CN106008507A

CN106008507A - Xanthine derivative

Info

Publication number: CN106008507A
Application number: CN201610365388.4A
Authority: CN
Inventors: 王颖; 向永哲; 岑国栋
Original assignee: Chengdu Easton Biopharmaceuticals Co Ltd
Current assignee: Chengdu Easton Biopharmaceuticals Co Ltd
Priority date: 2013-01-23
Filing date: 2013-01-23
Publication date: 2016-10-12
Anticipated expiration: 2033-01-23
Also published as: CN103936740B; CN106008507B; CN103936740A

Abstract

The invention discloses a xanthine derivative and an isomer thereof. Through an influence test on normal mouse glucose tolerance and an inhibition test on activity of DPP-IV in bodies of beagle dogs, the compound shows excellent DPP-IV inhibitory activity and can be used for preparing medicines for treating diseases related to DPP-IV.

Description

Xanthine derivative

Technical field

The present invention relates to medicinal chemistry art, be specifically related to a class xanthine derivative, its preparation method and derivant conduct thereof The medicine being administered once for one week is especially as the purposes of dipeptidyl peptidase IV (DPP-IV) inhibitor.

Background technology

Diabetes are the metabolic diseases of a kind of multi-pathogenesis, are characterized in chronic hyperglycemia, with because of insulin secretion and/or effect Sugar, fat and the protein metabolism disorder that defect causes.Diabetes are also the most ancient a kind of diseases, are due in human body In the blood that insulin relatively or definitely lacks and causes, concentration of glucose raises, and causes sugar to be discharged from urine in a large number, and with many Drink, polyuria, polyphagia, become thin, the symptom such as dizzy, weak.

In treating diabetes, exercise therapy and dietetic therapy are two kinds of requisite diabetes remedies.Work as both When therapy is not enough to symptom management, it is possible to use insulin or oral antidiabetic drug.But owing to these hypoglycemic medicines exist a lot Side effect, develops a kind of novel, low side effect and can effectively to treat the medicine of diabetes particularly important.

Dipeptidyl peptidase IV (DPP-IV) is a kind of serine protease, and it can contain a proline residue at secondary end N-end dipeptidase is cracked in peptide chain, although the physiological action of mammal is confirmed by (DPP-IV) the most completely, But it is at neural enzymes metabolism, and T-cell-stimulating, during cancer cell metastasis enters endothelium and inhibition of HIV entrance lymphoid cell All play very important effect (WO98/19998).

There are some researches show that (DPP-IV) can stop the secretion of glucagon like peptide (GLP)-1, N-end in cracking (GLP)-1 Group the-the third dipeptidase so that it is be degraded to inactive (GLP)-1 (7-36) amide from (GLP)-1 of activity form and be degraded to inactive (GLP)-1 (9-36) amide Endocrinology, 1999,140:5356-5363).Under physiological conditions, complete in circulating The half-life of whole (GLP)-1 is the shortest, and the inactive metabolite after DPP-IV is degraded to (GLP)-1 can be combined with (GLP)-1 receptor Antagonistic activity (GLP)-1 thus shorten the physiological reaction to (GLP)-1, and (DPP-IV) inhibitor can protect endogenous completely The most ectogenic (GLP)-1 is not inactivated by (DPP-IV), improves the physiologically active (5-10 times) of (GLP)-1 greatly, due to (GLP) secretion of-1 pair of pancreatic insulin is an important stimulator the distribution that can directly affect glucose, therefore Well effect (US6110949) is played in the treatment of non-insulin-dependent diabetes mellitus example by DPP-IV inhibitor.

Although having had listed several DPP-IV inhibitor at present, such as phosphoric acid sitagliptin, vildagliptin, benzoic acid Ah lattice Row spit of fland etc., but be one day and be administered once, in order to increase the compliance of patient, the DPP-IV needing be administered once for a week presses down , the most still there is the demand to new long-acting DPP-IV inhibitor in preparation.

Summary of the invention

The present invention relates to xanthine substitutive derivative and preparation method thereof and in application pharmaceutically, particularly lead to shown in formula (I) Xanthine substitutive derivative and all of stereoisomer thereof, and as the therapeutic agent being administered once for a week especially for two The activity inhibition of peptidyl peptidase IV (DPP-IV).

Present invention relates particularly to the compound shown in following logical formula (I) structure:

Wherein: R¹It is independently selected from hydrogen atom, fluorine atom, chlorine atom, bromine atoms, atomic iodine, amino or cyano group；

R²It is independently selected from hydrogen atom ,-SO₂R³、-PO(OR³)₂、-COCHR⁴R⁵、-COOR⁶Or-CONHR⁶；

R³For hydrogen atom, metal ion or C₁-C₅Straight or branched alkyl, wherein C₁_C₅On straight or branched alkyl arbitrarily Hydrogen atom can be replaced by hydroxyl, sulfydryl or amino further；Wherein metal ion is alkali metal ion or alkaline-earth metal ions；

R⁴For hydrogen atom or C₁-C₅Straight or branched alkyl, wherein C₁_C₅On straight or branched alkyl, any hydrogen is former Son can be replaced by hydroxyl, sulfydryl or amino further；

R⁵For hydroxyl, sulfydryl, amino or C₁-C₅Straight or branched alkyl, wherein C₁_C₅On straight or branched alkyl arbitrarily Hydrogen atom can be replaced by hydroxyl, sulfydryl or amino further；

R⁶For C₁-C₅Straight or branched alkyl, wherein C₁_C₅On straight or branched alkyl, any hydrogen atom can be further by hydroxyl Base, sulfydryl or amino replace.

Further, in general formula compound:

R¹It is independently selected from hydrogen atom, fluorine atom or chlorine atom；

R³For alkali metal ion, C₁_C₃Straight or branched alkyl；

R⁴For hydrogen atom or C₁_C₅Straight or branched alkyl, wherein C₁_C₅On straight or branched alkyl, any hydrogen atom can enter One step is replaced by hydroxyl or amino；

R⁵For hydroxyl, amino or C₁_C₃Straight or branched alkyl, wherein C₁_C₃Any hydrogen atom on straight or branched alkyl Can be replaced by hydroxyl or amino further；

R⁶For C₁_C₃Straight or branched alkyl, wherein C₁_C₃On straight or branched alkyl, any hydrogen atom can be further by hydroxyl Base or amino replace.

Further, in general formula compound:

R¹It is independently selected from (1,3-benzoxazoles-2-base) 5 substituted hydrogen atoms of methyl, fluorine atom or chlorine atom；

R²It is independently selected from hydrogen atom ,-SO₂R³、-PO(OR³)₂Or-COCHR⁴R⁵；

R³For C₁_C₃Straight chained alkyl；

R⁴For hydrogen atom or C₁_C₄Straight or branched alkyl, wherein C₁_C₄On straight or branched alkyl, any hydrogen atom can enter one Step is replaced by hydroxyl or amino；

R⁵For hydroxyl or amino.

Also include additionally, the present invention leads to the compound shown in formula (I) structure:

Wherein R¹It is independently selected from hydrogen atom, fluorine atom, chlorine atom, bromine atoms, atomic iodine, amino or cyano group；R²Independent choosing From COCHR⁴R⁵；R⁴、R⁵For different substituents；And R⁴For C₁_C₄Straight or branched alkyl, wherein C₁_C₄Directly When on chain or branched alkyl, any hydrogen atom can be replaced by hydroxyl or amino further, with R⁴、R⁵The chiral carbon atom connected For R, S or R and the mix-configuration of S.

The present invention is led to the preferred compound of the compound shown in formula (I) and is included, but are not limited to:

Compound described in formula of the present invention and the preparation method of stereoisomer thereof, comprise the following steps:

Under the conditions of room temperature (10～25 DEG C), bromo-with 1-for bromo-for initiation material 8-3-methylxanthine 2-butyne is reacted, generate Product a further with 2-bromomethyl-1, the derivant of 3-benzoxazoles be substituted reaction generate product b, intermediate b with (R), after-3-t-butoxycarbonyl amino piperidines reaction generation c, intermediate c with TFA reacts completely, dissociate into alkali and obtain compound D, by d and R²-X(R²For SO₂R³、PO(OR³)₂、OCCHR⁴R⁵、COOR⁶Or CONHR⁶, X be halogen or Hydroxyl) reaction generation product e.If raw material R²R in-X²For SO₂R³Or PO (OR³)₂, must after the product hydrolysis of generation To R³Corresponding product for hydrogen atom.If raw material R²R in-X²Containing blocking group, the product of generation sloughs protection further, I.e. can get target compound.

Detailed description of the invention

Below in conjunction with embodiment, the present invention is described in further detail, but not limitation of the present invention, all according to this The equivalent of any this area that bright disclosure is made, belongs to protection scope of the present invention.

The structure of compound be by mass spectrum (MS) or nuclear magnetic resonance, NMR (¹HNMR) determine；

Nuclear magnetic resonance, NMR (¹HNMR) displacement (δ) is given with the unit of 1/1000000th (ppm)；

Nuclear magnetic resonance, NMR (¹HNMR) mensuration is to use BrukerAVANCE-300 nuclear magnetic resonance spectrometer, and measuring solvent is six deuterated diformazans Base sulfoxide (DMSO-d₆), inside it being designated as tetramethylsilane (TMS), chemical shift is with 10^-6(ppm) give as unit Go out；

The mensuration of mass spectrum (MS) FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Therm, model: Finnigan LCQ advantage MAX)；

Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate；

It is carrier that column chromatography generally uses Yantai Huanghai Sea silica gel 200-300 mesh silica gel；

Without specified otherwise in embodiment, reaction is carried out the most under nitrogen atmosphere；

Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon of a 1L volume；

Without specified otherwise in embodiment, the solution in reaction refers to aqueous solution；

In embodiment, room temperature refers to the ambient temperature of 10 to 25 degrees Celsius.

Embodiment 1

The synthesis of first step compound 1a

Use known method, bromo-for 8-3 methyl-xanthine (5g, 20.4mmol) are dissolved in DMF (35ml) In, add DIPEA (2.633g, 49.4mmol), the bromo-2-butyne of 1-(2.714g, 36.2mmol), Overnight, thin layer chromatography follows the tracks of reaction completely to room temperature reaction, is poured into by reactant liquor in 400ml water, has solid to separate out, sucking filtration, Washing solid, dried the bromo-7-of 8-(2-butyne-1-base)-3 methyl-xanthine 1a (5.2g, yellow solid), yield: 85.8%.

MS m/z (ES): 297,299 [M+1]

The synthesis of second step compound 1b

Use known method, 2-bromomethyl-5-fluorine benzoxazoles (2.4g, 10.4mmol) is dissolved in N, N-dimethyl formyl In amine (70ml), add the bromo-7-of 8-(2-butyne-1-base)-3 methyl-xanthine 1a (3g, 10.4mmol), potassium carbonate (2.2g, 15.6mmol), overnight, thin layer chromatography follows the tracks of reaction completely to room temperature reaction, is poured into by reactant liquor in 800ml water, separates out solid Body, sucking filtration, wash solid, dried product compound 1b (4.1g, yellow solid), yield: 88.2%.

MS m/z (ES): 446,448 [M+1]

The synthesis of the 3rd step compound 1c

1b (4.1g, 9.19mmol) is dissolved in DMF (50ml), adds (R)-N-Boc-3-amino Piperidines (1.84g, 9.19mmol), potassium carbonate (1.9g, 13.8mmol) are heated to 75 DEG C and react 2 hours, thin layer chromatography Following the tracks of reaction completely, after question response system is cooled to room temperature, join in 1000ml water, separate out solid, sucking filtration, washing is solid Body, is dried to obtain product compound 1c (5g, yellow solid), yield: 96.1%.

MS m/z(ES):566[M+1]

The synthesis of the 4th step compound 1

1c (5g, 8.85mmol) is dissolved in dichloromethane (30ml), instillation trifluoroacetic acid (5ml) under room temperature, 30 Overnight, thin layer chromatography follows the tracks of reaction completely in degree reaction.After concentrating under reduced pressure, add dichloromethane (50ml) and dissolve, sodium carbonate Aqueous solution adjusts PH to extract once to alkalescence, separatory, dichloromethane, merges organic facies, is dried, column chromatography for separation after concentration Obtain product compound 1 (3.75g, yellow solid), yield: 91.2%.

MS m/z(ES):466[M+1]

¹H NMR(300MHz,DMSO)δ1.69-1.72(m,2H),1.80(s,3H),1.94-2.03(m,2H),3.00– 3.08 (m, 1H), 3.20-3.26 (m, 2H), 3.42-3.52 (m, 6H, NH₂), 3.71-3.75 (m, 1H), 4.97 (q, J=16.5Hz, 2H), 5.35 (s, 2H), 7.26 (td, J=9.3,2.4Hz, 1H), 7.58 (dd, J=9.0,2.4Hz, 1H), 7.76 (dd, J=9.0, 4.5Hz,1H)。

Embodiment 2

The first step is with embodiment 1 first step；

Second step is with embodiment 1 second step；

3rd step is with embodiment 1 the 3rd step；

4th step is with embodiment 1 the 4th step；

The synthesis of the 5th step compound 2

Use known method, compound 1 (100mg, 0.21mmol) is dissolved in dichloromethane (5ml), add three Ethamine (43mg, 0.43mmol), then instill methane sulfonyl chloride (27mg, 0.24mmol), room temperature reaction is overnight.Thin layer Chromatogram tracking reacts, and display consumption of raw materials is complete, washes with saturated aqueous common salt (5ml*2), separatory, is dried, through system after concentration Standby thin layer chromatography (dichloromethane: methanol=10:1) purification obtains product compound 2 (92mg, light yellow solid), yield: 79.3%.

MS m/z(ES):544[M+1]

¹H NMR(300MHz,DMSO)δ1.46-1.53(m,1H),1.67-1.71(m,1H),1.79-1.85(m,4H), 1.95-1.99(m,1H),2.92-3.09(m,5H),3.41-3.60(m,5H),3.72-3.77(m,1H),4.89(s,2H),5.34(s, 2H), 7.25 (td, J=9.3,2.7Hz, 1H), 7.34 (d, J=7.5Hz, 1H), 7.57 (dd, J=8.7,2.4Hz, 1H), 7.76 (dd, J=9.0,4.2Hz, 1H).

Embodiment 3

The first step is with embodiment 1 first step；

Second step is with embodiment 1 second step；

3rd step is with embodiment 1 the 3rd step；

4th step is with embodiment 1 the 4th step；

The synthesis of the 5th step compound 3

Use known method, compound 1 (100mg, 0.21mmol) is dissolved in dichloromethane (5ml), add three Ethamine (43mg, 0.43mmol), then instill diethyl chloro-phosphate (41mg, 0.24mmol), room temperature reaction is overnight.Thin Layer chromatography follows the tracks of reaction, and display consumption of raw materials is complete.Saturated aqueous common salt (5ml*2) is washed, and is dried, through preparing thin layer after concentration Chromatograph (dichloromethane: methanol=10:1) purification obtains product compound 3 (111mg, light yellow solid), yield: 84.1%.

MS m/z(ES):602[M+1]

¹H NMR (300MHz, DMSO) δ 1.23 (t, J=6.7Hz, 6H), 1.40-1.43 (m, 1H), 1.63-1.66 (m, 1H), 1.79-1.93(m,5H),2.84-3.03(m,2H),3.17-3.18(m,1H),3.40(s,3H),3.59-3.72(m,2H),3.90-3.95 (m, 4H), 4.89 (s, 2H), 5.12 (t, J=10.4Hz, 1H), 5.34 (s, 2H), 7.22-7.28 (m, 1H), 7.55-7.59 (m, 1H), 7.75 (dd, J=9.0,4.5Hz, 1H).

Embodiment 4

The first step is with embodiment 1 first step；

Second step is with embodiment 1 second step；

3rd step is with embodiment 1 the 3rd step；

4th step is with embodiment 1 the 4th step；

The synthesis of the 5th step compound 4e

Use known method, compound 1 (200mg, 0.43mmol) is dissolved in dichloromethane (5ml), depends under room temperature Secondary addition N-Boc-L-alanine (85mg, 0.45mmol), dicyclohexylcarbodiimide (106mg, 0.51mmol), I-hydroxybenzotriazole (65mg, 0.48mmol), sodium carbonate (100mg, 0.94mmol).Room temperature reaction overnight, thin layer Chromatogram tracking reacts, and display consumption of raw materials is complete, and sucking filtration, dichloromethane (5ml*3) filter wash cake, filtrate is concentrated to give product chemical combination Thing 4e (240mg, yellow solid), yield: 87.7%.

MS m/z(ES):637[M+1]

The synthesis of the 6th step compound 4

Use known method, compound 4e (240mg, 0.38mmol) is dissolved in dichloromethane (5ml), room temperature Lower instillation trifluoroacetic acid (0.5ml), 30 degree are reacted 3 hours, and thin layer chromatography follows the tracks of reaction, and display consumption of raw materials is complete.Decompression After concentration, residue is dissolved in dichloromethane (5ml), and sodium bicarbonate solution is adjusted to alkalescence, separatory, aqueous phase dichloromethane (5ml) extraction is once, merges organic facies, is dried, pure through preparing thin layer chromatography (dichloromethane: methanol=10:1) after concentration Change to obtain product compound 4 (170mg, faint yellow solid), yield: 84.2%.

MS m/z(ES):537[M+1]

¹H NMR (300MHz, DMSO) δ 1.14 (d, J=6.6Hz, 3H), 1.52-1.57 (m, 1H), 1.79-1.83 (m, 6H),2.97-3.04(m,1H),3.09-3.17(m,2H),3.29-3.31(m,1H),3.41(s,3H),3.57-3.68(m,2H), 3.86(s,br,2H,NH₂), 4.88 (s, 2H), 5.34 (s, 2H), 7.26 (td, J=9.3,2.4Hz, 1H), 7.58 (dd, J=8.7,2.4Hz, 1H), 7.76 (dd, J=8.7,4.2Hz, 1H), 7.97 (d, J=7.8Hz, 1H).

Test example I: the impact on normal glucose tolerance in mice

Test objective: research embodiment compound is administered once the effect to glucose tolerance in mice for one week, and with structure homologue Li Lali Spit of fland compares.

1.1.1, test material

(1) medicine

Instrument medicine: glucose, GC 99.5%, sigma company provide, lot number 101021941, specification 100g/ bottle；

Positive control drug: BI 1356 (linagliptin), Shanghai winning auspicious chemistry Science and Technology Ltd. provides, specification 2g,

CAT:YRY0687, LCT#:YR120503；

Embodiment 1 compound, is provided by Yuan Dong Pharma Inc. study on the synthesis room, Chengdu, pale solid, lot number: 20120925；

Embodiment 2 compound, is provided by Yuan Dong Pharma Inc. study on the synthesis room, Chengdu, faint yellow solid, lot number: 20120924；

Embodiment 3 compound, is provided by Yuan Dong Pharma Inc. study on the synthesis room, Chengdu, yellow solid, lot number: 20121011；

Embodiment 4 compound, is provided by Yuan Dong Pharma Inc. study on the synthesis room, Chengdu, faint yellow solid, lot number: 20121015；

The table 1 embodiment compound dosage regimen to the effect of glucose tolerance in mice

(2) test equipment:

FA2204B electronic balance, is provided by Shanghai precision instrument scientific instrument company limited；

METTLER-toledo analytical balance, XS-105 type, Mettler Toledo Inc. of Switzerland produce；

Blood sugar test paper: Luo Kang full vigor type blood sugar test paper, specification: 50 dresses, lot number 23435532, by Roche Diagnistics's product (Shanghai) Co., Ltd. provides；

Operating scissors, syringe etc.；

(3) experimental animal: KM mice, body weight 18～22g, male and female half and half, Da Shuo bio tech ltd, Chengdu provide, Production facility licence: SCXK (river) 2008-24.Animal is raised after buying back in Animal House, adaptability observation at least 3 days, inspection It is used for testing after epidemic disease is qualified.

1.1.2, test method:

(1) fasting at least 12 hours before on-test；

(2) packet: to its fasting blood sugar of the mouse assay after fasting, be divided into 6 groups according to its result according to table 1, often organize 10 Only, male and female half and half, no difference of science of statistics between group；

(3) being administered: after being grouped according to table 1, often group gavage gives accordingly by reagent, and blank group fills the distilled water of respective volume；

(4) 168 hours blood glucose pH-value determination pHs after being administered: being administered latter 167.5 hours, gavage gives glucose (8g/kg), surveys respectively Surely the blood glucose value of 30min, 60min after glucose is given；

(5) statistical method: use Excel to add up, test data uses (x ± SD) to represent, compares and adopt between many groups Carry out statistics by the bilateral T method of inspection to compare.

1.1.3, result of the test

The effect (5mg/kg is administered 168 hours, (x ± SD)) to glucose tolerance in mice of the table 2 embodiment compound

Note: compared with blank group,^*P ＜ 0.05,^*P ＜ 0.01；

Compared with positive group,^▲P ＜ 0.05,^▲▲P ＜ 0.01.

1.1.4, conclusion

Result shows, is administered latter 168 hours under 5mg/kg dosage, embodiment 1 compound, embodiment 2 compound, reality Execute example 3 compound, embodiment 4 compound all shows the blood sugar reducing function (P ＜ 0.05) being better than the positive, and of the present inventionization is described Compound has long-acting blood sugar reducing function.

Test example II: to DPP-IV active suppression test in beagle dog body

1, test objective:

Observe the activity suppression to DPP IV (DPP-IV) enzyme of normal beagle dog of the embodiment compound, and right Its action time carries out pre-test.

2, test material

(1) medicine

Positive control drug: BI 1356 (linagliptin), Shanghai winning auspicious chemistry Science and Technology Ltd. provides, specification 2g, CAT: YRY0687, LCT#:YR120503；

The dosage regimen that beagle dog DPP-IV activity is suppressed by table 3 embodiment compound

(2) test equipment:

Operating scissors, irrigation stomach device, dog fixed mount etc.；

(3) experimental animal: normal beagle dog, body weight 10kg, male, weight differences is less than 1kg, Chengdu reach large biology Science and Technology Ltd. provides, the animal quality certification number: SCXK (river) 2008-24.Animal is raised in Animal House after buying back, adapt to Property observe at least 3 days, quarantine qualified after for testing.

3, test method:

Fasting at least 12 hours before being administered for (1) first day；

(2) packet: be divided into 4 groups according to table 1, often group 5, no difference of science of statistics between group；

(3) being administered: after being grouped according to table 1, often group gavage gives accordingly by reagent, and blank group fills the steaming of respective volume Distilled water, before being administered, 0h, 1h, 4h, 7h, 12h, 24h, 48h, 72h, 96h, 120h, 144h, 168h take serum survey Determine the activity of DPP-IV.

4, assay method

Take 5uL blood serum sample, add 80mM MgCl₂Buffer 50uL, mixing, room temperature is incubated bath 5 minutes in advance, adds Entering 10uL0.1mM reaction substrate Gly-Pro-AMC and 40uL buffer, lucifuge, at interval of 3 minutes row one after mixing Secondary fluoremetry (excitation wave 380nm/ transmitted wave 460nm), until 18 minutes, survey 6 times altogether, when doing according to measurement result Between fluorescent value curve, obtaining slope is energy value, be administered before serum DPPIV energy value for 100%, based on following equation Calculate the Rate activity value of each time point serum DPPIV after being administered.

Energy value × 100% before energy value/administration after Rate activity value (%)=administration

5, statistical method: use Excel to add up, test data uses (x ± SD) to represent, compares employing between many groups The bilateral T method of inspection carries out statistics and compares.

6, result of the test

The table 4 embodiment compound inhibitory action (x ± SD) to beagle dog DPP-IV activity

Time (h) after administration	Blank group	Positive group	Embodiment 3 compound group	Embodiment 4 compound group
					0	100.0	100.0	100.0	100.0
1	91.0±2.1	9.7±0.5^*	10.3±2.6^*	9.3±1.5^*
					4	92.1±1.8	12.4±1.9^**	14.5±2.4^*	11.9±1.8^*
7	93.9±3.6	14.5±1.7^**	15.9±2.1^*	13.7±2.2^*
					12	95.5±4.1	17.5±3.4^**	19.1±6.1^*	16.8±5.2^*
24	98.2±3.8	98.2±3.8	23.5±7.3^*	19.5±4.5^*
					48	101.2±3.9	21.3±10.9^*	25.3±10.6^*	20.3±9.5^*
72	103.5±4.6	40.5±9.5^*	39.5±9.7^*	24.5±9.3^{* ▲}
					96	102.7±5.4	45.1±15.6^**	45.8±15.4^*	29.7±10.4^{* ▲}
120	103.3±4.9	56.1±15.9^*	47.1±15.5^*	30.1±14.5^{* ▲ ▲}
					144	105.4±4.2	68.9±19.8^*	49.5±16.5^{* ▲}	34.5±12.8^{* ▲ ▲}
168	107.0±5.1	107.0±5.1	52.5±18.8^{* ▲}	39.5±13.8^{* ▲ ▲}

Note: compared with blank group,^*P ＜ 0.05 '^*P ＜ 0.01；

Compared with positive group,^▲P ＜ 0.05,^▲▲P ＜ 0.01.

The above results shows that embodiment of the present invention compound demonstrates good DPP-IV inhibitory activity, embodiment 4 compound 144h after 96h and embodiment 3 compound are administered upon administration, and positive group compares and has significant difference (P ＜ 0.05), Be administered the suppression of DPP-IV activity after 168h and still reach 50%, DPP-IV suppression ratio > 50% time on be longer than positive drug, Can meet one week and be administered once.

Show that embodiment of the present invention compound demonstrates long-acting blood sugar reducing function according to the above results, common for this area Be apparent that in the spirit or scope without departing from the present invention for technical staff, can to the compounds of this invention, compositions and The multiple modification and transformation that method is carried out, therefore, the present invention comprises the modification and transformation to the present invention, as long as in claim In the range of its equivalent.

Claims

Compound the most as follows: