CN103910734B - A kind of DPP-4 inhibitor with piperazine structure - Google Patents
A kind of DPP-4 inhibitor with piperazine structure Download PDFInfo
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- 0 C=**N1CC2=C(C(F)(F)F)N[N+]N2CC1 Chemical compound C=**N1CC2=C(C(F)(F)F)N[N+]N2CC1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
The invention provides a kind of novel DPP IV (DPP-4) inhibitor formula (I) compound with piperazine structure.This compounds and each optical isomer thereof, pharmacy acceptable salt can be used for treatment diabetes, particularly non insulin dependent diabetes and other diseases relevant to DPP-4.In its formula of (I), the substituent definition of X is identical with the definition in specification sheets.
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to a kind of there is piperazine structure DPP IV (hereinafter referred to as DPP-4) inhibitor compounds and be used for the treatment of and the purposes with DPP-4 relative disease such as prevent diabetes.
Background technology
Diabetes are the chronic metabolic diseases caused by the various virulence factor effect such as inherited genetic factors, immunologic function disorder, infected by microbes and toxin thereof, free radical toxin, mental element, are principal feature clinically with hyperglycemia.The diabetes of type 1 diabetes (insulin-dependent), diabetes B (non-insulin-depending type), gestational diabetes and other specific types can be divided into.In diabetic subject, the ratio shared by diabetes B is about 95%.
Oral antidiabetic drug main at present has: sulfourea (SU), biguanides, alpha-glucosidase inhibitor, non-sulfourea insulinotropic hormone excretion and euglycemic agent: thiazolidinediones.These medicines effectively can not control the development of diabetes, and tolerance is limited.Along with going deep into of research, occur a series ofly acting on novel targets and can the antidiabetic thing of Sustainable Control glucose level.Of greatest concern is glucagon-like-peptide-1 (GLP-1) and DPP IV (DPP-4) in the recent period.GLP-1 stimulates biosynthesizing and the secretion of Regular Insulin, and having glucose dependency, is a kind of activity in vivo material of control blood sugar more better than Regular Insulin.But DPP-4 can occur in vivo; In addition, it can also depress appetite maincenter, thus can not put on weight while controlling blood sugar very well; It can also hold proline(Pro) or the L-Ala of the 2nd by cracking GLP-1 peptide chain N rapidly, causes the inactivation of GLP-1.So DPP-4 can increase the transformation period of GLP-1 and extend its advantageous effect; In pancreas islet; it can suppress the secretion of glicentin while stimulating β cells secrete insulin; and this mechanism of action is that to have glucose concn dependent; thus can prevent hypoglycemic slightly to suppress stomach emptying to greatest extent, delay sugar and absorb and there are some cardioprotections.DPP IV based on the development of secretin's mechanism is the novel targets of the treatment diabetes B through clinical confirmation, becomes the diabetes B new treatment having prospect.
After the crystalline structure report of DPP-4 in 2003, many new texture types in recent years, potent, the DPP-4 inhibitor that selectivity is high goes on the market in succession, as the sitagliptin phosphate (sitagliptinphosphate of Merck & Co., Inc.'s research and development, in October, 2006 goes on the market in the U.S.), vildagliptin (the vildagliptin of Novartis Co., Ltd's research and development, obtain EU Committee's approval in September, 2007) and the BMS-477118 (saxagliptin that develops cooperatively of Bristol-Myers Squibb Co. and Astrazeneca AB, in August, 2009 U.S. FDA approval listing), SYR-322 (the alogliptinbenzoate of Wu Tian company, in April, 2010 goes on the market in Japan) Linagliptin (BI-1356 of BoehringerIngeheim company, in May, 2011 U.S.'s listing).
The DPP-4 inhibitor sitagliptin (WO2003/04498) of the listing of being developed by Merck & Co., Inc., to DPP-4, there is selectivity, do not suppress the activity of DPP-8 and DPP-9, there are good security and resolvability, and body weight can not be caused to increase, oedema and risk of hypoglycemia can not be caused.Its structural formula is as follows:
DPP-4 inhibitor containing Aminocycloalkane or piperazine fragment becomes a new direction of ofhypoglycemic medicine exploitation, and the compound of the piperazine fragment of research structure novelty is significant to the DPP-4 inhibitor that exploitation is potential.Patent of invention CN101417987B (there is the dpp-iv inhibitor of sulfonamide formyl piperazine structure), CN101486689B (there is the dpp-iv inhibitor of sulfonamide formamide piperazine structure), CN101781274B (acylated piperazine dipeptidyl peptidase IV inhibitor) and patent of invention PCT/CN2010/072319[(R)-7-[3-amino-4-(2, 4, 5-Trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo also [1, 5-a] salt of pyrazine-1-carboxylate methyl ester] etc. disclose a series of DPP-4 inhibitor containing piperazine structure.But effectively the types of drugs for the treatment of diabetes is limited at present, can not meet clinical needs far away.In order to solve the misery of diabetic subject, the Regular Insulin of himself is played one's part to the full, blood sugar can utilize by body tissue cell, reach the object comprehensively controlling blood sugar, be badly in need of the more DPP-4 inhibitor medicaments of exploitation and meet clinical application.Bridged piperazine derivatives provided by the invention is that the research and development of DPP-4 inhibitor provide a new direction, significant to exploitation DPP-4 inhibitor.
Summary of the invention
The object of this invention is to provide a kind of DPP-4 inhibitor compounds with piperazine structure;
Another object of the present invention is to provide above-claimed cpd and is applied to preventing and/or treating of diabetes and other diseases relevant to DPP-4.
Object of the present invention can be reached by following measures:
Have a DPP-4 inhibitor compounds for piperazine structure, it is the compound shown in formula (I) structure,
Wherein:
representation carboxy, ester group, amide group or substituted amido.
Further, X representative-OX
1,-NHX
2,
or
X
1be selected from hydrogen atom, alkyl, cycloalkyl, benzyl;
X
2be selected from aryl, heteroaryl, alkyl, amino, alkylamino, wherein aryl, heteroaryl, alkyl further by one or more be selected from the group of halogen, trifluoromethyl, amino, alkylamino, hydroxyl, hydroxyalkyl, alkoxyl group, cyano group, nitro, aryl and heteroaryl replace;
Described amino-acid residue in amino acid amino lack a hydrogen after the replacement residue that formed;
Q is 4 ~ 8 yuan of substituted or non-substituted Heterocyclylalkyls at least containing an atom N, wherein contains one or more N, O, S atom in 5 ~ 8 yuan of heterocycles, and 4 ~ 8 yuan of heterocycles are selected from-C (O) X by one or more further
3, aryl, heteroaryl or cyano group group replaced;
X
3be selected from aryl, heteroaryl, alkyl;
R
1, R
2separately be selected from alkyl.
In a kind of scheme, X
1be selected from hydrogen atom, C
1-4alkyl, C
5-8cycloalkyl.
In a kind of scheme, X
2be selected from phenyl, pyridyl, C
1-4alkyl ,-NH
2, wherein phenyl, pyridyl, C
1-4alkyl is selected from fluorine, chlorine, trifluoromethyl or-NH by one or more further
2group replaced.
In a kind of scheme, Q is substituted or non-substituted piperazinyl, and described substituting group is selected from-C (O) X
3, phenyl, wherein X
3for halogenophenyl or-NH
2.
R in the preferred scheme of one
1, R
2separately be selected from C
1-4alkyl.
In a kind of scheme, amino-acid residue is
Shown below is the illustrative of compound of the present invention, nonrestrictive specific examples:
Or its pharmacy acceptable salt and isomer thereof.
Present invention also offers the preparation method of the compound of formula (I), but be not limited only to following method.
Embodiment 1 gives the preparation of Compound I-1 of the present invention.The preparation of key intermediate 4 of the present invention is given in the process of preparation Compound I-1.
The preparation of other compounds of the present invention can with key intermediate 4 for starting raw material, and carboxyl is reactive behavior point, carries out acylation reaction, esterification obtains a series of compound meeting formula (I) formula feature.
When in formula (I)
when representing ester group, the preparation method of formula (I) compound is as follows:
By formula intermediate 4 and alcohol compound X
1-OH (X
1definition define identical with the above-mentioned part of specification sheets) carry out esterification in organic solvent; and then de-BOC protecting group is obtained by reacting target compound under the effect of concentrated hydrochloric acid; described esterification is the esterification of this area routine, can carry out under the katalysis of the condensation catalysts such as diethyl azodiformate/triphenyl phosphorus or adopt alcohol/sulfur oxychloride to become ester method one-step synthesis ester and deprotection base.
When in formula (I)
when representing amide group or substituted amido, the preparation method of formula (I) compound is as follows:
By intermediate 4 with the ammoniac compounds containing amino or imino-in a solvent through amidate action, and then de-BOC protecting group is obtained by reacting target compound under the effect of concentrated hydrochloric acid, described amidate action is the amidate action of this area routine, can carry out under the effect of catalyzer, wherein catalyzer is selected from 1, 3-dicyclohexylcarbodiimide (DCC), N, N '-DIC (DIC), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC) and hydrochloride thereof, 1-(3-dimethyl aminopropyl)-3-ethylcarbonyl group diamines methiodide, N, N-diisopropylethylamine (DIEA), I-hydroxybenzotriazole (HoBt), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU), 6-Chloro-Benzotriazole-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester (HCTU), 2-(1H-benzo trisazo-L-1-yl)-1, 1, 3, 3-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), 2-succinimido-1, 1, 3, 3-tetramethyl-urea Tetrafluoroboric acid ester (TSTU), 5-norbornylene-2, 3-dicarbapentaborane-N, N, N ', one or more combination in N '-tetramethyl-urea Tetrafluoroboric acid ester (TNTU).The ratio of condensing agent is greatly about 1 ~ 3 times.Also can carry out amidation under the katalysis of the condensation catalyst such as diethyl azodiformate/triphenyl phosphorus in addition, ingredient proportion is formula II compound: diethyl azodiformate: triphenyl phosphorus: aminated compounds=1: 1 ~ 3: I ~ 3: 1.
Except as otherwise noted, the following term be used in claims and specification sheets has following implication:
" alkyl ", represent the saturated aliphatic radical of 1-20 carbon atom, comprise straight chain and the branched group (digital scope mentioned in the application's book, such as " 1-20 ", refer to this group, be now alkyl, can 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc. be contained, until comprise 20 carbon atoms).Alkyl containing 1-4 carbon atom is called low alkyl group.When low alkyl group does not have substituting group, be called unsubstituted low alkyl group.It is further preferred that alkyl is the medium sized alkyl having 1-10 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.Preferably, alkyl is the low alkyl group having 1-4 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be replacement or unsubstituted.
" Heterocyclylalkyl " in the present invention represents saturated rings (" condensing " ring means that each ring in system and other ring in system the share a pair carbon atom adjoined) group at least containing a heteroatomic monocycle or condense, wherein one or more rings do not have the π-electron system connected completely, and it generally has 3-10 carbon atom.
" aryl " in the present invention represents full carbon monocycle or the fused polycycle group of 6 to 12 carbon atoms, has the π-electron system of total conjugated.The limiting examples of aryl has phenyl, naphthyl and anthryl.Aryl can be replacement or unsubstituted.
" heteroaryl " in the present invention represents monocycle or the fused ring group of 5 to 12 annular atomses, and be selected from the ring hetero atom of N, O or S containing one, two, three or four, all the other annular atomses are C, has the π-electron system of total conjugated in addition.Unsubstituted heteroaryl ground limiting examples has pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, pyrimidine, quinoline, isoquinoline 99.9, purine, tetrazolium, triazine and carbazole.Heteroaryl can be replacement or unsubstituted.
" hydroxyl " represents-OH group.
" alkoxyl group " represents-O-(unsubstituted alkyl) and-O-(unsubstituted cycloalkyl).Representative example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
" halogen " represents fluorine, chlorine, bromine or iodine, is preferably fluorine or chlorine.
" trifluoromethyl " expression-CF
3.
" cyano group " represents-CN group.
" hydroxyalkyl " expression-alkyl-OH group.
" amino " expression-NH
2group.
" imino-" represents-NH-group.
" alkylamino " represents-NH-alkyl group.
" medicinal compositions " refers to one or more compounds described here or their pharmacy acceptable salt and prodrug and other chemical composition, the such as mixture of pharmaceutically acceptable carrier and vehicle.The object of medicinal compositions is the administration promoting compound on organism body.
Compound of the present invention has the ability suppressing DPP-4 enzymic activity, can be applicable to prepare the medicine preventing and/or treating diabetes medicament or other and DPP-4 relative disease.
Embodiment
Following examples further describe the present invention, but these embodiments are only for illustration of the present invention, instead of limitation of the scope of the invention.
The solvent that following examples part H-NMR tests is dimethyl sulfoxide (DMSO); Compound is called for short as follows: DMF:N, dinethylformamide; PE: sherwood oil; MeOH: methyl alcohol; DCM: methylene dichloride; EA: ethyl acetate; HOBT:1-hydroxybenzotriazole; DEAD: diethyl azodiformate; EDC.HCl:1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate.The implication of " ep " is molar equivalent.
Embodiment 1
Chemical equation:
The first step is reacted
The 2-bromine trifluoromethyl ethyl acetate mixing of the 2-Aminopyrazine and 16.78g that take 6.63g adds in 250mL round-bottomed flask, and measure 50mL dissolve with ethanol and stir, 95 DEG C of heated and stirred are spent the night.TLC detects (EA: MeOH=20: 1, ammoniacal liquor) reaction process, directly mix sample after the basic complete reaction of raw material and cross post collection product point (PE: EA=20: 1 ~ 1: 1), concentrate and obtain intermediate 1 about 5.5g, in faint yellow solid, yield about 30%.
Second step reacts
Measure about 100mLMeOH and dissolve 5.5g intermediate 1, add 1.1g palladium carbon catalyst, use hydrogen exchange again three times after nitrogen replacement three times, 30 DEG C of heated and stirred are spent the night, atmospheric pressure sealed hydrogen shield.TLC detects (EA: MeOH=20: 1, ammoniacal liquor) reaction process, room temperature cooling after the basic complete reaction of raw material, and elimination insolubles, uses a small amount of methanol rinse, and filtrate is concentrated obtains about 6.8g intermediate 2 crude product, is directly used in next step reaction.
Three-step reaction
Take 8.5g acid, 12.2gEDC.HCl, 8.6gHOBt, 6.4g triethylamine joins in 250mL round-bottomed flask, the DMF adding 80mL dissolves, stirring at room temperature 1h at 0 ~ 10 DEG C, the micro-Huang of solution, slightly muddy.Add in reaction solution after 6.8g intermediate 2 is dissolved with 20mLDMF, about stirring at room temperature 4h, TLC detects (DCM: MeOH=20: 1, ammoniacal liquor) reaction process, with the dilution of about 1L water after the basic complete reaction of raw material, faint yellow solid is had to separate out, suction filtration, filter cake, with putting into baking oven 50 DEG C of drying under reduced pressure after a small amount of water washing, is weighed and is obtained about 13.5g intermediate 3, TLC detects substantially without assorted point, yield about 90%.
Four-step reaction
Take 1.2g sodium hydroxide 100mL methyl alcohol, add about 5.8g intermediate 2,65 DEG C of heated and stirred, solution is faint yellow clarification, TLC detects (DCM: MeOH=15: 1, ammoniacal liquor) reaction process, after the basic complete reaction of raw material, concentrated removal methyl alcohol, adjusts pH to 5 ~ 6, methylene dichloride 50mL extracts 3 times, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains 0.8g intermediate 4.MS：551[M+H]。
5th step reaction
Take the 4th step product 0.6g methyl alcohol 15mL to dissolve, again 5mL concentrated hydrochloric acid is added in reaction solution, stirring at room temperature reacts 4 hours, and TLC detects, and raw material complete reaction terminates, concentrating under reduced pressure removing methyl alcohol, adjust pH to 5 ~ 6, dichloromethane extraction 3 times, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains the I-1 of 0.32g.
MS：451[M+H]，
H-NMR：δ7.42-7.33(m，1H)，7.26-7.22(m，1H)，5.16-5.08(m，2H)，4.36-4.31(m，1H)，4.14-4.00(m，2H)，3.95-3.90(m，2H)，3.27-2.90(m，2H)，2.85-2.80(m，2H)。
The preparation of embodiment 2 Compound I-2
Chemical equation:
0.2g intermediate 4 is dissolved in 10ml toluene; add triphenyl phosphorus (1.5ep) again; under ice-water bath condition, drip DEAD (1.5ep), finally 2.0ep methyl alcohol is joined in reaction solution; then stirring at room temperature reacts 24 hours; TLC detects, and raw material reaction is complete, concentrating under reduced pressure; the product obtained, through methyl alcohol/concentrated hydrochloric acid deprotection base, obtains target product I-2 and is about 100mg.
MS：465[M+H]，
H-NMR：δ7.44-7.35(m，1H)，7.29-7.26(m，1H)，5.19-5.06(m，2H)，4.34-4.30(m，1H)，4.12-4.02(m，2H)，3.94-3.84(m，5H)，3.20-2.89(m，2H)，2.83-2.81(m，2H)。
The preparation of embodiment 3 Compound I-7
Chemical equation:
In 100ml there-necked flask, add 0.50g intermediate 4,10mLDMF, 2.0ep triethylamine, 1.3epHOBT and 1.5epEDCHCl, stirring at room temperature 1h successively, add the tetrahydrofuran solution of the methylamine of 1.0ep, temperature control 31 DEG C of reactions are spent the night.TLC (DCM: MeOH=20: 1,2 ammoniacal liquor) follows the tracks of reaction and completes, and is poured into by reaction solution in 200ml frozen water; separate out a large amount of white solid, suction filtration, filter cake is washed; 45 DEG C of vacuum-dryings obtain gray solid 0.55g, the product obtained are taken off the reaction of boc protecting group, obtain Compound I-7.
MS：464[M+H]，
H-NMR：δ7.43-7.35(m，1H)，7.26-7.24(m，1H)，5.18-5.06(m，2H)，4.36-4.31(m，1H)，4.16-4.02(m，2H)，3.97-3.92(m，2H)，3.24-2.87(m，2H)，2.87-2.82(m，2H)，2.75(s，3H)。
Scheme with reference to embodiment 2 has prepared Compound I-3, Compound I-4, Compound I-5.
Scheme with reference to embodiment 3 has prepared Compound I-6, I-8, I-9 Compound I-10, Compound I-11, Compound I-12, Compound I-13, Compound I-14, Compound I-15, Compound I-16, Compound I-17, Compound I-18, Compound I-19, Compound I-20, Compound I-21, Compound I-22, Compound I-23, Compound I-24, Compound I-25, Compound I-26, Compound I-27, Compound I-28, Compound I-29, Compound I-30.
The experimental results of above compound is in table 1.
Table 1
Test case:
Biological assessment
Method is below used to the DPP-4 inhibit activities measuring the compounds of this invention.This present method have detected compound in the present invention and suppresses the rejection ability of DPP-4 enzymic activity, and the DPP-4 inhibitor sitagliptin that employing has been gone on the market in contrast.As can be seen from test result, the compounds of this invention has good inhibit activities to DPP-4, and part of compounds DPP-4 inhibit activities is better than sitagliptin, serves directive function to the DPP-4 inhibitor of Future Development brand new and structure of modification.
The mensuration of Compound D PP-4 inhibit activities
One, material
A, dimethyl sulfoxide (DMSO) (Sigma)
B, 96 orifice plates (Corning); 384 orifice plates (Corning)
C, damping fluid (10mM, Tris-HCl, pH8.0)
d、DPPIV-Glo(Promega)；
e、DPP4(BPS)
F, 0.1% bovine serum albumin (MP)
G, test sample
H, reference substance: sitagliptin (Selleckchem).
Two, testing method:
1,1X buffer preparation
Tris-HCl: concentration 10mM; PH8.0
BSA: concentration 0.1%
2, compound solution is prepared
1) with DMSO dissolve survey compound, obtaining concentration is 20mM testing compound solution.Prepare the DMSO solution that cycles of concentration is the solution each to be measured of 100X.The each compound solution of 100 μ l is transferred on 96 orifice plates.If the highest inhibition concentration that such as compound needs is 1 μ l, the just DMSO solution for standby of this compound of preparation 100 μ l.
2) 100%DMSO of 100 μ l is added in the emptying aperture of 96 same orifice plates, be labeled as blank plate.
3) intermediate plate is made
The compound solution of 2 μ L is transferred to new 96 orifice plates from original plate, is labeled as intermediate plate.In each hole of intermediate plate, add the damping fluid of the 1X of 48 μ L, add each compound solution, mixing 10min.
2, analysis plates is made
Compound in each hole of 96 orifice plates of intermediate plate is shifted two parts on 384 orifice plates, every part of each 2.5 μ L.Such as the A1 of 96 orifice plates is shifted A1 and A2 as 384 orifice plates on two parts to 384 orifice plates.
3, the substrate solution of 2 times of concentration is prepared
The DPPIV-Glo substrate solution of 2 times of preparation final operation concentration in analysis plates, its ultimate density is 10 μMs.This substrate solution needs incubated at room temperature 30 ~ 60min before the reaction.
4, the enzyme solution of 4 times of concentration is prepared
The DPP4 buffered soln of 4 times of preparation final operation concentration in analysis plates, its ultimate density is 0.005nM;
In each hole of analysis plates, add 2.5 μ L enzyme solution (except one of them hole), do not add enzyme solution in one of them hole and only add 2.5 μ L buffered soln; One minute is vibrated by under this analysis plates room temperature.
5, enzyme reaction
Carry out enzyme reaction in each hole 5 μ L compound solutions being added analysis plates, seal flat board by sealer, slowly mixing material in 96 holes with oscillator plate.At room temperature cultivate 30 minutes, detect count value in the multi-functional microplate reader of SyngerMax.
6, interpretation of result
1) RLU value is obtained from SyngerMax program.
2) RLU value is converted to inhibiting rate.
Inhibiting rate=(sample RLU value-minimum value)/(maximum value-minimum value) * 100.
" minimum value " refers to that the RLU without enzyme contrast refers to " maximum value " RLU that DMSO contrasts.
The IC of test sample
50result is as shown in the table:
Claims (5)
1. logical compound shown in formula I structure and pharmacy acceptable salt thereof or its isomer:
Wherein,
X representative-OX
1,-NHX
2,
or amino-acid residue, described amino-acid residue in amino acid amino lack a hydrogen after the replacement residue that formed;
X
1for benzyl;
X
2be selected from phenyl or-NH
2, wherein phenyl is selected from fluorine, chlorine, trifluoromethyl or-NH by one or more further
2group replaced;
Q is the piperazinyl of piperazinyl or replacement, and described substituting group is selected from-C (O) X
3, wherein X
3for phenyl or halogenophenyl;
Amino-acid residue is selected from
in one.
2. a compound and pharmacy acceptable salt thereof or its isomer:
3. a pharmaceutical composition, this pharmaceutical composition to comprise in the treatment free form of significant quantity or the claim 1 or 2 of pharmaceutical acceptable salt the compound that defines of any one as activeconstituents; One or more medicinal carrier substances and/or thinner.
4. the pharmaceutical composition of claim 3, its be diabetes and other diseases relevant to DPP-4 prevent and/or treat medicine.
5. the pharmaceutical composition of claim 3, what it was non insulin dependent diabetes prevents and/or treats medicine.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101468988A (en) * | 2007-12-26 | 2009-07-01 | 上海恒瑞医药有限公司 | Piperazine derivative, preparation thereof and use thereof in medicine |
| CN101824036A (en) * | 2009-03-05 | 2010-09-08 | 上海恒瑞医药有限公司 | Salt of tetrahydroimidazo [1,5-a] pyrazine derivative, preparation method and pharmaceutical application thereof |
| CN101899048A (en) * | 2009-05-27 | 2010-12-01 | 江苏恒瑞医药股份有限公司 | Salt of (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1- carboxylic acid methyl ester |
| CN103664962A (en) * | 2013-12-20 | 2014-03-26 | 南京华威医药科技开发有限公司 | Piperazines derivative |
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Address after: Cheng Wei Road Nanjing city Jiangsu province 210046 Xianlin University No. 9 Patentee after: Nanjing Huawei Medicine Technology Group Co Ltd Address before: Cheng Wei Road Nanjing city Jiangsu province 210046 Xianlin University No. 9 Patentee before: Nanjing Huawe Medical Science & Technology Development Co., Ltd. |
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