uses the method for catalytic hydrogenolysis to slough Bn protecting group and obtains 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, as triethylamine, diisopropyl ethyl amine (DIPEA) and DMAP (DMAP) etc.The condition of above-mentioned catalytic hydrogenolysis comprises and using such as Pd/C and Pd (OH)
2deng catalyzer, hydrogen source comprises hydrogen, HCO
2h, HCO
2nH
4with 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 be 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 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 hypoglycemic modelling verification in body.
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 can be decided 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.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
The preparation of embodiment 1 Compound I-1
2.53g (10mmol) Compound II per, 3.21g (10mmol) compound III, 2.06g (10mmol) N is added in the round-bottomed flask of a 100mL, 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 suction filtration removing solid, filtrate is evaporate to dryness on a rotary evaporator, and resistates column chromatography purification, obtains compound IV, white solid, ESI-MS, m/z=574 ([M+NH
4]
+).
3.34 (6mmol) compound IV is dissolved in 30mL THF, adds 0.10g 10%Pd/C, catalytic hydrogenolysis under room temperature, reacts and completed in 12 hours.Reaction mixture suction filtration removing catalyzer, filtrate pours in 200mL water after concentrating on a rotary evaporator, stirs, with 50mL × 3 dichloromethane extraction.Merge extraction phase, with brine It, anhydrous sodium sulfate drying, on a rotary evaporator evaporate to dryness, resistates column chromatography purification, obtain 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 and 0.49g (10mmol) DMAP (DMAP) stir and spend the night in the THF of 15mL drying.Reaction mixture suction filtration removing solid, filtrate is evaporate to dryness on a rotary evaporator, and resistates column chromatography purification, obtains compound VI I, white solid, ESI-MS, m/z=562 [M+NH
4]
+).
1.09g (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.Merge extraction phase, with brine It, anhydrous sodium sulfate drying, on a rotary evaporator evaporate to dryness, resistates column chromatography purification, obtain I sterling, white solid, ESI-MS, m/z=462 [M+NH
4]
+).
The preparation of embodiment 2 reference compound D1
For absolutely proving the beneficial effect of the compounds of this invention, applicant describes the following formula: compound D1 (unexposed) found in experimentation, as drug effect reference compound.
Its preparation method is as follows:
2.08g (10mmol) Compound II per, 3.21g (10mmol) compound III, 2.06g (10mmol) N is added in the round-bottomed flask of a 100mL, 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 suction filtration removing solid, filtrate is evaporate to dryness on a rotary evaporator, and resistates column chromatography purification, obtains compound IV, white solid, ESI-MS, m/z=529 ([M+NH
4]
+).
3.07 (6mmol) compound IV is dissolved in 30mL THF, adds 0.10g 10%Pd/C, catalytic hydrogenolysis under room temperature, reacts and completed in 12 hours.Reaction mixture suction filtration removing catalyzer, filtrate pours in 200mL water after concentrating on a rotary evaporator, stirs, with 50mL × 3 dichloromethane extraction.Merge extraction phase, with brine It, anhydrous sodium sulfate drying, on a rotary evaporator evaporate to dryness, resistates column chromatography purification, obtain 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 and 0.49g (10mmol) DMAP (DMAP) stir and spend the night in the THF of 15mL drying.Reaction mixture suction filtration removing solid, filtrate is evaporate to dryness on a rotary evaporator, and resistates column chromatography purification, obtains compound VI I, white solid, ESI-MS, m/z=517 [M+NH
4]
+).
1.00g (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.Merge extraction phase, with brine It, anhydrous sodium sulfate drying, on a rotary evaporator evaporate to dryness, resistates column chromatography purification, obtain I sterling, white solid, ESI-MS, m/z=417 [M+NH
4]
+).
Embodiment 3 compound measures the restraining effect of DPP-IV enzyme
Use the fluorescence DPP4 activity detection kit of BPS Biological Science Co., Ltd, measure the inhibit activities of compound of the present invention to DPP-IV enzyme.
Be respectively by gradient dilution concentration successively by sample: 5,10,30,100 and 200ng/kg, fluorescent reaction 96 orifice plate, according to the form below adds sample:
22 DEG C of water-baths, place 10min, Spectra Max M5 type fluorimetric detector exciting light 350nm, with 450nm fluorometric assay absorption value.IC is calculated according to concentration-fluorescence intensity curves
50value, the results are shown in following table.
Compound is to the IC of the suppression of DPP-IV enzyme
50value
As can be seen from the above table, compound of the present invention has very strong restraining effect to DPP-IV enzyme.
Claims (3)
1. there is compound or its pharmacy acceptable salt of formula I:
2. synthesize the method for compound or its pharmacy acceptable salt described in claim 1:
Compound II per reacts with III under condensing agent exists, and obtains compound IV; Compound IV uses the method for catalytic hydrogenolysis to slough Bn protecting group and obtains 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.
3. compound described in claim 1 or the application of its pharmacy acceptable salt in preparation treatment diabetes medicament.
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| WO2006012441A1 (en) * | 2004-07-23 | 2006-02-02 | Susan Marie Royalty | Peptidase inhibitors |
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| 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 |
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