CN101397294A - N-substituted pyrrolidine derivates and uses thereof - Google Patents
N-substituted pyrrolidine derivates and uses thereof Download PDFInfo
- Publication number
- CN101397294A CN101397294A CNA2008101613731A CN200810161373A CN101397294A CN 101397294 A CN101397294 A CN 101397294A CN A2008101613731 A CNA2008101613731 A CN A2008101613731A CN 200810161373 A CN200810161373 A CN 200810161373A CN 101397294 A CN101397294 A CN 101397294A
- Authority
- CN
- China
- Prior art keywords
- salt
- imidazolidyl
- oxo
- cyanopyrolidine
- ethanoyl
- 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.)
- Granted
Links
Abstract
The invention relates to N-substituted pyrrolidine derivatives with the structure of formula (I), and active substances thereof which are taken as a DDP-IV depressor for treating and/or preventing diabetes and other diseases relevant to DPP-IV.
Description
Technical field
The present invention relates to the pyrrolidin derivatives that a kind of N-replaces, belong to pharmaceutical field.
Background technology
Diabetes are a kind of lysis that is caused by multiple paathogenic factor, after fasting state or oral glucose tolerance test period are taken glucose, show as hyperglycemia or plasma glucose levels and raise.Diabetes have two kinds of common form, I type and type ii diabetes.Type i diabetes (or claiming insulin-dependent diabetes mellitus (IDDM)) patient seldom produces or does not produce fully Regular Insulin; Type ii diabetes (or claiming non insulin dependent diabetes (NIDDM)) patient compares with the ND, patient's plasma insulin level is often identical even higher, these patients' main insulin sensitivity tissue, muscle, liver and fatty tissue etc. have produced resistance to the hormesis of Regular Insulin, and Regular Insulin is difficult to bring into play its normal regulating and controlling blood sugar equilibrated effect.
Present hypoglycemic method and medicine are more, and the minimizing of physical activity and meals calorie intake may improve the symptom of diabetes, but acts on limited; Give with the sulfonylurea that can stimulate the more Regular Insulin of beta cell secretion (for example, tolbutamide and Glipizide) or meglitinide, and/or when sulfonylurea or meglitinide are invalid, increase the insulin level of blood plasma by insulin injection, to stimulate the tissue that Regular Insulin has been produced resistance, but the secretogogue that directly gives Regular Insulin or Regular Insulin has and causes hypoglycemic risk, the high-caliber insulin resistance that blood plasma hyperinsulinism concentration causes may occur simultaneously.Biguanides can improve insulin sensitivity, thereby hyperglycemia is relaxed to some extent, but biguanides such as phenformin and N1,N1-Dimethylbiguanide all can bring out lactic acidosis, feel sick or diarrhoea.Glitazones (promptly, 5-benzyl thiazolidine-2, the 4-diketone) is the new effective compound that improves the multiple symptom of type ii diabetes of a class, in the model of the animal of several type ii diabetes, these medicines have improved the insulin sensitivity in muscle, liver and the fatty tissue substantially, thus reduction blood plasma high glucose level that can part.
DPP IV (DPP-IV) be a kind of from the peptide class of H-Xaa-Pro (wherein Xaa is that amino acid, preferred a kind of lipophilic amino acid and Pro are proline(Pro) arbitrarily) beginning the serine protease of the terminal dipeptides of cracking N-.It also can be used as the peptide substrate class with sequence H-Xaa-Ala (wherein Ala is a L-Ala) beginning.DPP-IV extensively is present in epithelial lining, the mesoblastema in some tissue and the specific t lymphocyte subset group surface of various tissues, and is maximum with renal cortex content, is lung, suprarenal gland, jejunum, liver etc. secondly, to stride film and soluble formal representation.It belongs to a member of prolyl oligopeptidase family, is the high specific serine protease that exists with dimeric forms, and each subunit comprises two structural domains, i.e. a α/β lytic enzyme structural domain and an octahedral β-spirane structure territory; The large-scale cave that about a 30～45A of size is arranged between these two structural domains is the gangway of control substrate, and a bag shaped structure is arranged in it, is the reactive site of DPP-IV.The substrate of DPP-IV is the protein that has proline(Pro) (Pro) or L-Ala (Ala) on the N-terminal penultimate, can make many biologically active peptides inactivations from two amino-acid residues of N-terminal hydrolysis of peptide chain.
DPP-IV has the effect that activates in the T lymphocyte, and DPP-IV is identical with T cell protein CD26, and the DPP-IV inhibitor can be regulated t cell responses, it can be developed as novel immunomodulator; In addition, because of CD26 is the necessary coreceptor of HIV, so the DPP-IV inhibitor might be in order to treatment AIDS.
DPP-IV also has the degraded that the effect of immunity system outside: DPP-IV can increase glucagon-like-peptide-1 and-2 several peptide hormones such as (GLP-1 and GLP-2).Glucose plays keying action aspect the glucose balance according to patience pancreotropic hormone polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) in keeping body, it can stimulate human body to produce the situation that Regular Insulin raises with the reply glucose level, this external enwergy reduces the glucose that is produced by liver, slow down food absorption speed, produce the sensation of satiety and reduce appetite.The effect of type ii diabetes patient's GIP insulin secretion accelerating is obstructed, and only has GLP-1 can bring into play the effect of insulin secretion accelerating, thereby and suppresses the sensation that stomach emptying produces satiety and reduce appetite.So by suppressing DPP-IV, thereby increase the effect that the level of blood plasma glucagon-like-peptide-1 can produce diseases such as treatment type ii diabetes and impaired glucose tolerance indirectly.
At present, document discloses the inhibitor of part DPP-IV, though found some lead compounds from the random screening program, the major part work in this field concentrates on studies substrate analogue.In the research of substrate analogue, find; effective inhibitors is an aminoacyl tetramethyleneimine boric acid class, but they are unsettled, trend towards cyclisation; tetramethyleneimine that some other is more stable and tetrahydrothiazole derivates are lower to the affinity of enzyme, need heavy dose in clinical scenarios.The cyanopyrrole alkanes provides good compromise proposal, and they both had higher affinity to enzyme, has in the solution of free alkali the moderate transformation period of length again.Vildagliptin/Vildaglitin (figure below A) (US6166063) and saxagliptin (figure below B) (WO2004052850, international open day on June 4th, 2004) as the representative of Cyanopyrolidine derivatives, the former has got permission listing.
Also have in addition a plurality of Cyanopyrolidine derivatives be in clinical before and the development of clinical studies process in.(S)-1-ethanoyl-2-cyanopyrrole is these compound common drug activity groups.Jens-UwePeters to Cyanopyrolidine research work during the last ten years made a detailed review (Current Topicsin Medicinal Chemistry, 2007,7,579-595), therefrom can find still has many needs of work to carry out to the further research of this compounds.
Summary of the invention
Technical scheme of the present invention has provided a series of novel cpds that belong to the inhibitor of enzyme DPP-IV and be used for the treatment of some human body diseases.Another technical scheme of the present invention has provided the pharmaceutical composition that contains this compound.
The compounds of this invention is as described below by general formula I:
Wherein:
X is carbonyl, methylene radical or covalent linkage;
N is 0,1,2,3;
R is selected from C
1-C
8The give repeated exhortations various aromatic nucleus of base, isoquinolyl, indyl, pseudoindoyl and benzo-fused analogue thereof of alkyl, phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, rice azoles base, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinoline, they all can at random be substituted on one or more carbon atoms and substituting group is chosen from C
1-C
8Alkyl, hydroxyl, C
1-C
8Alkoxyl group, amino, C
1-C
8Alkylamino, C
1-C
8Amide group, halogen, trifluoromethyl, nitro, cyano group, carboxyl and C
1-C
8Alkoxy carbonyl.
The compound of general formula I has basic functional group, and they can form salt with acid thus, and the salt that forms with pharmaceutically acceptable acid is included in the scope of the present invention.The example of suitable acid includes but not limited to acetate, oxalic acid, trifluoroacetic acid, citric acid, fumaric acid, phenylformic acid, pamoic acid, methylsulfonic acid, nitric acid, sulfuric acid, phosphoric acid etc.
In embodiment preferred of the present invention, X is methylene radical or carbonyl.
In embodiment preferred of the present invention, n is 0,1, or 2.
Preferred compound includes but not limited among the present invention:
(S)-1-(2-(2-(3-phenmethyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(1, the 1-dimethyl ethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(1-methylethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-aminomethyl phenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-phenyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-cyclohexyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt;
(S)-1-(2-(2-(3-normal-butyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3-fluorophenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3,4-methylene-dioxy phenmethyl)-2-oxo-1-imidazolidyl) kharophen) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-p-methoxy-phenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) kharophen) ethanoyl-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-methylbenzene methyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt;
(S)-1-(2-(2-(3-(4-fluorophenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3, the 4-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3, the 5-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(2-phenylethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt.
Further preferably:
(S)-1-(2-(2-(3-phenyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-aminomethyl phenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate and/or its salt,
(S)-1-(2-(2-(3-(4-fluorophenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(2-phenylethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3, the 4-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3, the 5-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-phenmethyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt.
Further preferably: (S)-1-(2-(2-(3-(3, the 4-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3, the 5-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt.
The present invention also provides a kind of pharmaceutical composition that contains above-claimed cpd and pharmacy acceptable salt thereof simultaneously, and the preparation that becomes of these compounds, preparation of compositions, these preparations are to be prepared according to a conventional method behind the available auxiliary material through adding on the medicament by The compounds of this invention or composition, and its formulation includes but not limited to: tablet, granule, capsule, oral liquid and pharmaceutically acceptable other formulation.This pharmaceutical composition and preparation thereof can directly or indirectly produce the disease of clinical beneficial effect by the inhibition of DPP-VI or CD26 in treatment: directly effect comprises the lymphocytic activation of blocking-up T, and indirect action comprises by preventing the activity of these hormone degraded reinforcement peptide hormones.The example of disease include but not limited to autoimmune disease and such as the such inflammatory disease of enteritis and rheumatoid arthritis, cause growth hormone deficiency of short and small stature, polycystic ovary syndrome, impaired glucose tolerance and type ii diabetes.Particularly preferably be described compound and composition in treatment grape candy tolerance the purposes in the unusual and type ii diabetes and similarly be a kind of method of aforesaid these diseases of compounds for treating by giving significant quantity.
In order to find the inhibitor similar drug of the DPP-IV that activity is stronger, security is better, the contriver is by a large amount of research experiments, discovery has also been synthesized the cyanopyrrole hydride compounds that a class is new as described in the present invention, this class Cyanopyrolidine compound structure is different from the disclosed compound of prior art, the existing similar compound of the result of treatment of type ii diabetes had tangible advantage, faster, the better efficacy of onset can be selected for the patient provides a kind of better medication.
Compound of the present invention can prepare by method as known in the art.
Method one
With Boc-glycine and proline methyl ester is raw material; with DCC and HOBT condensation, can get the sweet dried meat methyl esters of Boc-II, II separates with the saturated methanol solution ammonia of ammonia can get the sweet dried meat acid amides of Boc-III; III through phosphorus oxychloride dewater IV, IV can get intermediate V with trifluoroacetic acid deprotection base again.
Method two
With ammonia VI is raw material and phosphinylidyne imidazoles or phosgene reaction generation isocyanic ester VII, and isocyanic ester VII and diethanolamine reaction generate intermediate VIII, and VIII cyclization behind halo makes intermediate compound I X, and IX generates compounds X with sweet dried meat dipeptidase derivant coupling again.
Method three
Aldehyde XI and reacting ethylenediamine generate single substituted ethylene diamine XII with sodium borohydride reduction again; XII cyclisation under the effect of phosphinylidyne imidazoles generates substituted imidazole alkane ketone XIII; XIII generates XIV with the methyl bromoacetate hydrocarbonylation; XIV reduce compounds X V, get X with the coupling of sweet dried meat dipeptidase derivant again after the XV methylsulfonylization.
Method four
Compounds X IV hydrolysis can get sour XVI, and XVI and sulfur oxychloride reaction generate acyl chlorides, and acyl chlorides and the reaction of sweet dried meat dipeptidase derivant generate target product X VII.
Embodiment
Further explaining these general methods among the embodiment down, but be not restriction content of the present invention.
Embodiment 1
(S)-and 1-(2-(2-(3-phenyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 1.
A1,1-two (2-hydroxyethyl)-3-phenylurea
(30g) is dissolved in the toluene with triphosgene, drip aniline (18.5g), finish and refluxed 5 hours, after unnecessary phosgene is removed in underpressure distillation, it is splashed in the dichloromethane solution of diethanolamine (24g), stirring is spent the night again, and is extremely clean with the saturated brine washing, dry concentrate 1,1-two (2-hydroxyethyl)-3-phenylurea (36g).
B1-bromotrifluoromethane-3-phenyl-2-imidazolidone
With 1,1-two (2-hydroxyethyl)-3-phenylurea (36g) is dissolved in the methylene dichloride, drips phosphorus tribromide (40.6g) under the ice bath cooling, finishes stirring at room 5 hours.Reaction solution is regulated pH with saturated sodium bicarbonate solution and is about 10, and stirring at room is 36 hours again.Tell organic phase, water dichloromethane extraction three times merge organic phase, saturated brine washing three times, and anhydrous sodium sulfate drying, concentrating under reduced pressure gets crude product.Silicagel column separates, and methylene dichloride: methyl alcohol (99:3) wash-out gets pure product (10g).ESI-MS：269，271。
C (S)-1-(2-(2-(3-phenyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate
1-bromotrifluoromethane-3-phenmethyl-2-imidazolidone (2.7g), (S)-1-(2-glycyl)-2-Cyanopyrolidine trifluoroacetate (2.6g) are dissolved in N; dinethylformamide; add potash solid (3.5g); be heated to 50 degree reactions 15 hours; reaction solution dilutes with ethyl acetate; saturated sodium bicarbonate solution, saturated brine respectively wash three times, anhydrous sodium sulfate drying, and concentrating under reduced pressure gets crude product.Silicagel column separates, and trichloromethane: methyl alcohol (95:5) wash-out gets (S)-1-(2-(2-(3-phenyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine (0.5g).It is dissolved in the Virahol again, splashes into equimolar oxalic acid aqueous isopropanol, filtration drying gets white solid (0.4g).
1H-NMR?δ(DMSO-d
6)：7.59(d，2H)；7.33(t，2H)；7.01(t，1H)；4.82(dd，1H)；4.05-3.93(m，2H)；3.81(t，2H)；3.62-3.59(m，1H)；3.51(t，4H)；3.44-3.40(m，1H)；3.10(t，2H)；2.21-2.16(m，2H)；2.05-2.00(m，2H).ESI-MS：342.
Embodiment 2
(S)-and 1-(2-(2-(3-(1, the 1-dimethyl ethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 2.
(S)-preparation of 1-(2-(2-(3-(1, the 1-dimethyl ethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate prepares by ordinary method with reference to embodiment one.
1H-NMR?δ(DMSO-d
6)：4.77(dd，1H，)；4.09-4.03(m，2H)；3.61-3.57(m，1H)；3.46-3.40(m，5H)；3.29-3.26(m，4H)；2.28-2.24(m，2H)；2.14-2.09(m，2H)；1.26(s，9H).ESI-MS：322.
Embodiment 3
(S)-and 1-(2-(2-(3-(4-p-methoxy-phenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 3.
(S)-preparation of 1-(2-(2-(3-(4-p-methoxy-phenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate prepares by ordinary method with reference to embodiment one.
1H-NMR?δ(DMSO-d
6)：7.48(d，2H)；6.92(d，2H)；4.83(dd，1H)；4.02-3.92(m，1H)；3.77(t，2H)；3.72(s，3H)；3.61-3.58(m，1H)；3.49-3.47(m，4H)；3.46-3.42(m，1H)；3.10(t，2H)；2.18-2.16(m，2H)；2.07-2.00(m，2H).ESI-MS：372.
Embodiment 4
(S)-and 1-(2-(2-(3-(1-methylethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 4.
(S)-preparation of 1-(2-(2-(3-(1-methylethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate prepares by ordinary method with reference to embodiment one.
1H-NMR?δ(DMSO-d
6)：4.82(dd，1H)；3.95-3.88(m，3H)；3.59-3.56(m，1H)；3.43-3.39(m，1H)；3.32(t，2H)；3.27(t，2H)；3.22(t，2H)；3.00(t，2H)；2.18-2.16(m，2H)；2.06-2.01(m，2H)；1.04(d，6H).ESI-MS：308。
Embodiment 5
(S)-and 1-(2-(2-(3-(4-aminomethyl phenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 5.
(S)-preparation of 1-(2-(2-(3-(4-aminomethyl phenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate prepares by ordinary method with reference to embodiment one.
1H-NMR?δ(DMSO-d
6)：7.45(d，2H)；7.13(d，2H)；4.82(dd，1H)；4.03-3.94(m，2H)；3.78(t，2H)；3.61-3.58(m，1H)；3.50-3.47(m，4H)；3.44-3.40(m，1H)；3.10(t，2H)；2.25(s，3H)；2.20-2.16(m，2H)；2.07-2.00(m，2H).ESI-MS：356。
Embodiment 6
(S)-and 1-(2-(2-(3-cyclohexyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 6.
(S)-preparation of 1-(2-(2-(3-cyclohexyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate prepares by ordinary method with reference to embodiment one.
1H-NMR?δ(DMSO-d
6)：4.83(dd，1H)；4.00-3.90(m，2H)；3.60-3.57(m，1H)；3.51-3.46(m，1H)；3.43-3.39(m，1H)；3.34(t，2H)；3.27(s，4H)；3.03(t，2H)；2.20-2.17(m，2H)；2.07-2.00(m，2H)；1.74(d，2H)；1.58(d，3H)；1.39-1.33(m，2H)；1.30-1.24(m，2H)；1.09-1.03(m，1H).ESI-MS：348.
Embodiment 7
(S)-and 1-(2-(2-(3-normal-butyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 7.
(S)-preparation of 1-(2-(2-(3-normal-butyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate prepares by ordinary method with reference to embodiment one.
1H-NMR?δ(DMSO-d
6)：4.83(dd，1H)；4.04-4.01(m，2H)；3.61-3.57(m，1H)；3.43-3.39(m，1H)；3.60(t，2H)；3.29(s，4H)；3.08-3.05(m，4H)；2.20-2.17(m，2H)；2.07-2.03(m，2H).ESI-MS：322。
Embodiment 8
(S)-and 1-(2-(2-(3-(3-fluorophenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 8.
(S)-preparation of 1-(2-(2-(3-(3-fluorophenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate prepares by ordinary method with reference to embodiment one.
1H-NMR?δ(DMSO-d
6)：7.44(d，1H)；7.38-7.34(m，1H)；7.31(d，1H)；6.81(t，1H)；4.82(dd，1H)；4.01-3.91(m，2H)；3.83(t，2H)；3.62-3.59(m，1H)；3.51(t，4H)；3.44-3.40(m，1H)；3.09(t，2H)；2.20-2.16(m，2H)；2.07-2.02(m，2H).ESI-MS：360.
Embodiment 9
(S)-and 1-(2-(2-(3-(4-fluorophenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 9.
(S)-preparation of 1-(2-(2-(3-(4-fluorophenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate prepares by ordinary method with reference to embodiment one.
1H-NMR?δ(DMSO-d
6)：7.60-7.58(m，2H)；7.17(t，2H)；4.83(dd，1H)；4.05-3.95(m，2H)；3.80(t，2H)；3.72-3.67(m，1H)；3.51-3.48(m，4H)；3.45-3.40(m，1H)；3.11(s，2H)；2.20-2.16(m，2H)；2.10-2.00(m，2H).ESI-MS：360.
Embodiment 10
(S)-and 1-(2-(2-(3-(2-phenylethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 10.
(S)-preparation of 1-(2-(2-(3-(2-phenylethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate prepares by ordinary method with reference to embodiment one.
1H-NMR?δ(DMSO-d
6)：7.28(t，2H)；7.23(d，2H)；7.19(t，1H)；4.82(dd，1H)；4.00-3.88(m，2H)；3.59-3.56(m，1H)；3.42-3.38(m，1H)；3.34-3.30(m，4H)；3.27(s，4H)；3.00(t，2H)；2.75(t，2H)；2.18-2.15(m，2H)；2.07-2.00(m，2H).ESI-MS：370.
Embodiment 11
(S)-and 1-(2-(2-(3-(3, the 4-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 11.
(S)-preparation of 1-(2-(2-(3-(3, the 4-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate prepares by ordinary method with reference to embodiment 1.
1H-NMR?δ(DMSO-d
6)：7.46(d，1H)；6.91(d，1H)；6.85(dd，1H)；4.82(dd，1H)；4.08-4.00(m，2H)；3.78(t，2H)；3.74(s，3H)；3.71(s，3H)；3.62-3.58(m，1H)；3.52-3.48(m，4H)；3.44-3.40(m，1H)；3.09(t，2H)；2.19-2.16(m，2H)；2.08-1.98(m，2H).ESI-MS：402.
Embodiment 12
(S)-and 1-(2-(2-(3-(3, the 5-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate, The compounds of this invention 12.
(S)-preparation of 1-(2-(2-(3-(3, the 5-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate prepares by ordinary method with reference to embodiment 1.
1H-NMR?δ(DMSO-d
6)：7.46(S，1H)；6.91(S，1H)；6.85(S，1H)；4.82(dd，1H)；4.08-4.00(m，2H)；3.79(t，2H)；3.76(s，3H)；3.71(s，3H)；3.62-3.59(m，1H)；3.52-3.48(m，4H)；3.43-3.40(m，1H)；3.08(t，2H)；2.19-2.16(m，2H)；2.07-1.98(m，2H).ESI-MS：402.
Embodiment 13
(S)-and 1-(2-(2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine hydrochloride, The compounds of this invention 13.
A 1-(4-methoxybenzyl)-2-imidazolidone
(24g) is dissolved in the methyl alcohol with quadrol, and the ice bath cooling adds p-tolyl aldehyde (27g) down, and gradation adds sodium borohydride (7.6g) again, insulated and stirred is spent the night, concentrating under reduced pressure except methyl alcohol after, with methylene dichloride dilution, saturated brine washs once, anhydrous sodium sulfate drying, add triethylamine (30g) again, be cooled to subzero 30 degree after, drip triphosgene (20g), reaction finishes back saturated brine washing to clean, dry concentrate crude product.Silicagel column separates, and gets 1-(4-methoxybenzyl)-2-imidazolidone (15g).
B 2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) methyl acetate
(1.8g) is suspended in the tetrahydrofuran (THF) with sodium hydride, the ice bath cooling adds 1-(4-methoxybenzyl)-2-imidazolidone (15g), room temperature reaction is dripping bromine methyl acetate (16.4g) after 1 hour, stirring is spent the night, use the ethyl acetate dilute reaction solution, saturated brine washing is to clean, dry concentrate crude product, petrol ether/ethyl acetate is crossed post and is got 2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) methyl acetate (8g).
C 1-(4-mehtoxybenzyl)-3-(2-hydroxyethyl)-2-imidazolidone
2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) methyl acetate (2.78g) is dissolved in the Virahol, cryosel is bathed cooling and is added sodium borohydride (0.38g) down, stirring is spent the night, concentrating under reduced pressure is removed Virahol, dilute with methylene dichloride again, saturated brine washing three times, anhydrous sodium sulfate drying, concentrating under reduced pressure get crude product (2.38g) .ESI-MS:251.
D methylsulfonyl 2-(3-(4-methoxybenzyl)-2-oxo-1-imidazolidyl) ethyl ester
1-(4-methoxybenzyl)-3-(2-hydroxyethyl)-2-imidazolidone (2.38g) is dissolved in the 20mL methylene dichloride, add triethylamine (2g), cryosel is bathed cooling and is added methylsulfonyl chloride (1.15g) down, stirred 1 hour, reaction solution dilutes with methylene dichloride, saturated brine washing three times, anhydrous sodium sulfate drying, concentrating under reduced pressure get crude product (3.12g).
E, (S)-1-(2-(2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine hydrochloride
With methylsulfonyl 2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) ethyl ester (3.12g) and (S)-1-(2-glycyl)-2-Cyanopyrolidine trifluoroacetate (2.67g) is dissolved in 30mL DMF; add potash solid (3.5g; 0.025mol); be heated to 50 degree reactions 15 hours; reaction solution dilutes with methylene dichloride; respectively wash three times with saturated sodium bicarbonate solution, saturated brine, anhydrous sodium sulfate drying, concentrating under reduced pressure gets crude product.Silicagel column separates, and trichloromethane: methyl alcohol (95:5) wash-out gets (S)-1-(2-(2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine (0.7g).It is dissolved in the Virahol again, splashes into equimolar ethanol solution of hydrogen chloride, filtration drying gets white solid (0.6g).
1H-NMR?δ(CDCl
3)：7.18(d，2H)；6.90(d，2H)；4.83(dd，1H)；4.21(s，2H)；4.01-3.91(m，2H)；3.73(s，3H)；3.60-3.57(m，1H)；3.42-3.40(m，1H)；3.40(t，2H)；3.30(t，2H)；3.15(t，2H)；3.05(t，2H)；2.19-2.17(m，2H)；2.06-2.02(m，2H).ESI-MS：386.
Embodiment 14
(S)-and 1-(2-(2-(3-phenmethyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine hydrochloride, The compounds of this invention 14.
(S)-preparation method of 1-(2-(2-(3-phenmethyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine hydrochloride prepares by ordinary method with reference to embodiment 11.
1H-NMR?δ(CDCl
3)：7.33-7.24(m，5H)；4.75(dd，1H)；4.36(s，2H)；3.62-3.59(m，1H)；3.47(s，2H)；3.44-3.40(m，1H)；3.38-3.30(m，2H)；3.20(t，2H)；2.87-2.80(m，2H)；2.31-2.25(m，2H)；2.6-2.12(m，2H)；1.99(br，1H).ESI-MS：356，378。
Embodiment 15
(S)-and 1-(2-(2-(3-(4-methylbenzene methyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine hydrochloride, The compounds of this invention 15.
(S)-preparation method of 1-(2-(2-(3-(4-methylbenzene methyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine hydrochloride prepares by ordinary method with reference to embodiment 11.
1H-NMR?δ(DMSO-d
6)：7.16-7.13(m，4H)；4.83(dd，1H)；4.24(s，2H)；4.01-3.92(m，2H)；3.59-3.57(m，1H)；3.42-3.39(m，3H)；3.30(t，2H)；3.16(t，2H)；3.05(t，2H)；2.28(s，3H)；2.19-2.17(m，2H)；2.07-2.00(m，2H).ESI-MS：370.
Embodiment 16
(S)-and 1-(2-(2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) kharophen) ethanoyl)-2-Cyanopyrolidine, The compounds of this invention 16.
2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) methyl acetate (2.78g) is dissolved in the 25mL ethanol, add sodium hydroxide solution, stirring at room 1 hour, regulating PH with 1N hydrochloric acid is 4, dilute with ethyl acetate, saturated brine washing three times, anhydrous sodium sulfate drying, concentrating under reduced pressure 2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) acetate gets crude product (2.64g).
2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) acetate (2.64g) is dissolved in the methylene dichloride; add thionyl chloride (23.8g); reflux 2 hours; concentrating under reduced pressure is removed unnecessary thionyl chloride; dilute with methylene dichloride again; it is splashed into the dichloromethane solution of (S)-1-(2-glycyl)-2-Cyanopyrolidine trifluoroacetate (2.67g) and triethylamine (3.03g); stirred 3 hours; reaction solution respectively washs three times with saturated sodium bicarbonate solution, 1N hydrochloric acid soln, saturated brine; anhydrous sodium sulfate drying, concentrating under reduced pressure gets crude product.Silicagel column separates, and trichloromethane: methyl alcohol (100:1) wash-out gets product (2.0g).
1H-NMR?δ(CDCl
3)：8.11(t，1H)；7.16(d，2H)；6.88(d，2H)；4.73(dd，1H)；4.20(s，2H)；3.93(dd，1H)；3.77(s，2H)；3.71(s，3H)；3.63-3.59(m，1H)；3.44(dd，1H)；3.31(t，2H)；3.13(t，2H)；2.15-2.10(m，2H)；2.05-1.98(m，2H).ESI-MS：400，422.
Embodiment 17
(S)-and 1-(2-(2-(3-(3,4-methylene-dioxy phenmethyl)-2-oxo-1-imidazolidyl) kharophen) ethanoyl)-2-Cyanopyrolidine, The compounds of this invention 17.
(S)-preparation of 1-(2-(2-(3-(3,4-methylene-dioxy phenmethyl)-2-oxo-1-imidazolidyl) kharophen) ethanoyl)-2-Cyanopyrolidine prepares by ordinary method with reference to embodiment 11 and 14.
1H-NMR?δ(CDCl
3)：7.06(s，1H)；6.79-6.73(m，3H)；5.94(s，2H)；4.75(dd，1H)；4.31(s，2H)；4.15(dd，1H)；3.98(dd，1H)；3.93(s，2H)；3.64-3.61(m，1H)；3.49-3.42(m，1H)；3.44-3.38(m，2H)；3.28(t，2H)；2.33-2.26(m，2H)；2.22-2.18(m，2H).ESI-MS：414.
The preparation of embodiment 18 The compounds of this invention 2 oral tablets
It is an amount of to get the The compounds of this invention 2 for preparing, and pulverizes, and mixes in right amount with Microcrystalline Cellulose, polyvidone, croscarmellose sodium, Magnesium Stearate, stirs, and direct compression promptly gets the oral tablet of The compounds of this invention 2.
The preparation of embodiment 19 The compounds of this invention 10 oral capsules
It is an amount of to get the The compounds of this invention 10 for preparing, and pulverizes, and mixes with Microcrystalline Cellulose, Magnesium Stearate, stirs, and branch is filled in No. 3 capsule shell, seals, and promptly gets the oral capsule of The compounds of this invention 10.
Below further specify beneficial effect of the present invention by the test of pesticide effectiveness.
The sample and HEPES damping fluid (the 25mM HEPES that add an amount of DPP-IV enzyme (SIGMA), 3 times of concentration gradient dilutions in the vitro detection test reaction system of test example 1 The compounds of this invention to the DPP-IV enzyme inhibition activity, 140Mm NaCl, 1% BSA, 80mM MgCl
2), (the positive control medicine is KR-62436 to set up blank (not containing enzyme and sample), negative control (not containing sample) and positive control simultaneously, SIGMA), room temperature reaction 10min, add substrate Gly-Pro-7-amido-4-methylcoumarin (SIGMA), room temperature lucifuge reaction 20min detects fluorescence, excitation wavelength 355nm, emission wavelength 460nm.Calculate inhibiting rate according to the fluorescence measured value, inhibiting rate=[1-(sample-blank)/(feminine gender-blank)] * 100%, the 4ParameteriLogistic Model that uses in the Xlfit software calculates IC50.The compound that the corresponding respectively embodiment 1 to embodiment 17 of numbering 1～17 compound prepares.
Table: Compound D PP-IV determination of activity result
Annotate: KR-62436 structural formula and reference paper are as follows:
Reference:
Kwang-Rok
Kim，Etc.KR-62436，6-{2-[2-(5-cyano-4，5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitrile，is?a?novel?dipeptidylpeptidase-IV(DPP-IV)inhibitor?with?anti-hyperglycemic?activity，Eur?J?Pharmacol?2005，Jul?25；518(1)：63-70
By The compounds of this invention the vitro detection of DPP-IV enzyme inhibition activity is tested as can be known, right with the positive KR-62436 compares according to medicine, the effect that all has inhibition DPP-IV enzymatic activity of chemical combination of the present invention, wherein Compound 1,5,9,10,11,12,14 7 compounds and all the other Compound Phase ratios have obviously Excellent activity, especially compound 11,12 active best.
Test example 2 The compounds of this invention are to the hypoglycemic experimental data of diabetic mice animal model
1, method:
Animal used as test: II type Spontaneous Diabetic mouse, body weight 25～30g, male and female half and half. Mouse is suitable Answering property raising one Zhou Tianhou behind the fasting 14h, utilizes the Luo Shi blood glucose meter to measure fasting blood-glucose (basis before the administration Blood sugar), according to the fasting blood sugar random packet, group is model control group, positive controls (Wei Gelie The spit of fland bulk drug), DPP-IV inhibitor 1 (The compounds of this invention 15) group, DPP-IV inhibitor 2 (this Invention compound 12) group and DPP-IV inhibitor 3 (The compounds of this invention 1) group; Alternative C57BL/6J Mouse is as the blank group.
Test method: each is organized mouse and is 14 respectively according to the form below 1 design dosage single-doses, and is blank right Give corresponding distilled water, 45min after the administration, the anhydrous Portugal of gavage 2.0g/kg according to group and model control group Grape sugar, and 30min, 60min, 120min measure blood sugar and blood sugar rate of rise thereof behind glucose load.
After finishing the single-dose carbohydrate tolerance test, in beginning 3 weeks of successive administration, dosage is the same. Continuously After 2 weeks of administration, 1h blood sugar behind mensuration fasting blood-glucose and the medicine;
Continuously after 3 weeks of administration, finish carbohydrate tolerance test behind the multiple dosing.
(table 1) mouse test dosage and grouping
2, result of the test:
(1) single-dose carbohydrate tolerance test (seeing Table 2)
Carbohydrate tolerance test blood sugar rate of rise behind table 2 single-dose (X ± S)
Annotate: and model control group is relatively, * P＜0.05, * * P＜0.01; Compare ▲ P＜0.05 with positive group.
Experimental result shows:
Blank group and model control group relatively, behind 30min, 60min and 120min behind the DEXTROSE ANHYDROUS of gavage 2g/kg the blood sugar rate of rise all than the blank group significantly raise (**P<0.01，
*P<
0.05)。
With model control group relatively, positive controls (vildagliptin) 30min, 60min and 120min behind the DEXTROSE ANHYDROUS of gavage 2g/kg all can significantly reduce the blood sugar rate of rise (*P＜0.05), shows this Positive drug can reduce postprandial blood sugar.
With model group relatively, DPP-IV inhibitor 1,2,3 groups 30min, 60min and 120min behind the DEXTROSE ANHYDROUS of gavage 2g/kg also all can significantly reduce the blood sugar rate of rise (**P<0.01，
*P＜0.05), Show that these 3 compounds can reduce Spontaneous Diabetic mouse postprandial blood sugar, behind glucose load 120min all can make mouse blood sugar substantially return to before the meal level.
Data show The compounds of this invention 15,12 and compound 1 all can significantly to reduce Spontaneous Diabetic little The mouse postprandial blood sugar; Compare with positive group (vildagliptin), behind the glucose load 30min, The compounds of this invention 12 and compound 1 reduce blood sugar more obvious (▲ P＜0.05); In general, The compounds of this invention 15 , 12 and compound 1, curative effect all is better than positive drug (vildagliptin), and DPP-IV inhibitor group 2 (this Invention compound 12) more outstanding.
(2), 1h blood sugar (seeing Table 3) behind administration 2 all rear fasting blood-glucoses and the medicine
Blood sugar behind table 32 all rear fasting blood-glucoses and the medicine
Annotate: and model group is relatively, * P＜0.05, * * P＜0.01; Compare with positive group, ▲ P＜0.05, ▲ ▲ P＜0.01.
Result of the test shows:
After 2 weeks, blank group and model control group compare in gavage, and fasting blood-glucose reaches to 1h behind the distilled water Blood glucose value all significantly reduces (* * P＜0.01, * P＜0.05), shows that the Spontaneous Diabetic mouse model is comparatively steady Fixed.
Positive controls and model group compare, and the 1h blood glucose value all significantly reduces behind fasting blood-glucose and the medicine (* P＜0.05) shows vildagliptin after 2 weeks of administration, can reduce diabetic mice fasting blood-glucose and many Blood glucose value behind the medicine after the inferior administration.
With model group relatively, DPP-IV inhibitor 1,2,3 groups also can significantly reduce sky after 2 weeks of administration 1h blood sugar behind abdomen blood sugar and the medicine shows that the DPP-IV inhibitor after administration a period of time, can reduce spontaneity Blood glucose value behind the medicine behind diabetic mice fasting blood-glucose and the multiple dosing.
Compare with positive controls (vildagliptin) simultaneously, DPP-IV inhibitor 2,3 groups of reduction blood sugar are more Be obviously (▲ P＜0.05, ▲ ▲ P＜0.01) that the blood sugar of DPP-IV inhibitor group 1 mouse is dense in addition Degree also is lower than positive controls.
Data show: the test-compound of DPP-IV inhibitor group 1,2,3 can be remarkable behind multiple dosing Blood sugar behind reduction fasting blood-glucose and the medicine, its blood sugar reducing function is better than positive drug (vildagliptin). In general, DPP-IV inhibitor group 2 (The compounds of this invention 12) is more outstanding, DPP-IV inhibitor group 3 (these Bright compound 1) effect is taken second place.
(3), sugar tolerance changes (seeing Table 4) after the administration (3 week)
Carbohydrate tolerance test blood sugar rate of rise behind (table 4) multiple dosing (3 week) (X ± S)
Annotate: compare * p＜0.05, * * P＜0.01 with model group; Compare with positive group, ▲ P＜0.05, ▲ ▲ P＜0.01.
Result of the test shows:
As can be known from the above table, 30min, 60min and 120min behind glucose load, DPP-IV inhibitor 1,2,3 groups of mouse blood sugar levels all significantly are lower than model group (* * P＜0.01, * P＜0.05); Show repeatedly After the administration, DPP-IV inhibitor 1,2,3 groups of meal that all can significantly reduce II type Spontaneous Diabetic mouse Rear blood sugar level.
With the vildagliptin positive controls relatively, DPP-IV inhibitor group 2 mouse load grape 30min, Behind 60min, the 120min, blood sugar level significantly reduces (▲ ▲ P＜0.01) than this positive group; DPP-IV Inhibitor group 3 mouse are behind load glucose 30min, 60min, 120min, and blood sugar level is than this positive Group significantly reduces (▲ P＜0.05); The blood level of DPP-IV inhibitor group 1 mouse is than this positive in addition Group also decreases.
Experimental result shows: the test-compound of DPP-IV inhibitor group 1,2,3 can show behind multiple dosing Work reduces postprandial blood sugar, and its blood sugar reducing function is better than positive drug (vildagliptin). In general, DPP-IV Inhibitor group 2 (The compounds of this invention 12) is more outstanding, DPP-IV inhibitor group 3 (The compounds of this invention 1) effect is taken second place.
(4), changes of weight (seeing Table 5) before and after the administration
14 days, 21 days body weight change (X ± S) before table 5 administration and after the administration
Annotate: and model is compared * p＜0.05, * * P＜0.01
Compare with model group, vildagliptin positive controls and DPP-IV inhibitor 1,2,3 groups of mouse Body weight all takes place significantly to increase, and shows that these tested medicines are in the blood sugar level that reduces diabetic mice Simultaneously to the not significant impact of Mouse Weight.
3, conclusion
Experimental data clearlys show that The compounds of this invention has definite to reducing fasting blood-glucose and postprandial blood sugar Effect, it is more obvious wherein to reduce postprandial blood sugar, and behind the multiple dosing, does not also cause the increase of body weight. From synthesis result, the The compounds of this invention drug effect is better than vildagliptin; DPP-IV inhibitor group 2 wherein (The compounds of this invention 12) is more outstanding, and DPP-IV inhibitor group 3 (The compounds of this invention 1) is taken second place.
Claims (9)
1, the compound of a kind of following general formula (I) and/or its receptible salt pharmaceutically,
Wherein:
X is carbonyl, methylene radical or covalent linkage;
N is 0 or 1 or 2 or 3;
R is selected from C
1-C
8Alkyl, phenyl, benzene alkyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, rice azoles base, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, the quinoline aromatic nucleus of base, isoquinolyl, indyl, pseudoindoyl and benzo-fused analogue thereof of giving repeated exhortations, and be substituted on one or more carbon atoms of above-mentioned group and substituting group is chosen from C
1-C
8Alkyl, hydroxyl, C
1-C
8Alkoxyl group, amino, C
1-C
8Alkylamino, C
1-C
8Amide group, halogen, trifluoromethyl, nitro, cyano group, carboxyl and C
1-C
8Alkoxy carbonyl.
2, compound as claimed in claim 1 and/or its salt is characterized in that, described R is selected from C
1-C
8Alkyl, phenyl, benzene alkyl, and on one or more carbon atom by C
1-C
8Alkyl, hydroxyl, C
1-C
8Alkoxyl group, amino, C
1-C
8Alkylamino, C
1-C
8Amide group, halogen, trifluoromethyl, nitro, cyano group, carboxyl and/or C
1-C
8Alkoxy carbonyl replace.
3, compound as claimed in claim 1 and/or its salt is characterized in that, described compound and/or salt are:
(S)-1-(2-(2-(3-phenmethyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(1, the 1-dimethyl ethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(1-methylethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-aminomethyl phenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-phenyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-cyclohexyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt;
(S)-1-(2-(2-(3-normal-butyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3-fluorophenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3,4-methylene-dioxy phenmethyl)-2-oxo-1-imidazolidyl) kharophen) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-p-methoxy-phenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) kharophen) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-mehtoxybenzyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-methylbenzene methyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt;
(S)-1-(2-(2-(3-(4-fluorophenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3, the 4-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3, the 5-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(2-phenylethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt.
4, compound as claimed in claim 3 and/or its salt is characterized in that: described compound and/or its salt are:
(S)-1-(2-(2-(3-phenyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(4-aminomethyl phenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine oxalate and/or its salt,
(S)-1-(2-(2-(3-(4-fluorophenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(2-phenylethyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3, the 4-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3, the 5-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-phenmethyl-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt.
5, compound as claimed in claim 4 and/or its salt is characterized in that: described compound and/or its salt are:
(S)-1-(2-(2-(3-(3, the 4-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt,
(S)-1-(2-(2-(3-(3, the 5-Dimethoxyphenyl)-2-oxo-1-imidazolidyl) ethylamino) ethanoyl)-2-Cyanopyrolidine and/or its salt.
6, as each described compound of claim 3-5 and/or its salt, it is characterized in that: described pharmaceutically receptible salt is by combining resulting salt with mineral acid or organic acid.
7, the described compound of claim 1 and/or its salt treat and/or prevent purposes in the disease relevant with DPP-IV in preparation.
8, the described compound of claim 1 and/or its salt are in preparation treatment type ii diabetes or impaired glucose tolerance, or/and the application in treatment autoimmune disease or the inflammatory disease medicine.
9, a kind of pharmaceutical composition, each described compound of claim 1-6 or its pharmacy acceptable salt that it contains significant quantity are activeconstituents, add the medicament that acceptable accessories or complementary composition are prepared from.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200810161373 CN101397294B (en) | 2007-09-24 | 2008-09-23 | N-substituted pyrrolidine derivates and uses thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710050091 | 2007-09-24 | ||
| CN200710050091.X | 2007-09-24 | ||
| CN 200810161373 CN101397294B (en) | 2007-09-24 | 2008-09-23 | N-substituted pyrrolidine derivates and uses thereof |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210329999.5A Division CN102838589B (en) | 2008-09-23 | 2008-09-23 | Method for preparing N substituted pyrrolidine derivative through acylation of methyl sulfone chloride |
| CN201210326088.7A Division CN102850330B (en) | 2008-09-23 | 2008-09-23 | Method for preparing N-substituted pyrrolidine derivative through bromination |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101397294A true CN101397294A (en) | 2009-04-01 |
| CN101397294B CN101397294B (en) | 2012-12-05 |
Family
ID=40516160
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200810161373 Active CN101397294B (en) | 2007-09-24 | 2008-09-23 | N-substituted pyrrolidine derivates and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101397294B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432599A (en) * | 2011-10-31 | 2012-05-02 | 成都地奥制药集团有限公司 | Crystal form of oxalate of dipeptidyl peptidase inhibitor and preparation method and application thereof |
| CN103848817A (en) * | 2012-12-03 | 2014-06-11 | 成都地奥制药集团有限公司 | Iodination preparation method for dipeptidyl peptidase inhibitor, chlorination and iodination intermediates of dipeptidyl peptidase inhibitor and preparation methods for intermediates |
| CN103848816A (en) * | 2012-12-03 | 2014-06-11 | 成都地奥制药集团有限公司 | Reductive amination preparation method for dipeptidyl peptidase inhibitor, and intermediate and preparation method thereof |
| CN105712920A (en) * | 2014-12-04 | 2016-06-29 | 南京优科生物医药研究有限公司 | Preparation method of vildagliptin |
-
2008
- 2008-09-23 CN CN 200810161373 patent/CN101397294B/en active Active
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432599A (en) * | 2011-10-31 | 2012-05-02 | 成都地奥制药集团有限公司 | Crystal form of oxalate of dipeptidyl peptidase inhibitor and preparation method and application thereof |
| CN102432599B (en) * | 2011-10-31 | 2014-07-30 | 成都地奥制药集团有限公司 | Crystal form of oxalate of dipeptidyl peptidase inhibitor and preparation method and application thereof |
| CN103848817A (en) * | 2012-12-03 | 2014-06-11 | 成都地奥制药集团有限公司 | Iodination preparation method for dipeptidyl peptidase inhibitor, chlorination and iodination intermediates of dipeptidyl peptidase inhibitor and preparation methods for intermediates |
| CN103848816A (en) * | 2012-12-03 | 2014-06-11 | 成都地奥制药集团有限公司 | Reductive amination preparation method for dipeptidyl peptidase inhibitor, and intermediate and preparation method thereof |
| CN103848816B (en) * | 2012-12-03 | 2016-06-15 | 成都地奥制药集团有限公司 | The reduction amination method for making of depeptidyl peptidase inhibitors, intermediate and method for making |
| CN103848817B (en) * | 2012-12-03 | 2016-07-06 | 成都地奥制药集团有限公司 | The iodo method for making of depeptidyl peptidase inhibitors, chloro, iodo intermediate and method for making |
| CN105712920A (en) * | 2014-12-04 | 2016-06-29 | 南京优科生物医药研究有限公司 | Preparation method of vildagliptin |
| CN105712920B (en) * | 2014-12-04 | 2018-12-21 | 南京优科生物医药研究有限公司 | A kind of preparation method of vildagliptin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101397294B (en) | 2012-12-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2259713T3 (en) | BETA-AMINO TETRAHYDROIMIDAZO (1,2-A) PIRAZINAS AND TETRAHIDROTRIAZOLO (4,3-A) PIRAZINAS AS INHIBITORS OF DIPEPTIDIL PEPTIDASE FOR THE TREATMENT OR PREVENTION OF DIABETES. | |
| CN101050194B (en) | Derivative of bicyclo-octanes class, preparation method, and application of medicine | |
| CN102316872B (en) | Treatment obesity and the bile acid recycling inhibitors of diabetes | |
| CN100348189C (en) | Combination of an dpp-iv inhibitor and a ppar-alpha compound | |
| CN100351251C (en) | Indolylmaleimide derivatives | |
| CN102918027A (en) | Modulators of the gpr119 receptor and the treatment of disorders related thereto | |
| NO333106B1 (en) | Compositions comprising an anti-diarrheal agent and an epothilone or epothilone derivative, and use thereof | |
| CN1980892A (en) | Dpp-IV inhibitors | |
| KR20080040643A (en) | Concomitant pharmaceutical agents and use thereof | |
| CN101679277A (en) | Novel peptide inhibitors of hepatitis c virus replication | |
| EA021794B1 (en) | 4-amino-4-oxobutanoyl peptide cyclic analogues, inhibitors of viral replication | |
| BRPI0906094B1 (en) | compound | |
| CN101896483A (en) | Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient | |
| BR112020022340A2 (en) | benzamides replaced by 1,3-thiazol-2-yl for the treatment of diseases associated with nerve fiber sensitization | |
| CN107074820A (en) | The new receptor modulators of GLP 1 | |
| JP2021526123A (en) | Autotaxin inhibitors and their use | |
| CN102803214A (en) | New compounds, pharmaceutical composition and methods relating thereto | |
| CN101397294B (en) | N-substituted pyrrolidine derivates and uses thereof | |
| CN102898400B (en) | GPR119 agonist and application thereof | |
| CN102227429B (en) | 3-aminocyclopentanecarboxamides as chemokine receptor modulators | |
| CN101528712A (en) | Substituted benzimidazolone derivatives, medicaments comprising them and their use | |
| CN103951615A (en) | Alkylamine derivative | |
| AU2020243454A1 (en) | Heteroaryl(heterocyclyl)methanol compounds useful in the treatment of hyperglycaemia | |
| CN102850330B (en) | Method for preparing N-substituted pyrrolidine derivative through bromination | |
| CN102206217A (en) | Heterocyclic compounds for treating or preventing diabetes mellitus as dipeptidyl peptidase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |