CN108003080A - A kind of N- amino acid cyanopyrrole alkane derivative and preparation method thereof - Google Patents

A kind of N- amino acid cyanopyrrole alkane derivative and preparation method thereof Download PDF

Info

Publication number
CN108003080A
CN108003080A CN201711320391.5A CN201711320391A CN108003080A CN 108003080 A CN108003080 A CN 108003080A CN 201711320391 A CN201711320391 A CN 201711320391A CN 108003080 A CN108003080 A CN 108003080A
Authority
CN
China
Prior art keywords
boc
amino acid
pyrrolidines
cyanopyrrole
method described
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201711320391.5A
Other languages
Chinese (zh)
Inventor
吴诗
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hubei University of Science and Technology
Original Assignee
Hubei University of Science and Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hubei University of Science and Technology filed Critical Hubei University of Science and Technology
Priority to CN201711320391.5A priority Critical patent/CN108003080A/en
Publication of CN108003080A publication Critical patent/CN108003080A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a kind of N amino acid cyanopyrrole alkane derivative and preparation method thereof, is related to a kind of synthetic method of compound and compound.Amides compound is obtained by amidation process and deprotection two-step reaction.Preliminary pharmacological evaluation shows that compound of the invention has stronger inhibitory activity to DPP IV, can be in the application in preparing type II diabetes resisting medicine, DPP IV inhibitor brand-new as structure.Rationally, briefly, mild condition is good for the environment the highway route design that the present invention synthesizes, and is easy to purification process, and yield is higher, suitable for practicality.

Description

A kind of N- amino acid cyanopyrrole alkane derivative and preparation method thereof
Technical field
The present invention relates to a kind of synthesis of compound, more particularly to a kind of N- amino acid cyanopyrrole alkane derivative and its preparation Method.
Background technology
With the further investigation of onset diabetes mechanism, the novel targets for acting on diabetes are gradually found, and result of study is shown There is good development prospect for the medicine of endogenous glucagon-like-peptide-1 (GLP-1) target spot research.GLP-1 is by small A kind of duodenin of intestines L cells secretion, discharges during nutrient in absorption of human body, there is glucose dependency to promote pancreas islet The effect of element secretion, it mainly exists in the form of two kinds of GLP-1 (7-36) acid amides and GLP-1 (7-37) in vivo.DPP-IV pair The main mechanism of GLP-1 is：The transmembrane serine protease that the DPP-IV of the mankind is made of 766 amino acid, its energy Two amino acid residue Xaa-Pro or Xaa-Ala (Xaa is arbitrary amino acid) are hydrolyzed from the penultimate position of peptide chain N-terminal, So that partially or completely inactivating occur in active peptides, and the N-terminal of GLP-1 (7-36) the 2nd is alanine (Ala), so it Inactive GLP-1 (9-36) can be hydrolyzed to rapidly by DPP-IV.
DPP-IV inhibitor has the danger for avoiding hypoglycemia from occurring, the development for fundamentally improving diabetic duration and long-term The advantages of using weight is not interfered with.DPP-IV inhibitor, can also be with other oral hypoglycemic agents in addition to it can individually take Thing is used in combination, and evident in efficacy.DPP-IV enzyme is a member in serine stretch protein enzyme family.Inside this big family, The grade isodynamic enzyme of also DPP- VIII, DPP- Ⅸ, structure and the DPP-IV of these enzymes have many similitudes, and the suppression to these enzymes may It can cause pathological change or the death of its hetero-organization.Meanwhile DPP-IV enzyme also has other physiology related substrates, to DPP-IV Suppression may result in the expressions of some active substances and change, so as to produce some side effects.
Achievement in research and discovery, this project based on more than devise one for GLP-1 in the histidine particularity of cracking section Cyanopyrrole alkanes DPP-IV inhibitor of the group containing similar histidine imidazole group, it is desirable to be able to more single-minded suppression DPP-IV enzyme GLP-1 is cracked, so that as a kind of medicine of new efficient treatment diabetes B.
The content of the invention
First purpose of the present invention is for the above problem existing for existing technology, there is provided there is one kind DPP-IV to suppress to live The N- amino acid cyanopyrrole alkane derivatives of property.
The purpose of the present invention can be realized by following technical proposal：
The general structure of the N- amino acid cyanopyrrole alkane derivative is as follows：
Wherein：
R is native amino acid residues；The R can be Boc-L- amino acid.
It is a further object to provide a kind of N- amino acid Cyanopyrolidine and its physiological acceptable salt preparation method, leads to Cross following steps realization：
Above-mentioned reaction expression is the reaction equation for being used to prepare target compound V, and step 1) makes Boc-L- ammonia under catalyst action Amidation process occurs in DMF for base acid and 2- Cyanopyrolidine tosilate, synthesizes (2S) -1- (Boc-L- aminoacyls) pyrrole Cough up alkane -2- formonitrile HCNs；1- (Boc-L- aminoacyls) pyrrolidines -2- formonitrile HCNs for making to obtain in step 1) are with trifluoroacetic acid in anhydrous dichloromethane Reacted in alkane, obtain target compound V (2S) -1- (L- aminoacyls) pyrrolidines -2- formonitrile HCNs (tfa salt)；
Wherein, the Boc-L- amino acid used in step 1) can be Boc-L- glutamic acid, Boc-L- histidines, Boc-L- ammonia One or more in acid, Boc-L- lysines, Boc-L- tyrosine, Boc-L- cysteines, Boc-L- tryptophans, Boc-L- The molar ratio of amino acid and Cyanopyrolidine is 1:0.9~1:1.2.
The catalyst used in step 1) is HOBt/EDCI, and the molar ratio of Boc-L- amino acid and catalyst is 1：2~1：4；Instead It is 0~5 DEG C to answer temperature, and when the reaction time is 20 small, the DMF used is anhydrous DMF；Immediately treat, that is, rotate after reaction Solvent, adds anhydrous ether, the crystallization of precipitation is product.
The trifluoroacetic acid used in step 2) is anhydrous trifluoroacetic acid, (2S) -1- (Boc-L- aminoacyls) pyrrolidines -2- formonitrile HCNs and three The ratio of fluoroacetic acid is 0.15:1mL~0.3g:1mL；Reaction temperature is 0 DEG C, the reaction time for 1~2 it is small when, the dichloromethane that uses Alkane is anhydrous methylene chloride.
Step 1) carries out under nitrogen protection with reaction 2), and is water-less environment.
Make a general survey of whole technological process, it can be seen that innovation of the invention：Using gentle reaction condition, above-mentioned several steps exist Carried out at 0~10 DEG C, be conducive to energy conservation and environmental protection.Secondly, raw material is cheap and easy to get, and reagent environmental pollution is small, and the reaction time is short, High income, be easy to purification process, is adapted to industrial production.
The synthesis of (2S) -1- (Boc-L- aminoacyls) pyrrolidines -2- formonitrile HCNs：With Boc- amino acid and 2- Cyanopyrolidines to toluene sulphur Hydrochlorate is raw material, HOBt/ECDI and N, and N dimethyl acetamide is catalyst, and DMF is solvent, and it is small to react 20 under nitrogen protection When；Remove DMF in reaction solution and obtain grease, dissolved with ethyl acetate, cross chromatographic column, obtain (2S) -1- (Boc-L- aminoacyls) Pyrrolidines -2- formonitrile HCNs；Specific reaction equation is as follows：
The synthesis of (2S) -1- (L- aminoacyls) pyrrolidines -2- formonitrile HCNs (tfa salt)：Under nitrogen protection, by (2S) -1- (Boc-L- ammonia Acyl) pyrrolidines -2- formonitrile HCNs are dissolved in anhydrous methylene chloride, trifluoroacetic acid is slowly added dropwise；When reaction 1~2 is small, after reaction, instead Answer liquid to be spin-dried for, add anhydrous ether, to be crystallized separate out is product；Specific reaction equation is as follows：
Further object of the present invention is to provide N- amino acid cyanopyrrole alkane derivatives and its physiological acceptable salt in 2 types that prepare Application in diabetes medicament, N- amino acid cyanopyrrole alkane derivative and its physiological acceptable salt obtained above are used to make Standby diabetes B medicine.Preliminary pharmacological evaluation shows：The most compounds of hair have DPP-IV strong inhibitor activity.
The present invention distinguishing feature be：By brief synthetic route, the brand-new DPP-IV inhibitor of a class formation is quickly obtained, Reaction condition is gentle, easily operated and industrialized production.Preliminary pharmacological evaluation shows：Most compounds have DPP-IV by force Inhibitory activity.
Brief description of the drawings
Fig. 1 is the 1H NMR spectras of V1 in the present embodiment one.
Fig. 2 is the 1C NMR spectras of V1 in the present embodiment one.
Fig. 3 is the 1H NMR spectras of V2 in the present embodiment two.
Fig. 4 is the 1C NMR spectras of V2 in the present embodiment two.
Fig. 5 is the 1H NMR spectras of V3 in the present embodiment three.
Fig. 6 is the 1C NMR spectras of V3 in the present embodiment three.
Fig. 7 is the 1H NMR spectras of V4 in the present embodiment four.
Fig. 8 is the 1C NMR spectras of V4 in the present embodiment four.
Fig. 9 is the 1H NMR spectras of V5 in the present embodiment five.
Figure 10 is the 1C NMR spectras of V5 in the present embodiment five.
Figure 11 is the 1H NMR spectras of V6 in the present embodiment six.
Figure 12 is the 1C NMR spectras of V6 in the present embodiment six.
Figure 13 is the 1H NMR spectras of V7 in the present embodiment seven.
Figure 14 is the 1C NMR spectras of V7 in the present embodiment seven.
Embodiment
It is the specific embodiment of the present invention and with reference to attached drawing below, technical scheme is further described, but this Invention is not limited to these embodiments.
Embodiment one：
(2S) -2- amino-paddy diacyl-two ((2S, 2S ') -2- Cyanopyrolidines) synthesis of (tfa salt) V1 includes following step Suddenly：
(1) synthesis of (2S) -1-Boc-L- paddy diaminourea-two (2S, 2S ') -2- formonitrile HCN pyrrolidines：
Under nitrogen protection, in the there-necked flask of the 50mL equipped with magnetic stirring apparatus, addition Boc-L- glutamic acid (0.379g, 1.54mmol, M=247), EDCI (0.516g, 2.792mmol), HOBT (0.566g, 4.20mmol) and DMF (10mL), 0 Magnetic agitation 4h at DEG C, adds 2- Cyanopyrolidines tosilate (0.749g, 2.792mmol) and diisopropylethylamine The DMF solution 5mL of (0.69mL, 4.20mmol), continues stirring reaction 20h, TLC monitoring reaction end [v (petroleum ether):V (second Acetoacetic ester)=1:1].Solvent is removed under reduced pressure at 50 DEG C and obtains yellow oil, reaction solution addition 50mL for oil pump after reaction Add saturated sodium bicarbonate after dichloromethane to wash twice (5mL × 2), NaCl twice (5mL × 2), use by organic layer Anhydrous sodium sulfate is dried, and filters concentration.Silica gel column purification [v (petroleum ether):V (ethyl acetate)=2:1], colorless oil can be obtained Thing, weight 0.317g (yield 51.2%).
1H NMR spectra data are as follows：1H NMR(400MHz,CD3OD):δ 5.46~5.44 (d, 1H, NH), 4.80~4.78 (q, 1H, CH-CN), 4.76~4.73 (q, 1H, CH-CN), 4.50~4.47 (t, 1H, CH-NH2), 4.02~4.00 (m, 1H, ), CH2 3.69~3.65 (m, 1H, CH2), 3.59~3.56 (m, 1H, CH2), 3.45~3.41 (m, 1H, CH2), 2.47~ 2.43 (m, 1H, CH2), 2.36~2.34 (m, 1H, CH2), 2.26~2.11 (m, 10H, 5CH2), 1.40 (s, 9H, 3CH3)
13C NMR spectra data are as follows：13C NMR(100MHz,CDCl3):δ 171.44 (C=O), 170.91 (C=O), 155.82 (C=O), 118.55 (CN), 118.26 (CN), 79.70 (C), 50.83 (CHNH2), 46.59 (CH-CN), 46.42 (CH-CN),46.30(CH2),29.94(CH2),29.73(CH2),29.24(CH2),28.22(CH2),25.28(CH2), 25.03(CH2),20.96(CH2),20.64(CH2).
(2) (2S) -2- amino-paddy diacyl-two ((2S, 2S ') -2- Cyanopyrolidines) (tfa salt) V1 synthesis：
Under nitrogen protection, (2S) -1-Boc-L- paddy diaminourea-two (2S, 2S ') -2- formonitrile HCN pyrroles are added in two mouthfuls of bottles of 50mL Alkane (0.202g, 0.5mmol) is coughed up, anhydrous methylene chloride (3mL) is steamed again, TFA (1mL) is added dropwise under the conditions of ice-water bath.It is added dropwise The reaction was continued in ice-water bath afterwards 30min, then 1h is stirred at room temperature.About 0.5mL is concentrated under reduced pressure into after reaction, adds nothing Water ether 10mL (pays attention to the moisture absorption, should operate under nitrogen protection) when adding anhydrous ether washing, produces white precipitate, low temperature fills Point stand, precipitation completely after, anhydrous ether washing precipitation twice (5mL × 2), oil pump vacuumize 40 DEG C of dryings 2 it is small when, can obtain in vain Color solid powder V1 (weight 0.177g, yield 84.6%).
1H NMR spectra data are as follows：1H NMR(400MHz,CD3OD):δ 4.85~4.84 (q, 1H, CH-CN), 4.79~ 4.76 (t, 1H, CH-NH2), 4.42~4.39 (q, 1H, CH-CN), 3.824~3.48 (m, 4H, 2CH2), 2.63~2.60 (t, 2H, CH2), 2.29~2.15 (m, 10H, 5CH2)
13C NMR spectra data are as follows：13C NMR(100MHz,DMSO):δ 170.07 (C=O), 168.01 (C=O), 158.70~157.70 (CF3COOH), 119.37 (CN), 118.85 (CN), 50.28 (CHNH2), 46.45 (CH-CN), 46.11 (CH-CN), 46.11 (CH2), 46.07 (CH2), 29.68 (CH2), 29.35 (CH2), 28.57 (CH2), 24.94 (CH2), 24.74(CH2).
Embodiment two
The synthesis of (2S) -1- (L- histidyl-s) pyrrolidines -2- formonitrile HCNs (tfa salt) V2：
(1) equally operated by embodiment one, the Boc-L- glutamic acid used in step (1) is only changed into Boc-L- histidines, is obtained To white solid powder, yield 57.7%.
1H NMR(600MHz,CDCl3):δ 8.05 (s, 1H), 7.19 (s, 1H), 5.40~5.39 (m, 1H), 4.74~4.71 (m, 2H), 3.72~3.67 (m, 2H), 3.57~3.53 (m, 1H), 2.97~2.89 (m, 2H), 2.21~2.20 (m, 1H), 2.13~2.08 (m, 2H), 1.61~1.59 (s, 9H), 1.43~1.40 (s, 9H)
(2) equally operate by embodiment one, be only changed into (2S) -1- (Boc-L- glutamy) pyrrolidines -2- formonitrile HCNs in step (2) (2S) -1- (Boc-L- histidyl-s) pyrrolidines -2- formonitrile HCN V2, obtain white solid, yield 74.5%.
1H NMR spectra data are as follows：
1H NMR(600MHz,MeOD):δ 8.90 (s, 1H, C4-H), 7.48 (s, 1H, C2-H), 4.86~4.84 (m, 1H, C12- H), 4.63~4.61 (t, 1H, C7-H), 3.72~3.71 (m, 1H, C15-H), 3.58~3.57 (m, 1H, C15-H), 3.43~ 3.34 (m, 2H, C6-H), 2.35~2.32 (m, 1H, C13-H), 2.28~2.25 (m, 1H, C13-H), 2.15~2.13 (t, 2H,C14-H).
13C NMR spectra data are as follows：
13C NMR(101MHz,DMSO):δ 167.23 (8-CO), 135.15 (4-N=C-N-), 126.75 (2-N-C=), 118.99 (1=C-N-), 118.98 (16-CN), 50.42 (7-CNH2), 47.00 (12-CHCN), 46.95 (15-CH2), 29.57(6-CH2),25.61(13-CH2-),25.02(14-CH2-).
Embodiment three
The synthesis of (2S) -1- (L- seryls) pyrrolidines -2- formonitrile HCNs (tfa salt) V3：
Equally operated by embodiment one, the Boc-L- glutamic acid used in step (1) is only changed into Boc-L- serines, is obtained To white crystal, yield 59.0%.
1H NMR spectra data are as follows：1H NMR(400MHz,CD3OD):δ 5.57 (d, 1H, NH) 4.77~4.76 (t, 1H, CH- ), NH 4.54~4.52 (q, 1H, CH-CN), 3.95~3.91 (q, 1H, CH2-OH), 3.83~3.74 (m, 3H, CH2-OH, ), CH2 2.34~2.16 (m, 4H, CH2-CH2), 1.46 (s, 9H, 3CH3)
13C NMR spectra data are as follows：13C NMR(100MHz,CD3OD):δ 170.59 (C=O), 155.69 (C=O), 118.09(CN),80.46(C),53.47(CHNH2),53.01(CH-CN),46.69(CH2),46.58(CH2),29.85 (CH2),28.30(CH3),25.52(CH2).
(2S) -1- (Boc-L- glutamy) pyrrolidines -2- formonitrile HCNs are changed into (2S) -1- (Boc-L- seryls) pyrroles in step (2) Alkane -2- formonitrile HCNs, obtain white solid powder V3, yield 85.7%.
Example IV
The synthesis of (2S) -1- (L- lysyls) pyrrolidines -2- formonitrile HCNs (tfa salt) V4：Equally operated by embodiment one, only by step (1) the Boc-L- glutamic acid used in is changed into Boc-L- lysines, obtains white crystal, yield 50.2%.
1H NMR spectra data are as follows：1H NMR(400MHz,CDCl3):δ 5.33 (d, 1H, NH), 4.79~4.78 (t, 1H, ), CH-NH 4.68 (b, 1H, NH), 4.39~4.34 (q, 1H, CH-CN), 3.71~3.65 (m, 2H, CH2), 3.12~3.11 (m, 2H, CH2), 2.27~2.18 (m, 4H, CH2-CH2), 1.66~1.43 (m, 24H, CH2CH2CH2,6CH3)
13C NMR spectra data are as follows：13C NMR(100MHz,DMSO):δ 171.37 (C=O), 155.59 (C=O), 155.45 (C=O), 119.27 (CN), 78.05 (C), 77.34 (C), 52.10 (CHNH2), 52.10 (CH-CN), 46.16 (CH2),46.03(CH2),30.27(CH2),29.28(CH2),29.15(CH2),28.26(CH3),28.19(CH3),24.99 (CH2),22.59(CH2).
(2S) -1- (Boc-L- glutamy) pyrrolidines -2- formonitrile HCNs are changed into (2S) -1- (Boc-L- lysyls) pyrroles in step (2) Alkane -2- formonitrile HCNs, obtain white solid powder V4, yield 85.7%.
1H NMR spectra data are as follows：1H NMR(400MHz,CD3OD):δ8.35(b,2H,NH2)7.90(b,2H,NH2)4.80 ~4.77 (q, 1H, CH-CN), 4.13 (b, 1H, CH-NH2), 3.66~3.54 (m, 2H, CH2), 2.77~2.75 (m, 2H, ), CH2 2.23~2.001 (m, 4H, CH2-CH2), 1.78~1.73 (m, 2H, CH2), 1.58~1.55 (m, 2H, CH2), 1.39 ~1.35 (m, 2H, CH2)
13C NMR spectra data are as follows：13C NMR(100MHz,DMSO):δ 168.17 (C=O), 159.23~158.23 (C= O,CF3COOH),118.95(CN),50.86(CHNH2),46.58(CH-CN),38.60(CH2),29.52(CH2),29.45 (CH2),28.56(CH2),26.59(CH2),25.03(CH2),21.11(CH2).
Embodiment five
The synthesis of (2S) -1- (L- tyrosyls) pyrrolidines -2- formonitrile HCNs (tfa salt) V5：
Equally operated by embodiment one, the Boc-L- glutamic acid used in step (1) is only changed into Boc-L- tyrosine, is obtained white Color solid powder, yield 59.3%.
(2S) -1- (Boc-L- glutamy) pyrrolidines -2- formonitrile HCNs are changed into (2S) -1- (Boc-L- tyrosyls) pyrroles in step (2) Alkane -2- formonitrile HCNs, obtain white solid V5, yield 85.7%.
1H NMR spectra data are as follows：
1HNMR(600MHz,D2O):δ 7.08~7.04 (d, 2H, C5,9-H), 6.79~6.74 (d, 2H, C6,8-H), 4.79~ 4.74 (m, 1H, C13-H), 4.34~4.31 (m, 1H, C3-H), 3.28~3.13 (m, 2H, C16-H), 2.99~2.55 (m, 2H, C4-H), 2.14~2.02 (m, 2H, C14-H), 1.81~1.60 (m, 2H, C15-H), 1.27~1.19 (m, 1H, NH2)
13C NMR spectra data are as follows：
13CNMR(101MHz,CDCl3):δ168.02(C1),157.28(C7),131.52(C5),131.11(C9),124.52 (C10),121.91(C18),118.67(C6),115.83(C8),52.83(C3),46.67(C13),46.54(C16),36.66 (C4),29.80(C14),25.02(C15).
Embodiment six
The synthesis of (2S) -1- (L- cysteinyls) pyrrolidines -2- formonitrile HCNs (tfa salt) V6：
Equally operated by embodiment one, the Boc-L- glutamic acid used in step (1) is only changed into Boc-L- cysteines, is obtained White crystal, yield 59.0%.
1H NMR spectra data are as follows：
1H NMR(400MHz,CD3OD):δ 5.06 (d, 1H, NH) 4.74~4.59 (m, 2H, CH-NH, CH-CN), 3.70~ 3.42 (m, 4H, CH2-SH, CH2), 2.16~1.92 (m, 4H, CH2-CH2), 1.40 (s, 9H, 3CH3)
13C NMR spectra data are as follows：
13C NMR(100MHz,CD3OD):δ 165.92 (C=O), 152.95 (C=O), 119.60 (CN), 80.02 (C), 48.79(CHNH2),48.55(CH-CN),48.55(CH2),46.58(CH2),30.32(CH2),28.38(CH3),25.46 (CH2).
(2S) -1- (Boc-L- glutamy) pyrrolidines -2- formonitrile HCNs are changed into (2S) -1- (Boc-L- cysteinyls) pyrrole in step (2) Alkane -2- formonitrile HCNs are coughed up, obtain white solid powder V6, yield 85.7%.
1H NMR spectra data are as follows：
1H NMR(400MHz,CD3OD):δ 4.84~4.82 (t, 1H, CH-CN), 4.27~4.25 (q, 1H, CH-NH2), 4.00 ~3.96 (q, 1H, CH2-OH), 3.83~3.79 (q, 1H, CH2-OH), 3.73~3.66 (m, 2H, CH2), 2.32~2.11 (m,4H,CH2-CH2).
13C NMR spectra data are as follows：
13C NMR(100MHz,CD3OD):δ 166.20 (C=O), 118.43 (CN), 60.89 (CHNH2), 50.07 (CH-CN), 48.90(CH2),46.51(CH2),30.26(CH2),24.44(CH2).
Embodiment seven
The synthesis of (2S) -1- (L- tryptophanyls) pyrrolidines -2- formonitrile HCNs (tfa salt) V7：
Equally operated by embodiment one, the Boc-L- glutamic acid used in step (1) is only changed into Boc-L- tryptophans, is obtained white Color solid powder, yield 62.3%.
(2S) -1- (Boc-L- glutamy) pyrrolidines -2- formonitrile HCNs are changed into (2S) -1- (Boc-L- tryptophanyls) pyrroles in step (2) Alkane -2- formonitrile HCNs, obtain brown solid powder V7, yield 55.4%.
1H NMR spectra data are as follows：
1H NMR(400MHz,DMSO):δ 7.61~7.59 (m, 1H, C12-H), 7.40~7.38 (m, 1H, C9-H), 7.16 (m, 1H,C6-H),7.12(m,1H,C10-H),7.04(m,1H,C11-H),4.79(m,1H,C16-H),4.30(m,1H,C3-H), 3.22~3.20 (m, 2H, C19-H), 2.80 (m, 1H, C4-H), 2.12~2.04 (m, 2H, C17-H), 1.82~1.81 (m, 1H, C4-H), 1.67~1.09 (m, 2H, C18-H)
13C NMR spectra data are as follows：
13C NMR(101MHz,CDCl3):δ168.54(C1),136.64(C8),127.34(C13),125.23(C6), 121.84(C10),119.37(C11),118.98(C12),118.51(C20),112.06(C9),106.91(C5),51.90 (C3),46.76(C16),46.60(C19),29.82(C4),27.19(C17),25.14(C18).
Embodiment eight
The compounds of this invention tests the external inhibitory activity of dipeptidyl peptidase IV
Ge Lieting is positive reference substance to the west of this experiment, and DPPIV albumen enzyme detection kit detection compounds are to human recombinant The inhibitory action of DPPIV proteinase activities.
Experiment material and instrument：Dipeptidyl Peptidase IV(BPS,Cat.NO.80040)、Sitagliptin phosphate hydrate(Selleck.Cat.No.S4002)、DPPIV-GloTM Protease Assay(Promega, Cat.No.G8350), 384-well plate (Corning, Cat.No.4512), EnVision multiple labeling detectors (PerkinElmer,EnVision multilabel reader)
Experimental method：
1) by DPPIV-GloTMBuffer solution in kit, which dissolves, to be warmed to room temperature；
2) before the use, the fluorescein detection reagent of lyophilized is warmed to room temperature；
3) substrate is resuspended with 110 μ l ultra-pure waters, is configured to the substrate that concentration is 10mM and stores；
4) DPPIV-Glo is usedTMBuffer solution 50ml be resuspended fluorescein detection reagent；
5) DPPIV-Glo is preparedTMReagent：By 100 μ l DPPIV-GloTMSubstrate add the 50ml fluoresceins that are resuspended in step 4 Detection reagent, is vortexed and mixes, and the concentration of substrate is 20 μM in the system；(appropriate prepare is needed according to experiment every time)；
6) before using, by DPPIV-GloTMReagent is placed in room temperature 30-60 minutes；
7) test sample is prepared
Buffer solution：Prepare trishydroxymethylaminomethane (Tris) buffer solution of the pH 8.0 of 10mM；
DPP IV enzymes：Prepare the buffer solution of the 1 μ g/L of DPP IV；
Sitagliptin：4 times of dilutions (DMSO for being dissolved in 100%), 10 concentration gradients since 1.0mM；
Test compound：4a, 4b, 4c, 4d respectively since 3.6mM, 2.0mM, 4.8mM and 1.5mM 4 times dilution, totally 10 it is dense Spend gradient.
8) it is loaded per hole
9) DPP4-Glo of 10 μ l is added in various kinds sample wellsTMReagent；
10) plate is placed in 300-500 on vibration plate machine to turn, 30 seconds, mixed；1000 revs/min of centrifuge centrifuges 10 seconds；
11) often react after five minutes, with Envision multiple labeling detector read plates.
Experiment statistics result and analysis:
The calculation formula of inhibiting rate：
The average value of parallel 2 experiments is inhibiting rate, and data processing is analyzed with graphpad prism5 softwares.As a result such as Table 1.
Inhibiting rate of 1 target compound of table to DPP-IV
a:The inhibition ratio was determined at 64nM
In conclusion N- amino acid cyanopyrrole alkane derivatives have inhibitory action to dipeptidyl peptidase IV, it is sugared available for preparing The sick medicine of urine, has application prospect.
Specific embodiment described herein is only to spirit explanation for example of the invention.The technical field of the invention Technical staff can do various modifications or additions to described specific embodiment or substitute in a similar way, but Without departing from spirit of the invention or beyond the scope of the appended claims.

Claims (10)

1. a kind of N- amino acid cyanopyrrole alkane derivative, has general structure V：
Wherein：
R is selected from native amino acid residues：Boc-L- glutamic acid, Boc-L- histidines, Boc-L- serines, Boc-L- lysines, Boc-L- tyrosine, Boc-L- methionine, Boc-L- tryptophans, Boc-L- aspartic acids, Boc-L- arginine, Boc-L- asparagus ferns Acid amides, Boc-L- threonines, Boc-L- glutamine, Boc-L- methionine, Boc-L- phenylalanines, Boc-L- proline, Boc-L- valines, Boc-L- isoleucines, Boc-L- leucines, Boc-L- alanine, one kind in Boc-L- glycine or It is a variety of.
2. a kind of preparation method of N- amino acid cyanopyrrole alkane derivative, it is characterised in that comprise the following steps：
1) under the conditions of existing for catalyst, make Boc-L- amino acid with 2- Cyanopyrolidines tosilate in N, N- diformazans Amidation process occurs in base formamide (DMF), synthesizes (2S) -1- (Boc-L- aminoacyls) pyrrolidines -2- formonitrile HCNs；
2) make (2S) -1- (Boc-L- aminoacyls) pyrrolidines -2- formonitrile HCNs for being obtained in step 1) with trifluoroacetic acid in methylene chloride De- Boc reactions occur, synthesize (2S) -1- (L- aminoacyls) pyrrolidines -2- formonitrile HCNs (tfa salt)；
Reaction equation：
3. according to the method described in claim 2, it is characterized in that, the catalyst used in step 1) is EDCI/HOBt, N, N- The molar ratio of diisopropylethylamine, Boc-L- amino acid and catalyst is 1：2~1：4.
4. according to the method described in claim 2, it is characterized in that, used in step 1), Boc-L- amino acid and 2- cyano group Pyrrolidines tosilate molar ratio is 1:0.9~1:1.2.
5. according to the method described in claim 2, it is characterized in that, the reaction temperature of step 1) is 0~5 DEG C, the reaction time is 20h, the DMF used are anhydrous DMF.
6. according to the method described in claim 2, it is characterized in that, (2S) -1- (Boc-L- aminoacyls) pyrrolidines in step 2) - 2- formonitrile HCNs are 0.15 with trifluoroacetic acid molar ratio:1mL~0.3g:1mL.
7. according to the method described in claim 2, it is characterized in that, step 2) take off Boc reaction temperature be 0~10 DEG C, reaction Time is 1~2h.
8. method according to claim 2, it is characterised in that the dichloromethane used in step 2) is anhydrous methylene chloride.
9. according to the method described in claim 2, it is characterized in that, the middle post processing of step 2) is：After reaction by reaction solution It is spin-dried for adding anhydrous ether crystallization.
10. according to the method described in claim 2, it is characterized in that, using N- amino acid cyanopyrrole alkane derivatives and Its physiological acceptable salt is applied in anti-diabetes B medicine is prepared；Can by N- amino acid cyanopyrrole alkane derivatives and its The preparation method of physiological acceptable salt is applied in anti-diabetes B medicine is prepared.
CN201711320391.5A 2017-12-12 2017-12-12 A kind of N- amino acid cyanopyrrole alkane derivative and preparation method thereof Pending CN108003080A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201711320391.5A CN108003080A (en) 2017-12-12 2017-12-12 A kind of N- amino acid cyanopyrrole alkane derivative and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201711320391.5A CN108003080A (en) 2017-12-12 2017-12-12 A kind of N- amino acid cyanopyrrole alkane derivative and preparation method thereof

Publications (1)

Publication Number Publication Date
CN108003080A true CN108003080A (en) 2018-05-08

Family

ID=62058573

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201711320391.5A Pending CN108003080A (en) 2017-12-12 2017-12-12 A kind of N- amino acid cyanopyrrole alkane derivative and preparation method thereof

Country Status (1)

Country Link
CN (1) CN108003080A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109369779A (en) * 2018-12-21 2019-02-22 江苏诺泰澳赛诺生物制药股份有限公司 A kind of synthetic method of Taltirelin
CN115322129A (en) * 2022-08-29 2022-11-11 湖北科技学院 Dicyano pyrrolidine derivative and preparation method and application thereof
CN115368344A (en) * 2022-08-22 2022-11-22 湖北科技学院 Histidine derivative and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1141033A (en) * 1993-12-03 1997-01-22 费林股份公司 Enzyme inhibitors
CN104003922A (en) * 2013-02-27 2014-08-27 中国药科大学 Substituted pyrrolidine derivative, preparation method thereof and use in medicine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1141033A (en) * 1993-12-03 1997-01-22 费林股份公司 Enzyme inhibitors
CN104003922A (en) * 2013-02-27 2014-08-27 中国药科大学 Substituted pyrrolidine derivative, preparation method thereof and use in medicine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DANIEL A BACHOVCHIN ET AL.: "A high-throughput, multiplexed assay for superfamily-wide profiling of enzyme activity", 《NATURE CHEMICAL BIOLOGY》 *
DOREEN M. ASHWORTH ET AL.: "2-cyanopyrrolidides as potent, stable inhibitors of dipeptidyl peptidase IV", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
JINGRONG LI ET AL.: "Aminoacylpyrrolidine-2-nitriles: Potent and Stable Inhibitors of Dipeptidyl-Peptidase IV (CD 26)", 《ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109369779A (en) * 2018-12-21 2019-02-22 江苏诺泰澳赛诺生物制药股份有限公司 A kind of synthetic method of Taltirelin
CN109369779B (en) * 2018-12-21 2021-12-10 江苏诺泰澳赛诺生物制药股份有限公司 Synthetic method of taltirelin
CN115368344A (en) * 2022-08-22 2022-11-22 湖北科技学院 Histidine derivative and preparation method and application thereof
CN115322129A (en) * 2022-08-29 2022-11-11 湖北科技学院 Dicyano pyrrolidine derivative and preparation method and application thereof

Similar Documents

Publication Publication Date Title
Gademann et al. Peptide folding induces high and selective affinity of a linear and small β-peptide to the human somatostatin receptor 4
CN108003080A (en) A kind of N- amino acid cyanopyrrole alkane derivative and preparation method thereof
DE69125537T2 (en) Alpha-keto-amide derivatives with protease inhibiting activity
Souto et al. Synthesis and antibacterial activity of conjugates between norfloxacin and analogues of the siderophore vanchrobactin
EP0235692B1 (en) Oligopeptidyl nitrile derivatives, the agents containing them, process for their preparation and their use
Peddie et al. Photocontrol of peptide secondary structure through non-azobenzene photoswitches
CN106674230B (en) The synthetic method of pro-his cyclic dipeptide
EP1114024B1 (en) Urokinase inhibitors
CN110177581A (en) Myeloperoxidase imaging agent
AT502145A1 (en) GLYCOSIDASE-INHIBITING IMINOALDITOL
Hong et al. Isothiocyanate can be used as a highly specific recognition site for fluorescent cysteine probes
Weber et al. Enantiopure 4-and 5-aminopiperidin-2-ones: regiocontrolled synthesis and conformational characterization as bioactive β-turn mimetics
Oliva et al. Bicyclic pyrrolidine-isoxazoline γ amino acid: A constrained scaffold for stabilizing α-turn conformation in isolated peptides
Seneci et al. Rational design, synthesis and characterization of potent, non-peptidic Smac mimics/XIAP inhibitors as proapoptotic agents for cancer therapy
Umashankara et al. Orchestration of structural, stereoelectronic, and hydrogen-bonding effects in stabilizing triplexes from engineered chimeric collagen peptides (ProX-ProY-Gly) 6 incorporating 4 (R/S)-aminoproline
DE69625230T2 (en) thrombin inhibitors
CN1044101A (en) From a kind of spider venom isolated polypeptide
CN105753795A (en) Alkaloid compound with 1,2,3-triazole structure segment and application of compound
Steiner et al. 1-Deoxygalactonojirimycin-lysine hybrids as potent D-galactosidase inhibitors
Kaur et al. Modifications of the pyroglutamic acid and histidine residues in thyrotropin-releasing hormone (TRH) yield analogs with selectivity for TRH receptor type 2 over type 1
Monga et al. Synthesis, receptor binding, and CNS pharmacological studies of new thyrotropin‐releasing hormone (TRH) analogues
Goričan et al. Synthesis and kinetic characterization of hyperbolic inhibitors of human cathepsins K and S based on a succinimide scaffold
T Vezenkov et al. Synthesis of new peptide derivatives of galanthamine designed for prevention and treatment of Alzheimer’s disease
Abdelwahab et al. Synthesis of potential metal-binding group compounds to examine the zinc dependency of the GPI de-N-acetylase metalloenzyme in Trypanosoma brucei
Safir et al. α-Bromoacid Amides and Ureas as Anticonvulsants

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20180508