CN105111280A - Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity - Google Patents
Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity Download PDFInfo
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- CN105111280A CN105111280A CN201510320667.4A CN201510320667A CN105111280A CN 105111280 A CN105111280 A CN 105111280A CN 201510320667 A CN201510320667 A CN 201510320667A CN 105111280 A CN105111280 A CN 105111280A
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- 0 C*(*)[C@@](*)(C(N(*)C1=CC=C(C)C=*=*)=C(C[C@@](C(C)=O)N2*)C1=CC)C2=O Chemical compound C*(*)[C@@](*)(C(N(*)C1=CC=C(C)C=*=*)=C(C[C@@](C(C)=O)N2*)C1=CC)C2=O 0.000 description 2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention provides a template-fixed beta-hairpin peptidomimetics with protease inhibitory activity or salts thereof. The template-fixed beta-hairpin peptidomimetics have a general formula (I) as described in the specification, wherein Z is a chain of 11 alpha-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid), are Gly, or Pro, or Pro (4NHCOPhe), or of certain types which, as remaining symbols in the formula, are defined in the specification and the claims. The template-fixed beta-hairpin peptidomimetics have the property of inhibiting protease (especially serine proteinase, and in particular, cathepsin G, elastase, or tryptase). The beta-hairpin peptidomimetics can be produced through a method based on the strategy of hybrid solid phase-liquid phase synthesis.
Description
The divisional application of the patent application of " there is β-hairpin peptidomimetics that the template of protease inhibiting activity is fixing " that the application is application number is 200580049141.1, the applying date, to be February 17, denomination of invention in 2005 be.
Technical field
The invention provides β-hairpin peptidomimetics that template is fixing, it template comprising 11 a-amino acid residues fixes chain, these residues are summarized, and their positions in chain are Gly or Pro or Pro (4NHCOPhe), or have some kind hereafter defined.β-hairpin peptidomimetics that these templates are fixed can be used as the inhibitor of proteolytic enzyme.They especially can be used as the inhibitor of different serine protease (such as, human cathepsin g, elastoser or tryptase).In addition, the invention provides a kind of method efficiently, if necessary, manufacture these compounds by the method with library form.
β-hairpin peptidomimetics of the present invention illustrates effect, the oral administration biaavailability of raising, the transformation period of improving, and most significantly, highly selective rate between different serine protease, this depends on the suitable selection to some type of a-amino acid residue, and their positions in described chain.In addition, these β-hairpin peptidomimetics illustrate for erythrocytic low hemolytic action and low cytotoxicity.
Background technology
The inhibitor of proteolytic enzyme shows promising therepic use in the treatment of disease, and described disease is cancer (R.P.Beckett, A.Davidson, A.H.Drummond, M.Whittaker, DrugDisc.Today1996,1,16-26 such as; L.L.Johnson, R.Dyer, D.J.Hupe, Curr.Opin.Chem.Biol.1998,2,466-71; D.Leung, G.Abbenante, andD.P.Fairlie, J.Med.Chem.2000,43,305-341, T.Rockway, ExpertOpin.Ther.Patents2003,13,773-786), parasite, fungi and virus infection [such as schistosomicide (M.M.Becker, S.A.Harrop, J.P.Dalton, B.H.Kalinna, D.P.McManus, D.P.Brindley, J.Biol.Chem.1995,270,24496-501); C.albicans (C.Abad-Zapetero, R.Goldman, S.W.Muchmore, C.Hutchins, K.Stewart, J.Navaza, C.D.Payne, T.L.Ray, ProteinSci.1996,5,640-52), HIV (A.Wlodawer, J.W.Erickson, Annu.Rev.Biochem.1993,62,543-85; P.L.Darke, J.R.Huff, Adv.Pharmacol.1994,5,399-454), hepatitis (J.L.Kim, K.A.Morgenstern, C.Lin, T.Fox, M.D.Dwyer, J.A.Landro, S.P.Chambers, W.Markland, C.A.Lepre, E.T.O ' Malley, S.L.Harbeson, C.M.Rice, M.A.Murcko, P.R.Caron, J.A.Thomson, Cell, 1996,87,343-55; R.A.Love, H.E.Parge, J.A.Wickersham, Z.Hostomsky, N.Habuka, E.W.Moomaw, T.Adachi, Z.Hostomska, Cell, 1996,87,331-342), bleb (W.Gibson, M.R.Hall, Drug.Des.Discov.1997,15,39-47)] and inflammatory, immunity, respiratory disease (P.R.Bernstein, P.D.Edwards, J.C.Williams, Prog.Med.Chem.1994,31,59-120; T.E.Hugli, TrendsBiotechnol.1996,14,409-12), cardiovascular disorder (M.T.Stubbs, W.A.Bode, Thromb.Res.1993,69,1-58; H.Fukamietal, CurrentPharmaceuticalDesign1998,4,439-453) and neurodegeneration defect, comprise alzheimer's disease (R.Vassar, B.D.Bennett, S.Babu-Kahn, S.Kahn, E.A.Mendiaz, Science, 1999,286,735-41), blood vessel occurs (people such as KaatinenM, Atherosklerosis1996,1231-2,123-131) and the multiple sclerosis (people such as IbrahimMZ, J.Neuroimmunol1996,70,131-138.
Because most of proteolytic enzyme and their substrate with extend or beta chain conformation be combined, therefore good inhibitor must can simulate this conformation.Thus ideally, the conformation that β-hairpin mimetic is applicable to extending pins peptide sequence.
In proteolytic enzyme, serine protease constitutes important therapeutic targets.By its substrate specificity (residue type of particularly P1 position discovery), serine protease is categorized as: (be preferred at the residue Lys/Arg of P1 bit strip positive charge) of trypsin-like, (P1 position is little hydrophobic residue Ala/Val) of elastoser sample or chymotrypsin-like (being large hydrophobic residue Phe/Tyr/Leu in P1 position).Can PDB database (PDB:
www.rcsb.org/pdb) upper those serine proteases obtaining its proteinase inhibitor X-ray crystal data comprise trypsinase, alpha-chymotrypsin, γ-Quimotrase, people's Neutrophil elastase, zymoplasm, subtilisin, human cytomegalic inclusion disease virus, protease A, achromobacter (achromobacter), human cathepsin g, glutamate specific proteolytic enzyme, carboxypeptidase D, proconvertin a, pig thrombin 1XA, mesentery (mesenterico) peptase, HCV proteolytic enzyme and hot enzyme (thermitase).Other serine protease with treatment benefit comprises tryptase, complement saccharase, hepatitis C-NS3 proteolytic enzyme.Zymoplasm (such as J.L.Metha, L.Y.Chen, W.W.Nichols, C.Mattsson, D.Gustaffson, T.G.P.Saldeen, J.Cardiovasc.Pharmacol.1998,31,345-51, C.Lila, P.Gloanec, L.Cadet, Y.Herve, J.Fournier, F.Leborgne, T.J.Verbeuren, G.DeNanteuil, Synth.Comm.1998, 28, 4419-29) with factor Xa (such as J.P.Vacca, Annu.Rep.Med.Chem.1998, 33, inhibitor 81-90) is just used as anti-coagulant in clinical assessment, inhibitor (the J.R.Williams of elastoser, R.C.Falcone, C.Knee, R.L.Stein, A.M.Strimpler, B.Reaves, R.E.Giles, R.D.Krell, Am.Rev.Respir.Dis.1991, 144, 875-83) be in for pulmonary emphysema with in the clinical trial of other pulmonary disorder, and (C.Seife in tryptase inhibitors is in for asthma at present phase ii clinical trial, Science1997, 277, 1602-3), urokinase inhibitors is used for mammary cancer, chymase inhibitor is used for cardiac-related diseases.Finally, cathepsin G and elastoser participate in the adjustment of the activity of cytokine and acceptor thereof closely.Particularly on the position of inflammation, the wetting property polymorphonuclear cell from the level raised with inflammatory cytokine with close temporal dependency discharges cathepsin G, elastoser and protease 3, this shows strongly, these proteolytic enzyme participates in the control (U.Bank to cytokine bioactivity and availability, S.Ansorge, J.Leukoc.Biol.2001,69,177-90).Therefore, the inhibitor of elastoser and cathepsin G constitutes the valuable target (OhbayashiH, EpertOpin.Investig.Drugs2002,11,965-980) of the new drug candidates being used in particular for chronic obstructive disease of lung.
In the multiple proteins serpin existed, one is 14 amino acid whose cyclic peptides, and it is from sunflower seed, be called as Sunflower Receptacle trypsin inhibitor (SFTI-1) (S.Luckett, R.SantiagoGarcia, J.J.Barker, A.V.Konarev, P.R.Shewry, A.R.Clarke, R.L.Brady, J.Mol.Biol.1999,290,525-533; Y.-Q.Long, S.-L.Lee, C.-Y.Lin, I.J.Enyedy, S.Wang, P.Li, R.B.Dickson, P.P.Roller, Biorg. & Med.Chem.Lett.2001,11,2515-2519), its display has the similarity in sequence and conformation with the reactive ring of the trypsinase of the serpin of Bowman-Birk family.This inhibitor and ox β-tryptic avtive spot in conjunction with time adopt β-hairpin conformation.SFTI-1 suppresses β-trypsin K
i<0.1nM), cathepsin G (K
i~ 0.15nM), elastoser (K
i~ 105 μMs), Quimotrase (K
i~ 7.4 μMs) and zymoplasm (K
i~ 136mM).
We illustrate the means of inhibitor design at this, it comprise the beta-hairpin loop from naturally occurring peptide is transplanted to induction hair clip template on.Based on the 3D structure of the β-hairpin mimetic fully defined, can design library of compounds, this finally causes demonstrating the inhibitor some proteinoid enzymes to the novelty of different specific characteristics.
At document (D, Obrecht, M.Altorfer, J.A.Robinson, Adv.Med.Chem.1999,4,1-68; J.A.Robinson, Syn.Lett.2000,4,429-441) in describe the hair clip simulating peptide be combined with template, at international patent application WO2003/054000A1 and DescoursA, MoehleK., RenardA, RobinsonJ.ChemBioChem2002,3, described the template fixed peptide analogue suppressing serine protease and the method for synthesizing them in 318-323, but these molecules previously disclosed do not show highly selective and extra high effect.But, establish now the ability (L.Jiang, the K.Moehle that use combination and Parallel Synthesis Procedure to produce β-hairpin peptidomimetics, B.Dhanapal, D.Obrecht, J.A.Robinson, Helv.Chim.Acta.2000,83,3097-3112).
Aforesaid method allows synthesis and screens large hairpin mimetic libraries, this so facilitate to a great extent structure-activity research, and thereby promote to have highly effectively and optionally serine stretch protein enzyme inhibition activity, oral administration biaavailability, to the low hemolytic activity of HRBC and the discovery of low Cytotoxic recruit.
Summary of the invention
β-hairpin peptidomimetics of the present invention is the compound of following general formula, and their pharmacy acceptable salt,
Wherein
The group of one of following formula:
Wherein,
Gly, or the residue of L-a-amino acid, wherein B is formula-NR
20cH (R
71)-residue, or the enantiomer of one of A1 to the A69 group hereafter defined;
The group of one of following formula:
R
1h, low alkyl group or aryl lower alkyl;
R
2h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
3h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
4h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
p(CHR
61)
scOOR
57,-(CH
2)
p(CHR
61)
scONR
58r
59,-(CH
2)
p(CHR
61)
spO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
5alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
6h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
7alkyl, thiazolinyl ,-(CH
2)
q(CHR
61)
soR
55,-(CH
2)
q(CHR
61)
snR
33r
34,-(CH
2)
q(CHR
61)
soCONR
33r
75,-(CH
2)
q(CHR
61)
snR
20cONR
33r
82,-(CH
2)
r(CHR
61)
scOOR
57,-(CH
2)
r(CHR
61)
scONR
58r
59,-(CH
2)
r(CHR
61)
spO (OR
60)
2,-(CH
2)
r(CHR
61)
ssO
2r
62or-(CH
2)
r(CHR
61)
sc
6h
4r
8;
R
8h, Cl, F, CF
3, NO
2, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61) NR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
scOR
64;
R
9alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
10alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
11h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
12h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
r(CHR
61)
scOOR
57,-(CH
2)
r(CHR
61)
scONR
58r
59,-(CH
2)
r(CHR
61)
spO (OR
60)
2,-(CH
2)
r(CHR
61)
ssO
2r
62or-(CH
2)
r(CHR
61)
sc
6h
4r
8;
R
13alkyl, thiazolinyl ,-(CH
2)
q(CHR
61)
soR
55,-(CH
2)
q(CHR
61)
ssR
56,-(CH
2)
q(CHR
61)
snR
33r
34,-(CH
2)
q(CHR
61)
soCONR
33r
75,-(CH
2)
q(CHR
61)
snR
20cONR
33r
82,-(CH
2)
q(CHR
61)
scOOR
57,-(CH
2)
q(CHR
61)
scONR
58r
59,-(CH
2)
q(CHR
61)
spO (OR
60)
2,-(CH
2)
q(CHR
61)
ssO
2r
62or-(CH
2)
q(CHR
61)
sc
6h
4r
8;
R
14h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
q(CHR
61)
scOOR
57,-(CH
2)
q(CHR
61)
scONR
58r
59,-(CH
2)
q(CHR
61)
spO (OR
60)
2,-(CH
2)
q(CHR
61)
ssOR
62or-(CH
2)
q(CHR
61)
sc
6h
4r
8;
R
15alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
16alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
17alkyl, thiazolinyl ,-(CH
2)
q(CHR
61)
soR
55,-(CH
2)
q(CHR
61)
ssR
56,-(CH
2)
q(CHR
61)
snR
33r
34,-(CH
2)
q(CHR
61)
soCONR
33r
75,-(CH
2)
q(CHR
61)
snR
20cONR
33r
82,-(CH
2)
q(CHR
61)
scOOR
57,-(CH
2)
q(CHR
61)
scONR
58r
59,-(CH
2)
q(CHR
61)
spO (OR
60)
2,-(CH
2)
q(CHR
61)
ssO
2r
62or-(CH
2)
q(CHR
61)
sc
6h
4r
8;
R
18alkyl, thiazolinyl ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
ssR
56,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
p(CHR
61)
scOOR
57,-(CH
2)
p(CHR
61)
scONR
58r
59,-(CH
2)
p(CHR
61)
spO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
19low alkyl group ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
ssR
56,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
p(CHR
61)
scOOR
57,-(CH
2)
p(CHR
61)
scONR
58r
59,-(CH
2)
p(CHR
61)
spO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8or
R
18and R
19can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
20h, alkyl, thiazolinyl or aryl lower alkyl;
R
21h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
22h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
23alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
24alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
25h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
26h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8or
R
25and R
26can be formed together :-(CH
2)
2-6-,-(CH
2)
ro (CH
2)
r-,-(CH
2)
rs (CH
2)
r-or-(CH
2)
rnR
57(CH
2)
r-;
R
27h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
28alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
s-OR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
29alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
30h, alkyl, thiazolinyl or aryl lower alkyl.
R
31h, alkyl, thiazolinyl ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
32h, low alkyl group or aryl lower alkyl;
R
33h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
34r
63,-(CH
2)
m(CHR
61)
soCONR
75r
82,-(CH
2)
m(CHR
61)
snR
20cONR
78r
82,-(CH
2)
o(CHR
61)
scOR
64,-(CH
2)
o(CHR
61)
s-CONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
34h, low alkyl group, aryl or aryl lower alkyl;
R
33and R
34can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
35h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
p(CHR
61)
scOOR
57,-(CH
2)
p(CHR
61)
scONR
58r
59,-(CH
2)
p(CHR
61)
spO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
p(CHR
61)
sc
6h
4r
8;
R
36h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
p(CHR
61)
scOOR
57,-(CH
2)
p(CHR
61)
scONR
58r
59,-(CH
2)
p(CHR
61)
spO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
37h, F, Br, Cl, NO
2, CF
3, low alkyl group ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
38h, F, Br, Cl, NO
2, CF
3, alkyl, thiazolinyl ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
39h, alkyl, thiazolinyl or aryl lower alkyl;
R
40h, alkyl, thiazolinyl or aryl lower alkyl;
R
41h, F, Br, Cl, NO
2, CF
3, alkyl, thiazolinyl ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
42h, F, Br, Cl, NO
2, CF
3, alkyl, thiazolinyl ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
43h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
44alkyl, thiazolinyl ,-(CH
2)
r(CHR
61)
soR
55,-(CH
2)
r(CHR
61)
ssR
56,-(CH
2)
r(CHR
61)
snR
33r
34,-(CH
2)
r(CHR
61)
soCONR
33r
75,-(CH
2)
r(CHR
61)
snR
20cONR
33r
82,-(CH
2)
r(CHR
61)
scOOR
57,-(CH
2)
r(CHR
61)
scONR
58r
59,-(CH
2)
r(CHR
61)
spO (OR
60)
2,-(CH
2)
r(CHR
61)
ssO
2r
62or-(CH
2)
r(CHR
61)
sc
6h
4r
8;
R
45h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
s(CHR
61)
scONR
58r
59,-(CH
2)
s(CHR
61)
spO (OR
60)
2,-(CH
2)
s(CHR
61)
ssO
2r
62or-(CH
2)
s(CHR
61)
sc
6h
4r
8;
R
46h, alkyl, thiazolinyl or-(CH
2)
o(CHR
61)
pc
6h
4r
8;
R
47h, alkyl, thiazolinyl or-(CH
2)
o(CHR
61)
soR
55;
R
48h, low alkyl group, low-grade alkenyl or aryl lower alkyl;
R
49h, alkyl, thiazolinyl ,-(CHR
61)
scOOR
57, (CHR
61)
scONR
58r
59, (CHR
61)
spO (OR
60)
2,-(CHR
61)
ssOR
62or-(CHR
61)
sc
6h
4r
8;
R
50h, low alkyl group or aryl lower alkyl;
R
51h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
ppO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
p(CHR
61)
sc
6h
4r
8;
R
52h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
ppO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
p(CHR
61)
sc
6h
4r
8;
R
53h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
ppO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
p(CHR
61)
sc
6h
4r
8;
R
54h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61) COOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
55h, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH
2)
m(CHR
61)
soR
57,-(CH
2)
m(CHR
61)
snR
34r
63,-(CH
2)
m(CHR
61)
soCONR
75r
82,-(CH
2)
m(CHR
61)
snR
20cONR
78r
82,-(CH
2)
o(CHR
61)
s-COR
64,-(CH
2)
o(CHR
61) COOR
57or-(CH
2)
o(CHR
61)
scONR
58r
59;
R
56h, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH
2)
m(CHR
61)
soR
57,-(CH
2)
m(CHR
61)
snR
34r
63,-(CH
2)
m(CHR
61)
soCONR
75r
82,-(CH
2)
m(CHR
61)
snR
20cONR
78r
82,-(CH
2)
o(CHR
61)
s-COR
64or-(CH
2)
o(CHR
61)
scONR
58r
59;
R
57h, low alkyl group, low-grade alkenyl, aromatic yl elementary alkyl or heteroaryl lower alkyl;
R
58h, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl or heteroaryl-lower alkyl;
R
59h, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl or heteroaryl-lower alkyl; Or
R
58and R
59can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
60h, low alkyl group, low-grade alkenyl, aryl or aryl lower alkyl;
R
61alkyl, thiazolinyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-lower alkyl ,-(CH
2)
moR
55,-(CH
2)
mnR
33r
34,-(CH
2)
moCONR
75r
82,-(CH
2)
mnR
20cONR
78r
82,-(CH
2)
ocOOR
37,-(CH
2)
onR
58r
59or-(CH
2)
opO (COR
60)
2;
R
62low alkyl group, low-grade alkenyl, aryl, heteroaryl or aryl lower alkyl;
R
63h, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-lower alkyl ,-COR
64,-COOR
57,-CONR
58r
59,-SO
2r
62or-PO (OR
60)
2;
R
34and R
63can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
64h, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-lower alkyl ,-(CH
2)
p(CHR
61)
soR
65,-(CH
2)
p(CHR
61)
ssR
66or-(CH
2)
p(CHR
61)
snR
34r
63,-(CH
2)
p(CHR
61)
soCONR
75r
82,-(CH
2)
p(CHR
61)
snR
20cONR
78r
82;
R
65h, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl, heteroaryl-lower alkyl ,-COR
57,-COOR
57or-CONR
58r
59;
R
66h, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl, heteroaryl-lower alkyl or-CONR
58r
59;
M is 2-4; O is 0-4; P is 1-4; Q is 0-2; R is 1 or 2; S is 0 or 1;
Z is the chain of 11 a-amino acid residues, the position of described amino-acid residue in described chain counts from-terminal amino acid, thus, depend on their positions in chain, these amino-acid residues are Gly, Pro, Pro (4NHCOPhe) or have formula-A-CO-, or there is formula-B-CO-, or there is one of following type:
C:-NR
20CH(R
72)CO-；
D:-NR
20CH(R
73)CO-；
E:-NR
20CH(R
74)CO-；
F:-NR
20cH (R
84) CO-; And
H:-NR
20-CH (CO-)-(CH
2)
4-7-CH (CO-)-NR
20-,-NR
20-CH (CO-)-(CH
2)
psS (CH
2)
p-CH (CO-)-NR
20-,-NR
20-CH (CO-)-(-(CH
2)
pnR
20cO (CH
2)
p-CH (CO-)-NR
20-and-NR
20-CH (CO-)-(-(CH
2)
pnR
20cONR
20(CH
2)
p-CH (CO-)-NR
20-;
R
71low alkyl group, low-grade alkenyl ,-(CH
2)
p(CHR
61)
soR
75,-(CH
2)
p(CHR
61)
ssR
75,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
75,-(CH
2)
pcONR
58r
59,-(CH
2)
ppO (OR
62)
2,-(CH
2)
psO
2r
62or-(CH
2)
o-C
6r
67r
68r
69r
70r
76;
R
72h, low alkyl group, low-grade alkenyl ,-(CH
2)
p(CHR
61)
soR
85or-(CH
2)
p(CHR
61)
ssR
85;
R
73-(CR
86r
87)
or
77,-(CH
2)
ro (CH
2)
or
77,-(CH
2)
rs (CH
2)
or
77or-(CH
2)
rnR
20(CH
2)
or
77;
R
74-(CH
2)
pnR
78r
79,-(CH
2)
pnR
77r
80,-(CH
2)
pc (=NR
80) NR
78r
79,-(CH
2)
pc (=NOR
50) NR
78r
79,-(CH
2)
pc (=NNR
78r
79) NR
78r
79,-(CH
2)
pnR
80c (=NR
80) NR
78r
79,-(CH
2)
pn=C (NR
78r
80) NR
79r
80,-(CH
2)
pc
6h
4nR
78r
79,-(CH
2)
pc
6h
4nR
77r
80,-(CH
2)
pc
6h
4c (=NR
80) NR
78r
79,-(CH
2)
pc
6h
4c (=NOR
50) NR
78r
79,-(CH
2)
pc
6h
4c (=NNR
78r
79) NR
78r
79,-(CH
2)
pc
6h
4nR
80c (=NR
80) NR
78r
79,-(CH
2)
pc
6h
4n=C (NR
78r
80) NR
79r
80,-(CH
2)
ro (CH
2)
mnR
78r
79,-(CH
2)
ro (CH
2)
mnR
77r
80,-(CH
2)
ro (CH
2)
pc (=NR
80) NR
78r
79,-(CH
2)
ro (CH
2)
pc (=NOR
50) NR
78r
79,-(CH
2)
ro (CH
2)
pc (=NNR
78r
79) NR
78r
79,-(CH
2)
ro (CH
2)
mnR
80c (=NR
80) NR
78r
79,-(CH
2)
ro (CH
2)
mn=C (NR
78r
80) NR
79r
80,-(CH
2)
ro (CH
2)
pc
6h
4cNR
78r
79,-(CH
2)
ro (CH
2)
pc
6h
4c (=NR
80) NR
78r
79,-(CH
2)
ro (CH
2)
pc
6h
4c (=NOR
50) NR
78r
79,-(CH
2)
ro (CH
2)
pc
6h
4c (=NNR
78r
79) NR
78r
79,-(CH
2)
ro (CH
2)
pc
6h
4nR
80c (=NR
80) NR
78r
79,-(CH
2)
rs (CH
2)
mnR
78r
79,-(CH
2)
rs (CH
2)
mnR
77r
80,-(CH
2)
rs (CH
2)
pc (=NR
80) NR
78r
79,-(CH
2)
rs (CH
2)
pc (=NOR
50) NR
78r
79,-(CH
2)
rs (CH
2)
pc (=NNR
78r
79) NR
78r
79,-(CH
2)
rs (CH
2)
mnR
80c (=NR
80) NR
78r
79,-(CH
2)
rs (CH
2)
mn=C (NR
78r
80) NR
79r
80,-(CH
2)
rs (CH
2)
pc
6h
4cNR
78r
79,-(CH
2)
rs (CH
2)
pc
6h
4c (=NR
80) NR
78r
79,-(CH
2)
rs (CH
2)
pc
6h
4c (=NOR
50) NR
78r
79,-(CH
2)
rs (CH
2)
pc
6h
4c (=NNR
78r
79) NR
78r
79,-(CH
2)
rs (CH
2)
pc
6h
4nR
80c (=NR
80) NR
78r
79,-(CH
2)
pnR
80cOR
64,-(CH
2)
pnR
80cOR
77,-(CH
2)
pnR
80cONR
78r
79,-(CH
2)
pc
6h
4nR
80cONR
78r
79huo – (CH
2)
pnR
20cO-[(CH
2)
u-X]
t-CH
3wherein X is-O-,-NR
20-or-S-; U is 1-3, and t is 1-6;
R
75low alkyl group, low-grade alkenyl or aryl lower alkyl;
R
33and R
75can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
75and R
82can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
76h, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH
2)
ooR
72,-(CH
2)
osR
72,-(CH
2)
onR
33r
34,-(CH
2)
ooCONR
33r
75,-(CH
2)
onR
20cONR
33r
82,-(CH
2)
ocOOR
75,-(CH
2)
ocONR
58r
59,-(CH
2)
opO (OR
60)
2,-(CH
2)
psO
2r
62or-(CH
2)
ocOR
64;
R
77-C
6r
67r
68r
69r
70r
76or the heteroaryl of one of following formula
R
78h, low alkyl group, aryl or aryl lower alkyl;
R
78and R
82can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
79h, low alkyl group, aryl or aryl lower alkyl, or
R
78and R
79can be together :-(CH
2)
2-7-,-(CH
2)
2o (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
80h or low alkyl group;
R
81h, low alkyl group or aryl lower alkyl;
R
82h, low alkyl group, aryl, heteroaryl or aryl lower alkyl;
R
33and R
82can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
83h, low alkyl group, aryl or-NR
78r
79;
R
84-(CH
2)
m(CHR
61)
soH ,-(CR
86r
87) pOR
80,-(CR
86r
87) pCOOR
80,-(CH
2)
m(CHR
61)
ssH ,-(CR
86r
87) pSR
80,-(CH
2)
pcONR
78r
79,-(CH
2)
pnR
80cONR
78r
79,-(CH
2)
pc
6h
4cONR
78r
79,-(CH
2)
pc
6h
4nR
80cONR
78r
79,-(CR
86r
87)
opO (OR
60)
2,-(CR
86r
87)
psO
2r
60,-(CR
86r
87)
psOR
60,-(CH
2)
m(CHR
61)
soPO (OR
60)
2or-(CH
2)
m(CHR
61)
soSO
2r
60;
R
85low alkyl group or low-grade alkenyl;
R
86h, H low alkyl group that can be optionally substituted by halogen or halogen;
R
87h, H low alkyl group that can be optionally substituted by halogen or halogen;
Condition is: in the chain of described 11 a-amino acid residue Z,
If-n is 11, so the amino-acid residue of 1 to 11 is:
-P1:C type or D type or E type or F type;
-P2:C type or D type or E type or F type;
-P3:C type or F type, or this residue is Gly;
-P4:C type or D type or F type or E type, or this residue is Gly or Pro;
-P5:E type or C type or F type, or this residue is Gly or Pro;
-P6:D type or F type or E type or C type, or this residue is Gly or Pro;
-P7:C type or E type or F type, or there is formula-A-CO-, or this residue is Gly or Pro;
-P8:D type or C type or F type, or there is formula-A-CO, or this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or E type or F type;
-P10:D type or C type or F type or E type, and
-P11:C type or D type or E type or F type, or
-P2 can form the group of H type together with P10, and further condition is: if template is
dpro
lthe amino-acid residue of Pro, P1 to P11 position be not following these:
-P1:Arg
-P2: the Cys being connected P10 position Cys by disulfide linkage
-P3:Thr
-P4:Lys
-P5:Ser
-P6:Ile
-P7:Pro
-P8:Pro
-P9:Ile
-P10: the Cys being connected P10 position Cys by disulfide linkage, and
-P11:Phe
According to the present invention, these β-hairpin peptidomimetics are prepared by following method, and described method comprises:
A () by by the derivative coupling of the suitable N-protected of amino acid whose warp of 5,6 or 7 in suitably functionalized solid support and the end product wanted, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
B () removes N-protected group from thus obtained product;
C (), by the derivative coupling closer to the suitable N-protected of that amino acid whose warp of a-terminal amino acid residue position in thus obtained product and the end product wanted, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
D () removes N-protected group from thus obtained product;
E () repeating step (c) and (d), until introduced-terminal amino acid residue;
F () is by the compound coupling of thus obtained product and following general formula
Wherein
As hereinbefore defined, and X is N-protected group, or, if
Above (a1) or (a2) group,
(fa) by the product of acquisition in step (e) and the derivative coupling of the suitable N-protected of the amino acid whose warp of following general formula, described general formula is:
HOOC-B-HIII or HOOC-A-HIV
Wherein, as hereinbefore defined, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected B and A equally;
(fb) N-protected group is removed from thus obtained product; And
(fc) by thus obtained product and the derivative coupling of the suitable N-protected of amino acid whose warp being respectively above-mentioned general formula I V and III, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally; And, respectively, if
Above group (a3),
(fa') by the derivative coupling of the product of acquisition and the suitable N-protected of amino acid whose warp of above-mentioned general formula III in step (e), any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(fb') N-protected group is removed from thus obtained product; And
(fc') by the derivative coupling of the suitable N-protected of amino acid whose warp of thus obtained product and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
G product that () obtains from step (f) or (fc) or (fc') removes N-protected group;
H (), by thus obtained product and the derivative coupling of the suitable N-protected of amino acid whose warp of the 11st in the end product wanted, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
I () removes N-protected group from thus obtained product;
(j) by thus obtained product and the end product wanted from the derivative coupling of the suitable N-protected of that amino acid whose warp of the 11st farther, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
K () removes N-protected group from thus obtained product;
L () repeating step (j) and (k), until introduced all amino-acid residues;
M () if necessary, is gone protection to the one or more shielded functional group selectivity existed in molecule, and is suitably replaced the reaction active groups discharged thus;
N () if necessary, forms interchain key between the side chain of the suitable amino-acid residue of the 2nd and 10;
O thus obtained product and solid support depart from by ();
P () is by the product cyclisation from cracking on solid support;
Q any blocking group that the functional group of any member of () removing amino-acid residue chain exists, and, if necessary, other any blocking group that may exist in removing molecule; And
R () if necessary, be its pharmacy acceptable salt by thus obtained product conversion, or thus obtained pharmacy acceptable salt or unacceptable salt are converted into corresponding formula I free cpds, or are converted into different, pharmacy acceptable salt.
Or peptide mimics of the present invention is prepared by following step:
(a') by the compound coupling through suitably functionalized solid support and following general formula
Wherein
As hereinbefore defined, and X is N-protected group, or, if
Above group (a1) or (a2),
(a'a) by the derivative coupling of solid support suitably functionalized for described warp and the suitable N-protected of the amino acid whose warp of following general formula, described general formula is
HOOC-B-HIII or HOOC-A-HIV
Wherein, as hereinbefore defined, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected B and A equally;
(a'b) N-protected group is removed from thus obtained product; And
(a'c) by thus obtained product and the derivative coupling of the suitable N-protected of amino acid whose warp being respectively above-mentioned general formula I V and III, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally; And, respectively, if
Above group (a3),
(a'a') by the derivative coupling of the suitable N-protected of amino acid whose warp of solid support suitably functionalized for described warp and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(a'b') N-protected group is removed from thus obtained product; And
(a'c') by the derivative coupling of the suitable N-protected of amino acid whose warp of thus obtained product and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(b') product obtained from step (a'), (a'c) or (a'c') removes N-protected group;
(c') by thus obtained product and the derivative coupling of the suitable N-protected of amino acid whose warp of the 11st in the end product wanted, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(d') N-protected group is removed from thus obtained product;
(e') by thus obtained product and the end product wanted from the derivative coupling of the suitable N-protected of that amino acid whose warp of the 11st farther, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(f') N-protected group is removed from thus obtained product;
(g') repeating step (e') and (f'), until introduced all amino-acid residues;
(h') if necessary, protection is gone to the one or more shielded functional group selectivity existed in molecule, and the reaction active groups discharged thus is suitably replaced;
(i') if necessary, between the side chain of the suitable amino-acid residue of the 2nd and 10, interchain key is formed;
(j') thus obtained product and solid support are departed from;
(k') by the product cyclisation from cracking on solid support;
(l') any blocking group that the functional group of any member of amino-acid residue chain exists is removed, and, if necessary, other any blocking group that may exist in removing molecule; And
(m') if necessary, be its pharmacy acceptable salt by thus obtained product conversion, or thus obtained pharmacy acceptable salt or unacceptable salt are converted into corresponding formula I free cpds, or are converted into different, pharmacy acceptable salt.
Peptide mimics of the present invention can also be the enantiomer of formula I.These enantiomers, by preparing the improvement of aforesaid method, wherein use the enantiomer of all chiral raw material.
When using in this manual, term " alkyl " refers to have the straight chain of 24 at the most (preferably at the most 12) carbon atoms or branched saturated hydrocarbyl alone or in combination.Similarly, term " thiazolinyl " refer to have 24 at the most (preferably at the most 12) carbon atoms, containing at least one or depend on the chain length straight chain of four olefinic double bonds or band branched hydrocarbyl at the most.Term " rudimentary " refers to have group and the compound of 6 carbon atoms at the most.Therefore, such as, term " low alkyl group " refers to have the straight chain of 6 carbon atoms at the most or branched saturated hydrocarbyl, such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl etc.Term " aryl " refers to the aromatic carbon ring alkyl containing one or two six-ring, such as phenyl or naphthyl, and it can be replaced by three substituting groups at the most, and described substituting group is such as Br, Cl, F, CF
3, NO
2, low alkyl group or low-grade alkenyl.Term " heteroaryl " refers to the aromatic heterocyclic group containing one or two five-ring and/or six-ring, in described ring, at least one contains the heteroatoms of three at the most, described heteroatoms is selected from the group be made up of O, S and N, and described ring is substituted or is not substituted; The representative example of the heteroaryl that examples of such optional is substituted is hereinbefore about to R
77definitional part list.
Structural element-A-CO-refers to amino acid building blocks, and itself and structural element-B-CO-are combined to form template (a1) and (a2).Structural element-B-CO-and another structural element-B-CO-are combined to form template (a3).Template (a3) is more not preferred in formula I.Template (a) to (p) constitutes has the N-end of positioned at intervals in the following manner and the structural unit of C-end, and described mode makes the distance between these two groups can between 4.0-5.5A.Peptide chain Z is connected with N-end with the C-end of template (a) to (p) with C-end by corresponding N-end, makes template and chain formation ring texture, such as, shown in formula I.When the distance such as herein between template N-end and C-end at 4.0-5.5A, template will induce H-key net, and this H-key net is required for being formed in peptide chain Z β-hairpin conformation.Thus, template and peptide chain formation β-hairpin mimetic.
The serine stretch protein enzyme inhibition activity height correlation of β-hairpin conformation and β-hairpin mimetic of the present invention.The Chain Conformational Properties of the stable β-hair clip of template (a) to (p) not only has keying action for selective inhibitory activity; it also has keying action to building-up process defined above, because template is mixed in the place in the middle of the beginning or vicinity of linear protected peptide precursor significantly can strengthen cyclization yields.
Structural unit A1-A69 belongs to such class of amino acid, and wherein, N-end is the secondary amine of the part forming ring.In the amino acid of genes encoding, only proline(Pro) falls into such.The configuration of structural unit A1 to A69 is (D), and they combine with the structural unit-B-CO-of (L)-configuration.Preferably combination about template (a1) is-
da1-CO-
lb-CO-extremely
da69-CO-
lb-CO-.Therefore, such as,
dpro-
lpro constitutes the prototype of template (a1).The more preferred but still more unfeasible combination forming template (a2) in addition :-
la1-CO-
db-CO-to-
la69-CO-
db-CO-combines.Therefore, such as,
lpro-
dpro constitutes the prototype of template (a2).
Will be appreciated that, the structural unit-A1-CO-to-A69-CO-that wherein A has (D)-configuration carries the radicals R on the alpha-position being in N-end
1.R
1preferably H and low alkyl group, R
1most preferably H and methyl.One skilled in the art will know that, A1-A69 shows, for R with (D)-configuration
1be the situation of H and methyl, it corresponds to (R)-configuration.According to Cahn, Ingold and Prelog rule, summarize R
1the priority of other value, this configuration also can be represented as (S).
Except R
1outside, structural unit-A1-CO-to-A69-CO-can carry and be called as R
2to R
17other substituting group.This other substituting group can be H, if it is not H, it is small size extremely middle-sized aliphatics or aromatic group preferably.R
2to R
17the example of preferred value be:
-R
2: H, low alkyl group, low-grade alkenyl, (CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl), (CH
2)
msR
56(wherein R
56: low alkyl group or low-grade alkenyl), (CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; R
57: H or low alkyl group), (CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
3: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group), (CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
4: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
5: low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group), (CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group), (CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: alkyl, thiazolinyl, aryl and aryl lower alkyl, heteroaryl-lower alkyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
6: H, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
7: low alkyl group, low-grade alkenyl ,-(CH
2)
qoR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
qsR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
qnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
qoCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group), (CH
2)
qnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
qn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
rcOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
qcONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
rpO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl), (CH
2)
rsO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl), (CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
9: low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
10: low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
11: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
12: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or; R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
rcOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
rcONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
rpO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
13: low alkyl group, low-grade alkenyl ,-(CH
2)
qoR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
qsR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
qnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
qoCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
qnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
qn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
rcOO
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
qcONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
rpO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
rsO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
14: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H, low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) ,-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
15: low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group), (CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl), particularly advantageous NR
20cO low alkyl group (R
20=H or low alkyl group) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
16: low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
17: low alkyl group, low-grade alkenyl ,-(CH
2)
qoR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
qsR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
qnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
qoCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
qnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
qn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
rcOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
qcONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
rpO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
rsO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
In structural unit A1 to A69, following these are preferred: R
2a5, A8, A22, A25, R of H
2a38, A42, A47 and A50 of H.The most preferably structural unit of A8' type:
Wherein, R
20h or low alkyl group, further, R
64alkyl, thiazolinyl, [(CH
2)
u-X]
t-CH
3(wherein X is-O-,-NR
20or-S-, u are 1-3, and t is 1-6), aryl, aryl lower alkyl or heteroaryl-lower alkyl, particularly wherein R
64n-hexyl (A8'-1), n-heptyl (A8'-2), 4-(phenyl) phenmethyl (A8'-3), diphenyl methyl (A8'-4), 3-amino-propyl (A8'-5), 5-Amino-pentyl (A8'-6), methyl (A8'-7), ethyl (A8'-8), sec.-propyl (A8'-9), isobutyl-(A8'-10), n-propyl (A8'-11), cyclohexyl (A8'-12), cyclohexyl methyl (A8'-13), normal-butyl (A8'-14), phenyl (A8'-15), phenmethyl (A8'-16), (3-indyl) methyl (A8'-17), 2-(3-indyl) ethyl (A8'-18), (4-phenyl) phenyl (A8'-19), n-nonyl (A8'-20), CH
3-OCH
2cH
2-OCH
2-and CH
3-(OCH
2cH
2)
2-OCH
2-those.
Structural unit A70 belongs to the alpha-amino group acids of open chain alpha-substitution, and structural unit A71 and A72 belongs to corresponding beta-amino acids analogue class, and structural unit A73-A104 belongs to the cyclic analogs class of A70.This type of amino acid derivative has demonstrated little peptide (C.M.Venkatachalam, Biopolymers, 1968,6, the 1425-1434 of inflection or the U-shaped conformation that can hold onto and fully define; W.Kabsch, CSander, Biopolymers1983,22,2577).Ideally, this type of structural unit or template are suitable for the β-hairpin conformation (D.Obrecht in stabilized peptide ring, M.Altorfer, J.A.Robinson, " NovelPeptideMimeticBuildingBlocksandStrategiesforEfficie ntLeadFinding ", Adv.MedChem.1999, Vol.4,1-68; P.Balaram, " Non-standardaminoacidsinpeptidedesignandproteinengineeri ng ", Curr.Opin.Struct.Biol.1992,2,845-851; M.Crisma, G.Valle, C.Toniolo, S.Prasad, R.B.Rao, P.Balaram, " β-turnconformationsincrystalstructuresofmodelpeptidesconta ining α, α-disubstitutedaminoacids ", Biopolymers1995,35,1-9; V.J.Hruby, F.Al-Obeidi, W.Kazmierski, Biochem.J.1990,268,249-262).
Show: two kinds of enantiomerism physical efficiencys of the structural unit-A70-CO-to A104-CO-of the structural unit-B-CO-of combination L-configuration are stablized expeditiously and induce β-hairpin conformation (D.Obrecht, M.Altorfer, J.A.Robinson, " NovelPeptideMimeticBuildingBlocksandStrategiesforEfficie ntLeadFinding ", Adv.MedChem.1999, Vol.4,1-68; D.Obrecht, C.Spiegler, P.
k.M ü ller, H.Heimgartner, F.Stierli, Helv.Chim.Acta1992,75,1666-1696; D.Obrecht, U.Bohdal, J.Daly, C.Lehmann, P.
k.M ü ller, Tetrahedron1995,51,10883-10900; D.Obrecht, C.Lehmann, C.Ruffieux, P.
k.M ü ller, Helv.Chim.Acta1995,78,1567-1587; D.Obrecht, U.Bohdal, C.Broger, D.Bur, C.Lehmann, R.Ruffieux, P.
c.Spiegler, Helv.Chim.Acta1995,78,563-580; D.Obrecht, H.Karajiannis, C.Lehmann, P.
c.Spiegler, Helv.Chim.Acta1995,78,703-714).
Therefore, with regard to object of the present invention, template (a1) also can be made up of to A104-CO--A70-CO-, wherein, structural unit A70 to A104 has (D)-or (L)-configuration, and its combination has the structural unit-B-CO-of (L)-configuration.
R in A70 to A104
20preferably H or low alkyl group, wherein methyl is the most preferred.R in structural unit A70 to A104
18, R
19and R
21to R
29preferred value as follows:
-R
18: low alkyl group.
-R
19: low alkyl group, low-grade alkenyl ,-(CH
2)
poR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
psR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
pnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl, R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
poCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
pcOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
pcONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
psO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
oc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
21: H, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl), (CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or (CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
22: low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
23: H, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-, wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl), particularly advantageously NR
20cO low alkyl group (R
20=H or low alkyl group) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
-R
24: low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl), particularly advantageously NR
20cO low alkyl group (R
20=H or low alkyl group) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group, or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
-R
25: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
26: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or, R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-or, R
25and R
26-(CH can be formed together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group).
-R
27: H, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl, R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
28: low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59:-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
29: low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl), particularly advantageously NR
20cO low alkyl group (R
20=H or low alkyl group) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
R
23, R
24and R
29preferably-NR
20-CO-low alkyl group, wherein R
20h or low alkyl group.
For template (b) to (p), such as (b1) and (l), the preferred value of multiple symbol is as follows:
-R
1: H or low alkyl group;
-R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H or low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
20: H or low alkyl group.
-R
30: H, methyl.
-R
31: H, low alkyl group, low-grade alkenyl ,-(CH
2)
poR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
pnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
poCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl), (-CH
2)
ocONR
58r
59(wherein R
58: low alkyl group, or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
rc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy); Most preferably-CH
2cONR
58r
59(R
58: H or low alkyl group; R
59: low alkyl group or low-grade alkenyl).
-R
32: H, methyl.
-R
33: low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
34r
63(wherein R
34: low alkyl group or low-grade alkenyl; R
63: H or low alkyl group; Or R
34and R
63formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group), (CH
2)
moCONR
75r
82(wherein R
75: low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
75and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
78r
82(wherein R
20: H or low alkyl group; R
78: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
78and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group).
-R
34: H or low alkyl group.
-R
35: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group).
-R
36: low alkyl group, low-grade alkenyl or aryl lower alkyl.
-R
37: H, low alkyl group, low-grade alkenyl ,-(CH
2)
poR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
pnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
poCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
38: H, low alkyl group, low-grade alkenyl ,-(CH
2)
poR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
pnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
poCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
78formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
39: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group).
-R
40: low alkyl group, low-grade alkenyl or aryl lower alkyl.
-R
41: H, low alkyl group, low-grade alkenyl ,-(CH
2)
poR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
pnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
poCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
42: H, low alkyl group, low-grade alkenyl ,-(CH
2)
poR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
pnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
poCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
43: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60: low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62: low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
44: low alkyl group, low-grade alkenyl ,-(CH
2)
poR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
psR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
pnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
poCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
78formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
pn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
pcOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
pcONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) or-(CH
2)
oc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
45: H, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
soCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) or-(CH
2)
sc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
46: H, low alkyl group, low-grade alkenyl ,-(CH
2)
soR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
ssR
56(wherein R
56: low alkyl group or low-grade alkenyl) ,-(CH
2)
snR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
soCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
snR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
sn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) or-(CH
2)
sc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
47: H or OR
55(wherein R
55: low alkyl group or low-grade alkenyl).
-R
48: H or low alkyl group.
-R
49: H; Low alkyl group ,-(CH
2)
ocOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) or (CH
2)
sc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
50: H, methyl.
-R
51: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group), (CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
pcOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
pcONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) or-(CH
2)
rc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
52: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
pcOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
pcONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) or-(CH
2)
rc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
53: H, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55: low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33: low alkyl group or low-grade alkenyl; R
34: H or low alkyl group; Or R
33and R
34formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33: H or low alkyl group or low-grade alkenyl; R
75: low alkyl group; Or R
33and R
75formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20: H or low alkyl group; R
33: H or low alkyl group or low-grade alkenyl; R
82: H or low alkyl group; Or R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20: H or low alkyl group; R
64: low alkyl group or low-grade alkenyl) ,-(CH
2)
pcOOR
57(wherein R
57: low alkyl group or low-grade alkenyl) ,-(CH
2)
pcONR
58r
59(wherein R
58: low alkyl group or low-grade alkenyl; And R
59: H, low alkyl group; Or R
58and R
59formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57: H or low alkyl group) or-(CH
2)
rc
6h
4r
8(wherein R
8: H, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
-R
54: low alkyl group, low-grade alkenyl or aryl lower alkyl.
Most preferably, R
1h; R
20h; R
30h; R
31carboxymethyl or lower alkoxycarbonylmethyl; R
32h; R
35it is methyl; R
36it is methoxyl group; R
37h and R
38h.
In structural unit A70 to A104, following is preferred: R
22a74, A75, A76, R of H
22a77, A78 and A79 of H.
Structural unit-B-CO-in template (a1), (a2) and (a3) refers to L-amino-acid residue.-NR concerning value preferred B
20cH (R
71)-and R
2a5, A8, A22, A25, R of H
2the enantiomer of A38, A42, A47 and A50 group of H, most preferably:
In addition, the most preferred value of B also comprises the A8 of (L)-configuration " group of type:
Wherein R
20h or low alkyl group, R
64alkyl, thiazolinyl ,-[(CH
2)
u-X]
t-CH
3(wherein X is-O-,-NR
20-or-S-, u be 1-3 and t be 1-6), aryl, aryl lower alkyl or heteroaryl-lower alkyl, especially wherein R
64n-hexyl (A8 "-21), n-heptyl (A8 "-22), 4-(phenyl) phenmethyl (A8 "-23), diphenyl methyl (A8 "-24), 3-amino-propyl (A8 "-25), 5-Amino-pentyl (A8 "-26), methyl (A8 "-27), ethyl (A8 "-28), sec.-propyl (A8 "-29), isobutyl-(A8 "-30), n-propyl (A8 "-31), cyclohexyl (A8 "-32), cyclohexyl methyl (A8 "-33), normal-butyl (A8 "-34), phenyl (A8 "-35), phenmethyl (A8 "-36), (3-indyl) methyl (A8 "-37), 2-(3-indyl) ethyl (A8 "-38), (4-phenyl) phenyl (A8 "-39), n-nonyl (A8 "-40), CH
3-OCH
2cH
2-OCH
2-(A8 "-41) and CH
3-(OCH
2cH
2)
2-OCH
2those of-(A8 "-42).
Usually, to belong to the amino-acid residue of one of following radicals to define the peptide chain Z of β-hairpin mimetic as herein described:
-group C-NR
20cH (R
72) CO-; " hydrophobic: small size is to middle-sized "
-group D-NR
20cH (R
73) CO-; " hydrophobic: large aromatic series or heteroaromatic "
-group E-NR
20cH (R
74) CO-; " polarity is cationic " and " urea derives "
-group F-NR
20cH (R
84) CO-; " polarity is uncharged or negatively charged ion "
-group H-NR
20-CH (CO-)-(CH
2)
4-7-CH (CO-)-NR
20-,-NR
20-CH (CO-)-(CH
2)
psS (CH
2)
p-CH (CO-)-NR
20-,-NR
20-CH (CO-)-(-(CH
2)
pnR
20cO (CH
2)
p-CH (CO-)-NR
20-and-NR
20-CH (CO-)-(-(CH
2)
pnR
20cONR
20(CH
2)
p-CH (CO-)-NR
20-;
" interchain key "
In addition, the amino-acid residue in chain Z can also have formula-A-CO-or formula-B-CO-, and wherein, A and B as hereinbefore defined.Finally, Gly also can be the amino-acid residue in chain Z, and Pro and Pro (4-NHCOPhe) also can be the amino-acid residue in chain Z, but except the position of interchain key (H) may be had.
Group C comprises and has small size to middle-sized hydrophobic side chain group (according to for substituent R
72general definition) amino-acid residue.Hydrophobic residue refers to neutral and the amino acid side chain repelled by aqueous solution at physiological ph.In addition, these side chains usually not hydrogen bonds donor groups, such as (but being not limited to) firsts and seconds acid amides, firsts and seconds amine and its protonated salt, mercaptan, alcohol, phosphonate/ester, phosphate/ester, urea or thiocarbamide accordingly.Such as, but they can contain Hydrogen Bond Acceptors group, ether, thioether, ester, teritary amide, alkyl or aryl phosphonic acid ester and phosphoric acid ester or tertiary amine.Small size to the middle-sized amino acid of genes encoding comprises L-Ala, Isoleucine, leucine, methionine(Met) and α-amino-isovaleric acid.
Group D comprises and has aromatic series and heteroaromatic side-chain radical (according to for substituent R
73general definition) amino-acid residue.Aromatic amino acid residue refers to the hydrophobic amino acid with following side chain, and described side chain contains at least one ring, and this ring has the π-electronic system (aromatic group) of conjugation.In addition, they can contain hydrogen bond donor group (such as but not limited to primary amide and secondary amide, primary amine and secondary amine and its corresponding protonated salt, mercaptan, alcohol, phosphonate/ester, phosphate/ester, urea or thiocarbamide) and Hydrogen Bond Acceptors group (such as but not limited to ether, thioether, ester, teritary amide, alkyl or aryl phosphonic acid ester and phosphoric acid ester or tertiary amine).The die aromatischen Aminosaeuren of genes encoding comprises phenylalanine and tyrosine.
Heteroaromatic amino acid residue refers to the hydrophobic amino acid residue with following side chain, and described side chain has at least one ring, and this ring has the π-electronic system of conjugation, comprising at least one heteroatoms, such as but not limited to O, S and N (according to for substituent R
77general definition).In addition, this type of residue can contain hydrogen bond donor group (such as but not limited to primary amide and secondary amide, primary amine and secondary amine and its corresponding protonated salt, mercaptan, alcohol, phosphonate/ester, phosphate/ester, urea or thiocarbamide) and Hydrogen Bond Acceptors group (such as but not limited to ether, thioether, ester, teritary amide, alkyl or aryl phosphonic acid ester and phosphoric acid ester or tertiary amine).The heteroaromatic amino acid of genes encoding comprises tryptophane and Histidine.
Group E comprises the amino acid containing following side chain, and described side chain has the derivative residue of polarity positively charged ion, amido and urea (according to for substituent R
74general definition).Polarity positively charged ion refers to the basic side chain be protonated at physiological ph.The polarity cationic amino acid of genes encoding comprises arginine, Methionin and Histidine.Citrulline is the example of the amino-acid residue that urea derives.
Group F comprises the amino acid containing following side chain, and described side chain has polarity without electric charge or negatively charged ion residue (according to for substituent R
84general definition).Polarity refers to hydrophilic side-chains without electric charge or negatively charged ion residue, and it is neutral and be negatively charged ion (carboxylic acid is included) respectively at physiological ph, but it can not be repelled by aqueous solution.Typically, this type of side chain contains hydrogen bond donor group, such as but not limited to primary amide and secondary amide, carboxylic acid and ester, primary amine and secondary amine, mercaptan, alcohol, phosphonate/ester, phosphate/ester, urea or thiocarbamide.These groups can form hydrogen bond net with water molecules.In addition, they also can contain Hydrogen Bond Acceptors group, such as but not limited to ether, thioether, ester, teritary amide, carboxylic acid and carboxylicesters (salt), alkyl or aryl phosphonic acid ester and phosphoric acid ester or tertiary amine.The polarity of genes encoding comprises l-asparagine, halfcystine, glutamine, Serine and Threonine without charge amino acid, also comprises aspartic acid and L-glutamic acid.
Group H is included in beta chain region relative position preferably (L)-amino acid whose side chain, and it can form interchain key.The key be widely known by the people most is the disulfide linkage formed by the halfcystine and height-halfcystine that are positioned at beta chain relative position.There will be a known multiple method to form disulfide linkage, comprise the people Synthesis1979 such as J.P.Tam, 955-957; The people such as Stewart, SolidPhasePeptideSynthesis, 2dEd., PierceChemicalCompany, III., 1984; The people J.Biol.Chem.1975 such as Ahmed, 250,8477-8482; With the people such as Pennington, Peptides, 164-166 page, GiraltandAndreu, Eds., ESCOMLeiden, Holland, those described in 1990.The most advantageously, for scope of the present invention, to halfcystine, acetylamino methyl (Acm)-blocking group can be used to prepare disulfide linkage.The interchain key of abundant foundation is the formation by amido linkage, is coupled together respectively by ornithine with Methionin with the L-glutamic acid and asparagicacid residue that are positioned at relative beta chain position.For the side-chain amino group of ornithine and Methionin, preferred blocking group is allyloxycarbonyl (Alloc), is allyl ester for aspartic acid and L-glutamic acid.Finally, also by with reagent such as N, N-carbonylic imidazoles, will the relative Methionin of beta chain position be positioned at and the amino of ornithine couples together, to form ring-type urea to set up interchain key.
As mentioned before, the position for interchain key is the P2 and 10 be combined.This type of interchain key is known can stablize β-hairpin conformation, and is therefore configured for the important feature element designing β-hairpin mimetic.
In chain Z, most preferred amino-acid residue is from derivative those of natural alpha-amino acid.Hereinafter list the amino acid (or their residue) being suitable for object of the present invention, abbreviation corresponds to the common practice usually adopted:
Three-letter codes using single letter code
AlaL-L-Ala A
ArgL-arginine R
AsnL-l-asparagine N
AspL-aspartic acid D
CysL-halfcystine C
GluL-L-glutamic acid E
GlnL-glutamine Q
Gly glycine G
HisL-Histidine H
IleL-Isoleucine I
LeuL-leucine L
LysL-Methionin K
MetL-methionine(Met) M
PheL-phenylalanine F
ProL-proline(Pro) P
dproD-proline(Pro)
dp
SerL-Serine S
ThrL-Threonine T
TrpL-tryptophane W
TyrL-tyrosine Y
ValL-α-amino-isovaleric acid V
Other a-amino acid (or its residue) being suitable for object of the present invention comprising:
For the particularly preferred residue of group C be:
For the particularly preferred residue of group D be:
For the particularly preferred residue of group E be:
For the particularly preferred residue of group F be:
Usually, the peptide chain Z in β-hairpin mimetic of the present invention comprises 11 amino-acid residues.In chain Z, P1 to the P11 position of each amino-acid residue is clearly defined as follows: P1 represents first amino acid in chain Z, it is with the C-end of its N-end and template (b)-(p), or in template (a1) in the C-end of-B-CO-group, template (a2)-A-CO-group C-end, form the C-end coupling of-B-CO-group of the C-end of template (a3); P11 represents last amino acid in chain Z, it is with the N-end of its C-end and template (b)-(p), or in template (a1) in the N-end of-A-CO-group, template (a2)-B-CO-group N-end, form the N-end coupling of-B-CO-group of the N-end of template (a3).Each preferably containing the amino-acid residue belonging to one of above-mentioned C, D, E, F, H type in P1 to P11 position, or there is formula-A-CO-or there is formula-B-CO-, or, be Gly, Pro or Pro (4NHCOPhe), as described below:
Generally speaking, the a-amino acid residue of 1 to 11 of chain Z is preferably:
-P1:C type or D type or E type or F type;
-P2:E type or F type or C type;
-P3:C type or F type, or this residue is Gly;
-P4:C type or E type or F type, or this residue is Gly or Pro;
-P5:E type or F type, or this residue is Gly or Pro;
-P6:C type or D type or F type, or this residue is Gly or Pro;
-P7:F type or formula-A-CO-, or this residue is Gly or Pro;
-P8:D type or C type or formula-A-CO-, or this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or E type or F type;
-P10:F type or C type or E type:
-P11:E type or F type or C type or D type; Or
-P2 forms the group of H type together with P10;
Condition is: if template is
dpro-
lpro, so the amino-acid residue of P1 to P11 position is not:
-P1:Arg
-P2: the Cys be connected with the Cys of P10 position by disulfide linkage
-P3:Thr
-P4Lys
-P5Ser
-P6Ile
-P7Pro
-P8Pro
-P9Ile
The Cys that-P10 is connected with the Cys of P10 position by disulfide linkage; And
-P11Phe。
The a-amino acid residue of 1 to 11 is most preferably:
-P1:Nle, Ile, Aoc, hLeu, Chg, OctG, hPhe, 4AmPhe, Cha, Phe, Tyr, 2Cl-Phe, Trp, 1-Nal, Leu, Cha or Arg;
-P2:Cys, Glu, Nle, Thr or Gln;
-P3:Thr, Ala or Abu;
-P4:Lys, Nle, Ala, Abu or Thr;
-P5:Ser, AlloThr or Dpr;
-P6:Ile, c5al, Leu, Nle, Aoc, OctG, Cha, hLeu, hPhe, Chg, t-BuA, Glu or Asp;
-P7:Pro；
-P8:Pro, Ala or Pro (4NHCOPhe);
-P9:Tyr, Phe, Ile, Nle, Cha, Gln, Arg, Lys, His, Thr or Ala;
-P10:Cys, Arg, Nle, Gln, Lys, Met, Thr or Ser;
-P11:Tyr, Gln, Arg, Ser, Nle, 2-Nal, 2Cl-Phe, Cha, Phg, Tyr, Phe, Asp, Asn or Thr; And
-Cys, if existed at P2 and P10, it can form disulfide linkage.
With regard to the inhibitor of cathepsin G, the a-amino acid residue of 1 to 11 of chain Z is preferably:
-P1:C type or D type or E type;
-P2:F type or C type;
-P3:F type;
-P4:C type or E type;
-P5:E type or F type;
-P6:F type;
-P7:F type or formula-A-CO-, or this residue is Gly or Pro;
-P8:C type or formula-A-CO-, or this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or F type;
-P10:F type or C type or E type;
-P11:E type or D type or F type; Or
-P2 forms the group of H type together with P10.
With regard to the inhibitor of cathepsin G, the a-amino acid residue of 1 to 11 most preferably:
-P1:Phe, hPhe, 4AmPhe, Nle, Chg, Ile, Tyr, Arg, Trp, 2Cl-Phe, Arg, 1-Nal or Cha;
-P2:Cys, Glu or Nle;
-P3:Thr；
-P4:Lys or Nle;
-P5:Ser, AlloThr or Dpr;
-P6:Asp or Glu;
-P7:Pro；
-P8:Pro；
-P9:Ile, Nle, Cha, Gln, Tyr or Ala;
-P10:Cys, Arg or Nle;
-P11:Thr, Asp, Ser, Tyr, Phe, Asn or Arg; And
-Cys, if existed at P2 and P10, it can form disulfide linkage.
With regard to the inhibitor of elastoser, the a-amino acid residue of 1 to 11 of chain Z is preferably:
-P1:C type or D type;
-P2:F type;
-P3:F type or C type;
-P4:C type or F type;
-P5:F type;
-P6:C type;
-P7: formula-A-CO-, or this residue is Gly or Pro;
-P8: formula-A-CO-, or this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:D type or F type or C type;
-P10:F type or C type or E type;
-P11:E type or F type or D type; Or
-P2 forms the group of H type together with P10.
With regard to the inhibitor of elastoser, the a-amino acid residue of 1 to 11 most preferably:
-P1:Ile, Nle, Aoc, hLeu, Chg, OctG or hPhe;
-P2:Cys, Glu, Thr or Gln;
-P3:Thr, Ala or Abu;
-P4:Ala, Thr or Abu;
-P5:Ser；
-P6:OctG, Ile, Cha, Leu, c5al, Nle, Aoc, Chg, tBuA or hLeu;
-P7:Pro；
-P8:Pro or Pro (4NHCOPhe);
-P9:Gln, Tyr, ILe or Phe;
-P10:Cys, Lys, Gln, Thr, Met or Arg;
-P11:Tyr, Ser, Arg, Gln, Nle, 2-Nal, 2Cl-Phe, Phe, Cha or Phg; And
-Cys, if existed at P2 and P10, it can form disulfide linkage.
With regard to the inhibitor of tryptase, the a-amino acid residue of 1 to 11 of chain Z is preferably:
-P1:C type or D type or E type;
-P2:F type;
-P3:F type;
-P4:E type;
-P5:F type;
-P6:C type or D type;
-P7:F type or formula-A-CO-, or this residue is Gly or Pro;
-P8:C type or formula-A-CO-, or this residue is Gly or Pro;
-P9:C type or E type or F type;
-P10:F type;
-P11:E type or D type; Or
-P2 forms the group of H type together with P10;
Condition is: if template is
dpro-
lpro, so the amino-acid residue of P1 to P11 position is not:
-P1:Arg
-P2: the Cys be connected with the Cys of P10 position by disulfide linkage
-P3:Thr
-P4Lys
-P5Ser
-P6Ile
-P7Pro
-P8Pro
-P9Ile
The Cys that-P10 is connected with the Cys of P10 position by disulfide linkage; And
-P11Phe。
With regard to the inhibitor of tryptase, the a-amino acid residue of 1 to 11 of chain Z most preferably:
-P1:Cha, Tyr or Trp
-P2:Cys
-P3:Thr
-P4:Lys
-P5:Ser
-P6:Leu
-P7:Pro
-P8:Pro
-P9:Lys
-P10:Cys
-P11:Arg; And
The Cys residue that P2 and P10 position exists can form disulfide linkage.
Particularly preferred beta-peptide stand-in of the present invention comprise disclosed those as cathepsin G's inhibitor of embodiment 5,19,20,22,23,38,39,40 and 75; Disclosed those as elastase inhibitor of embodiment 91,121,153,154,155,156,157,158,159,160,161177 and 178; And disclosed those as tryptase inhibitors of embodiment 193,194 and 195.
Method of the present invention can be used as parallel array synthesis and advantageously implements, the library of the β-hairpin peptidomimetics fixed with the template producing above-mentioned general formula I.This type of parallel projects allows the array obtaining a large amount of (usual 24 to 192 kinds, preferably, 96 kinds) compound of Formula I with high yield and the purity determined, minimizes the formation of dipolymer and fluorinated polymer.Therefore, the suitable selection through functionalized solid support (namely solid support adds linkers), template and cyclisation site is played an important role.
The polystyrene of preferred 1-5% Vinylstyrene can be had from being cross-linked, being coated with the polystyrene (Tentagel of polyethylene glycol spacer (spacer)
r) and polyacrylamide resin obtain easily and (also see ObrechtD. through functionalized solid support; Villalgordo, J.-M, " Solid-SupportedCombinatorialandParallelSynthesisofSmall-Molecular-WeightCompoundLibraries ", TetrahedronOrganicChemistrySeries, Vol.17, Pergamon, ElsevierScience, 1998).
Carry out functionalized by joint and difunctional spacer molecule to solid support, this difunctional spacer molecule is at one end containing anchoring group, for attachment on solid support, contain the functional group of alternative cracking at the other end, for chemical conversion subsequently and cracking program.With regard to object of the present invention, use the joint of two types:
1 type joint is designed to discharge amide group (RinkH, TetrahedronLett.1987,28,3783-3790) in acid condition.The joint of this type forms the acid amides of amino acid carboxyl, 4-[(((2 is comprised by the example of the functionalized resin of this type of joint design, 4-Dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetylamino) aminomethyl] PS resin, 4-[(((2, 4-Dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetylamino) aminomethyl]-4-methylbenzhydrylamine PS resin (Rink acid amides MBHAPS resin) and 4-[(((2, 4-Dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetylamino) aminomethyl] benzhydryl amine PS-resin (Rink acid amides BHAPS resin).Preferably, there is the polystyrene of most preferably 1-5% Vinylstyrene to obtain upholder from crosslinked, and carry out functionalized with 4-(((2,4-Dimethoxyphenyl) Fmoc-aminomethyl) phenoxyacetylamino) joint to it.
2 type joints are designed to finally discharge carboxyl in acid condition.The joint of this type and amino acid whose carboxyl form the unstable ester of acid, phenmethyl, diphenyl-methyl and trityl ester that normally acid is unstable; The example of this type of joint design comprises 2-methoxyl group-4-hydroxy methyl phenyloxy (Sasrin
rjoint), 4-(2,4-Dimethoxyphenyl-methylol)-phenoxy group (Rink joint), 4-(4-methylol-3-methoxyphenoxy) butyric acid (HMPB joint), trityl and 2-chlorine trityl.Preferably, there is the polystyrene of most preferably 1-5% Vinylstyrene to obtain upholder from crosslinked, and carry out functionalized with 2-chlorine trityl joint to it.
When method of the present invention is implemented as parallel array synthesis, it can according to hereinafter described advantageously implementing, but to those skilled in the art, how changing these programs when thinking the single above-mentioned formula I of synthesis one, will be directly apparent.
To a large amount of reaction vessels (usual 24 to 192 equaling the compound sum that will be synthesized by parallel mode, typically, 96) middle loading 25 to 1000mg, preferably, 100mg's is suitable for functionalized solid phase upholder, it preferably has the polystyrene of 1 to 3% Vinylstyrene to obtain from crosslinked, or obtains from Tentagel resin.
The solvent used must be able to make resin expand, and includes but not limited to methylene dichloride (DCM), dimethyl formamide (DMF), N-Methyl pyrrolidone (NMP), dioxane, toluene, tetrahydrofuran (THF) (THF), ethanol (EtOH), trifluoroethanol (TFE), Virahol etc.Solvent mixture containing at least one component polar solvent (such as, 20%TFE/DCM, 35%THF/NMP) for guaranteeing and dissolving and the high reaction activity of peptide chain of resin-bonded and solvation are favourable (Fields, G.B., Fields, C.G., J.Am.Chem.Soc.1991,113,4202-4207).
Along with on discharging C-terminal carboxylic acid group under mildly acidic conditions and not affecting the exploitation of multiple joint of the acid-unstable group of functional group in protection side chain, sizable development is achieved to the synthesis of protected peptide fragment.Joint (the Sasrin of 2-methoxy-4-phenol methanol-derivative
rjoint; the people such as Mergler; TetrahedronLett.1988; 294005-4008) the available diluted trifluoroacetic acid TFA of 0.5-1% (in the DCM) cracking; and go protective condition to be stable to Fmoc during peptide symthesis, the Additional Protection group based on Boc/tBu is compatible with this protection scheme.Other joint being suitable for method of the present invention comprises: the 4-(2 that super acid is unstable, 4-Dimethoxyphenyl-methylol)-phenoxy group joint (Rink joint, Rink, H.TetrahedronLett.1987,28,3787-3790), wherein, remove peptide need in DCM 10% acetic acid or DCM in 0.2% trifluoroacetic acid; The derivative joint of 4-(4-methylol-3-methoxyphenoxy) butyric acid (HMPB-joint,
aMP.AMp.Amp Riniker, Peptides1991,1990131), it can also by 1%TFA/DCM cracking, to produce the peptide fragment containing the unstable side chain protected group of all acid; And also have, 2-chlorine trityl chloride joint people such as (, TetrahedronLett.1989,30,3943-3946) Barlos, it allows to use the mixture process of Glacial acetic acid/trifluoroethanol/DCM (1:2:7) peptide to be dissociated in 30 minutes.
The suitable blocking group being respectively used to amino acid and their residue is, such as:
-such as, for amino (as existed, also existing in lysine side-chain)
-for carboxyl (as exist, such as also exist in aspartic acid and glutamate side chain), by being converted into ester to carry out by the component of alcohol
-for guanidine radicals (as exist, such as, exist in arginine side chain)
-for hydroxyl (as exist, such as, exist in Threonine and lysine side chains)
The tBu tertiary butyl
Bn phenmethyl
Trt trityl
-and for sulfydryl (as exist, such as exist in cysteine side chain)
Preferably, with the amino acid derivative of 9-fluorenylmethyloxycarbonyl (Fmoc)-protection as structural unit, the beta-hairpin loop mimetics that the template for building formula I is fixing.For carry out protection, that is, cut Fmoc group, can use in DMF 20% piperidines or DMF in 2%DBU/2% piperidines.
The amount of reactant (i.e. amino acid derivative) is generally 1 to 20 equivalent, this is based on the milliequivalent through functionalized solid phase upholder every gram of load (meq/g) (p-poly-phenyl ethenoid resin, typically is 0.1 to 2.85meq/g) that be weighed into reaction tube at first.If necessary, the reactant of extra equivalent can be used, complete within the rational time to drive reaction.Reaction tube Combined test-tube frame parts (holderblock) and manifold (manifold) reinsert reservoir part (reservoirblock), and device is fixed to together.Initialize flows through the air-flow of manifold, to provide controlled environment, and such as nitrogen, argon gas, air etc.Air-flow also can be heated or cooled before flowing through manifold.To the heating of reacting hole or be cooled through reacting by heating platform or carry out, to cause the building-up reactions wanted with coolings such as Virahol/dry ice.Stir and realized by vibration or magnetic agitation (in reaction tube).Preferred workstation (but being not limited thereto) is Combi-chem workstation and the MultiSynTech's-Syro synthesizer of Labsource.
Amido linkage is formed to be needed to activate α-carboxyl, for acylation step.When the carbodiimide class by commonly using, such as dicyclohexylcarbodiimide (DCC, Sheehan & Hess, J.Am.Chem.Soc.1955,77,1067-1068) or DIC (DIC, the people Biochem.Biophys.Res.Commun.1976 such as Sarantakis, 73,336-342) when carrying out this activation, the dicyclohexylurea obtained and di-isopropyl urea are insoluble and solvable respectively in solvent usually used.Carbodiimide method one change in, comprise I-hydroxybenzotriazole (HOBt,
aMP.AMp.Amp Geiger, Chem.Ber1970,103,788-798) join in conjugate mixtures as additive.HOBt prevents dehydration, contains activated amino acid whose racemization, and plays a role as catalyzer, to advance linked reaction slowly.Some phosphorus reagent is tried out as direct coupling reagent, such as benzotriazole-1-base-oxygen base-three-(dimethylamino)-phosphorus hexafluorophosphate (people such as BOP, Castro, TetrahedronLett.1975,14,1219-1222; Synthesis, 1976,751-752) or benzotriazole-1-base-oxygen base-three-pyrrolidyl-phosphorus hexafluorophosphate (Py-BOP, Coste etc., TetrahedronLett.1990,31,205-208) or 2-(1H-benzotriazole-1-base-) 1,1,3,3-tetramethyl-urea four (tera) fluoroborate (TBTU) or hexafluorophosphate (HBTU, the people such as Knorr, TetrahedronLett.1989,30,1927-1930); These phosphorus reagent are also suitable for forming HOBt ester with shielded amino acid derivative original position.Over closer year, also use diphenyl phosphoryl azide compound (DPPA) or O-(7-azepine-benzotriazole-1-base)-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TATU) or O-(7-azepine-benzotriazole-1-base)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU)/7-azepine-I-hydroxybenzotriazole (HOAt, the people such as Carpino, TetrahedronLett.1994,35,2279-2281) as coupling reagent.
Owing to necessarily carrying out, close to quantitative linked reaction, therefore needing the experimental evidence of having reacted.Can after each coupling step rapidly and easily carry out the ninhydrin reaction (people such as Kaiser, Anal.Biochemistry1970,34,595), wherein, the existence of primary amine is indicated for decile quantitatively with the positive colorimetric reaction of the peptide of resin-bonded.Fmoc chemical process allows to carry out Spectrophotometric Assays people such as (, Int.J.PeptideProteinRes.1979,13,35-42) Meienhofer to during alkali release Fmoc chromophoric group to it.
To in each reaction tube and the intermediate product of resin-bonded wash, make it not containing excessive retention reagent, solvent and by product, wash and carried out to pure solvent by repeated exposure, this realizes by one of following two kinds of methods:
1) in reacting hole, solvent is loaded (preferably, 5ml), reaction tube and test-tube stand parts and manifold are immersed, stir 5 to 300 minutes, preferably, 15 minutes, and discharged by gravity, then by discharging solvent through the air pressure (closing outlet) of manifold inlet application simultaneously;
2) remove menifold from test-tube stand parts, scatter by the decile (preferably, 5ml) of reaction tube top by solvent, drained in receiving vessel (such as test tube or tubule) through filter by gravity.
Above-mentioned two kinds of washing procedures repeat about 50 times at the most (preferably, about 10 times), are carried out the efficiency of monitoring reagent, solvent and by product removing by the methods such as TLC, GC or observation washes.
Each to transform continuously, all repeat mentioned above compound and reagent with resin-bonded to be reacted the program then removing excess reagent, by product and solvent in reacting hole, until obtain last with the linear peptide be fully protected that is resin-bonded.
By this linear peptide be fully protected from before solid support dissociates, if necessary, selective deprotecting can be carried out to the one or more shielded functional group existed in molecule, and suitably replace the reaction active groups discharged thus.For reaching this effect, must at first with selectively remove and can not have influence on all the other blocking groups of existence blocking group protection think functional group to be processed.Alloc (allyloxycarbonyl) selectively removes (such as to pass through CH
2cl
2in phenyl silane and Pd °) and the example of this type of amido protecting group of all the other blocking groups (such as Fmoc) existed in molecule can not be affected.Then can with the reaction active groups being suitable for introducing the substituent agent treated wanted and discharging thus.Such as, thus, by corresponding to the acylating reagent of acyl substituent that will introduce to amino in addition acidylate.For forming the amino acid of pegization, such as IPegK or SPegK, preferably, by HATU (phosphofluoric acid N-[(dimethylamino)-1H-1 of 5 equivalents in dry DMF, 2, 3-triazolo [4, 5-b] pyridine-1-methylene]-N-methyl first ammonium N-oxide compound) and solution and anhydrous DMF in DIPEA (diisopropylethylamine) solution of 10 equivalents, and respectively, 2-[2-(2-methoxy ethoxy) oxyethyl group] acetic acid (lPeg) of 5 equivalents and 2-(2-methoxy ethoxy) acetic acid (sPeg) are applied to amino upper 3 hour discharged of suitable amino acid side chain.After this, after resin being filtered and washs, this program 3 hours are repeated again by the fresh solution of reagent.
By this linear peptide be fully protected from before solid support disintegrates down, if necessary, interchain key can also be formed between the Suitable amino acid residues side chain on 2 and 10.
The explanation that the group about H type carries out has been combined above, interchain key and formation thereof are discussed, the group of H type can be such as by the halfcystine on the relative position of beta chain and the disulfide linkage that formed between homocysteine residue, or by amido linkage by the L-glutamic acid be connected with lysine residue with ornithine be respectively positioned on relative beta chain position and asparagicacid residue, or the lactam bridges formed by the glutaminic acid residue be connected with 2,4-diamino-butanoic residue.The formation of this type of interchain key realizes by method well known in the art.
For forming disulfide linkage, preferably, the iodine solution of 10 equivalents being applied in DMF, or being applied to CH
2cl
2in/MeOH mixture 1.5 hours, after filtration iodine solution, repeat again to carry out 3 hours again with fresh iodine solution, or the mixture iodine solution of 10 equivalents being applied to DMSO and acetic acid solution is (with the NaHCO of 5%
3be buffered to pH5-6) in 4 hours, or within 24 hours, being applied it to by stirring is adjusted in the water of pH8 with solution of ammonium hydroxide, or be applied in the presence of the air and be adjusted in the ammonium acetate buffer of pH8, or be applied to (preferably, 50 equivalents) in NMP and tri-n-butyl phosphine.
By reaction tube and test-tube stand parts and manifold being immersed the reacting hole containing lytic reagent solution (preferably, 3 to 5ml), the linear peptide realizing being fully protected is from dissociating solid support.Gas flow, temperature control, stir and reaction monitoring carries out according to mentioned above and demand, to realize dissociation reaction.Reaction tube and pipe support parts and manifold is removed from reservoir part, to be promoted to higher than solution water plane but lower than edge on reacting hole, via manifold inlet application air pressure (closing outlet) simultaneously, so that end product solution efficient discharge is entered in storage holes.Then according to mentioned above, the solvent suitable with 3 to 5ml washs 2 to 5 times resin remaining in reaction tube, to extract (washing out) dissociating product as much as possible.Merge thus obtained reaction mixture, carefully carry out, to avoid intersecting mixing.Then various solution/extract is operated according to demand, to isolate final compound.Typical operation includes but not limited to: other in evaporation, concentrated, liquid/liquid extractions, acidifying, alkalization, neutralization or solution reacts.
Evaporate with the solution of the linear peptide derivatives be fully protected crossed containing cutting from solid support and use in alkali.Then use solvent, such as DCM, DMF, dioxane, THF etc. carry out cyclisation in the solution.The multiple coupling reagent mentioned above all can be used for cyclisation.Cyclisation continues about 6-48 hour, preferably, and about 16 hours.Such as follow the tracks of reaction process by RP-HPLC (reversed-phased high performace liquid chromatographic).Then by evaporation of solvent, the cyclic peptide derivative be fully protected is dissolved in water in immiscible solvent (such as DCM), and with the mixture extraction solution of water or water miscible solvent, to remove any excessive coupling reagent.
Finally, with 95%TFA, 2.5%H
2o, 2.5%TIS or process the peptide derivant be fully protected for other combination of the scavenging agent realizing cracking blocking group.The scission reaction time is generally 30 minutes to 12 hours, preferably, and about 2.5 hours.Volatile matter is evaporated to dry, in the 20%AcOH that rough peptide is dissolved in the water, extracts with isopropyl ether or other solvent of being suitable for this.Collect aqueous layer, be evaporated to dry, obtain by the cyclic peptide derivative of complete de-protected formula I as end product.
Or, can to realize dissociating from solid support by hand in Glass Containers, cyclisation and thoroughly go to protect the peptide be fully protected.
According to its purity, this peptide derivant can be directly used in biological test, or must be further purified it, such as, carry out purifying by preparation property HPLC.
As mentioned before; if necessary; can be pharmacy acceptable salt by complete de-protected product conversion by thus obtained formula I afterwards; or thus obtained pharmaceutically acceptable or unacceptable salt is converted into the free cpds of corresponding formula I, or be converted into different, pharmacy acceptable salt.Any one in these operations is all undertaken by method well known in the art.
For the formula II in method of the present invention template raw material, described for (pre-startingmaterials) material of raw material before it and these raw materials and being prepared in the International Application Serial No. PCT/EP02/01711 of same applicant of front raw material, this application is open as WO02/070547A1.
β-hairpin peptidomimetics of the present invention can be used in the application of wide scope, wherein, inflammatory diseases or pulmonary disorder or infection or Immunological diseases or cardiovascular disorder or neurodegenerative disease are mediated by serine protease or cause, or wherein, cancer is mediated by serine protease or causes.For control or the prevention of the illness for the treatment of given available proteinase inhibitor or disease, β-hairpin peptidomimetics itself can be used or it can be used as the appropriate formulation together with carrier well known in the art, thinner or vehicle to apply.
Be used for the treatment of when β-hairpin peptidomimetics or prevent pulmonary emphysema, rheumatoid arthritis, osteoarthritis, arteriosclerosis, psoriasis, cystic fibrosis, multiple sclerosis, adult respiratory distress syndrome, pancreatitis, asthma, allergic rhinitis, inflammatory dermatoses, postangioplasty restenosis, cardiac hypertrophy, in heart failure or cancer (such as but not limited to, mammary cancer or to vascularization or shift relevant cancer) etc. disease time, β-hairpin peptidomimetics can be used separately, mixture as multiple β-hairpin peptidomimetics is used, with other anti-inflammatory agents or Antimicrobial agent or anticancer agent combined administration, and/or with other, there is forms of pharmacologically active agents combined administration.β-hairpin peptidomimetics can former state be used, or uses as pharmaceutical composition.
Can by traditional mixing, dissolving, granulation, manufacture coated tablet, fine grinding, emulsification, encapsulated, entrain into (entrap) or freeze drying process produces the pharmaceutical composition comprising β-hairpin peptidomimetics of the present invention.One or more physiology acceptable carriers, thinner, vehicle or assistant agent (it is conducive to active β-hairpin peptidomimetics to be processed as pharmaceutically spendable preparation) can be used, carry out compounding pharmaceutical composition with traditional means.Suitable preparation depends on selected application process.
For topical application, β-hairpin peptidomimetics of the present invention can be formulated as solution, gelifying agent, ointment, creme, suspension etc., this is well known in the art.
Systematicness preparation comprises those that be designed for and used by injection (in such as subcutaneous, intravenously, intramuscular, sheath or peritoneal injection), and be designed for transdermal, thoroughly mucous membrane, per os or use through lung those.
For injection, can β-hairpin peptidomimetics of the present invention be formulated in applicable solution, such as, preferably, in the damping fluid of PHYSIOLOGICALLY COMPATIBLE, in Hink ' s solution, Ringer's solution or normal saline buffer solution.Solution can contain formula material, such as suspension agent, stablizer and/or dispersion agent.Or β-hairpin peptidomimetics of the present invention can be powder type, for combining with suitable medium (such as through the pyrogen-free water of sterilizing) before use.
For saturating mucosal administration, use in the formulation for permeate agent suitable the barrier that will penetrate, this is known in the art.
For oral administration, by by β-hairpin peptidomimetics of the present invention and pharmaceutically acceptable carrier combinations known in the art, be easy to prepare them.Examples of such carriers can make β-hairpin peptidomimetics of the present invention be configured to tablet, pill, drageeing, capsule, liquid, gelifying agent, syrup, slurry, suspension etc., for by patient's oral preparations to be treated.For oral preparations (such as powder, capsule and tablet), suitable vehicle comprises filler (such as sugar, such as lactose, sucrose, mannitol and Sorbitol Powder; Cellulose preparations, such as W-Gum, wheat starch, rice fecula, yam starch, gelatin, tragacanth, methylcellulose gum, HPMC, Xylo-Mucine and/or polyvinylpyrrolidone (PVP)), granulation agent and tackiness agent.If necessary, disintegrating agent can be added, such as, through crosslinked polyvinylpyrrolidone class, agar or alginic acid or its salt (such as sodium alginate).If necessary, standard technique can be used solid dosage sugar coating or bag casing.
For oral liquid (such as suspension, elixir and solution), suitable carrier, vehicle or thinner, comprise water, glycol, oil, alcohol etc.In addition, tender taste agent, sanitas, tinting material etc. can also be added.
For using through cheek, composition can adopt the form such as tablet, lozenge of preparation usually.
For being used by suction, use suitable propelling agent, such as Refrigerant 12, trichlorofluoromethane, carbonic acid gas or other suitable gas, can send the β-hairpin peptidomimetics of the present invention of aerosol spray presentation easily from pressurized package or atomizer.In the aerocolloidal situation of pressurization, by providing valve delivery through the amount of metering to determine dose unit.The powdered mixture containing β-hairpin peptidomimetics of the present invention and suitable powdered substrate (such as lactose or starch) can be configured to for the capsule of the such as gelatin in sucker or insufflator and cartridge case.
Compound also can be configured to rectum or compositions for vaginal use, such as, suppository together with suitable suppository base (such as theobroma oil or other glyceryl ester).
Except described preparation above, β-hairpin peptidomimetics of the present invention also can be configured to depot formulation.This type of prolonged action preparation is by implanting (such as subcutaneous or intramuscular is implanted) or being used by intramuscularly.For producing this type of depot formulation, β-hairpin peptidomimetics of the present invention can be formulated together with suitable polymkeric substance or hydrophobic material (such as the emulsion in acceptable oil) or ion exchange resin, or prepares as sl. sol. salt.
In addition, other medicines delivery system can be used, such as liposome well known in the art and emulsion.Some organic solvent can also be used, such as methyl-sulphoxide.In addition, can use slow-released system, the semipermeable matrices of such as, solid polymer containing healing potion sends β-hairpin peptidomimetics of the present invention.Determined multiple slow-release material, they well known to a person skilled in the art.Slow releasing capsule can discharge compound continued for several weeks until more than 100 days, and this depends on their chemical property.According to chemical property and the biological stability of healing potion, extra strategy can be used for protein stabilization.
Because β-hairpin peptidomimetics of the present invention may contain charged residue, they can be typically entrapped within any above-mentioned preparation by former state, or include as pharmacy acceptable salt.Than corresponding free form, the solubleness of pharmacy acceptable salt in water-based or other protic solvent trends towards larger.
β-hairpin peptidomimetics of the present invention or its composition use with the amount effectively realizing the object wanted usually.Should be appreciated that amount used will depend on specific application.
For carrying out topical application, to be treated the disease of available beta hairpin stand-in treatment or to prevent, can use, the in vitro tests such as, provided in embodiment is to measure treatment effective dose.Can at disease as seen or even application for the treatment of when it is also sightless time.Those of ordinary skill in the art need not carry out too much experiment, can determine the treatment significant quantity for the treatment of local disease.
For systemic applications, treatment significant quantity can be estimated from vitro tests at first.Such as, can be prepared in animal model to dosage, to obtain circulation β-hairpin peptidomimetics concentration range, it comprises the IC measured in cell culture
50.This type of information can be used for the effective dose determined more accurately in the mankind.
Can use technology well known in the art, data in body, such as animal model determines predose.Those of ordinary skill in the art easily can optimize using for the mankind based on animal data.
Individuation can regulate the dosage be used for as serpin application, to provide the blood plasma level being enough to the β-hairpin peptidomimetics of the present invention keeping result for the treatment of.The effective serum level for the treatment of is obtained by daily many doses.
When topical application or selective absorbing, effective partial concn of β-hairpin peptidomimetics of the present invention may have nothing to do with plasma concentration.Those of ordinary skill in the art can optimize the effective local dose for the treatment of, and without the need to carrying out too much experiment.
Certainly, the amount of the β-hairpin peptidomimetics used by depend on be treated experimenter, experimenter's body weight, the severity of sufferer, method of application and prescriber judgement.
Usually, the treatment effective dose of β-hairpin peptidomimetics as herein described will provide treatment benefit, and can not cause substantial toxicity.
In cell culture or laboratory animal, the toxicity of β-hairpin peptidomimetics of the present invention is measured, such as, by measuring LD by standard pharmaceutical procedures
50(causing the dosage of 50% death in colony) or LD
100(causing the dosage of colony 100% death) obtains.Dose ratio between toxicity and result for the treatment of is therapeutic index.The compound showing high therapeutic index is preferred.The data obtained from these cell culture assay and zooscopy can be used for preparation to dosage range nontoxic for the mankind.The dosage of β-hairpin peptidomimetics of the present invention is preferably in the circulation composition of following ranges, and this concentration comprises not to be had or almost do not have virose effective dose.Dosage can change within the scope of this, and this depends on the dosage form of use and route of administration used.Status of patient can be considered select preparation, route of administration and dosage accurately by individual doctor.(see, such as, the people such as Fingl 1975: ThePharmacologicalBasisofTherapeutics, Ch.1, p.1).
Embodiment
Following embodiment sets forth the present invention in more detail, but not for being limited scope of the present invention by any way.Following abbreviation is employed in these embodiments:
HBTU:1-benzotriazole-1-base-tetramethyl-urea hexafluorophosphate (the people TetrahedronLett.1989 such as Knorr, 30,1927-1930);
HOBt:1-hydroxybenzotriazole;
DIEA: diisopropylethylamine;
HOAT:7-azepine-I-hydroxybenzotriazole;
HATU:O-(7-azepine-benzotriazole-1-base)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (the people TetrahedronLett.1994 such as Carpino, 35,2279-2281).
Embodiment
1. peptide symthesis
By the first shielded amino-acid residue and resin coupling
0.5g2-chlorine trityl chloride resin people TetrahedronLett.1989 such as (, 30,3943-3946) Barlos (0.83mMol/g, 0.415mmol) is loaded in dry flask.By Resin Suspension in CH
2cl
2(2.5ml), in, Keep agitation 30 minutes, expands under being allowed to condition at room temperature.By the first of 0.415mMol (1 equivalent) by the amino-acid residue (seeing below) suitably protected and CH
2cl
2(2.5ml) 284 μ l (4 equivalents) diisopropylethylamine (DIEA) in is processed resin, and mixture was 25 DEG C of vibrations 4 hours.Color of resin becomes purple, and solution keeps light yellow.Vibration resin (CH
2cl
2/ MeOH/DIEA:17/2/1), 30ml continues 30 minutes; Then wash in the following sequence: use CH
2cl
2(1x), DMF (1x), CH
2cl
2(1x), MeOH (1x), CH
2cl
2(1x), MeOH (1x), CH
2cl
2(2x), Et
2o (2x) washes, and dry 6 hours under vacuo.
Typically, heap(ed) capacity is 0.6-0.7mMol/g.
Prepare the resin of following preload: Fmoc-Pro-2-chlorine trityl resin, Fmoc-Asp (OtBu)-2-chlorine trityl resin, Fmoc-Pro (5RPhe)-2-chlorine trityl resin, Fmoc-Leu-2-chlorine trityl resin, Fmoc-Glu (OtBu)-2-chlorine trityl resin, Fmoc-Asp (OtBu)-2-chlorine trityl resin, Fmoc-Phe-2-chlorine trityl resin, Fmoc-Gln (Trt)-2-chlorine trityl resin, Fmoc-Ser (OtBu)-2-chlorine trityl resin, Fmoc-Val-2-chlorine trityl resin, Fmoc-Thr (OtBu)-2-chlorine trityl resin and Fmoc-Ile-2-chlorine trityl resin.
Synthesize the peptide fragment be fully protected
Use 24 to 96 reaction vessels, use Syro-peptide synthesizer (Multisyntech) to synthesize.The above-mentioned resin of 60mg (weight resin before loading) is placed in each container.Set following reaction cycle, and make it carry out:
Repeating step 3 to 6, to add each amino acid.
After the synthesis terminating the peptide fragment be fully protected, adopt program A hereinafter described or program B subsequently, this depends on whether will form interchain key on (i.e. two sulphur beta chain keys).
Program A: main chain is by the cyclisation of the peptide of cyclisation and aftertreatment
The peptide fragment that cracking is fully protected
After completing synthesis, by Resin Suspension in CH
2cl
2in 1ml (0.39mMol) 1%TFA (v/v) in, suspend 3 minutes, filter, use CH
2cl
2in 1ml (1.17mMol, 3 equivalents) 20%DIEA (v/v) neutralization filtrate.This program repeats twice, to have guaranteed cracking.By 0.5ml cleavage mixture, protection is gone completely to equal sample (200 μ L) filtrate; described cleavage mixture contain 95% trifluoroacetic acid (TFA), 2.5% water and 2.5% tri isopropyl silane (TIS); by anti-phase-LCMS, filtrate is analyzed, to monitor the efficiency of linear peptides synthesis.
The cyclisation of linear peptides
The linear peptides be fully protected is dissolved in DMF (8ml, concentration is 10mg/ml).Add the DIEA (1.44mMol) of 4 equivalents in the HATU (0.72mMol) of 2 equivalents in 1mlDMF and 1mlDMF, at room temperature mixture is carried out to the stirring of 16 hours.Evaporating volatile substances is to dry.Rough cyclisation peptide is dissolved in 7mlCH
2cl
2in, with 10% acetonitrile extraction in water (4.5ml) three times.By CH
2cl
2layer is evaporated to dry.
Cyclic peptide go protection and purifying
The cyclic peptide of acquisition is dissolved in 3ml cleavage mixture, containing the trifluoroacetic acid (TFA) of 95%, the water of 2.5% and 2.5% tri isopropyl silane (TIS) in this mixture.Mixture is placed 2.5 hours at 20 DEG C, then concentrates under vacuo.Rough peptide is dissolved in the 20%AcOH in water (7ml), extracts three times by diisopropyl ether (4ml).Collect aqueous layer, be evaporated to dry, by the anti-phase LC-MS Purification of preparation property.
After freeze-drying, obtain the product of white powder, analyzed by LC-MS.The analytical data comprising purity obtained after preparation property HPLC and ESI-MS is shown in table 1.
Analytical procedure:
Use JupiterProteo90A, 150x2.0mm, (code 00F4396-B0-Phenomenex) carrys out determination and analysis HPLC retention time (RT, in minute), wherein uses following solvents: solvent orange 2 A (H
2and solvent B (CH O+0.1%TFA)
3cN+0.1%TFA), and use following gradient: 0 minute: 95%A, 5%B; 20 minutes: 40%A, 60%B; 21-23 minute: 0%A, 100%B; 23.1-30 minute: 95%A, 5%B.
Program B: there is the main chain of two sulphur beta chain keys by the cyclisation of the peptide of cyclisation and aftertreatment
Form two sulphur beta chain keys
After completing synthesis, resin is expanded 1 hour in the dry DMF of 3ml.Then in reactor, add the iodine solution of 10 equivalents in DMF (6ml), then stir 1.5 hours.Filter resin, add fresh iodine (10 equivalents) solution in DMF (6ml), then stir 3 hours again.Filter resin, with DMF (3x) and CH
2cl
2(3x) wash.
Backbone cyclized, the cracking of peptide and purifying
After forming two sulphur beta chain keys, by Resin Suspension in CH
2cl
2in 1ml (0.39mMol) 1%TFA (v/v) in, suspend 3 minutes, filter, use CH
2cl
2in 20%DIEA (v/v) neutralization filtrate of 1ml (1.17mMol, 3 equivalents).This program repeats twice to guarantee that cracking is complete.Use 2mlCH
2cl
2washing resin.Evaporation CH
2cl
2layer is to dry.
The linear peptides be fully protected is dissolved in the dry DMF of 8ml.Then in peptide, add the DIPEA of 4 equivalents in the HATU of 2 equivalents in dry DMF (1ml) and dry DMF (1ml), then stir 16 hours.Volatile matter is evaporated to dry.The rough peptide through cyclisation is dissolved in 7mlCH
2cl
2in, with 10% acetonitrile extraction in water (4.5ml) three times.Evaporation CH
2cl
2layer is to dry.For going protection completely to peptide, add 3ml cracking mixed solution TFA:TIS:H
2o (95:2.5:2.5), mixture places 2.5 hours.Volatile matter is evaporated to dry, and rough peptide is dissolved in the 20%AcOH in water (7ml), extracts three times by diisopropyl ether (4ml).Collect water layer, be evaporated to dry, by the anti-phase LC-MS Purification of preparation property.
After freeze-drying, obtain the product of white powder, analyzed by ESI-MS analytical procedure mentioned above.The analytical data comprising purity obtained after preparation property HPLC and ESI-MS is shown in table 1.
Embodiment 1-45,52-63,65-67,70-71,75-114,129,131-162 and 179-196 be shown in table 1.From with the amino acid Pro of resin grafting synthetic peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dpro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Embodiment 1-6,9-45,52-63,65-67,70-71,75-103,112-114,129,131,133,136-138,140-141,143-146,148-153,155,157-162 and 179-196 be according to described in program B; cracking from resin, carries out disulfide formation, cyclisation, goes protection and purifying.Embodiment 82,123,149,159,161 and 178 according to described in program B from cracking resin.Use following program to form disulfide linkage:
Rough product is dissolved in (concentration: 1mg raw product in every ml) in ammonium acetate buffer 0.1M (pH regulator is 8).At room temperature stir the mixture in the presence of air.By anti-phase LC-MS monitoring reaction.After reacting completely, evaporating solns is extremely dry, by the anti-phase LC-MS Purification of preparation property.
According to the cyclisation carrying out main chain described in program A.Following program is used to carry out protection:
For going protection completely to peptide, add 5ml cracking mixed solution TFA:H
2o: phenol: Thioanisol: dithioglycol (82.5:5:5:5:2.5), mixture at room temperature places 5 hours.Precipitation of peptides is carried out by adding cold diethyl ether (10ml).After centrifugal, removing supernatant liquid phase.With 5ml diethyl ether, three times are washed to throw out, carry out purifying by the anti-phase LC-MS of preparation property.
After freeze-drying, obtain the product of white powder, analyzed by ESI-MS analytical procedure mentioned above.
Embodiment 7,8,104-111,132,134,135,139,142,147,154 and 156 according to described in program A from cracking resin, carry out cyclisation, remove protection and purifying.
Use above-mentioned analytical procedure, measure HPLC-retention time (minute):
Embodiment 1 (15.37), embodiment 2 (11.54), embodiment 3 (7.82), embodiment 4 (8.62), embodiment 5 (16.51), embodiment 6 (13.67), embodiment 7 (3.61), embodiment 8 (4.11), embodiment 9 (5.82), embodiment 10 (7.98), embodiment 11 (8.38), embodiment 12 (6.80), embodiment 13 (7.41), embodiment 14 (6.20), embodiment 15 (8.68), embodiment 16 (9.82), embodiment 17 (5.59), embodiment 20 (7.32), embodiment 21 (8.66), embodiment 22 (8.68), embodiment 23 (12.66), embodiment 24 (8.67), embodiment 25 (7.53), embodiment 26 (9.02), embodiment 27 (8.06), embodiment 28 (9.62), embodiment 29 (8.78), embodiment 30 (10.49), embodiment 31 (5.50), embodiment 32 (7.45), embodiment 33 (8.39), embodiment 34 (10.16), embodiment 35 (9.04), embodiment 36 (10.98), embodiment 37 (7.56), embodiment 38 (9.29), embodiment 39 (8.32), embodiment 40 (10.11), embodiment 41 (7.23), embodiment 42 (8.83), embodiment 43 (7.92), embodiment 44 (9.87), embodiment 45 (8.26), embodiment 52 (6.20), embodiment 53 (8.68), Ex54 (9.82), embodiment 55 (5.59), embodiment 56 (6.06), embodiment 57 (6.47), embodiment 58 (7.32), embodiment 59 (8.68), embodiment 60 (10.66), embodiment 61 (8.54), embodiment 62 (9.83), embodiment 63 (16.54), embodiment 65 (15.71), embodiment 66 (17.50), embodiment 67 (15.87), embodiment 70 (12.87), embodiment 71 (13.48), embodiment 75 (14.22), embodiment 76 (4.47), embodiment 77 (5.15), embodiment 78 (10.93), embodiment 79 (10.70), embodiment 80 (12.09), embodiment 81 (11.63), embodiment 82 (5.71), embodiment 83 (5.45), embodiment 84 (11.14), embodiment 85 (10.90), embodiment 86 (13.78), embodiment 87 (13.98), embodiment 88 (14.35), embodiment 89 (15.21), embodiment 90 (14.72), embodiment 91 (11.97), embodiment 92 (11.77), embodiment 93 (15.25), embodiment 94 (14.61), embodiment 95 (20.46), embodiment 96 (15.08), embodiment 97 (20.78), embodiment 98 (18.28), embodiment 99 (14.62), embodiment 100 (13.90), embodiment 101 (13.76), embodiment 102 (20.53), embodiment 103 (14.14), embodiment 104 (11.60), embodiment 105 (11.90), embodiment 106 (11.63), embodiment 107 (11.78), embodiment 108 (13.03), embodiment 109 (15.22), embodiment 110 (12.40), embodiment 111 (12.10), embodiment 112 (5.49), embodiment 113 (5.67), embodiment 114 (5.55), embodiment 129 (17.22), embodiment 131 (11.97), embodiment 132 (13.56), embodiment 133 (14.57), embodiment 134 (14.72), embodiment 135 (17.53), embodiment 136 (18.28), embodiment 137 (14.72), embodiment 138 (14.35), embodiment 139 (15.40), embodiment 140 (11.14), embodiment 141 (5.71), embodiment 142 (13.97), embodiment 143 (13.94), embodiment 144 (15.08), embodiment 145 (20.87), embodiment 146 (17.91), embodiment 147 (17.11), embodiment 148 (7.83), embodiment 149 (16.22), embodiment 150 (20.09), embodiment 151 (20.72), embodiment 152 (21.38), embodiment 153 (17.97), embodiment 154 (16.58), embodiment 155 (19.46), embodiment 156 (15.66), embodiment 157 (22.04), embodiment 158 (15.65), embodiment 159 (17.89), embodiment 160 (18.72), embodiment 161 (19.91), embodiment 162 (17.79), embodiment 179 (4.25), embodiment 180 (11.43), embodiment 181 (12.30), embodiment 182 (12.83), embodiment 183 (10.51), embodiment 184 (12.12), embodiment 185 (10.14), embodiment 186 (10.09), embodiment 187 (10.14), embodiment 188 (10.65), embodiment 189 (10.73), embodiment 190 (10.10), embodiment 191 (10.17), embodiment 192 (10.19), embodiment 193 (11.02), embodiment 194 (9.92), embodiment 195 (10.74), embodiment 196 (9.94).
Embodiment 46 is shown in Table 1.From with the amino acid Pro of resin grafting synthetic peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dasp (OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 46 (8.94).
Embodiment 47 is shown in Table 1.From with the amino acid Asp of resin grafting the synthesis of peptide.Initial resin is Fmoc-Asp (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Asp (OtBu)-
dpro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 47 (7.29).
Embodiment 48 is shown in Table 1.From with the amino acid Pro (5RPhe) of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro (5RPhe)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro (5RPhe)-
dpro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 48 (10.07).
Embodiment 49 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dala-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 49 (8.09);
Embodiment 50 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dile-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 50 (9.78).
Embodiment 51 is shown in Table 1.From with the amino acid Leu of resin grafting the synthesis of peptide.Initial resin is Fmoc-Leu-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Leu-
dpro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 51 (8.94);
Embodiment 64 is shown in Table 1.From with the amino acid Glu of resin grafting the synthesis of peptide.Initial resin is Fmoc-Glu (OtBut)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Glu (OtBu)-
dpro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 64 (13.17).
Embodiment 68 is shown in Table 1.From with the amino acid Asp of resin grafting the synthesis of peptide.Initial resin is Fmoc-Asp (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Asp (OtBu)-
dala-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 68 (12.44).
Embodiment 69 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dasn (Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 69 (12.97).
Embodiment 72 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dthr (OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 72 (13.34).
Embodiment 73 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dile-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 73 (9.78).
Embodiment 74 is shown in Table 1.From with the amino acid Leu of resin grafting the synthesis of peptide.Initial resin is Fmoc-Leu-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Leu-
dpro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 74 (8.94).
Embodiment 115 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dasp (OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 115 (4.82).
Embodiment 116 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dphe-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 116 (5.98).
Embodiment 117 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
darg (Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 117 (4.48).
Embodiment 118 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dser (OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 118 (4.73).
Embodiment 119 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dval-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 119 (5.47).
Embodiment 120 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dpic-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 120 (5.48).
Embodiment 121 is shown in Table 1.From with the amino acid Asp of resin grafting the synthesis of peptide.Initial resin is Fmoc-Asp (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Asp (OtBu)-
dpro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 121 (4.56).
Embodiment 122 and 167 is shown in Table 1.From with the amino acid Phe of resin grafting the synthesis of peptide.Initial resin is Fmoc-Phe-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Phe-
dpro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 122 (5.75); 167 (5.75).
Embodiment 123,164,169,170,172,173,175,177 and 178 is shown in Table 1.From with the amino acid Gln of resin grafting the synthesis of peptide.Initial resin is Fmoc-Gln (Trt)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Gln (Trt)-
dpro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 123 (4.35), 164 (13.20), 169 (16.81), 170 (14.57), 172 (16.78), 173 (13.57), 175 (15.94), 177 (16.78), 178 (17.45).
Embodiment 124 is shown in Table 1.From with the amino acid Ser of resin grafting the synthesis of peptide.Initial resin is Fmoc-Ser (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Ser (OtBu)-
dpro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 124 (4.46).
Embodiment 125 is shown in Table 1.From with the amino acid Val of resin grafting the synthesis of peptide.Initial resin is Fmoc-Val-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Val-
dpro-P11-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 125 (18.42).
Embodiment 126 is shown in Table 1.From with the amino acid Thr of resin grafting the synthesis of peptide.Initial resin is Fmoc-Thr (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Thr (OtBu)-
dthr (OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 126 (4.35).
Embodiment 127,163,165 and 174 is shown in Table 1.From with the amino acid Glu of resin grafting the synthesis of peptide.Initial resin is Fmoc-Glu (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Glu (OtBu)-
dlys (Boc)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 127 (4.11), 163 (14.93), 165 (14.40), 174 (12.73).
Embodiment 128 is shown in Table 1.From with the amino acid Thr of resin grafting the synthesis of peptide.Initial resin is Fmoc-Thr (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Thr (OtBu)-
dphe-P11-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 128 (5.26).
Embodiment 130 is shown in Table 1.From with the amino acid Pro of resin grafting the synthesis of peptide.Initial resin is Fmoc-Pro-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Pro-
dala-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 130 (14.79).
Embodiment 166 is shown in Table 1.From with the amino acid Ile of resin grafting the synthesis of peptide.Initial resin is Fmoc-Ile-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Ile-
dphe-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 166 (16.80).
Embodiment 168 is shown in Table 1.From with the amino acid Asp of resin grafting the synthesis of peptide.Initial resin is Fmoc-Asp (OtBu)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Asp (OtBu)-
dpro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 168 (4.56).
Embodiment 171 and 176 is shown in Table 1.From with the amino acid Gln of resin grafting the synthesis of peptide.Initial resin is Fmoc-Gln (Trt)-2-chlorine trityl resin, and it is according to preparation mentioned above.According to previously described program, the peptide of synthesizing linear on solid support, it is following sequence: resin-Gln (Trt)-
dgln (Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Afterwards, form disulfide linkage according to described in program B, cut peptide from resin, carry out cyclisation, remove protection and purifying.
Use analytical procedure mentioned above, measure HPLC-retention time (minute):
Embodiment 171 (15.40), 176 (13.67).
Embodiment 1-6,9-103,112-131,133,136-138,140-141,143-146,148-153, in 155,157-196 the 2nd and the Cys of 10 define disulfide linkage.
2. biological method
2.1. peptide sample is prepared
Unless otherwise noted, the peptide of freeze-drying that microbalance (MettlerMT5) is weighed, is dissolved in aqua sterilisa, is 1mM to final concentration.Storage liquid keeps in Dark Place in+4 DEG C.
2.2. enzyme test
Enzyme and substrate condition are shown in Table 2.
Kinetic measurement is to carry out in the 96 hole flat undersides (Greiner) of the total reaction volume of 100 μ l in Genios plate reader (Tecan).Enzyme and peptide (inhibitor) are merged in damping fluid, described damping fluid contains 100mMHEPES (pH7.5), 50mMCaCl
2, 0.025% tween 20,5%DMSO and 1mM substrate.The speed of substrate hydrolysis is measured, linear with confirmatory reaction curve by the 405nm absorbancy change of monitoring 30 minutes.All calculating is used to from the mean rate of the 1st minute to the 10th minute.Use carry out Background subtraction from the Magellan software (the 5th edition) of Tecan, initial calculation that mean rate, bipartite average and % suppress.By by the suppression data fitting from 6 kinds of different inhibitor concentration in following 4 parameter equation, use the Grafit (version 5.0.10) from ErithacusSoftware to calculate IC50%:
In this equation, s is slope coefficient, and x is inhibitor concentration, and y is that the % of given control of the concentration agent suppresses.
K
m/ K
imeasure
The K of serine stretch protein enzyme substrates is measured from Lineweaver-Burke figure (Grafitv5)
m.Use formula K
i=IC50%/(1+ ([substrate]/K
m)) calculate the Ki value of inhibitor.
The substrate that concentration increases gradually and enzyme reaction, map to concentration of substrate by the speed (ABS/mSec) of every secondary response.Also draw figure (Lineweaver-Burke) reciprocal, to provide K
mand V
max(illustration) (reference 1 that vide infra described).
Table 2
2.3. cell toxicity test
Use MTT reduction test [reference 2 and 3 in seeing below], measure the cytotoxicity of peptide to HELA cell (Acc57) and COS-7 cell (CRL-1651).The method is summarized as follows: respectively with every hole 7.0x10
3individual cell and 4.5x10
3individual cell inoculation HELA cell and COS-7 cell, and make them in 96 hole microtiter plates, in 37 DEG C, 5%CO
2lower growth 24 hours.At this point, by MTT reduction (seeing below) minute zero point (Tz).Discard the supernatant liquor in remaining hole, the peptide of fresh culture and 12.5,25 and 50 μMs of serial dilutions is moved in hole.The each peptide concentration of triplicate mensuration.At 37 DEG C, 5%CO
2the incubation of lower continuation cell 48 hours.Then phosphate buffered saline (PBS) (PBS) hole flushing is used, subsequently to adding 100 μ lMTT reagent (0.5mg/ml, respectively in RPMI1640 and DMEM substratum) in hole.This was 37 DEG C of incubations 2 hours, and sucking-off substratum subsequently, adds 100 μ l Virahols in each hole.Measure the absorbancy (OD of product at 595nm place dissolved
595peptide).For each concentration, all carry out calculating mean value from triplicate measured value.Growth percentage calculation is as follows: (OD
595peptide-OD
595tz-OD
595emptying aperture)/(OD
595tz-OD
595emptying aperture) x100%, by it to each concentration of peptide.
Use (50,25,12.5 and 0 μm), the Trendline function of the EXCEL (MicrosoftOffice2000) of corresponding growth per-cent and value-50, (=TREND (C50:C0, %50:%0,-50) the LC50 value (lethal concentration is defined as the concentration of killing 50% cell) of often kind of peptide), is measured.
By working concentration (50,25,12.5 and 0 μ g/ml), the Trendline function of corresponding percentage and value 50, (TREND (C
50: C
0, %
50: ‰, 50)), calculate GI50 (growth-inhibiting) concentration of often kind of peptide.
2.4. haemolysis
To peptide test they for the hemolytic activity of human erythrocyte (hRBC).By at 2000xg centrifugal 10 minutes, with phosphate buffered saline (PBS) (PBS), fresh hRBC is washed three times.Be the peptide of 100 μMs and 20%v/vhRBC by concentration 37 DEG C of incubations 1 hour.Final red blood cell concentration is approximately every milliliter of 0.9x10
9individual cell.By only having PBS and there is H respectively
2incubation hRBC when 0.1%TritonX-100 in O, measures the value of the lysis of 0% and 100% respectively.Carry out centrifugal to sample, in PBS damping fluid, 20 times of dilutions are carried out to supernatant liquor, measure the optical density(OD) (OD) of 540nM place sample.100% cracking value (OD
540h
2o) OD of about 1.3-1.8 is given
540.Per-cent haemolysis is calculated as: (OD
540peptide/OD
540h
2o) x100%.
2.5 plasma stability
405 μ l blood plasma/albumin solns are put into polypropylene (PP) pipe, with the 45 μ l compound fusion from 100mM solution B (being obtained by the peptide in the PBS of 135 μ lPBS and 15 μ l1mMpH7.4).The equal sample of 150 μ l is transferred in each hole of 10kDa screen plate (MilliporeMAPPB1010Biomax film).For " contrast in 0 minute ", 270 μ lPBS are put into PP pipe, add 30 μ l and store liquid B, concussion mixing.150 μ l contrast solutions put into a hole of screen plate and be used as " filtered contrast ".
Separately get 150 μ l contrast solutions, directly put into receiver hole (for filtrate is reserved), be used as " contrast of filtered ".Comprise the whole plate of evaporation lid 37 DEG C of incubations 60 minutes.4300rpm (3500g) and 15 DEG C to plasma sample (rat plasma: HarlanSera laboratory, UK; Human plasma: BlutspendezentrumZ ü rich) centrifugal at least 2 hours, to produce 100 μ l filtrates.For " plasma-albumin " sample (mankind's white protein of fresh preparation: SigmaA-4327; Rat white protein: SigmaA-6272, concentration is all the 40mg/ml in PBS), about 1 hour centrifugal just enough.According to hereinafter described, by LC/MS, the filtrate in the PP plate received is analyzed: post: JupiterC18 (Phenomenex), moving phase: in (A) water 0.1% formic acid and (B) acetonitrile, gradient: 5%-100% (B) in 2 minutes, electro-spray ionization, MRM detects (triple quadrupole).Measure the area at peak, and in addition average to the triplicate value measured.In conjunction with (time point of filtered and filtered 0 minute) contrast 1 and contrast 2:100-(100xT
60/ T
0) per-cent represent.Then the mean value of these values is calculated.
2.6. pharmacokinetic study (PK)
In rat single oral (tube feed) and intravenously use after pharmacokinetic study
Pharmacokinetic study after (i.v.) and per os (p.o., tube feed) in single dose intravenous are used has been carried out to the compound of embodiment 75 (" Ex.75 ").Use in research from RCCLtd, laboratory animal portion, CH-4414F ü llinsdorf, 332g (± 10g) the male Wistar mouse that Switzerland obtains.Add medium physiological saline, make final compound concentration be 2.5mg/ml.Using volume to intravenously is 2ml/kg, is 10ml/kg for oral administration volume, and the peptide of injection embodiment 75, provides the final intravenous dosages of 5mg/kg and the oral dosage of 50mg/kg.According to scheme hereinafter described, at different time points, use DiLabAccuSampler by automatic blood specimen collection, blood sample (about 0.24ml) is taken in the pipe of heparinization.At following point in time sampling: 0,5 minutes (only intravenously), 15,30 minutes and 1,2,4,8,16,24 and 36 (only per os) hour, and join in the pipe of heparinization.Shift out blood plasma from the cell of precipitation after centrifugal, before HPLC-MS analyzes, be frozen in-80 DEG C.
Prepare blood plasma correcting sample
Use " blank " rat plasma from undressed animal.By the equal sample blood plasma of every part of 0.1ml and 50ng Proprasylyte (interior mark, IS), (by
hLB cartridge case (Waters) carries out solid phase extractions and prepares sample) and known quantity embodiment 75 peptide mixing, to obtain scope for part blood plasma correcting sample of 9 between 5-2000ng/ml.Use 1ml methyl alcohol, then use the 1ml1%NH in water
3regulate
upper HLB cartridge case.Then 400 μ l1%NH in water are used
3dilute sample, and loading.With the 1ml methyl alcohol/1%NH in water
3(5/95) plate is washed.The 1ml0.1%TFA in methyl alcohol is used to carry out wash-out.
Plate containing eluate is introduced concentrator system, makes it dry.Resistates is dissolved in 100 μ l formic acid 0.1%/acetonitrile 95/5 (v/v), and uses gradient elution (mobile phase A: 0.1% formic acid in water; B: acetonitrile, from 5%B to 100%B in 2 minutes), inverse analysis post (JupiterC18,50x2.0mm, 5 μm, Phenomenex) is analyzed in HPLC/MS.
Prepare plasma sample
100 μ l blood plasma are got for extracting from every increment product.As fruit volume is less than 100 μ l, so add " blank " mice plasma of appropriate amount, to keep matrix identical with calibration curve.Then by sample and IS fusion, process according to about described in calibration curve.
Pharmacodynamic assessments
Use software PK solution 2.0
tM(SummitResearchService, Montrose, CO81401USA), carries out PK analysis to the data (usual n=2 or 3) of collecting.The area A UC under calculated curve is carried out by linear trapezoidal law.By AUC
(t-∞)be estimated as Ct/b (b: elimination rate constant).AUC
(t-∞)aUC
(0-t)and AUC
(t-∞)and.Calculated by the linear regression at least three data points of the phase of elimination and remove the transformation period.By relation conefficient (r
2) assess the transformation period measure selected by the timed interval, relation conefficient should be at least be greater than 0.85 and optimum be greater than 0.96.When intravenously is used, by curve extrapolation, determine t by two time points from
zerotime initial concentration.Finally, by by use relative to intravenously normalized intraperitoneal use after AUC
(0-∞)ratio, calculates the bioavailability after intraperitoneal is used.
3.0 result
The results are shown in hereafter in table 3 of experiment above described in 2.2-2.5.
The result of experiment described in 2.5 above has hereafter been shown in table 4.
Table 4
The result of 2.6 (PK) described experiment above has hereafter been shown in table 5.
Table 5
After single oral is used, significantly (intravenously uses %C.V=6-68% to the large interindividual variation of the peptide plasma concentration of embodiment 75, except a value 173% when minimum survey concentration; Oral administration %C.V.:113-173%).
Intravenously is used
After using the peptide of embodiment 75 with the dosage level intravenously of 5mg/kg body weight, the peptide of embodiment 75 follows intravenously dynamic characteristic.After PK analyzes, the peptide display of embodiment 75, the C of extrapolation
initialfor 14069ng/ml, the C observed time 5 minutes (0.083 hour)
maxfor 10762ng/ml.15 minutes and 30 minutes time blood plasma level be dropped rapidly to 5774 and 3455ng/ml respectively.From 1 to 2 hour, blood plasma level was with the end t of 0.46 hour
1/2be reduced to 4 little 18ng/ml constantly.AUC
0.
tand AUC
0-
∞be respectively 6044 and 6047ngxh/ml, initial distribution volume is 355ml/kg.Apparent volume of distribution is 547ml/kg.
Oral administration
After with the peptide of the dosage level oral administration embodiment 75 of 50mg/kg body weight, the blood plasma level of the peptide of embodiment 75 follows the dynamic characteristic of oral administration.After PK analyzes, the peptide display of embodiment 75, the C observed when 0.25 hour (15 minutes)
maxfor 464ng/ml.From 0.25 hour, blood plasma level was with the end t of 0.87 hour
1/2be reduced to 4 little 24ng/ml constantly.AUC
0-tand AUC
0-∞be respectively 782 and 813ngxh/ml.Consider the absorption of 1.3%, apparent volume of distribution is 1008ml/kg.
The comparison that oral administration and intravenously are used
The dosage level using group due to oral administration group and intravenously is different, is compared after dosage normalization method to value.
Than normalized AUC after intravenously uses the peptide (100%:6047ng-h/ml) of embodiment 75
0-∞value, the per-cent (F) of the peptide of the embodiment 75 absorbed after oral administration is 1.3% (81ngxh/ml), normalized C after oral administration
maxbe worth low about 234 times of (46 couples of 10762ng/ml; Table 3).Apparent volume of distribution after oral administration is high about 1.8 times (1008 couples of 547ml/kg) after using than intravenously.
Reference
1.Barrtt,A.J.MethodsinEnzymology1981,80,561-565；Leatherbarrow,R.J.1992,GraFit,ErithacusSoftwareLtd.,Staines,U.K.
2.MossmanT.J.Immunol.Meth.1983,65:55-63
3.BerridgeMV,TanAS.Arch.Biochem.Biophys.1993,303:474-482
Claims (62)
1. the compound of following general formula, and their pharmacy acceptable salt,
Wherein
The group of one of following formula:
Wherein
Gly, or the residue of L-a-amino acid, B is formula-NR
20cH (R
71)-the enantiomer of one of residue or A1 to the A69 group that hereafter defines;
The group of one of following formula:
R
1h, low alkyl group or aryl lower alkyl;
R
2h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
3h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
4h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
p(CHR
61)
scOOR
57,-(CH
2)
p(CHR
61)
scONR
58r
59,-(CH
2)
p(CHR
61)
spO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
5alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
6h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
7alkyl, thiazolinyl ,-(CH
2)
q(CHR
61)
soR
55,-(CH
2)
q(CHR
61)
snR
33r
34,-(CH
2)
q(CHR
61)
soCONR
33r
75,-(CH
2)
q(CHR
61)
snR
20cONR
33r
82,-(CH
2)
r(CHR
61)
scOOR
57,-(CH
2)
r(CHR
61)
scONR
58r
59,-(CH
2)
r(CHR
61)
spO (OR
60)
2,-(CH
2)
r(CHR
61)
ssO
2r
62or-(CH
2)
r(CHR
61)
sc
6h
4r
8;
R
8h, Cl, F, CF
3, NO
2, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61) NR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
scOR
64;
R
9alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
10alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
11h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
12h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
r(CHR
61)
scOOR
57,-(CH
2)
r(CHR
61)
scONR
58r
59,-(CH
2)
r(CHR
61)
spO (OR
60)
2,-(CH
2)
r(CHR
61)
ssO
2r
62or-(CH
2)
r(CHR
61)
sc
6h
4r
8;
R
13alkyl, thiazolinyl ,-(CH
2)
q(CHR
61)
soR
55,-(CH
2)
q(CHR
61)
ssR
56,-(CH
2)
q(CHR
61)
snR
33r
34,-(CH
2)
q(CHR
61)
soCONR
33r
75,-(CH
2)
q(CHR
61)
snR
20cONR
33r
82,-(CH
2)
q(CHR
61)
scOOR
57,-(CH
2)
q(CHR
61)
scONR
58r
59,-(CH
2)
q(CHR
61)
spO (OR
60)
2,-(CH
2)
q(CHR
61)
ssO
2r
62or-(CH
2)
q(CHR
61)
sc
6h
4r
8;
R
14h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
q(CHR
61)
scOOR
57,-(CH
2)
q(CHR
61)
scONR
58r
59,-(CH
2)
q(CHR
61)
spO (OR
60)
2,-(CH
2)
q(CHR
61)
ssOR
62or-(CH
2)
q(CHR
61)
sc
6h
4r
8;
R
15alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
16alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
17alkyl, thiazolinyl ,-(CH
2)
q(CHR
61)
soR
55,-(CH
2)
q(CHR
61)
ssR
56,-(CH
2)
q(CHR
61)
snR
33r
34,-(CH
2)
q(CHR
61)
soCONR
33r
75,-(CH
2)
q(CHR
61)
snR
20cONR
33r
82,-(CH
2)
q(CHR
61)
scOOR
57,-(CH
2)
q(CHR
61)
scONR
58r
59,-(CH
2)
q(CHR
61)
spO (OR
60)
2,-(CH
2)
q(CHR
61)
ssO
2r
62or-(CH
2)
q(CHR
61)
sc
6h
4r
8;
R
18alkyl, thiazolinyl ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
ssR
56,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
p(CHR
61)
scOOR
57,-(CH
2)
p(CHR
61)
scONR
58r
59,-(CH
2)
p(CHR
61)
spO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
19low alkyl group ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
ssR
56,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
p(CHR
61)
scOOR
57,-(CH
2)
p(CHR
61)
scONR
58r
59,-(CH
2)
p(CHR
61)
spO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8or
R
18and R
19can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
20h, alkyl, thiazolinyl or aryl lower alkyl;
R
21h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
22h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
23alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
24alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
25h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
26h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8or
R
25and R
26can be formed together :-(CH
2)
2-6-,-(CH
2)
ro (CH
2)
r-,-(CH
2)
rs (CH
2)
r-or-(CH
2)
rnR
57(CH
2)
r-;
R
27h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
28alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
s-OR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
29alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
30h, alkyl, thiazolinyl or aryl lower alkyl.
R
31h, alkyl, thiazolinyl ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
32h, low alkyl group or aryl lower alkyl;
R
33h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
34r
63,-(CH
2)
m(CHR
61)
soCONR
75r
82,-(CH
2)
m(CHR
61)
snR
20cONR
78r
82,-(CH
2)
o(CHR
61)
scOR
64,-(CH
2)
o(CHR
61)
s-CONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
34h, low alkyl group, aryl or aryl lower alkyl;
R
33and R
34can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
35h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
p(CHR
61)
scOOR
57,-(CH
2)
p(CHR
61)
scONR
58r
59,-(CH
2)
p(CHR
61)
spO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
p(CHR
61)
sc
6h
4r
8;
R
36h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
p(CHR
61)
scOOR
57,-(CH
2)
p(CHR
61)
scONR
58r
59,-(CH
2)
p(CHR
61)
spO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
37h, F, Br, Cl, NO
2, CF
3, low alkyl group ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
38h, F, Br, Cl, NO
2, CF
3, alkyl, thiazolinyl ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
39h, alkyl, thiazolinyl or aryl lower alkyl;
R
40h, alkyl, thiazolinyl or aryl lower alkyl;
R
41h, F, Br, Cl, NO
2, CF
3, alkyl, thiazolinyl ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
42h, F, Br, Cl, NO
2, CF
3, alkyl, thiazolinyl ,-(CH
2)
p(CHR
61)
soR
55,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
43h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
spO (OR
60)
2,-(CH
2)
o(CHR
61)
ssO
2r
62or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
44alkyl, thiazolinyl ,-(CH
2)
r(CHR
61)
soR
55,-(CH
2)
r(CHR
61)
ssR
56,-(CH
2)
r(CHR
61)
snR
33r
34,-(CH
2)
r(CHR
61)
soCONR
33r
75,-(CH
2)
r(CHR
61)
snR
20cONR
33r
82,-(CH
2)
r(CHR
61)
scOOR
57,-(CH
2)
r(CHR
61)
scONR
58r
59,-(CH
2)
r(CHR
61)
spO (OR
60)
2,-(CH
2)
r(CHR
61)
ssO
2r
62or-(CH
2)
r(CHR
61)
sc
6h
4r
8;
R
45h, alkyl, thiazolinyl ,-(CH
2)
o(CHR
61)
soR
55,-(CH
2)
o(CHR
61)
ssR
56,-(CH
2)
o(CHR
61)
snR
33r
34,-(CH
2)
o(CHR
61)
soCONR
33r
75,-(CH
2)
o(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
s(CHR
61)
scONR
58r
59,-(CH
2)
s(CHR
61)
spO (OR
60)
2,-(CH
2)
s(CHR
61)
ssO
2r
62or-(CH
2)
s(CHR
61)
sc
6h
4r
8;
R
46h, alkyl, thiazolinyl or-(CH
2)
o(CHR
61)
pc
6h
4r
8;
R
47h, alkyl, thiazolinyl or-(CH
2)
o(CHR
61)
soR
55;
R
48h, low alkyl group, low-grade alkenyl or aryl lower alkyl;
R
49h, alkyl, thiazolinyl ,-(CHR
61)
scOOR
57, (CHR
61)
scONR
58r
59, (CHR
61)
spO (OR
60)
2,-(CHR
61)
ssOR
62or-(CHR
61)
sc
6h
4r
8;
R
50h, low alkyl group or aryl lower alkyl;
R
51h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
ppO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
p(CHR
61)
sc
6h
4r
8;
R
52h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
ppO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
p(CHR
61)
sc
6h
4r
8;
R
53h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
ssR
56,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59,-(CH
2)
o(CHR
61)
ppO (OR
60)
2,-(CH
2)
p(CHR
61)
ssO
2r
62or-(CH
2)
p(CHR
61)
sc
6h
4r
8;
R
54h, alkyl, thiazolinyl ,-(CH
2)
m(CHR
61)
soR
55,-(CH
2)
m(CHR
61)
snR
33r
34,-(CH
2)
m(CHR
61)
soCONR
33r
75,-(CH
2)
m(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61) COOR
57,-(CH
2)
o(CHR
61)
scONR
58r
59or-(CH
2)
o(CHR
61)
sc
6h
4r
8;
R
55h, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH
2)
m(CHR
61)
soR
57,-(CH
2)
m(CHR
61)
snR
34r
63,-(CH
2)
m(CHR
61)
soCONR
75r
82,-(CH
2)
m(CHR
61)
snR
20cONR
78r
82,-(CH
2)
o(CHR
61)
s-COR
64,-(CH
2)
o(CHR
61) COOR
57or-(CH
2)
o(CHR
61)
scONR
58r
59;
R
56h, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH
2)
m(CHR
61)
soR
57,-(CH
2)
m(CHR
61)
snR
34r
63,-(CH
2)
m(CHR
61)
soCONR
75r
82,-(CH
2)
m(CHR
61)
snR
20cONR
78r
82,-(CH
2)
o(CHR
61)
s-COR
64or-(CH
2)
o(CHR
61)
scONR
58r
59;
R
57h, low alkyl group, low-grade alkenyl, aromatic yl elementary alkyl or heteroaryl lower alkyl;
R
58h, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl or heteroaryl-lower alkyl;
R
59h, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl or heteroaryl-lower alkyl; Or
R
58and R
59can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
60h, low alkyl group, low-grade alkenyl, aryl or aryl lower alkyl;
R
61alkyl, thiazolinyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-lower alkyl ,-(CH
2)
moR
55,-(CH
2)
mnR
33r
34,-(CH
2)
moCONR
75r
82,-(CH
2)
mnR
20cONR
78r
82,-(CH
2)
ocOOR
37,-(CH
2)
onR
58r
59or-(CH
2)
opO (COR
60)
2;
R
62low alkyl group, low-grade alkenyl, aryl, heteroaryl or aryl lower alkyl;
R
63h, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-lower alkyl ,-COR
64,-COOR
57,-CONR
58r
59,-SO
2r
62or-PO (OR
60)
2;
R
34and R
63can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
64h, low alkyl group, low-grade alkenyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl-lower alkyl ,-(CH
2)
p(CHR
61)
soR
65,-(CH
2)
p(CHR
61)
ssR
66or-(CH
2)
p(CHR
61)
snR
34r
63,-(CH
2)
p(CHR
61)
soCONR
75r
82,-(CH
2)
p(CHR
61)
snR
20cONR
78r
82;
R
65h, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl, heteroaryl-lower alkyl ,-COR
57,-COOR
57or-CONR
58r
59;
R
66h, low alkyl group, low-grade alkenyl, aryl, aryl lower alkyl, heteroaryl-lower alkyl or-CONR
58r
59;
M is 2-4; O is 0-4; P is 1-4; Q is 0-2; R is 1 or 2; S is 0 or 1;
Z is the chain of 11 a-amino acid residues, the position of described amino-acid residue in described chain counts from-terminal amino acid, thus, according to they positions in chain, these amino-acid residues are Gly, Pro, Pro, Pro (4NHCOPhe) or have formula-A-CO-, or there is formula-B-CO-, or there is one of following type:
C:-NR
20CH(R
72)CO-；
D:-NR
20CH(R
73)CO-；
E:-NR
20CH(R
74)CO-；
F:-NR
20cH (R
84) CO-; And
H:-NR
20-CH (CO-)-(CH
2)
4-7-CH (CO-)-NR
20-,-NR
20-CH (CO-)-(CH
2)
psS (CH
2)
p-CH (CO-)-NR
20-,-NR
20-CH (CO-)-(-(CH
2)
pnR
20cO (CH
2)
p-CH (CO-)-NR
20-and-NR
20-CH (CO-)-(-(CH
2)
pnR
20cONR
20(CH
2)
p-CH (CO-)-NR
20-;
R
71low alkyl group, low-grade alkenyl ,-(CH
2)
p(CHR
61)
soR
75,-(CH
2)
p(CHR
61)
ssR
75,-(CH
2)
p(CHR
61)
snR
33r
34,-(CH
2)
p(CHR
61)
soCONR
33r
75,-(CH
2)
p(CHR
61)
snR
20cONR
33r
82,-(CH
2)
o(CHR
61)
scOOR
75,-(CH
2)
pcONR
58r
59,-(CH
2)
ppO (OR
62)
2,-(CH
2)
psO
2r
62or-(CH
2)
o-C
6r
67r
68r
69r
70r
76;
R
72h, low alkyl group, low-grade alkenyl ,-(CH
2)
p(CHR
61)
soR
85or-(CH
2)
p(CHR
61)
ssR
85;
R
73-(CR
86r
87)
or
77,-(CH
2)
ro (CH
2)
or
77,-(CH
2)
rs (CH
2)
or
77or-(CH
2)
rnR
20(CH
2)
or
77;
R
74-(CH
2)
pnR
78r
79,-(CH
2)
pnR
77r
80,-(CH
2)
pc (=NR
80) NR
78r
79,-(CH
2)
pc (=NOR
50) NR
78r
79,-(CH
2)
pc (=NNR
78r
79) NR
78r
79,-(CH
2)
pnR
80c (=NR
80) NR
78r
79,-(CH
2)
pn=C (NR
78r
80) NR
79r
80,-(CH
2)
pc
6h
4nR
78r
79,-(CH
2)
pc
6h
4nR
77r
80,-(CH
2)
pc
6h
4c (=NR
80) NR
78r
79,-(CH
2)
pc
6h
4c (=NOR
50) NR
78r
79,-(CH
2)
pc
6h
4c (=NNR
78r
79) NR
78r
79,-(CH
2)
pc
6h
4nR
80c (=NR
80) NR
78r
79,-(CH
2)
pc
6h
4n=C (NR
78r
80) NR
79r
80,-(CH
2)
ro (CH
2)
mnR
78r
79,-(CH
2)
ro (CH
2)
mnR
77r
80,-(CH
2)
ro (CH
2)
pc (=NR
80) NR
78r
79,-(CH
2)
ro (CH
2)
pc (=NOR
50) NR
78r
79,-(CH
2)
ro (CH
2)
pc (=NNR
78r
79) NR
78r
79,-(CH
2)
ro (CH
2)
mnR
80c (=NR
80) NR
78r
79,-(CH
2)
ro (CH
2)
mn=C (NR
78r
80) NR
79r
80,-(CH
2)
ro (CH
2)
pc
6h
4cNR
78r
79,-(CH
2)
ro (CH
2)
pc
6h
4c (=NR
80) NR
78r
79,-(CH
2)
ro (CH
2)
pc
6h
4c (=NOR
50) NR
78r
79,-(CH
2)
ro (CH
2)
pc
6h
4c (=NNR
78r
79) NR
78r
79,-(CH
2)
ro (CH
2)
pc
6h
4nR
80c (=NR
80) NR
78r
79,-(CH
2)
rs (CH
2)
mnR
78r
79,-(CH
2)
rs (CH
2)
mnR
77r
80,-(CH
2)
rs (CH
2)
pc (=NR
80) NR
78r
79,-(CH
2)
rs (CH
2)
pc (=NOR
50) NR
78r
79,-(CH
2)
rs (CH
2)
pc (=NNR
78r
79) NR
78r
79,-(CH
2)
rs (CH
2)
mnR
80c (=NR
80) NR
78r
79,-(CH
2)
rs (CH
2)
mn=C (NR
78r
80) NR
79r
80,-(CH
2)
rs (CH
2)
pc
6h
4cNR
78r
79,-(CH
2)
rs (CH
2)
pc
6h
4c (=NR
80) NR
78r
79,-(CH
2)
rs (CH
2)
pc
6h
4c (=NOR
50) NR
78r
79,-(CH
2)
rs (CH
2)
pc
6h
4c (=NNR
78r
79) NR
78r
79,-(CH
2)
rs (CH
2)
pc
6h
4nR
80c (=NR
80) NR
78r
79,-(CH
2)
pnR
80cOR
64,-(CH
2)
pnR
80cOR
77,-(CH
2)
pnR
80cONR
78r
79,-(CH
2)
pc
6h
4nR
80cONR
78r
79huo – (CH
2)
pnR
20cO-[(CH
2)
u-X]
t-CH
3
Wherein X is-O-,-NR
20-or-S-; U is 1-3, and t is 1-6;
R
75low alkyl group, low-grade alkenyl or aryl lower alkyl;
R
33and R
75can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
75and R
82can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
76h, low alkyl group, low-grade alkenyl, aryl lower alkyl ,-(CH
2)
ooR
72,-(CH
2)
osR
72,-(CH
2)
onR
33r
34,-(CH
2)
ooCONR
33r
75,-(CH
2)
onR
20cONR
33r
82,-(CH
2)
ocOOR
75,-(CH
2)
ocONR
58r
59,-(CH
2)
opO (OR
60)
2,-(CH
2)
psO
2r
62or-(CH
2)
ocOR
64;
R
77-C
6r
67r
68r
69r
70r
76or the heteroaryl of one of following formula
R
78h, low alkyl group, aryl or aryl lower alkyl;
R
78and R
82can be formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
79h, low alkyl group, aryl or aryl lower alkyl, or
R
78and R
79can together :-(CH
2)
2-7-,-(CH
2)
2o (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
80h or low alkyl group;
R
81h, low alkyl group or aryl lower alkyl;
R
82h, low alkyl group, aryl, heteroaryl or aryl lower alkyl;
R
33and R
82formed together :-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-;
R
83h, low alkyl group, aryl or-NR
78r
79;
R
84-(CH
2)
m(CHR
61)
soH ,-(CR
86r
87) pOR
80,-(CR
86r
87) pCOOR
80,-(CH
2)
m(CHR
61)
ssH ,-(CR
86r
87) pSR
80;-(CH
2)
pcONR
78r
79,-(CH
2)
pnR
80cONR
78r
79,-(CH
2)
pc
6h
4cONR
78r
79,-(CH
2)
pc
6h
4nR
80cONR
78r
79,-(CR
86r
87)
opO (OR
60)
2,-(CR
86r
87)
psO
2r
60,-(CR
86r
87)
psOR
60,-(CH
2)
m(CHR
61)
soPO (OR
60)
2,or-(CH
2)
m(CHR
61)
soSO
2r
60;
R
85low alkyl group or low-grade alkenyl;
R
86h, H low alkyl group that can be optionally substituted by halogen or halogen;
R
87h, H low alkyl group that can be optionally substituted by halogen or halogen;
Condition is: in the chain of described 11 a-amino acid residue Z,
The amino-acid residue of-1 to 11 is:
-P1:C type or D type or E type or F type;
-P2:C type or D type or E type or F type;
-P3:C type or F type, or this residue is Gly;
-P4:C type or D type or F type or E type, or this residue is Gly or Pro;
-P5:E type or C type or F type, or this residue is Gly or Pro;
-P6:E type or F type or E type or C type, or this residue is Gly or Pro;
-P7:C type or E type or F type, or there is formula-A-CO-, or this residue is Gly or Pro;
-P8:D type or C type or F type, or there is formula-A-CO, or this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or E type or F type;
-P10:D type or C type or F type or E type, and
-P11:C type or D type or E type or F type, or
-P2 can form the group of H type together with P10, and
Condition is: if template is
dpro
lthe amino-acid residue of Pro, P1 to P11 position is not:
-P1:Arg
-P2: the Cys being connected P10 position Cys by disulfide linkage
-P3:Thr
-P4:Lys
-P5:Ser
-P6:Ile
-P7:Pro
-P8:Pro
-P9:Ile
-P10: the Cys being connected P10 position Cys by disulfide linkage, and
-P11:Phe。
2. compound according to claim 1, wherein
It is the group of formula (a1) or (a2) or (a3).
3. compound according to claim 2, wherein, A is the group of one of formula A1 to A69;
R
1h or low alkyl group;
R
2h, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein: R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
3h, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein: R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group), (CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
4h, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein: R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
5low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group), (CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group), (CH
2)
on (R
20) COR
64(wherein: R
20h or low alkyl group; R
64alkyl, thiazolinyl, aryl, aryl lower alkyl or heteroaryl-lower alkyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
6h, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
7low alkyl group, low-grade alkenyl ,-(CH
2)
qoR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
qsR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
qnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
qoCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group), (CH
2)
qnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
qn (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
rcOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
qcONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
rpO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl), (CH
2)
rsO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl), (CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
9low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
10low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
11h, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
3and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
12h, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
rcOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
rcONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
rpO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
13low alkyl group, low-grade alkenyl ,-(CH
2)
qoR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
qsR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
qnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
qoCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
qnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
qn (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
rcOO
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
qcONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
rpO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
rsO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
14h, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
msR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20h, low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) ,-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
15low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group), (CH
2)
on (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl), particularly advantageous NR
20cO low alkyl group (R
20=H or low alkyl group) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
16low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy); And
R
17low alkyl group, low-grade alkenyl ,-(CH
2)
qoR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
qsR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
qnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
qoCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
qnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
qn (R
20) COR
64(wherein: R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
rcOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
qcONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
rpO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
rsO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
4. compound according to claim 3, wherein, A is formula A5 (wherein R
2h), A8, A22, A25, A38 (wherein R
2h), the group of one of A42 and A50.
5. compound according to claim 4, wherein, A is the group of following formula:
Wherein, R
20h or low alkyl group; And R
64alkyl, thiazolinyl ,-[(CH
2)
u-X]
t-CH
3(wherein X is-O-,-NR
20or-S-, u are 1-3, and t is 1-6), aryl, aryl lower alkyl or heteroaryl-lower alkyl.
6. compound according to claim 5, wherein R
64n-hexyl, n-heptyl, 4-(phenyl) phenmethyl, diphenyl methyl, 3-amino-propyl, 5-Amino-pentyl, methyl, ethyl, sec.-propyl, isobutyl-, n-propyl, cyclohexyl, cyclohexyl methyl, normal-butyl, phenyl, phenmethyl, (3-indyl) methyl, 2-(3-indyl) ethyl, (4-phenyl) phenyl, n-nonyl, CH
3-OCH
2cH
2-OCH
2-and CH
3-(OCH
2cH
2)
2-OCH
2-.
7. compound according to claim 2, wherein, A is the group of one of formula A70 to A104:
R
20h or low alkyl group;
R
18it is low alkyl group;
R
19low alkyl group, low-grade alkenyl ,-(CH
2)
poR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
psR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
pnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl, R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
poCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
pnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
pn (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
pcOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
pcONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h or low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
psO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
oc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
21h, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl), (CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or (CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
22low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF, low alkyl group, low-grade alkenyl or lower alkoxy);
R
23h, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-, wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl), particularly advantageous NR
20cO low alkyl group (R
20=H or low alkyl group) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
24low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein: R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl), particularly advantageous NR
20cO low alkyl group (R
20=H or low alkyl group) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
25h, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
26h, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein: R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or, R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy); Or, alternately, R
25and R
26-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
34(CH
2)
2-;
R
27h, low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl, R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or
-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy);
R
28low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein: R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59:-(CH
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy); And
R
29low alkyl group, low-grade alkenyl ,-(CH
2)
ooR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
osR
56(wherein R
56low alkyl group or low-grade alkenyl) ,-(CH
2)
onR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
ooCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
onR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
on (R
20) COR
64(wherein: R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl), particularly advantageous NR
20cO low alkyl group (R
20=H or low alkyl group) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
8. compound according to claim 7, wherein R
23, R
24and R
29-NR
20-CO-low alkyl group, wherein R
20h or low alkyl group.
9., according to the compound of claim 7 or 8, wherein A is formula A74 (wherein R
22h), A75, A76, A77 (wherein R
22h), the group of one of A78 and A79.
10. according to the compound of any one in claim 2 to 9, wherein, B is formula-NR
20cH (R
71)-group or group A5 (wherein R
22h), A8, A22, A25, A38 (wherein R
2h), the enantiomer of one of A42, A47 and A50.
11. compounds according to claim 10, wherein B-CO is Ala, Arg, Asn, Cys, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Pro (5RPhe), Ser, Thr, Trp, Tyr, Val, Cit, Orn, tBuA, Sar, t-BuG, 4AmPhe, 3AmPhe, 2AmPhe, Phe (mC (NH
2)=NH, Phe (pC (NH
2)=NH, Phe (mNHC (NH
2)=NH, Phe (pNHC (NH
2)=NH, Phg, Cha, C
4al, C
5al, Nle, 2-Nal, 1-Nal, 4Cl-Phe, 3Cl-Phe, 2Cl-Phe, 3,4Cl
2phe, 4F-Phe, 3F-Phe, 2F-Phe, Tic, Thi, Tza, Mso, AcLys, Dpr, A
2bu, Dbu, Abu, Aha, Aib, Y (Bzl), Bip, S (Bzl), T (Bzl), hCha, hCys, hSer, hArg, hPhe, Bpa, Pip, OctG, MePhe, MeNle, MeAla, MeIle, MeVal or MeLeu.
12. compounds according to claim 10, wherein, B is the following formula group with (L)-configuration
Wherein R
20h or low alkyl group; And R
64it is alkyl; Thiazolinyl;-[(CH
2)
u-X]
t-CH
3, wherein X is-O-,-NR
20-or-S-, u be 1-3 and t be 1-6; Aryl; Aryl lower alkyl or heteroaryl-lower alkyl.
13. compound according to claim 12, wherein R
64n-hexyl, n-heptyl, 4-(phenyl) phenmethyl, diphenyl methyl, 3-amino-propyl, 5-Amino-pentyl, methyl, ethyl, sec.-propyl, isobutyl-, n-propyl, cyclohexyl, cyclohexyl methyl, normal-butyl, phenyl, phenmethyl, (3-indyl) methyl, 2-(3-indyl) ethyl, (4-phenyl) phenyl, n-nonyl, CH
3-OCH
2cH
2-OCH
2-or CH
3-(OCH
2cH
2)
2-OCH
2-.
14. compounds according to claim 1, wherein
It is the group of formula (b1) or (1);
R
1h or low alkyl group;
R
20h or low alkyl group;
R
30h or methyl;
R
31h, low alkyl group, low-grade alkenyl ,-(CH
2)
poR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
pnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
poCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
pnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
pn (R
20) COR
64(wherein: R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl), (-CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
rc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy); Most preferably-CH
2cONR
58r
59(R
58h or low alkyl group; And R
59low alkyl group or low-grade alkenyl);
R
32h or methyl;
R
33low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
34r
63(wherein R
34low alkyl group or low-grade alkenyl; R
63h or low alkyl group; Or R
34and R
63-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group), (CH
2)
moCONR
75r
82(wherein R
75low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
75and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mnR
20cONR
78r
82(wherein R
20h or low alkyl group; R
78h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
78and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group);
R
34h or low alkyl group;
R
35h, low alkyl group, low-grade alkenyl ,-(CH
2)
moR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
mnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
moCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
mn (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group);
R
36low alkyl group, low-grade alkenyl or aryl lower alkyl;
R
37h, low alkyl group, low-grade alkenyl ,-(CH
2)
poR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
pnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
poCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
pnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
pn (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy); And
R
38h, low alkyl group, low-grade alkenyl ,-(CH
2)
poR
55(wherein R
55low alkyl group or low-grade alkenyl) ,-(CH
2)
pnR
33r
34(wherein R
33low alkyl group or low-grade alkenyl; R
34h or low alkyl group; Or R
33and R
34-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
poCONR
33r
75(wherein R
33h or low alkyl group or low-grade alkenyl; R
75it is low alkyl group; Or R
33and R
75-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
pnR
20cONR
33r
82(wherein R
20h or low alkyl group; R
33h or low alkyl group or low-grade alkenyl; R
82h or low alkyl group; Or R
33and R
82-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
pn (R
20) COR
64(wherein R
20h or low alkyl group; R
64low alkyl group or low-grade alkenyl) ,-(CH
2)
ocOOR
57(wherein R
57low alkyl group or low-grade alkenyl) ,-(CH
2)
ocONR
58r
59(wherein R
58low alkyl group or low-grade alkenyl; And R
59h, low alkyl group; Or R
58and R
59-(CH together
2)
2-6-,-(CH
2)
2o (CH
2)
2-,-(CH
2)
2s (CH
2)
2-or-(CH
2)
2nR
57(CH
2)
2-; Wherein R
57h or low alkyl group) ,-(CH
2)
opO (OR
60)
2(wherein R
60low alkyl group or low-grade alkenyl) ,-(CH
2)
osO
2r
62(wherein R
62low alkyl group or low-grade alkenyl) or-(CH
2)
qc
6h
4r
8(wherein R
8h, F, Cl, CF
3, low alkyl group, low-grade alkenyl or lower alkoxy).
15. compounds according to claim 14, wherein, R
1h; R
20h; R
30h; R
31carboxymethyl or lower alkoxycarbonylmethyl; R
32h; R
35it is methyl; R
36it is methoxyl group; R
37h and R
38h.
16. according to the compound of any one in claim 1 to 15, and wherein in Z chain, the a-amino acid residue of 1 to 11 is:
-P1:C type or D type or E type or F type;
-P2:E type or F type or C type;
-P3:C type or F type, or this residue is Gly;
-P4:C type or E type or F type, or this residue is Gly or Pro;
-P5:E type or F type, or this residue is Gly or Pro;
-P6:C type or D type or F type, or this residue is Gly or Pro;
-P7:F type or there is formula-A-CO-, or this residue is Gly or Pro;
-P8:D type or C type or there is formula-A-CO, or this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or E type or F type;
-P10:F type or C type or E type:
-P11:E type or F type or C type or D type; Or
-P2 forms the group of H type together with P10;
Condition is: if template is
dpro-
lpro, so the amino-acid residue of P1 to P11 position is not:
-P1:Arg
-P2: the Cys be connected with the Cys of P10 position by disulfide linkage
-P3:Thr
-P4Lys
-P5Ser
-P6Ile
-P7Pro
-P8Pro
-P9Ile
The Cys that-P10 is connected with the Cys of P10 position by disulfide linkage; And
-P11Phe。
17. compounds according to claim 16, wherein in Z chain, the a-amino acid residue of 1 to 11 is:
-P1:Nle, Ile, Aoc, hLeu, Chg, OctG, hPhe, 4AmPhe, Cha, Phe, Tyr, 2Cl-Phe, Trp, 1-Nal, Leu, Cha or Arg;
-P2:Cys, Glu, Nle, Thr or Gln;
-P3:Thr, Ala or Abu;
-P4:Lys, Nle, Ala, Abu or Thr;
-P5:Ser, AlloThr or Dpr;
-P6:Ile, c5al, Leu, Nle, Aoc, OctG, Cha, hLeu, hPhe, Chg, t-BuA, Glu or Asp;
-P7:Pro；
-P8:Pro, Ala or Pro (4NHCOPhe);
-P9:Tyr, Phe, Ile, Nle, Cha, Gln, Arg, Lys, His, Thr or Ala;
-P10:Cys, Arg, Nle, Gln, Lys, Met, Thr or Ser;
-P11:Tyr, Gln, Arg, Ser, Nle, 2-Nal, 2Cl-Phe, Cha, Phg, Tyr, Phe, Asp, Asn or Thr; And
-Cys, if existed at P2 and P10, it can form disulfide linkage.
18. according to the compound of any one in claim 1 to 15, and wherein in Z chain, the a-amino acid residue of 1 to 11 is:
-P1:C type or D type or E type;
-P2:F type or C type;
-P3:F type;
-P4:C type or E type;
-P5:E type or F type;
-P6:F type;
-P7:F type or there is formula-A-CO-, or this residue is Gly or Pro;
-P8:C type or there is formula-A-CO-, or this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:C type or D type or F type;
-P10:F type or C type or E type;
-P11:E type or D type or F type; Or
-P2 forms the group of H type together with P10.
19. compounds according to claim 18, wherein the a-amino acid residue of 1 to 11 is:
-P1:Phe, hPhe, 4AmPhe, Nle, Chg, Ile, Tyr, Arg, Trp, 2Cl-Phe, Arg, 1-Nal or Cha;
-P2:Cys, Glu or Nle;
-P3:Thr；
-P4:Lys or Nle;
-P5:Ser, AlloThr or Dpr;
-P6:Asp or Glu;
-P7:Pro；
-P8:Pro；
-P9:Ile, Nle, Cha, Gln, Tyr or Ala;
-P10:Cys, Arg or Nle;
-P11:Thr, Asp, Ser, Tyr, Phe, Asn or Arg; And
-Cys, if existed at P2 and P10, it can form disulfide linkage.
20. according to the compound of any one in claim 1 to 15, and wherein in Z chain, the a-amino acid residue of 1 to 11 is:
-P1:C type or D type;
-P2:F type;
-P3:F type or C type;
-P4:C type or F type;
-P5:F type;
-P6:C type;
-P7: there is formula-A-CO-, or this residue is Gly or Pro;
-P8: there is formula-A-CO-, or this residue is Gly or Pro or Pro (4NHCOPhe);
-P9:D type or F type or C type;
-P10:F type or C type or E type;
-P11:E type or F type or D type; Or
-P2 forms the group of H type together with P10.
21. compounds according to claim 20, wherein the a-amino acid residue of 1 to 11 is:
-P1:Ile, Nle, Aoc, hLeu, Chg, OctG or hPhe;
-P2:Cys, Glu, Thr or Gln;
-P3:Thr, Ala or Abu;
-P4:Ala, Thr or Abu;
-P5:Ser；
-P6:OctG, Ile, Cha, Leu, c5al, Nle, Aoc, Chg, tBuA or hLeu;
-P7:Pro；
-P8:Pro or Pro (4NHCOPhe);
-P9:Gln, Tyr, ILe or Phe;
-P10:Cys, Lys, Gln, Thr, Met or Arg;
-P11:Tyr, Ser, Arg, Gln, Nle, 2-Nal, 2Cl-Phe, Phe, Cha or Phg; And
-Cys, if existed at P2 and P10, it can form disulfide linkage.
22. according to the compound of any one in claim 1 to 15, and wherein in Z chain, the a-amino acid residue of 1 to 11 is:
-P1:C type or D type or E type;
-P2:F type;
-P3:F type;
-P4:E type;
-P5:F type;
-P6:C type or D type;
-P7:F type or there is formula-A-CO-, or this residue is Gly or Pro;
-P8:C type or there is formula-A-CO-, or this residue is Gly or Pro;
-P9:C type or E type or F type;
-P10:F type;
-P11:E type or D type; Or
-P2 forms the group of H type together with P10;
Condition is: if template is
dpro-
lpro, so the amino-acid residue of P1 to P11 position is not:
-P1:Arg
-P2: the Cys be connected with the Cys of P10 position by disulfide linkage
-P3:Thr
-P4Lys
-P5Ser
-P6Ile
-P7Pro
-P8Pro
-P9Ile
The Cys that-P10 is connected with the Cys of P10 position by disulfide linkage; And
-P11Phe。
23. compounds according to claim 22, wherein the a-amino acid residue of 1 to 11 of Z chain is:
-P1:Cha, Tyr or Trp
-P2:Cys
-P3:Thr
-P4:Lys
-P5:Ser
-P6:Leu
-P7:Pro
-P8:Pro
-P9:Lys
-P10:Cys
-P11:Arg; And
The Cys residue that P2 and P10 position exists can form disulfide linkage.
24. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Phe；
-P2:Cys；
-P3:Thr；
-P4:Lys；
-P5:Ser；
-P6:Asp；
-P7:Pro；
-P8:Pro；
-P9:Ile；
-P10:Cys；
-P11:Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
25. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Ile；
-P2:Cys；
-P3:Thr；
-P4:Lys；
-P5:Ser；
-P6:Asp；
-P7:Pro；
-P8:Pro；
-P9:Nle；
-P10:Cys；
-P11:Arg；
The Cys of P2 and P10 position forms disulfide linkage.
26. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Ile；
-P2:Cys；
-P3:Thr；
-P4:Lys；
-P5:Ser；
-P6:Asp；
-P7:Pro；
-P8:Pro；
-P9:Cha；
-P10:Cys；
-P11:Arg；
The Cys of P2 and P10 position forms disulfide linkage.
27. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Ile；
-P2:Cys；
-P3:Thr；
-P4:Nle；
-P5:Ser；
-P6:Asp；
-P7:Pro；
-P8:Pro；
-P9:Ile；
-P10:Cys；
-P11:Arg
The Cys of P2 and P10 position forms disulfide linkage.
28. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Phe；
-P2:Cys；
-P3:Thr；
-P4:Nle；
-P5:Ser；
-P6:Asp；
-P7:Pro；
-P8:Pro；
-P9:Ile；
-P10:Cys；
-P11:Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
29. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Chg；
-P2:Cys；
-P3:Thr；
-P4:Lys；
-P5:Ser；
-P6:Asp；
-P7:Pro；
-P8:Pro；
-P9:Ile；
-P10:Cys；
-P11:Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
30. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Arg；
-P2:Cys；
-P3:Thr；
-P4:Lys；
-P5:Ser；
-P6:Asp；
-P7:Pro；
-P8:Pro；
-P9:Ile；
-P10:Cys；
-P11:Phe；
The Cys of P2 and P10 position forms disulfide linkage.
31. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Nle；
-P2:Cys；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:Ile；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Cys；
-P11:Gln；
The Cys of P2 and P10 position forms disulfide linkage.
32. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Nle；
-P2:Cys；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:Ile；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Cys；
-P11:Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
33. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:hPhe；
-P2:Cys；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:OctG；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Cys；
-P11:Gln
The Cys of P2 and P10 position forms disulfide linkage.
34. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:OctG；
-P2:Gln；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:Ile；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Thr；
-P11:Tyr。
35. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:hPhe；
-P2:Cys；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:Cha；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Cys；
-P11:Phe；
The Cys of P2 and P10 position forms disulfide linkage.
36. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:OctG；
-P2:Glu；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:Ile；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Lys；
-P11:Tyr。
37. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:OctG；
-P2:Cys；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:Cha；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Cys；
-P11:Phe；
The Cys of P2 and P10 position forms disulfide linkage.
38. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:hPhe；
-P2:Cys；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:Cha；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Cys；
-P11:Gln；
The Cys of P2 and P10 position forms disulfide linkage.
39. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:OctG；
-P2:Cys；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:Cha；
-P7:Pro；
-P8:Pro(4NHCOPhe)；
-P9:Gln；
-P10:Cys；
-P11:Gln；
The Cys of P2 and P10 position forms disulfide linkage.
40. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:hPhe；
-P2:Cys；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:OctG；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Cys；
-P11:Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
41. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Chg；
-P2:Cys；
-P3:Thr；
-P4:Lys；
-P5:Ser；
-P6:Asp；
-P7:Pro；
-P8:Pro；
-P9:Ile；
-P10:Cys；
-P11:Thr；
The Cys of P2 and P10 position forms disulfide linkage.
42. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Chg；
-P2:Cys；
-P3:Thr；
-P4:Lys；
-P5:Ser；
-P6:Asp；
-P7:Pro；
-P8:Pro；
-P9:Ile；
-P10:Cys；
-P11:Asp；
The Cys of P2 and P10 position forms disulfide linkage.
43. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:OctG；
-P2:Cys；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:Cha；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Cys；
-P11:Gln；
The Cys of P2 and P10 position forms disulfide linkage.
44. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:OctG；
-P2:Cys；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:Ile；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Cys；
-P11:Tyr；
The Cys of P2 and P10 position forms disulfide linkage.
45. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:OctG；
-P2:Cys；
-P3:Thr；
-P4:Ala；
-P5:Ser；
-P6:OctG；
-P7:Pro；
-P8:Pro；
-P9:Gln；
-P10:Cys；
-P11:Gln；
The Cys of P2 and P10 position forms disulfide linkage.
46. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Cha；
-P2:Cys；
-P3:Thr；
-P4:Lys；
-P5:Ser；
-P6:Leu；
-P7:Pro；
-P8:Pro；
-P9:Lys；
-P10:Cys；
-P11:Arg；
The Cys of P2 and P10 position forms disulfide linkage.
47. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Tyr；
-P2:Cys；
-P3:Thr；
-P4:Lys；
-P5:Ser；
-P6:Leu；
-P7:Pro；
-P8:Pro；
-P9:Lys；
-P10:Cys；
-P11:Arg；
The Cys of P2 and P10 position forms disulfide linkage.
48. formula I according to claim 1, wherein, described template is
dpro-
lpro, and the amino-acid residue of 1 to 11 is:
-P1:Trp；
-P2:Cys；
-P3:Thr；
-P4:Lys；
-P5:Ser；
-P6:Leu；
-P7:Pro；
-P8:Pro；
-P9:Lys；
-P10:Cys；
-P11:Arg；
The Cys of P2 and P10 position forms disulfide linkage.
The enantiomer of the 49. formula I defined according to claim 1.
The compound of any one in 50. Claims 1-4 9, it is used as treatment effective substance.
51. according to the compound of claim 50, it has selectivity protease inhibiting activity, particularly for the inhibit activities of cathepsin G or elastoser or tryptase and/or antitumour activity and/or anti-inflammatory activity and/or anti-infection activity and/or anti-cardiac vascular activity and/or anti-immunocompetence and/or anti-neurodegeneration active.
52. pharmaceutical compositions, wherein containing compound and the pharmaceutical inert carriers of any one in good grounds Claims 1-4 9.
53. composition according to claim 52, it is in being suitable for per os, locally, transdermal, through cheek, thoroughly mucous membrane or use through lung, or being adapted to pass through injection or sucking the form used.
54. according to the compound of claim 52 or 53, and it is the form of tablet, drageeing, capsule, solution, liquid, gelifying agent, plaster, creme, ointment, syrup, slurry, suspension, spraying, atomizer or suppository.
55. according to the compound of any one in Claims 1-4 9 for the preparation of the purposes of medicine being used as proteinase inhibitor.
56. purposes according to claim 55, wherein, described proteolytic enzyme suppresses medicine to be used to prevent the infection in healthy individuals, or for the infection of slowing down in infected patient, or mediate for protease activity or cause cancer, or mediate for protease activity or cause Immunological diseases, or mediate for protease activity or cause inflammation, or mediate for protease activity or cause immunoreactive situation.
57. according to the compound of any one in claim 18,19 and 24-30 for the preparation of the purposes of medicine of inhibitor being used as cathepsin G.
58. according to the compound of any one in claim 20,21 and 31-42 for the preparation of the purposes of medicine of inhibitor being used as elastoser.
59. according to the compound of any one in claim 22,23 and 43-45 for the preparation of the purposes of medicine of inhibitor being used as tryptase.
The method of the compound of any one in 60. production claim 1-48, the method comprises:
A () by by the derivative coupling of the suitable N-protected of amino acid whose warp of 5,6 or 7 in suitably functionalized solid support and the end product wanted, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
B () removes N-protected group from thus obtained product;
(c) by thus obtained product and the end product wanted again near the derivative coupling of the suitable N-protected of that amino acid whose warp of-terminal amino acid residue one, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
D () removes N-protected group from thus obtained product;
E () repeating step (c) and (d), until introduced-terminal amino acid residue;
F () is by the compound coupling of thus obtained product and following general formula
Wherein
There is the implication defined in claim 1, and X is N-protected group, or, if
(a1) or (a2) that define in claim 1,
(fa) by the product of acquisition in step (e) and the derivative coupling of the suitable N-protected of the amino acid whose warp of following general formula, described general formula is:
HOOC-B-HIII or HOOC-A-HIV
Wherein, B and A has the implication defined in claim 1, and any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(fb) N-protected group is removed from thus obtained product; And
(fc) by thus obtained product and the derivative coupling of the suitable N-protected of amino acid whose warp being respectively above-mentioned general formula I V and III, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally; And, respectively, if
The group (a3) of definition in claim 1,
(fa') by the derivative coupling of the product of acquisition and the suitable N-protected of amino acid whose warp of above-mentioned general formula III in step (e), any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(fb') N-protected group is removed from thus obtained product; And
(fc') by the derivative coupling of the suitable N-protected of amino acid whose warp of thus obtained product and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
G product that () obtains from step (f) or (fc) or (fc') removes N-protected group;
H (), by thus obtained product and the derivative coupling of the suitable N-protected of amino acid whose warp of the 11st in the end product wanted, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
I () removes N-protected group from thus obtained product;
(j) by thus obtained product and the end product wanted from the 11st again away from the derivative coupling of the suitable N-protected of that amino acid whose warp of, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
K () removes N-protected group from thus obtained product;
L () repeating step (j) and (k), until introduced all amino-acid residues;
M () if necessary, is gone protection to the one or more shielded functional group selectivity existed in molecule, and is suitably replaced the reaction active groups discharged thus;
N () if necessary, forms interchain key between the side chain of the suitable amino-acid residue of the 2nd and 10;
O thus obtained product and solid support depart from by ();
P () is by the product cyclisation from cracking on solid support;
Q any blocking group that the functional group of any member of () removing amino-acid residue chain exists, and, if necessary, other any blocking group that may exist in removing molecule; And
R () if necessary, be pharmacy acceptable salt by thus obtained product conversion, or thus obtained pharmacy acceptable salt or unacceptable salt are converted into corresponding formula I free cpds, or are converted into different, pharmacy acceptable salt.
The method of the compound of any one in 61. production claim 1-48, the method comprises:
(a') by the compound coupling through suitably functionalized solid support and following general formula
Wherein
There is the implication defined in claim 1, and X is N-protected group, or, if
Group (a1) or (a2) of definition in claim 1,
(a'a) by the derivative coupling of solid support suitably functionalized for described warp and the suitable N-protected of the amino acid whose warp of following general formula,
HOOC-B-HIII or HOOC-A-HIV
Wherein, B and A has the implication defined in claim 1, and any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(a'b) N-protected group is removed from thus obtained product; And
(a'c) by thus obtained product and the derivative coupling of the suitable N-protected of amino acid whose warp being respectively above-mentioned general formula I V and III, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally; And, respectively, if
The group (a3) defined in claim 1,
(a'a') by the derivative coupling of the suitable N-protected of amino acid whose warp of solid support suitably functionalized for described warp and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(a'b') N-protected group is removed from thus obtained product; And
(a'c') by the derivative coupling of the suitable N-protected of amino acid whose warp of thus obtained product and above-mentioned general formula III, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(b') product obtained from step (a'), (a'c) or (a'c') removes N-protected group;
(c') by thus obtained product and the derivative coupling of the suitable N-protected of amino acid whose warp of the 11st in the end product wanted, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(d') N-protected group is removed from thus obtained product;
(e') by thus obtained product and the end product wanted from the 11st again away from the derivative coupling of the suitable N-protected of that amino acid whose warp of, any functional group that can exist in the amino acid derivative of described N-protected is suitably protected equally;
(f') N-protected group is removed from thus obtained product;
(g') repeating step (e') and (f'), until introduced all amino-acid residues;
(h') if necessary, protection is gone to the one or more shielded functional group selectivity existed in molecule, and the reaction active groups discharged thus is suitably replaced;
(i') if necessary, between the side chain of the Suitable amino acid residues of the 2nd and 10, interchain key is formed;
(j') thus obtained product and solid support are departed from;
(k') by the product cyclisation from cracking on solid support;
(l') any blocking group that the functional group of any member of amino-acid residue chain exists is removed, and, if necessary, other any blocking group that may exist in removing molecule; And
(m') if necessary, be its pharmacy acceptable salt by thus obtained product conversion, or thus obtained pharmacy acceptable salt or unacceptable salt are converted into corresponding formula I free cpds, or are converted into different, pharmacy acceptable salt.
62. the improvement of the method according to claim 60 or 61, for the production of the compound according to claim 49, wherein, use the enantiomer of all chiral raw material.
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| WO2022111713A1 (en) * | 2020-11-30 | 2022-06-02 | 中国医学科学院药物研究所 | Polypeptide containing disulfide bonds and capable of inhibiting activity of serine protease, derived hybrid peptide thereof, and use thereof |
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| WO2022111713A1 (en) * | 2020-11-30 | 2022-06-02 | 中国医学科学院药物研究所 | Polypeptide containing disulfide bonds and capable of inhibiting activity of serine protease, derived hybrid peptide thereof, and use thereof |
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