CN104003922A - Substituted pyrrolidine derivative, preparation method thereof and use in medicine - Google Patents
Substituted pyrrolidine derivative, preparation method thereof and use in medicine Download PDFInfo
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- CN104003922A CN104003922A CN201310061161.7A CN201310061161A CN104003922A CN 104003922 A CN104003922 A CN 104003922A CN 201310061161 A CN201310061161 A CN 201310061161A CN 104003922 A CN104003922 A CN 104003922A
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The present invention relates to new pyrrolidine derivative, i.e. a compound shown as general formula (I) or its pharmaceutically acceptable salts, a preparation method and application of the compound as a drug, especially application as a dipeptidyl peptidase (DPPIV) inhibitor for treatment of diabetes. The definitions of R1, R2 and R3 are described in the specification. (formula I).
Description
Technical field
The present invention relates to new pyrrolidines derivative, its preparation method and this compound as the application of medicine, especially as dipeptidyl peptidase (DPPIV) inhibitor, treat diabetes.
Background technology
Diabetes are a kind of incretion metabolism diseases that hyperglycemia is principal character, serious harm health of take, and are the third-largest non-infectious chronic diseases in the world.According to IDF (IDF) latest data, show, within 2007, approximately there are 2.39 hundred million diabetic subjects in the whole world.Estimate that the year two thousand thirty will reach 4.38 hundred million.China diabetic subject number has occupied second place of the world at present, estimates within 2025, to reach 5,931 ten thousand.2006, diabetes occupied the tenth of the Chinese inpatient cause of disease, the 6th of city resident's cause of death.Therefore, the control of diabetes is key subjects of international diabetes circle research.
Antidiabetic medicine is of a great variety at present, type is different, the type ii diabetes medicine using clinically mainly contains euglycemic agent, glycogen formation inhibitor, glucosidase inhibitor and novel antidiabetic drug DPP IV (DPPIV) inhibitor such as sulfonylurea and non-sulfonylurea Drugs Promoting Insulin Secretion, biguanides, thiazolidinediones, but the result for the treatment of of these medicines is the undesirable or larger side effect of existence also, therefore the diabetes medicament that, research and development have novel chemical structure, a high-efficiency low-toxicity remains the vital task in diabetes control work.
DPP IV (DPPIV) is a kind of serine protease, cracking N-end pepx in the peptide chain that it can contain a proline residue at inferior end.GLP-1 is a kind of endogenic hormone, rising along with postprandial blood sugar, L emiocytosis in small intestine produces, and then secretion (the Drug Discov Today Ther Strateg of stimulation Regular Insulin, 2004,1 (2), 207-212) DPPIV in vivo can be rapidly and the deputy proline(Pro) of cracking GLP-1 peptide chain N-terminal or Beta Alanine specifically, the inactivation (Crit Rev Clin Lab Sci, 2003,40 (3) that cause GLP-1,209-294), therefore, suppress DPPIV and just can strengthen the activity of GLP-1, thereby improve glucose-tolerant level.
At present existing a plurality of DPPIV inhibitor go on the market in countries in the world.DPPIV inhibitor has following features 1, blood sugar dependency insulin secretion accelerating; 2, glucagon suppression secretion; 3, control reposefully glucose level and can not produce hypoglycemia; 4, maintain the B cell that even improves diabetes B patient, delay disease process; 5, reduce patient's body weight.But there is the feature of poor chemical stability in this quasi-molecule mostly.Therefore, be necessary to develop the better DPPIV inhibitor of new generation of chemical stability.
Summary of the invention
One of object of the present invention is to provide a kind of pyrrolidines derivative and corresponding intermediate; Two of object is to provide the preparation method of described compound; Three of object is to provide described compound at purposes, especially anti-diabetic aspect pharmaceutically.
For achieving the above object, the present invention adopts following technical scheme:
1. the present invention relates to a kind of compound or its pharmacy acceptable salt being represented by general formula (I):
Wherein:
R
1be selected from the group of alkyl, cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyl cycloalkyl, hydroxyl bicyclic alkyl, hydroxyl tricyclic alkyl, aryl or heteroaryl;
R
2, R
3respectively be selected from hydrogen atom, amino, azido-, hydroxyl, straight chained alkyl, branched-chain alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical ,-NR
4r
5,-OR
6, fluorine atom, chlorine atom, bromine atoms;
Or R
2with R
3jointly represent cycloalkyl, the thiazolinyl of 3 to 10 carbon;
R
4, R
5, R
6respectively be selected from hydrogen atom, straight chained alkyl, branched-chain alkyl, cycloalkyl, acyl group, alkylsulfonyl, aryl, heteroaryl, heterocyclic radical;
Or R
4with R
5common representative is containing the cycloalkyl of 2 to 10 carbon;
The carbon that No. 1 carbon and No. 2 carbon are optically pure chiral carbon or racemization.
Further, the present invention includes compound or its pharmacy acceptable salt that following general formula (IA) represents:
Wherein:
R
2, R
3respectively be selected from hydrogen atom, amino, azido-, hydroxyl, straight chained alkyl, branched-chain alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical ,-NR
4r
5,-OR
6, fluorine atom, chlorine atom, bromine atoms;
Or R
2with R
3jointly represent cycloalkyl, the thiazolinyl of 3 to 10 carbon;
R
4, R
5, R
6respectively be selected from hydrogen atom, straight chained alkyl, branched-chain alkyl, cycloalkyl, acyl group, alkylsulfonyl, aryl, heteroaryl, heterocyclic radical;
Or R
4with R
5common representative is containing the cycloalkyl of 2 to 10 carbon;
R
7, R
8respectively be selected from hydrogen atom or hydroxyl.
Further, described salt is the salt that is selected from following acid: hydrochloric acid, trifluoroacetic acid, methylsulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid.
Particularly, described compound and the intermediate thereof of general formula of the present invention (I) comprises that following compound is not limited in this:
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl) the fluoro-2-formamyl of-4-tetramethyleneimine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl) fluoro-2-Cyanopyrolidine of-4-;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl) fluoro-2-Cyanopyrolidine of-4-;
(2S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4, the fluoro-2-formamyl of 4-bis-tetramethyleneimine;
(2S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4, the fluoro-2-Cyanopyrolidine of 4-bis-;
(2S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4, the fluoro-2-Cyanopyrolidine of 4-bis-;
(2S, 4S)-1-(1,1-dimethyl ethoxy carbonyl)-4-azido--2-formamyl tetramethyleneimine;
(2S, 4S)-4-azido--2-formamyl tetramethyleneimine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-formamyl tetramethyleneimine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-acetylaminohydroxyphenylarsonic acid 2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(2-phenyl acetyl is amino)-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-methylsulfonyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-p-toluenesulfonyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(1-pyrrolidyl)-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-acetylaminohydroxyphenylarsonic acid 2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(2-phenyl acetyl is amino)-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-methylsulfonyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-p-toluenesulfonyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(1-pyrrolidyl)-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-phenmethyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(nitrogen-phenmethyl-nitrogen-methylamino)-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-phenmethyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(nitrogen-phenmethyl-nitrogen-methylamino)-2-Cyanopyrolidine
2. the invention provides a kind of method of preparing compound (I) and intermediate thereof, it is characterized in that comprising the steps:
A kind of synthetic method of pyrrolidines derivative
In above formula, R
1, R
2, R
3definition as previously mentioned.Wherein No. 1 with No. 2 carbon atoms can respectively do for oneself R or S configuration, wherein dipeptide compound can be the mixture that single steric configuration also can be raceme or non-corresponding isomer.
Step (1): the amino acid of nitrogen tertbutyloxycarbonyl protection is reacted with the tetramethyleneimine acid amides of replacement and generates amido linkage, the realization of this process can by condensing agent or by carboxylic acid being become to acyl chlorides or acid anhydrides carrys out activating carboxy acid, wherein condensing agent be selected from DCC, EDC, DCI, BOP, PIC, BDDC, HOBt, HATU, HBTU, HCTU; Form mixed acid anhydride can with following reagent react, isoveryl chloride, Vinyl chloroformate, EDDQ, PNP, HOBt, HOAt; Form acyl chlorides and can use thionyl chloride, oxalyl chloride;
Step (2): convert amido linkage to itrile group under the effect of dewatering agent, wherein dewatering agent can be sulfur oxychloride, five phosphorus oxide, cyanuric chloride, trifluoroacetic anhydride, phosphorus oxychloride, phosphorus pentachloride;
Step (3): slough BOC protecting group under sour effect, acid used is selected from hydrochloric acid, trifluoroacetic acid.
3. the present invention carries out the vitro detection test of DPPIV enzyme inhibition activity to synthesized compound
Instrument: microplate reader, SpectraMax M5 (Molecular Devices, USA)
Material: people source restructuring DPPIV enzyme (Cat:SE434-9090, Biomol); 50mM Tris damping fluid, pH=7.5; Fluorogenic substrate GP-AMC (Cat:P189-9090, Biomol); Positive control P32/98 (Cat:PI142-9090, Biomol); Positive control BMS-477118, self-control; Test-compound 1-13, self-control.
Method:
A) 96 hole blackboards are equilibrated to room temperature.
B) use 1: 50 times of dilution 500 μ M AMC substrates of reaction buffer, the reaction final concentration that makes AMC substrate is 5 μ M, the substrate solution that each hole needs 50 μ l to dilute.
C) with 13 testing compounds of reaction buffer dilution, making its final screening concentration is 10 μ M and 100nM, and each extent of dilution is done a multiple hole.
D) to the testing compound of all different concns on 96 hole Sptting plates, measure in hole and add 25 μ l reaction buffers, and add successively the compound of the different concns that 10 μ l have diluted in corresponding reacting hole.For negative control and blank hole, add respectively 35 μ l and 50 μ l reaction buffers.For positive control hole, add 25 μ l reaction buffers and 10 μ l P32/98.For positive control hole, add 25 μ l reaction buffers and 10 μ l P32/98.All reference compound holes and control wells are done a multiple hole.
E) use 1: 50 times of dilution DPPIV enzyme of reaction buffer, in all reacting holes except blank hole, the DPPIV that adds 15 μ l to dilute, the enzyme amount that makes DPPIV in reacting hole is 0.26MU/ hole.
F) to the AMC substrate solution that adds 50 μ l to dilute in all reacting holes, carry out initial action.
G) normal temperature was hatched after 10 minutes, reading Ex:380nm/Em:460nm on SpectraMax M5.
The calculating of testing compound inhibiting rate:
A) calculate the average signal value of each sample.
B) signal value of each concentration of specimens deducts average background signal value.
C) calculate the inhibiting rate of each sample.Calculate the inhibiting rate of each sample.100% active hole reading is deducted respectively after each testing compound different concns corresponding aperture reading, divided by 100% active hole reading, be multiplied by 100 obtain respectively each testing compound different concns inhibiting rate.
% inhibiting rate=[100% active hole-sample aperture]/100% active hole * 100
The experiment of measuring DPPIV enzyme inhibition activity shows, compound of Formula I of the present invention has the effect of significant inhibition DPPIV enzymic activity.Above-mentioned experimental result prompting, the compounds of this invention or its pharmacy acceptable salt can be for the preparation of the medicines of prevention or treatment diabetes and cardiovascular disorder.
Accompanying drawing explanation
Fig. 1 is (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl) the fluoro-2-cyanopyrrole of-4-hydride compounds proton nmr spectra;
Fig. 2 is (2S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4, the fluoro-2-cyanopyrrole of 4-bis-hydride compounds proton nmr spectra;
Fig. 3 is (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-cyanopyrrole hydride compounds proton nmr spectra;
Fig. 4 is (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-cyanopyrrole hydride compounds proton nmr spectra;
Fig. 5 is (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl) the fluoro-2-cyanopyrrole of-4-hydride compounds mass spectrum
Embodiment
Below by embodiment, illustrate content of the present invention.In the present invention, the embodiment of the following stated is in order better to set forth the present invention, is not for limiting the scope of the invention.
The structure of compound is determined by nucleus magnetic resonance (NMR) and mass spectrum (MS).The mensuration of NMR is by Bruker Avance AV-300 and Bruker Avance AV-500 type nuclear magnetic resonance analyser.Mensuration solvent is deuterochloroform, deuterated dimethyl sulfoxide, deuterated methanol, is inside designated as trimethyl silane.The mensuration of MS is to adopt Waters Q-TOF (ESI) mass spectrograph.
Embodiment 1
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl) fluoro-2-Cyanopyrolidine of-4-
(1) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl) the fluoro-2-formamyl of-4-tetramethyleneimine
By 0.159mL acetonitrile; 0.0535 milliliter of diisopropylethylamine; 0.053mL ethyl acetate mixes stand-by; order is by solid (S)-N-(1; 1-dimethyl ethoxy carbonyl)-2-(3-hydroxyadamantane base-1-yl) glycine 53.5mg (0.164mmol); (2S; the fluoro-2-formamyl of 4S)-4-tetramethyleneimine tosilate 50mg (0.164mmol); I-hydroxybenzotriazole 22.14mg (0.164mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride 37.7mg (0.197mmol) mixes.In the situation that stirring, the mixing liquid mixing is slowly added dropwise in solid, finishes, stir 15 hours stopped reaction.In reaction solution, add ethyl acetate 30mL, 1mol/L hydrochloric acid 10mL, jolts layering, retain organic layer, then use successively 1mol/L sodium hydroxide 15mL, saturated aqueous common salt 15mL washes organic layer, anhydrous sodium sulfate drying, concentrates to obtain white solid product 46mg (63.8%).
1H-NMR(500MHz，CDCl
3)1.49(s，9H)，1.49-1.72(m，12H)，2.06(br?s，2H)，2.23(m，1H)，2.81(m，1H)，3.92-4.10(m，2H)，4.19(d，J＝9.45，1H)，4.74(m，1H)，5.23-5.33(m，2H)，5.78(br?s，1H)，6.58(br?s，1H)；
13C-NMR(125MHz，CDCl
3)28.3，29.66，30.1，33.7，33.9，37.3，37.6，40.6，44.3，45.9，54.8，55.0，58.9，68.4，80.1，91.3，92.7，155.9，172.0，172.5；ESI-MS?m/z：440.3[M+H]
+.
(2) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl) fluoro-2-Cyanopyrolidine of-4-
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl) the fluoro-2-formamyl of-4-tetramethyleneimine 50mg (0.114mmol) is dissolved in 0.7mL tetrahydrofuran (THF), is cooled to 0 degree.Add pyridine 0.046mL (0.569mmol), after in the situation that stirring, slowly add trifluoroacetic anhydride 0.04mL (0.285mmol), 0 degree stirs stopped reaction half an hour.By reaction solution evaporate to dryness, reaction mixture is dissolved in 0.7mL methyl alcohol, in the situation of stirring at room, add 10% salt of wormwood 0.32mL, stir 12 hours stopped reaction.By reaction solution ethyl acetate and water dilution, layering, retains organic layer, and with 1mol/L hydrochloric acid, 1mol/L sodium hydroxide, saturated common salt washing organic layer, anhydrous sodium sulfate drying, concentrates to obtain target product 38mg (79%) successively.
1H-NMR(300MHz，CDCl
3)1.40-1.76(m，12H)，1.41(s，9H)，2.26(br?s，2H)，2.39(m，1H)，2.64(m，1H)，3.99-4.11(m，3H)，5.03(m，1H)，5.23(d，J＝9.33，1H)，5.31-5.48(d，J＝51.9，1H)；
13C-NMR(75MHz，CDCl
3)29.66，31.1，31.5，36.5，37.1，37.4，38.2，38.9，42.1，45.7，47.4，55.2，55.5，60.2，69.9，81.6，92.3，94.7，118.7，157.3，172.0；ESI-MS?m/z：422.2[M+H]
+.
(3) (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl) fluoro-2-Cyanopyrolidine of-4-
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl) the fluoro-2-Cyanopyrolidine of-4-28mg (0.0665mmol) is dissolved in 0.7mL methylene dichloride; the in the situation that of stirring at room, slowly add trifluoroacetic acid 0.7mL, stirring at room stopped reaction after half an hour.By reaction solution evaporate to dryness, with ether, grind, filter, collect filter cake, obtain target product 18mg (65%).
1H-NMR(300MHz，CD
3OD)1.50-1.78(m，12H)，2.27(br?s，2H)，2.35-2.71(m，2H)，3.75-3.96(m，1H)，3.95(s，1H)，4.07-4.18(m，1H)，5.09(d，J＝9.21，1H)，5.31-5.48(d，J＝51，1H)；
13C-NMR(75MHz，CD
3OD)31.4，35.9，36.6，36.9，37.6，38.0，40.8，44.7，44.9，46.1，46.3，55.1，55.4，59.9，68.6，92.8，95.1，118.8，168.2；ESI-MS?m/z：322.2[M+H]
+.
Embodiment 2
(2S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4, the fluoro-2-Cyanopyrolidine of 4-bis-
(1) (2S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4, the fluoro-2-formamyl of 4-bis-tetramethyleneimine
By 0.18mL acetonitrile; 0.06 milliliter of diisopropylethylamine; 0.06mL ethyl acetate mixes stand-by; order is by solid (S)-N-(1; 1-dimethyl ethoxy carbonyl)-2-(3-hydroxyadamantane base-1-yl) glycine 51.35mg (0.158mmol); (2S; 4S)-4; the fluoro-2-formamyl of 4-bis-tetramethyleneimine tosilate 51mg (0.158mmol); I-hydroxybenzotriazole 23.49mg (0.174mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride 36.3mg (0.1896mmol) mixes.In the situation that stirring, the mixing liquid mixing is slowly added dropwise in solid, finishes and stir 15 hours stopped reaction.In reaction solution, add ethyl acetate 30mL, 1mol/L hydrochloric acid 10mL, jolts layering, retain organic layer, then use successively 1mol/L sodium hydroxide 15mL, saturated aqueous common salt 15mL washes organic layer, anhydrous sodium sulfate drying, concentrates to obtain white solid product 45mg (62%).
1H-NMR(300MHz，CDCl
3)1.49(s，9H)，1.43-1.66(m，12H)，2.22(br?s，2H)，2.56-2.96(m，2H)，3.87-4.29(m，3H)，4.74(m，1H)，5.33(m，1H)，6.05(br?s，1H)，6.75(br?s，1H)；
13C-NMR(75MHz，CDCl
3)28.3，29.6，30.2，35.2，37.1，37.6，41.0，44.2，45.6，54.5，54.9，57.4，58.9，68.6，80.2，125.8，155.6，171.3；ESI-MSm/z：458.2[M+H]
+.
(2) (2S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4, the fluoro-2-Cyanopyrolidine of 4-bis-
By (2S)-1-, ((S)-2-(1; 1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4; the fluoro-2-Cyanopyrolidine of 4-bis-61mg (0.1335mmol) is dissolved in 0.8mL tetrahydrofuran (THF), is cooled to 0 degree.Add pyridine 0.054mL (0.667mmol), after in the situation that stirring, slowly add trifluoroacetic anhydride 0.05mL (0.334mmol), 0 degree stirs stopped reaction half an hour.By reaction solution evaporate to dryness, reaction mixture is dissolved in 0.8mL methyl alcohol, in the situation of stirring at room, add 10% salt of wormwood 0.38mL, stir 12 hours stopped reaction.By reaction solution ethyl acetate and water dilution, layering, retains organic layer, and with 1mol/L hydrochloric acid, 1mol/L sodium hydroxide, saturated common salt washing organic layer, anhydrous sodium sulfate drying, concentrates to obtain target product 54mg (90%) successively.
1H-NMR(300MHz，CD
3OD)1.42-1.71(m，12H)，1.41(s，9H)，2.29(br?s，2H)，2.78-2.94(m，2H)，4.04(s，1H)，4.19(m，2H)，5.06(m，1H)；
13C-NMR(75MHz，CD
3OD)27.5，28.6，28.7，36.2，36.4，37.5，37.8，38.2，38.4，41.6，45.0，45.2，46.6，54.0，54.5，60.7，68.9，80.9，118.1，157.3，172.2；ESI-MSm/z：440.2[M+H]
+.
(3) (2S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4, the fluoro-2-Cyanopyrolidine of 4-bis-
By (2S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4; the fluoro-2-Cyanopyrolidine of 4-bis-41mg (0.093mmol) is dissolved in 1mL methylene dichloride; the in the situation that of stirring at room, slowly add trifluoroacetic acid 1mL, stirring at room stopped reaction after half an hour.By reaction solution evaporate to dryness, with ether, grind, filter, collect filter cake, obtain target product 23mg (54.8%).
1H-NMR(300MHz，CD
3OD)1.61-1.71(m，12H)，2.27(br?s，2H)，2.83-2.95(m，2H)，3.95(s，1H)，4.12-4.22(m，2H)，5.13(m，1H)；
13C-NMR(75MHz，CD
3OD)31.4，35.9，37.3，37.7，37.8，39.0，40.8，44.7，44.8，45.7，46.1，54.0，54.4，54.8，60.0，68.6，117.6，126.5，168.4；ESI-MS?m/z：340.2[M+H]
+.
Embodiment 3
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-Cyanopyrolidine
(1) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-formamyl tetramethyleneimine
By 3mL acetonitrile; 0.826 milliliter of diisopropylethylamine; 1mL ethyl acetate mixes stand-by; order is by solid (S)-N-(1; 1-dimethyl ethoxy carbonyl)-2-(3-hydroxyadamantane base-1-yl) glycine 700mg (2.154mmol); (2S; 4S)-4-azido--2-formamyl tetramethyleneimine tosilate 704.4mg (2.154mmol); I-hydroxybenzotriazole 290mg (2.154mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride 495.5mg (2.585mmol) mixes.In the situation that stirring, the mixing liquid mixing is slowly added dropwise in solid, finishes and stir 15 hours stopped reaction.In reaction solution, add ethyl acetate 300mL, 1mol/L hydrochloric acid 100mL, jolts layering, retain organic layer, then use successively 1mo1/L sodium hydroxide 150mL, saturated aqueous common salt 150mL washes organic layer, anhydrous sodium sulfate drying, concentrates to obtain white solid product 829mg (83.3%).
1H-NMR(300MHz，CDCl
3)1.49(s，9H)，1.49-1.67(m，12H)，2.22(br?s，2H)，2.48(m，2H)，3.50(m，1H)，4.08-4.21(m，3H)，4.60(m，1H)，5.40(d，J＝9.42，1H)，6.12(br?s，1H)，6.76(br?s，1H)；
13C-NMR(75MHz，CDCl
3)28.3，30.1，32.4，35.2，37.3，37.7，40.8，44.2，45.7，53.2，58.8，59.0，68.4，79.9，155.8，171.5，172.6；ESI-MSm/z：463.3[M+H]
+.
(2) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-formamyl tetramethyleneimine 776mg (1.68mmol) is dissolved in 11.5mL tetrahydrofuran (THF), is cooled to 0 degree.Add pyridine 0.677mL (8.398mmol), after in the situation that stirring, slowly add trifluoroacetic anhydride 0.58mL (4.199mmol), 0 degree stirs stopped reaction half an hour.By reaction solution evaporate to dryness, reaction mixture is dissolved in 11.5mL methyl alcohol, in the situation of stirring at room, add 10% salt of wormwood 5.17mL, stir 12 hours stopped reaction.By reaction solution ethyl acetate and water dilution, layering, retains organic layer, and with 1mol/L hydrochloric acid, 1mol/L sodium hydroxide, saturated common salt washing organic layer, anhydrous sodium sulfate drying, concentrates to obtain target product 593mg (77%) successively.
1H-NMR(300MHz，CDCl
3)1.40-1.77(m，12H)，1.40(s，9H)，2.25(br?s，2H)，2.46(m，2H)，3.72(m，2H)，3.99(m，1H)，4.10(d，J＝9.9，1H)，4.40(m，1H)，4.87(m，1H)，5.26(d，J＝9.33，1H)；
13C-NMR(75MHz，CDCl
3)28.3，30.1，34.5，35.1，36.8，37.5，40.7，44.3，44.4，46.0，52.5，58.8，59.8，68.5，80.2，117.2，155.9，170.5；ESI-MSm/z：445.2[M+H]
+.
(3) (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-Cyanopyrolidine 35mg is dissolved in 0.85mL methylene dichloride; the in the situation that of stirring at room, slowly add trifluoroacetic acid 0.85mL, stirring at room stopped reaction after half an hour.By reaction solution evaporate to dryness, with ether, grind, filter, collect filter cake, obtain target product 30mg (84%).
1H-NMR(300MHz，DMSO-d6)1.30-1.59(m，12H)，2.15(br?s，2H)，2.30(m，2H)，3.75-3.82(m，2H)，3.80(s，1H)，4.65(m，2H)，4.93(m，1H)；
13C-NMR(75MHz，DMS0-d6)29.4，33.9，34.7，35.9，36.4，44.0，44.2，44.7，44.8，52.6，57.7，59.7，66.3，118.0，166.9；ESI-MS?m/z：345.2[M+H]
+.
Embodiment 4
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine
(1) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-Cyanopyrolidine 429mg is dissolved in 16mL ethanol; add 10% palladium carbon 42.9mg, logical 1.5 hours stopped reaction of hydrogen stirring at room.Remove by filter palladium carbon, concentration of reaction solution obtains 321mg (78%) target product.
1H-NMR(300MHz，DMSO-d6)1.36-1.54(m，12H)，1.36(s，9H)，1.88(m，1H)，2.08(br?s，2H)，2.34(m，1H)，3.48(m，1H)，3.78(m，1H)，4.00(d，J＝9.3，1H)，4.40(m，1H)，4.67(m，1H)，6.69(d，J＝9.33，1H)；
13C-NMR(75MHz，CDCl
3)28.3，30.2，35.1，37.1，37.2，37.9，41.0，44.3，44.4，44.6，46.3，51.3，55.7，58.8，68.4，79.9，118.4，155.8，170.5；ESI-MSm/z：419.3[M+H]
+.
(2) (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine 40mg is dissolved in 1mL methylene dichloride; the in the situation that of stirring at room, slowly add trifluoroacetic acid 1mL, stirring at room stopped reaction after half an hour.By reaction solution evaporate to dryness, with ether, grind, filter, collect filter cake, obtain target product 45mg (86.5%).
1H-NMR(300MHz，DMSO-d6)1.30-1.70(m，12H)，2.15(br?s，2H)，2.28(m，1H)，2.83(m，1H)，3.73(m，1H)，3.90(s，1H)，4.04(m，1H)，4.22(m，1H)，4.77(m，1H)；
13C-NMR(75MHz，DMSO-d6)29.4，32.5，34.7，36.2，36.5，44.0，44.9，45.1，47.1，49.9，58.1，66.3，117.8，167.0；ESI-MSm/z：319.2[M+H]
+.
Embodiment 5
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-acetylaminohydroxyphenylarsonic acid 2-Cyanopyrolidine
(1) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-acetylaminohydroxyphenylarsonic acid 2-Cyanopyrolidine
12.4mg (0.158mmol) Acetyl Chloride 98Min. is dissolved in 1mL methylene dichloride stand-by; by (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine 60mg (0.144mmol) is dissolved in 1mL anhydrous methylene chloride, adds 0.04mL triethylamine.Under 0 degree, ready chloride solution is added in reaction system, stir 1 hour stopped reaction.With methylene dichloride and water dilute reaction solution, which floor rear layering remains with, and successively with 1N HCl, 1N NaOH, saturated common salt washing organic layer, anhydrous magnesium sulfate drying, by column chromatography for separation (CH
2cl
2/ MeOH=50/1) obtain sterling 50mg (78%).
1H-NMR(500MHz，CDCl
3)1.46-1.69(m，12H)，1.46(s，9H)，2.06(s，3H)，2.24(br?s，2H)，2.29(m，1H)，2.52(m，1H)，3.67(m，1H)，4.06(m，1H)，4.12(d，J＝9.75，1H)，4.60(m，1H)，4.80(m，1H)，5.34(d，J＝9.05，1H)，6.5(d，J＝5.55，1H)；
13C-NMR(125MHz，CDCl
3)23.1，28.3，30.2，35.0，35.1，36.3，37.7，40.9，44.3，44.7，46.0，49.6，52.6，58.9，68.6，80.1，118.5，155.7，170.7；ESI-MSm/z：461.3[M+H]
+.
(2) (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-acetylaminohydroxyphenylarsonic acid 2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-acetylaminohydroxyphenylarsonic acid 2-Cyanopyrolidine 50mg is dissolved in 1.2mL methylene dichloride; the in the situation that of stirring at room, slowly add trifluoroacetic acid 1.2mL, stirring at room stopped reaction after half an hour.By reaction solution evaporate to dryness, with ether, grind, filter, collect filter cake, obtain target product 46mg (90%).
1H-NMR(500MHz，DMSO-d6)1.40-1.57(m，12H)，1.83(s，3H)，2.10(m，1H)，2.12(brs，2H)，2.61(m，1H)，3.21(m，1H)，3.96(s，1H)，4.12(m，1H)，4.21(m，1H)，4.75(m，1H)，8.19(d，J＝6.65，1H)；
13C-NMR(125MHz，DMSO-d6)22.5，28.3，29.4，33.6，34.7，36.2，36.4，44.0，44.1，44.6，45.1，47.4，51.4，58.0，66.3，118.2，166.8，169.5；ESI-MSm/z：361.2[M+H]
+.
Embodiment 6
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(2-phenyl acetyl is amino)-2-Cyanopyrolidine
(1) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(2-phenyl acetyl is amino)-2-Cyanopyrolidine
0.0174mL (0.1316mmol) Acetyl Chloride 98Min. is dissolved in 0.8mL methylene dichloride stand-by; by (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine 50mg (0.12mmol) is dissolved in 0.8mL anhydrous methylene chloride, adds 0.03mL triethylamine.Under 0 degree, ready phenyllacetyl chloride solution is added in reaction system, stir 1 hour stopped reaction.With methylene dichloride and water dilute reaction solution, which floor rear layering remains with, and with 1N HCl, 1N NaOH, saturated common salt washing, which floor has successively, and anhydrous magnesium sulfate drying, by column chromatography for separation (CH
2cl
2/ MeOH=80/1) obtain sterling 45mg (70%).
1H-NMR(300MHz，CDCl
3)1.40-1.67(m，12H)，1.40(s，9H)，2.21(m，3H)，2.48(m，1H)，3.60(m，1H)，3.61(s，2H)，4.00(m，1H)，4.07(d，J＝9.51，1H)，4.57(m，1H)，4.75(m，1H)，5.24(d，J＝9.33，1H)，6.00(m，1H)，7.27-7.37(m，5H)；
13C-NMR(75MHz，CDCl
3)28.3，29.7，30.1，34.9，35.1，36.9，37.1，40.8，43.5，44.3，44.6，46.0，49.8，52.7，58.8，68.5，80.1，118.1，127.6，129.2，129.4，134.0，155.7，170.6，171.3；ESI-MSm/z：537.3[M+H]
+.
(2) (2S; 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(2-phenyl acetyl is amino)-2-Cyanopyrolidine is by (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(2-phenyl acetyl is amino)-2-Cyanopyrolidine 45mg is dissolved in 0.9mL methylene dichloride; the in the situation that of stirring at room, slowly add trifluoroacetic acid 0.9mL, stirring at room stopped reaction after half an hour.By reaction solution evaporate to dryness, with ether, grind, filter, collect filter cake, obtain target product 40mg (89.9%).
1H-NMR(500MHz，CD
3OD)1.59-1.70(m，12H)，2.23(br?s，2H)，2.30(m，1H)，2.71(m，1H)，3.46(m，1H)，3.54(s，2H)，3.96(s，1H)，4.11(m，1H)，4.37(m，1H)，7.23-7.31(m，5H)；
13C-NMR(75MHz，CD
3OD)31.4，35.0，35.9，37.8，37.9，40.6，43.6，44.8，46.2，46.3，50.1，52.8，60.2，68.6，118.8，128.0，129.6，130.1，136.5，168.2，174.6；ESI-MSm/z：437.3[M+H]
+.
Embodiment 7
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-methylsulfonyl amino-2-Cyanopyrolidine
(1) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-methylsulfonyl amino-2-Cyanopyrolidine
0.009mL (0.12mmol) Methanesulfonyl chloride is dissolved in 0.75mL methylene dichloride stand-by; by (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine 45mg (0.11mmol) is dissolved in 0.75mL anhydrous methylene chloride, adds 0.03mL triethylamine.Under 0 degree, ready phenyllacetyl chloride solution is added in reaction system, stir 1 hour stopped reaction.With methylene dichloride and water dilute reaction solution, which floor rear layering remains with, and successively with 1N HCl, saturated common salt washing organic layer, anhydrous magnesium sulfate drying, by column chromatography for separation (CH
2cl
2/ MeOH=70/1) obtain sterling 45mg (84%).
1H-NMR(300MHz，CDCl
3)1.40-1.68(m，12H)，1.42(s，9H)，2.25(br?s，2H)，2.44-2.64(m，2H)，3.06(s，3H)，3.73(m，1H)，4.16(m，3H)，4.77(m，1H)，5.39(d，J＝9.3，1H)，6.19(m，1H)；
13C-NMR(75MHz，CDCl
3)28.3，30.1，30.2，35.0，35.4，35.9，41.0，41.5，44.2，44.3，44.5，46.3，52.4，52.9，59.1，68.6，80.1，118.0，155.8，170.7；ESI-MSm/z：497.2[M+H]
+.
(2) (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-methylsulfonyl amino-2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-methylsulfonyl amino-2-Cyanopyrolidine 33.5mg is dissolved in 0.73mL methylene dichloride; the in the situation that of stirring at room, slowly add trifluoroacetic acid 0.73mL, stirring at room stopped reaction after half an hour.By reaction solution evaporate to dryness, with ether, grind, filter, collect filter cake, obtain target product 30mg (87.2%).
1H-NMR(300MHz，CD
3OD)1.57-1.72(m，12H)，2.23(br?s，2H)，2.23(m，1H)，2.76(m，1H)，3.01(s，3H)，3.57(m，1H)，3.97(s，1H)，4.00-4.13(m，2H)，4.82(m，1H)；
13C-NMR(75MHz，CD
3OD)31.4，35.9，37.8，37.9，40.6，44.8，46.1，46.2，53.0，54.0，60.2，68.6，118.6，168.1；ESI-MSm/z：397.2[M+H]
+.
Embodiment 8
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-p-toluenesulfonyl amino-2-Cyanopyrolidine
(1) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-p-toluenesulfonyl amino-2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine 60mg (0.144mmol) is dissolved in 1.5mL anhydrous methylene chloride, adds 0.04mL triethylamine.Under 0 degree, solid Tosyl chloride 30.1mg (0.158mmol) is added in reaction system, stir 1 hour stopped reaction.With methylene dichloride and water dilute reaction solution, rear layering retains organic layer, and successively with 1N HCl, saturated common salt washing organic layer, anhydrous magnesium sulfate drying, by column chromatography for separation (CH
2cl
2/ MeOH=80/1) obtain sterling 60mg (73.2%).
1H-NMR(300MHz，CDCl
3)1.41-1.66(m，12H)，1.41(s，9H)，2.23(br?s，2H)，2.23-2.44(m，2H)，2.44(s，3H)，3.63(m，1H)，3.96(m，2H)，4.07(d，J＝9，1H)，4.67(m，1H)，5.33(d，J＝6，1H)，6.16(m，1H)，7.35(d，J＝9，2H)，7.79(d，J＝9，2H)；
13C-NMR(75MHz，CDCl
3)21.5，28.3，30.1，30.2，35.0，36.3，37.7，40.9，44.1，44.2，44.5，46.3，52.2，52.7，59.0，68.6，80.0，117.8，127.2，130.0，136.7，144.1，155.7，170.7；ESI-MSm/z：573.3[M+H]
+.
(2) (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-p-toluenesulfonyl amino-2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-p-toluenesulfonyl amino-2-Cyanopyrolidine 40mg is dissolved in 0.75mL methylene dichloride; the in the situation that of stirring at room, slowly add trifluoroacetic acid 0.75mL, stirring at room stopped reaction after half an hour.By reaction solution evaporate to dryness, with ether, grind, filter, collect filter cake, obtain target product 35mg (82%).
1H-NMR(300MHz，DMSO-d6)1.44-1.54(m，12H)，2.01(m，1H)，2.08(br?s，2H)，2.32(m，1H)，2.36(s，3H)，3.32(m，1H)，3.84(s，1H)，3.92(m，1H)，4.68(m，1H)，7.42(d，J＝9，2H)，7.71(d，J＝9，2H)；
13C-NMR(75MHz，DMSO-d6)21.4，28.7，29.8，34.4，35.2，36.6，37.0，44.6，45.0，45.5，51.5，52.4，58.5，66.8，118.5，127.1，130.2，137.8，143.6，167.3；ESI-MSm/z：473.2[M+H]
+.
Embodiment 9
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(1-pyrrolidyl)-2-Cyanopyrolidine
(1) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(1-pyrrolidyl)-2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine 40mg (0.096mmol) is dissolved in 1mL nitrogen dimethylformamide; add triethylamine 0.053mL (0.38mmol); Isosorbide-5-Nitrae dibromobutane 0.023mL (0.191mmol).This mixed solution is heated to 60 degree, and stopped reaction after 6 hours, is cooled to zero degree by reaction solution, adds a small amount of saturated sodium bicarbonate solution under stirring, after add ethyl acetate, layering, retains organic layer, dry.Column chromatography purification (CH
2cl
2/ MeOH=60: 1) obtain sterling 35.9mg (79.8%).
1H-NMR(300MHz，CDCl
3)1.43-1.87(m，12H)，1.43(s，9H)，2.20-2.26(m，5H)，2.30-2.65(m，7H)，2.84-2.89(m，1H)，3.54(m，1H)，3.98(m，1H)，4.20(d，J＝9，1H)，4.65(m，1H)，5.30(d，J＝9，1H)；
13C-NMR(75MHz，CDCl
3)23.5，28.3，29.7，30.2，35.0，35.1，37.0，37.4，41.2，44.3，45.0，46.2，52.6，52.9，58.8，62.7，68.5，79.9，117.6，155.8，170.3；ESI-MSm/z：473.3[M+H]
+.
(2) (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(1-pyrrolidyl)-2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(1-pyrrolidyl)-2-Cyanopyrolidine 25mg is dissolved in 0.55mL methylene dichloride; the in the situation that of stirring at room, slowly add trifluoroacetic acid 0.55mL, stirring at room stopped reaction after half an hour.By reaction solution evaporate to dryness, with ether, grind, filter, collect filter cake, obtain target product 20mg (77.2%).
1H-NMR(300MHz，CD
3OD)1.62-1.72(m，12H)，2.14(m，4H)，2.28(br?s，2H)，2.47-2.55(m，1H)，3.00-3.09(m，1H)，3.30-3.32(m，4H)，3.67-3.73(m，1H)，3.89-3.96(m，1H)，4.07(s，1H)，4.51-4.56(m，1H)，4.87-4.90(m，1H)；
13C-NMR(75MHz，CD
3OD)24.1，31.5，33.0，35.9，37.8，37.9，40.8，44.8，46.1，46.4，50.2，54.9，60.3，62.1，68.6，117.8，168.3；ESI-MSm/z：373.3[M+H]
+.
Embodiment 10
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-phenmethyl amino-2-Cyanopyrolidine
(1) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-phenmethyl amino-2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine 102mg (0.244mmol) is dissolved in 2mL methyl alcohol, adds phenyl aldehyde 0.027mL (0.268mmol) under stirring.Stirring at room adds itrile group sodium borohydride 33mg (2.5mmol) after one hour, continue to stir 18 hours.Remove solvent under reduced pressure, by ethyl acetate, dilute residual reactants, saturated common salt washing one time, dry.Column chromatography purification (CH
2cl
2/ MeOH=80: 1) obtain sterling 100mg (80.6%).
1H-NMR(300MHz，CDCl
3)1.42-1.75(m，12H)，1.43(s，9H)，2.22(br?s，2H)，2.22-2.41(m，2H)，3.52(m，2H)，3.79(m，2H)，3.90(m，2H)，4.20(d，J＝9，1H)，4.75(m，1H)，5.28(d，J＝9，1H)，7.30(m，5H)；
13C-NMR(75MHz，CDCl
3)28.3，30.2，35.1，35.2，36.9，37.4，41.0，44.3，44.4，44.7，46.2，51.9，53.5，56.7，58.7，68.5，79.9，118.2，127.4，128.1，128.6，139.2，155.7，170.5；ESI-MSm/z：509.3[M+H]
+.
(2) (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-phenmethyl amino-2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-phenmethyl amino-2-Cyanopyrolidine 25mg is dissolved in 0.5mL methylene dichloride; the in the situation that of stirring at room, slowly add trifluoroacetic acid 0.5mL, stirring at room stopped reaction after half an hour.By reaction solution evaporate to dryness, with ether, grind, filter, collect filter cake, obtain target product 20mg (72.2%).
1H-NMR(300MHz，CD
3OD)1.62-1.76(m，12H)，2.29(br?s，2H)，2.30(m，1H)，3.00(m，1H)，3.62(m，1H)，3.93(m，1H)，4.01(s，1H)，4.30(s，2H)，4.50(m，1H)，7.46-7.54(m，5H)；
13C-NMR(75MHz，CD
3OD)31.5，33.1，35.9，37.9，40.8，44.8，46.2，46.4，50.5，51.9，55.4，60.4，68.6，118.0，130.4，130.8，132.6，168.3；ESI-MSm/z：409.3[M+H]
+.
Embodiment 11
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(nitrogen-phenmethyl-nitrogen-methylamino)-2-Cyanopyrolidine
(1) (2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(nitrogen-phenmethyl-nitrogen-methylamino)-2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-phenmethyl amino-2-Cyanopyrolidine 25mg (0.05mmol) dissolves in 1mL methyl alcohol, adds paraformaldehyde 3mg (0.1mmol) under stirring.Stirring at room adds itrile group sodium borohydride 7.8mg (0.125mmol) after four hours, continue to stir 18 hours.Remove solvent under reduced pressure, by ethyl acetate, dilute residual reactants, saturated common salt washing one time, dry.Column chromatography purification (CH
2cl
2/ MeOH=80: 1) obtain sterling 20mg (74%).
1H-NMR(300MHz，CDCl
3)1.43-1.67(m，12H)，1.43(s，9H)，2.23(s，5H)，2.30-2.34(m，1H)，2.54-2.59(m，1H)，3.13(m，1H)，3.47-3.61(m，3H)，3.13-3.20(m，2H)，4.62-4.67(m，1H)，5.26(d，J＝9，1H)，7.33(m，5H)；
13C-NMR(75MHz，CDCl
3)28.3，29.7，30.2，35.1，37.0，37.4，39.7，41.1，44.3，44.9，46.2，51.2，58.9，60.2，62.6，68.5，79.9，117.7，127.5，128.5，128.8，155.8，170.5；ESI-MSm/z：523.3[M+H]
+.
(2) (2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(nitrogen-phenmethyl-nitrogen-methylamino)-2-Cyanopyrolidine
By (2S; 4S)-1-((S)-2-(1; 1-dimethyl ethoxy carbonyl amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(nitrogen-phenmethyl-nitrogen-methylamino)-2-Cyanopyrolidine 20mg is dissolved in 0.4mL methylene dichloride; the in the situation that of stirring at room, slowly add trifluoroacetic acid 0.4mL, stirring at room stopped reaction after half an hour.By reaction solution evaporate to dryness, with ether, grind, filter, collect filter cake, obtain target product 15mg (70%).
1H-NMR(500MHz，CD
3OD)1.62-1.75(m，12H)，2.28(br?s，2H)，2.55(m，1H)，2.72(s，3H)，3.07(m，1H)，3.76-3.80(m，1H)，3.91(m，1H)，4.01(s，1H)，4.33(s，2H)，4.50(m，1H)，7.49-7.53(m，5H)；
13C-NMR(125MHz，CD
3OD)31.5，32.4，35.9，37.9，39.1，40.8，44.8，46.2，46.4，50.2，60.3，60.7，63.3，68.6，118.0，130.4，131.0，132.0，168.3；ESI-MSm/z：423.3[M+H]
+.
Embodiment 12
The vitro detection test of the compounds of this invention to DPPIV enzyme inhibition activity
Instrument: microplate reader, SpectraMax M5 (Molecular Devices, USA)
Material: people source restructuring DPPIV enzyme (Cat:SE434-9090, Biomol); 50mM Tris damping fluid, pH=7.5; Fluorogenic substrate GP-AMC (Cat:P189-9090, Biomol); Positive control P32/98 (Cat:PI142-9090, Biomol), positive control BMS-477118, self-control; Test-compound 1-13, self-control.
Method:
A) 96 hole blackboards are equilibrated to room temperature.
B) use 1: 50 times of dilution 500 μ M AMC substrates of reaction buffer, the reaction final concentration that makes AMC substrate is 5 μ M, the substrate solution that each hole needs 50 μ l to dilute.
C) with 13 testing compounds of reaction buffer dilution, making its final screening concentration is 10 μ M and 100nM, and each extent of dilution is done a multiple hole.
D) to the testing compound of all different concns on 96 hole Sptting plates, measure in hole and add 25 μ l reaction buffers, and add successively the compound of the different concns that 10 μ l have diluted in corresponding reacting hole.For negative control and blank hole, add respectively 35 μ l and 50 μ l reaction buffers.For positive control hole, add 25 μ l reaction buffers and 10 μ l P32/98.For positive control hole, add 25 μ l reaction buffers and 10 μ l P32/98.All reference compound holes and control wells are done a multiple hole.
E) use 1: 50 times of dilution DPPIV enzyme of reaction buffer, in all reacting holes except blank hole, the DPPIV that adds 15 μ l to dilute, the enzyme amount that makes DPPIV in reacting hole is 0.26MU/ hole.
F) to the AMC substrate solution that adds 50 μ l to dilute in all reacting holes, carry out initial action.
G) normal temperature was hatched after 10 minutes, reading Ex:380nm/Em:460nm on SpectraMax M5.
The calculating of testing compound inhibiting rate:
A) calculate the average signal value of each sample.
B) signal value of each concentration of specimens deducts average background signal value.
C) calculate the inhibiting rate of each sample.Calculate the inhibiting rate of each sample.100% active hole reading is deducted respectively after each testing compound different concns corresponding aperture reading, divided by 100% active hole reading, be multiplied by 100 obtain respectively each testing compound different concns inhibiting rate.
% inhibiting rate=[100% active hole-sample aperture]/100% active hole * 100
DPPIV enzyme inhibition activity result
The DPPIV enzyme inhibition rate test result of representative compound of the present invention is as shown in table 1:
A table 113 testing compound inhibiting rate
Claims (9)
1. the invention provides compound that following general formula (I) represents and pharmacy acceptable salt thereof as the purposes of DPPIV inhibitor:
Wherein:
R
1be selected from the group of alkyl, cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyl cycloalkyl, hydroxyl bicyclic alkyl, hydroxyl tricyclic alkyl, aryl or heteroaryl;
R
2, R
3respectively be selected from hydrogen atom, amino, azido-, hydroxyl, straight chained alkyl, branched-chain alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical ,-NR
4r
5,-OR
6, fluorine atom, chlorine atom, bromine atoms;
Or R
2with R
3jointly represent cycloalkyl, the thiazolinyl of 3 to 10 carbon;
R
4, R
5, R
6respectively be selected from hydrogen atom, straight chained alkyl, branched-chain alkyl, cycloalkyl, acyl group, alkylsulfonyl, aryl, heteroaryl, heterocyclic radical;
Or R
4with R
5common representative is containing the cycloalkyl of 2 to 10 carbon;
The carbon that No. 1 carbon and No. 2 carbon are optically pure chiral carbon or racemization.
2. according to the compound or its salt of claim 1, further, the present invention includes compound or its pharmacy acceptable salt that following general formula (IA) represents:
Wherein:
R
2, R
3respectively be selected from hydrogen atom, amino, azido-, hydroxyl, straight chained alkyl, branched-chain alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical ,-NR
4r
5,-OR
6, fluorine atom, chlorine atom, bromine atoms;
Or R
2with R
3jointly represent cycloalkyl, the thiazolinyl of 3 to 10 carbon;
R
4, R
5, R
6respectively be selected from hydrogen atom, straight chained alkyl, branched-chain alkyl, cycloalkyl, acyl group, alkylsulfonyl, aryl, heteroaryl, heterocyclic radical;
Or R
4with R
5common representative is containing the cycloalkyl of 2 to 10 carbon;
R
7, R
8respectively be selected from hydrogen atom or hydroxyl.
3. according to claim 1,2 compound or its salt, described salt is the salt that is selected from following acid: hydrochloric acid, trifluoroacetic acid, methylsulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid.
4. according to claim 1,2 and 3 compound or its salt, described compound and the intermediate thereof of general formula of the present invention (I) comprises that following compound is not limited in this:
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl) the fluoro-2-formamyl of-4-tetramethyleneimine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl) fluoro-2-Cyanopyrolidine of-4-;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl) fluoro-2-Cyanopyrolidine of-4-;
(2S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4, the fluoro-2-formamyl of 4-bis-tetramethyleneimine;
(2S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4, the fluoro-2-Cyanopyrolidine of 4-bis-;
(2S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4, the fluoro-2-Cyanopyrolidine of 4-bis-;
(2S, 4S)-1-(1,1-dimethyl ethoxy carbonyl)-4-azido--2-formamyl tetramethyleneimine;
(2S, 4S)-4-azido--2-formamyl tetramethyleneimine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-formamyl tetramethyleneimine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-azido--2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-acetylaminohydroxyphenylarsonic acid 2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(2-phenyl acetyl is amino)-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-methylsulfonyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-p-toluenesulfonyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(1-pyrrolidyl)-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-acetylaminohydroxyphenylarsonic acid 2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(2-phenyl acetyl is amino)-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-methylsulfonyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-p-toluenesulfonyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(1-pyrrolidyl)-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-phenmethyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-(1,1-dimethyl ethoxy carbonyl is amino)-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(nitrogen-phenmethyl-nitrogen-methylamino)-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-phenmethyl amino-2-Cyanopyrolidine;
(2S, 4S)-1-((S)-2-amino-2-(3-hydroxyl-1-adamantyl) ethanoyl)-4-(nitrogen-phenmethyl-nitrogen-methylamino)-2-Cyanopyrolidine.
5. a method of preparing compound (I) and intermediate thereof, is characterized in that comprising the steps:
A kind of synthetic method of pyrrolidines derivative
In above formula, R
1, R
2, R
3definition as previously mentioned.Wherein No. 1 with No. 2 carbon atoms can respectively do for oneself R or S configuration, wherein dipeptide compound can be the mixture that single steric configuration also can be raceme or non-corresponding isomer.
Step (1): the amino acid of nitrogen tertbutyloxycarbonyl protection is reacted with the tetramethyleneimine acid amides of replacement and generates amido linkage, the realization of this process can by condensing agent or by carboxylic acid being become to acyl chlorides or acid anhydrides carrys out activating carboxy acid, wherein condensing agent be selected from DCC, EDC, DCI, BOP, PIC, BDDC, HOBt, HATU, HBTU, HCTU; Form mixed acid anhydride can with following reagent react, isoveryl chloride, Vinyl chloroformate, EDDQ, PNP, HOBt, HOAt; Form acyl chlorides and can use thionyl chloride, oxalyl chloride;
Step (2): convert amido linkage to itrile group under the effect of dewatering agent, wherein dewatering agent can be sulfur oxychloride, five phosphorus oxide, cyanuric chloride, trifluoroacetic anhydride, phosphorus oxychloride, phosphorus pentachloride;
Step (3): slough BOC protecting group under sour effect, acid used is selected from hydrochloric acid, trifluoroacetic acid.
6. a drug regimen, it is characterized in that, it contains compound described in claim 1 to 4, general formula (I) and pharmacy acceptable salt thereof, solvate, various crystal formation and medically acceptable vehicle or carrier mix, and its form can be tablet, capsule, granule, dripping pill and injection.
7. a compound described in claim 1 to 4, the purposes of general formula (I) and pharmacy acceptable salt thereof, solvate, various crystal formations, is characterized in that, for the preparation of the inhibitor of dipeptidyl peptidase (DPPIV).
8. compound described in a claim 1 to 4, the purposes of general formula (I) and pharmacy acceptable salt thereof, solvate, various crystal formations, it is characterized in that, be used for the treatment of, the medicine of prevention and the alleviation disease relevant to dipeptidyl peptidase (DPPIV).
9. purposes as claimed in claim 8, is characterized in that, the described disease relevant to dipeptidyl peptidase (DPPIV) is selected from diabetes, obesity or hyperlipidemia.
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| CN104496876A (en) * | 2015-01-13 | 2015-04-08 | 佛山市赛维斯医药科技有限公司 | Hydroxyl diamantane amide derivative, preparation method and use thereof |
| CN104529855A (en) * | 2015-01-13 | 2015-04-22 | 佛山市赛维斯医药科技有限公司 | Derivative containing hydroxyl adamantane and amide structure and preparation method and application thereof |
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| CN104496876A (en) * | 2015-01-13 | 2015-04-08 | 佛山市赛维斯医药科技有限公司 | Hydroxyl diamantane amide derivative, preparation method and use thereof |
| CN104529855A (en) * | 2015-01-13 | 2015-04-22 | 佛山市赛维斯医药科技有限公司 | Derivative containing hydroxyl adamantane and amide structure and preparation method and application thereof |
| US11957657B2 (en) | 2016-09-07 | 2024-04-16 | Trustees Of Tufts College | Combination therapies using immuno-dash inhibitors and PGE2 antagonists |
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| WO2021165927A1 (en) * | 2020-02-21 | 2021-08-26 | Wockhardt Bio Ag | 2-cyanopyrroldines, -piperidines or -dazepines as hyperglycemic agents |
| KR20220122511A (en) * | 2021-02-26 | 2022-09-02 | 고려대학교 산학협력단 | Novel adamantyl derivative or its pharmaceutically acceptable salts and use thereof |
| KR102567944B1 (en) * | 2021-02-26 | 2023-08-18 | (주)캔테라피 | Novel adamantyl derivative or its pharmaceutically acceptable salts and use thereof |
| KR20230124853A (en) * | 2021-02-26 | 2023-08-28 | (주)캔테라피 | Composition for preventing or treating diabetes comprising a novel adamantyl derivative or a pharmaceutically acceptable salt thereof |
| KR102596326B1 (en) | 2021-02-26 | 2023-11-01 | (주)캔테라피 | Composition for preventing or treating diabetes comprising a novel adamantyl derivative or a pharmaceutically acceptable salt thereof |
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