CN101805340A - Beta-chain simulative and methods involving thereof - Google Patents
Beta-chain simulative and methods involving thereof Download PDFInfo
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Abstract
The invention discloses the structure constrained compounds of simulation biologically active peptides and proteinic beta chain zone secondary structure.Such beta-chain simulative structure has applicability in the extensive fields scope, comprise as diagnostic reagent and therapeutical agent.This paper also discloses the storehouse of containing beta-chain simulative structure of the present invention, and it is screened to differentiate biological activity member's method.
Description
The application is to be May 30, application number in 2003 the dividing an application for the Chinese patent application of " beta-chain simulative and methods involving thereof " that be 03826816.7 (PCT/US2003/017188), denomination of invention the applying date.
Technical field
The present invention relates generally to beta-chain simulative (β-strand mimetic) structure, also relate to its relevant compound library, and uses thereof.
Background technology
Active for determining molecule as the possibility of therapeutical agent, it is carried out random screening existed for many years, and cause the discovery of a large amount of important drugs.Although it is growing that the progress of molecular biology and calculational chemistry has caused the interest that is called as " rationalizing medicinal design (rational drug design) ", this technology does not confirm as initial desired quick or reliable.Therefore, people's interest turns to drug screening at random again in recent years.Therefore, aspect screening biological activity member's the new technology, obtaining special progress based on the development in combination of compounds storehouse with in this storehouse.
Usually, the combination of compounds storehouse only is the set of molecule.This storehouse changes along with the chemical species in the storehouse, and along with being used for producing the library member and differentiating which member changes with the interactional method of the biological targets of being concerned about.Though this field still belongs to the initial stage, the method that is used to generate and screen the storehouse has become considerably various and ripe.For example, the nearest summary about various combination of compounds storehouse has been confirmed some such technology (Dolle, J.Com.Chem., 2 (3): 383-433,2000), comprise mark and use unlabelled library member (Janda, Proc.Natl.Acad.Sci.USA 91:10779-10785,1994).
At first, the combination of compounds storehouse mainly is limited to the member of peptide source or nucleosides acid source.Therefore, people's such as Houghten technical specification be called the example of " dual definition iteration (dual-definediterative) " method, it compiles solubility combined peptide storehouse (Nature (London) 354:84-86,1991 by splitting synthetic (split synthesis) technology of branch; Biotechniques 13:412-421,1992; Bioorg.Med.Chem.Lett.3:405-412,1993).Obtained to contain tens million of members' soluble peptide storehouse by this technology.This storehouse demonstrates effect (Dooley and Houghten in the identification of the opioid peptides of for example methionine-enkephalin and leucine enkephalin; Life Sci.52; 1509-1517; 1993); and N-acylated peptide storehouse has been used to discern acetalins; it is effective opioid antagonists (Dooley etc., Proc.Natl.Acad.Sci.USA 90:10811-10815,1993).Recently, made up full D-amino acid opioid peptides storehouse, and its analgesic activities to mu (" μ ") Opioid Receptors has been carried out screening (Dooley etc., Science 266:2019-2022,1994).
Have important value though contain peptide source and Nucleotide source member's combinatorial libraries, still need to contain different source members' storehouse in this field.For example, traditional peptide storehouse only changes aminoacid sequence to a great extent and produces the library member.Though will admit that really the secondary structure of peptide is most important to biological activity, limited secondary structure can't be given its library member in this peptide storehouse.
Therefore, some researchists make the peptide cyclisation with disulphide bridges, attempt the secondary structure (Tumelty etc., J.Chem.Soc.1067-68,1994 that provide more limited; Eichler etc., Peptide Res.7:300-306,1994).Yet the peptide of this cyclisation still is very easy to distortion usually, is difficult to carry out biologic applications, has therefore only obtained limited success.
Recently, developed non-peptide compound, it has very closely simulated the secondary structure of the inflection of finding in biological activity protein or peptide.For example, the disclosed PCT application of No. the 5th, 440,013, the United States Patent (USP) of Kahn and Kahn WO94/03494 discloses the limited non-peptide compound of structure, and it has imitated the three-dimensional structure of inflection.
Though in the synthetic and identification of the limited peptide mimics of structure, obtained significant progress, still needed the small molecules of simulating peptide secondary structure in this field.This field also needs to contain this member's storehouse, and the library member's of synthetic and target spot, particularly biological targets that screening is paid close attention to technology, with identification biological activity library member.For example, No. the 5th, 929,237, the United States Patent (USP) of Kahn and part continuation application United States Patent (USP) thereof also disclose the structure constrained compounds of inflection region two-stage structure in simulation biologically active peptides and the protein for the 6th, 013, No. 458.
The present invention has also satisfied these needs, and by the structure constrained compounds is provided, the secondary structure of simulation biologically active peptides and proteinic beta chain structure further provides relevant advantage.
Summary of the invention
Briefly, the present invention relates to simulate the structure constrained compounds of the secondary structure of biologically active peptides and protein beta chain structure.The invention also discloses the storehouse and the synthetic and screening thereof that contain these compounds.
Compound of the present invention has following general formula (I):
Wherein A be-(CH)-,-N-or-CH
2-N-, B be-(C=O)-or-(CH
2)
m-, W is-(C=O)-,-Y (C=O)-,-NH (C=O)-or do not exist, X is-NH-,-NH (C=O)-or do not exist, Y is oxygen or sulphur, and Z is oxygen or hydrogen, and L is hydrogen, R
5,-C (O) NHR
3Or its Equivalent, n=0 or 1 and m=1 or 2; R
1, R
2, R
3, R
4And R
5Can be identical or different, and be independently selected from hydrogen, amino acid side chain moiety or derivatives thereof, molecule remainder, connect base and solid carrier, and steric isomer.
In an embodiment of the invention, X does not exist, and A is-N-, and B is-(C=O)-, L is-C (O) NHR
3, other group defines in the structure (I) as mentioned, and therefore, compound of the present invention has following structure (I '):
Randomly, W does not exist and Z is an oxygen.
In an embodiment of the invention, X does not exist, and A is-N-that B is-(CH
2)
m-, L is-C (O) NHR
3, other group is as mentioned about the definition of structure (I), and therefore, compound of the present invention has following structure (I "):
Randomly, W does not exist and Z is an oxygen.
In an embodiment of the invention, X is-NH-, A is-(CH)-, B is-(CH
2)
m-, L is-C (O) NHR
3, other group is as mentioned about the definition of structure (I), and therefore, compound of the present invention has following structure (I ' "):
Randomly, when Z was oxygen, W did not exist.
In an embodiment of the invention, A is-CH
2-N-, B are-(CH
2)
m-, L is-C (O) NHR
3, other group is as mentioned about the definition of structure (I), and therefore, compound of the present invention has following structure (I " "):
Randomly, Y is an oxygen, and/or W do not exist, and/or Z is an oxygen.
The invention still further relates to the storehouse of the compound that contains structure (I) above, (I '), (I "), (I ' ") and (I " "), and the method in synthetic such storehouse and it is screened to differentiate the method for bioactive compounds.The invention also discloses and contain the compound compositions of the present invention that combines with pharmaceutically acceptable carrier or thinner.
With reference to following detailed description and accompanying drawing, these aspects of the present invention and others will be conspicuous.
Description of drawings
Fig. 1 and Fig. 2 have illustrated the synthetic method for preparing storehouse of the present invention and compound of the present invention.
Fig. 3 has illustrated the synthetic method for preparing storehouse of the present invention and compound of the present invention, and embodiment 9 has carried out more detailed description to it.
Fig. 4 has illustrated the synthetic method for preparing storehouse of the present invention and compound of the present invention, and embodiment 10 has carried out more detailed description to it.
Embodiment
The invention discloses the structure constrained compounds of the secondary structure in simulation biologically active peptides and protein beta chain zone.Such beta-chain simulative structure has applicability in the field of broad range, comprise as diagnostic reagent and therapeutical agent.The invention also discloses the storehouse of containing beta-chain simulative structure of the present invention, and it is screened to differentiate biological activity member's method.
On the one hand, the present invention relates to beta-chain simulative structure and the compound library that contains the beta-chain simulative structure.Beta-chain simulative structure of the present invention can be used as biologically active agent, includes, but is not limited to as diagnostic reagent, preventive and/or therapeutical agent.Beta-chain simulative structure of the present invention storehouse can be used for the discriminating of such biologically active agent.In enforcement of the present invention, the storehouse can be contained from tens to the individual single beta-chain simulative structure of hundreds of and even several thousand (or more) (being also referred to as " member " herein).
In one aspect of the invention, the beta-chain simulative structure with following structure (I) is disclosed:
Wherein A be-(CH)-,-N-or-CH
2-N-, B be-(C=O)-or-(CH
2)
m-, W is-(C=O)-,-Y (C=O)-,-NH (C=O)-or do not exist, X is-NH-,-NH (C=O)-or do not exist, Y is oxygen or sulphur, Z is that (when Z was hydrogen, C=Z represented CH for oxygen or hydrogen
2), L is hydrogen, R
5,-C (O) NHR
3Or its Equivalent, n=0 or 1 and m=1 or 2; R
1, R
2, R
3, R
4, and R
5Can be identical or different, and be independently selected from hydrogen, amino acid side chain moiety or derivatives thereof, molecule remainder, connect base and solid carrier, and the steric isomer of this structure.
In one aspect of the invention, R
1, R
2, R
3, R
4And R
5Be independently selected from amino C
2-5Alkyl, guanidine radicals C
2-5Alkyl, C
1-4Alkyl guanidine radicals C
2-5Alkyl, two C
1-4Alkyl guanidine radicals-C
2-5Alkyl, amidino groups C
2-5Alkyl, C
1-4Alkyl amidine C
2-5Alkyl, two C
1-4Alkyl amidine C
2-5Alkyl, C
1-3(wherein substituting group is independently selected from one or more amino, amidino groups, guanidine radicals, diazanyl, amino hydrazone group, C for alkoxyl group, phenyl, substituted-phenyl
1-4Alkylamino, C
1-4Dialkyl amido, halogen, perfluor C
1-4Alkyl, C
1-4Alkyl, C
1-3Alkoxyl group, nitro, carboxyl, cyano group, alkylsulfonyl or hydroxyl), benzyl, (wherein the substituting group on the benzyl is independently selected from one or more amino, amidino groups, guanidine radicals, diazanyl, amino hydrazone group, C to substituted benzyl
1-4Alkylamino, C
1-4Dialkyl amido, halogen, perfluor C
1-4Alkyl, C
1-3Alkoxyl group, nitro, carboxyl, cyano group, alkylsulfonyl or hydroxyl), naphthyl, (wherein substituting group is independently selected from one or more amino, amidino groups, guanidine radicals, diazanyl, amino hydrazone group, C to substituted naphthyl
1-4Alkylamino, C
1-4Dialkyl amido, halogen, perfluor C
1-4Alkyl, C
1-4Alkyl, C
1-3Alkoxyl group, nitro, carboxyl, cyano group, alkylsulfonyl or hydroxyl), two phenyl methyl, (wherein substituting group is independently selected from one or more amino, amidino groups, guanidine radicals, diazanyl, amino hydrazone group, C to replace two phenyl methyls
1-4Alkylamino, C
1-4Dialkyl amido, halogen, perfluor C
1-4Alkyl, C
1-4Alkyl, C
1-3Alkoxyl group, nitro, carboxyl, cyano group, alkylsulfonyl or hydroxyl), pyridyl, (wherein substituting group is independently selected from one or more amino amidino groups, guanidine radicals, diazanyl, amino hydrazone group, C to substituted pyridinyl
1-4Alkylamino, C
1-4Dialkyl amido, halogen, perfluor C
1-4Alkyl, C
1-4Alkyl, C
1-3Alkoxyl group, nitro, carboxyl, cyano group, alkylsulfonyl or hydroxyl), pyridyl C
1-4 alkyl, substituted pyridinyl C
1-4(wherein the substituting group of pyridine is independently selected from one or more amino, amidino groups, guanidine radicals, diazanyl, amino hydrazone group, C to alkyl
1-4Alkylamino, C
1-4Dialkyl amido, halogen, perfluor C
1-4Alkyl, C
1-4Alkyl, C
1-3Alkoxyl group, nitro, carboxyl, cyano group, alkylsulfonyl or hydroxyl), pyrimidyl C
1-4Alkyl, substituted pyrimidyl C
1-4(wherein the substituting group of pyrimidine is independently selected from one or more amino, amidino groups, guanidine radicals, diazanyl, amino hydrazone group, C to alkyl
1-4Alkylamino, C
1-4Dialkyl amido, halogen, perfluor C
1-4Alkyl, C
1-4Alkyl, C
1-3Alkoxyl group or nitro, carboxyl, cyano group, alkylsulfonyl or hydroxyl), triazine-2-base-C
1-4Alkyl, replacement triazine-2-base-C
1-4(wherein the substituting group of triazine is independently selected from one or more amino, amidino groups, guanidine radicals, diazanyl, amino hydrazone group, C to alkyl
1-4Alkylamino, C
1-4Dialkyl amido, halogen, perfluor C
1-4Alkyl, C
1-4Alkyl, C
1-3Alkoxyl group, nitro, carboxyl, cyano group, alkylsulfonyl or hydroxyl), imidazo C
1-4Alkyl, substituted imidazole and C
1-4(wherein the substituting group of imidazoles is independently selected from one or more amino, amidino groups, guanidine radicals, diazanyl, amino hydrazone group, C to alkyl
1-4Alkylamino, C
1-4Dialkyl amido, halogen, perfluor C
1-4Alkyl, C
1-4Alkyl, C
1-3Alkoxyl group, nitro, carboxyl, cyano group, alkylsulfonyl or hydroxyl), imidazolinyl C
1-4Alkyl, N-amidino groups piperazinyl-N-C
0-4Alkyl, hydroxyl C
2-5Alkyl, C
1-5Alkylamino C
2-5Alkyl, C
1-5Dialkyl amido C
2-5Alkyl, N-amidinopiperidinyl C
1-4Alkyl and 4-aminocyclohexyl C
0-2Alkyl.
In one embodiment, R
1, R
2And R
3Can be identical or different, and the remainder of representation compound, R
4Be selected from the amino acid side chain moiety or derivatives thereof.In another embodiment, L representative-C (=O) NHR
3, R
1, R
2And R
3Can be identical or different, and the remainder of representation compound or amino acid side chain moiety or derivatives thereof, and R
4Be hydrogen
As used herein, existing amino acid side chain moiety in any natural protein represented in term " amino acid side chain moiety ", comprises the pendant moiety of the natural amino acid that states clearly in (but being not limited to) table 1.Other natural amino acid pendant moiety of the present invention comprises (but being not limited to) 3, the pendant moiety of 5-Dibromotyrosine, iodogorgoic acid, hydroxylysine, gamma carboxyglutamate (ester), Tyrosine O-phosphate and phosphoserine.In addition, in practical application of the present invention, also glycosylated amino acid side chain be can use, (but being not limited to) glycosylated Threonine, Serine and asparagine comprised.
Table 1
Except that the natural amino acid pendant moiety, amino acid side chain moiety of the present invention also comprises their various derivatives.As used herein, " derivative " of amino acid side chain moiety comprises the modifier and/or the changing matter of natural amino acid pendant moiety.For example, the amino acid side chain moiety of L-Ala, Xie Ansuan, leucine, Isoleucine and phenylalanine can be categorized as low alkyl group, aryl or arylalkyl part usually.The derivative of amino acid side chain moiety comprise other straight or branched, ring-type or acyclic, replacement or unsubstituted, saturated or unsaturated low alkyl group, aryl or arylalkyl part.
As used herein, term " remainder of compound " and " remainder of molecule " are used to refer to any structural molecular moiety of beta-chain simulative, reagent, compound, carrier, molecule, linking group, amino acid, peptide or protein of being covalently bound to.Preferred combination is at R
1And/or R
2And/or R
3On the position.This term also comprises amino acid side chain moiety and derivative thereof.
As used herein, " low alkyl group part " contains 1-12 carbon atom, and " low chain aryl moiety " contains 6-12 carbon atom, and " low chain arylalkyl part " contains 7-12 carbon atom.Therefore, in one embodiment, the amino acid side chain derivative is selected from C
1-12Alkyl, C
6-12Aryl and C
7-12Arylalkyl, in a preferred embodiment, the amino acid side chain derivative is selected from C
1-7Alkyl, C
6-10Aryl and C
The 7-11 virtueThe base alkyl.
Amino acid side chain derivative of the present invention further comprises the substitutive derivative of low alkyl group, aryl and arylalkyl part, and wherein substituting group is selected from (but being not limited to) one or more following chemical parts:
-OH ,-OR ,-COOH ,-COOR ,-CONH
2,-NH
2,-NHR ,-NRR ,-SH ,-SR ,-SO
2R ,-SO
2H ,-SOR and halogen (comprising F, Cl, Br and I), wherein the existence of each R be independently selected from straight or branched, ring-type or acyclic, replacement or unsubstituted, saturated or undersaturated low alkyl group, aryl and arylalkyl part.On the one hand, substituting group contains less than 18 carbon atoms.In addition, ring-type of the present invention is hanged down alkyl group, aryl and arylalkyl and is partly comprised naphthalene, and heterogeneous ring compound, for example thiophene, pyrroles, furans, imidazoles, oxazole, thiazole, pyrazoles, 3-pyrroline, tetramethyleneimine, pyridine, pyrimidine, purine, quinoline, isoquinoline 99.9 and carbazole.The amino acid side chain derivative further comprises the assorted alkyl derivative of the moieties of low alkyl group and aralkyl moiety, includes, but is not limited to alkyl and aralkyl phosphoric acid ester (salt) and silane.
In one aspect of the invention, R
1, R
2And R
3Partly be selected from-OH ,-OR ,-COR ,-COOR ,-CONH
2,-CONR ,-CONRR ,-NH
2,-NHR ,-NRR ,-SO
2R and-COSR, wherein the existence of each R is as hereinbefore defined.
In another embodiment, except can being that the amino acid side chain moiety or derivatives thereof is (perhaps at R
1, R
2And R
3Situation under be the remainder of compound), R
1, R
2And R
3It can be the linking group that promotes that compound is connected with another part or compound.For example, compound of the present invention can be connected to one or more and is used to diagnose or the known compound of screening test the biological example element.And, R
1, R
2And R
3Can be that compound is connected to the solid carrier linking group of (for example being used for the synthetic carrier of solid-phase peptide), perhaps in addition randomly, itself can be carrier.In this embodiment, preferably at R
1, R
2Or R
3On the position, more preferably at R
3On the position, be connected to another part or compound, perhaps be connected on the solid carrier.
Do not exist at X, A is N, B is-(C=O)-and L be-C (O) NHR
3Embodiment in, beta chain compound of the present invention has following structure (I '):
R wherein
1, R
2, R
3, R
4, W, Y, Z and n as hereinbefore defined.In preferred embodiment, R
2And R
3The remainder of representation compound, R
1And R
4Be selected from amino acid side chain moiety.
Do not exist at X, A is N, and B is-(CH
2)
m-and L be-C (O) NHR
3Embodiment in, beta-chain simulative structure of the present invention comprises following structure (I "):
R wherein
1, R
2, R
3, R
4, W, Y, Z, m and n as hereinbefore defined.In preferred embodiment, R
2And R
3The remainder of representation compound, R
1And R
4Be selected from amino acid side chain moiety.
At one more specifically in the embodiment, wherein X be-NH-, A be-(CH)-, B is-(CH
2)
m-and L be-C (O) NHR
3, the beta-chain simulative structure has following structure (I ' "):
R wherein
1, R
2, R
3, R
4, W, Y, Z, m and n as hereinbefore defined.
At one more specifically in the embodiment, A is-CH
2-NH-, B are-(CH
2)
m-and L be-C (O) NHR
3, compound of the present invention has following structure (I " "):
Randomly, R wherein
1, R
2, R
3, R
4, W, X, Y, Z, m and n as hereinbefore defined, W does not exist, Z is an oxygen, Y is an oxygen.
Can prepare beta-chain simulative structure of the present invention by using suitable initial ingredient (hereinafter being called " composition fragment ").In brief, in the beta-chain simulative structure with structure (I ') synthetic, form the fragment coupling with first and second, to form bonded the first-the second intermediate, if necessary, form the fragment coupling with the 3rd and/or the 4th, to form bonded the 3rd-Di four intermediates (perhaps, if have commercially available, can use the 3rd independent intermediate), so with bonded the first-the second intermediate and the 3rd-Di four intermediates (or the 3rd intermediate) coupling, so that the first-the second-Di, three-Di, four intermediates (perhaps the first-the second-Di, three intermediates) to be provided, with this intermediate cyclisation, generate beta-chain simulative structure of the present invention.In addition alternatively, can be by with the continuous coupling in solution step by step of independent composition fragment, perhaps the solid phase synthesis of using always in synthetic by solid-phase peptide prepares the beta-chain simulative structure of structure (I ').
In the context of the present invention, " the first composition fragment " has following structure 1:
R wherein
2, A and B as hereinbefore defined, R is applicable to peptide synthetic protecting group.Suitable R group comprises alkyl, and in preferred embodiment, R is a methyl.The first composition fragment like this can be passed through CH (OR)
2-(CH
2)
m-CHO and H
2N-R
2The bonded reductive amination is perhaps by CH (OR)
2-(CH
2) substitution reaction of m-Br and easily synthetic.
" the second composition fragment " of the present invention has following structure 2:
Wherein L and R
4As hereinbefore defined, P is applicable to peptide synthetic amino protecting group, and X represents the leavings group of activatory hydroxy-acid group.Preferred protecting group comprises tertiary butyl dimethylsilyl (TBDMS), BOC, FMOC and Alloc (allyloxy carbonyl).When L is-C (O) NHR
3The time ,-NHR
3It can be the carbonyl-protection base.The amino acid of N-protected is commercially available, for example can obtain FMOC amino acid from multiple source.The activation of the amino acid hydroxy-acid group by N-protected can easily be carried out the amino acid of these N-protecteds and form segmental conversion to the present invention second.Suitable activatory hydroxy-acid group comprises that X wherein is the acyl halide of the halogen of chlorine or bromine and so on, wherein X is the active ester of acid anhydrides, for example N-hydroxy-succinamide ester and pentafluorophenyl group ester of the acyl group of ethanoyl and so on and other active intermediate, the active intermediate that for example uses the carbodiimide of dicyclohexylcarbodiimide (DCC) and so on to form in linked reaction.
Serve as second at amino acid whose azido derivant and form under the segmental situation, such compound can be by the disclosed reaction of people such as Zaloom (J.Org.Chem.46:5173-76,1981), by corresponding amino acid preparation.
" the 3rd composition fragment " of the present invention has following structure 3:
R
1-NH
2Or R
3-NH
2
R wherein
1And R
3As hereinbefore defined.The 3rd suitable composition fragment can be the commercially available prod in multiple source, perhaps can prepare easily by synthetic primary amine standard organic synthesis technology commonly used.
More specifically, by making first to form the fragment and the second composition fragment reaction, generate bonded the first-the second intermediate, make then bonded the first-the second intermediate and the 3rd form fragment or with third and fourth form the fragment successive reaction, bonded the first-the second-Di three-Di is provided four intermediates, make this intermediate cyclisation generating the beta-chain simulative structure then, the beta-chain simulative structure of the present invention of composite structure (I ').
Can finish by following technology and have structure I ' beta-chain simulative structure general synthetic.Use the coupling reagent of phosgene for example to form fragment 1 and 2 couplings of the second composition fragment with first, after the N-deprotection, bonded the first-the second intermediate 1-2 is described below:
Wherein, A, B, L, R, R
2, R
4, P, X and n as hereinbefore defined.X
2C (=S) be the example of a coupling reagent, can also adopt the coupling reagent of other type.It is segmental synthetic to have described the representational composition of the present invention among the embodiment.Can by with the synthetic similar technology of above disclosed built-up type component, prepare the beta-chain simulative compound of structure (I "), but carry out suitable modification forming fragment to (I ' ").
Another aspect of the present invention discloses the storehouse of containing beta-chain simulative structure of the present invention.Finish in case compile, can screen, to differentiate the single member of biologically active storehouse of the present invention.For instance, it is active that this screening for storehouse biological activity member can relate to the combination of estimating the library member, perhaps estimates the effect of library member in functional analysis.Usually by being contacted with for example target spot of being paid close attention to of antibody, enzyme, acceptor or clone, library member's (perhaps hypotype of library member) finishes screening.Can be referred to herein as " biological activity library member " or " biological activity stand-in " with the interactional library member of the target spot of being paid close attention to.For example, the biological activity stand-in can be the library members that can be attached on antibody or the acceptor, library member that can inhibitory enzyme, or for example can cause or resist library member with the reaction of clone function associated.In other words, the screening in storehouse of the present invention has been determined which library member can interact with one or more particular organisms target spots of paying close attention to.When taking place really, then can from the library member, identify interactional biological activity stand-in (or a plurality of biological activity stand-in) when interacting.From the storehouse, differentiate the biological activity stand-in of single (or limited quantity), produced the beta-chain simulative structure of biologically active own, therefore diagnostic reagent, preventive or therapeutical agent can be used as, the discriminating of lead compound in these fields can also be further used for greatly developing.
Can use known peptide synthetic technology, in conjunction with of the present invention first, second, third, and the optional the 4th form fragment, finishes peptide mimics synthetic in storehouse of the present invention.More particularly, can on the N-of structure constrained compounds end and/or C-end, add aminoacid sequence arbitrarily.Therefore, can by the synthetic stand-in of known technology (for example PAM resin) on solid phase carrier (referring to, for example, John M.Stewart and Janis D.Young, Solid PhasePeptide Synthesis, 1984, Pierce Chemical Comp., Rockford, III.), perhaps connect (alcohol attachment) synthetic stand-in (referring to Randolph etc., J.Am Chem.Soc.117:5712-14,1995) on the resin that silyl connects by alcohol.
In addition, can be used in combination solution and solid phase synthesis technique and synthesize peptide mimics of the present invention.For example, can adopt solid carrier synthesizing linear peptide sequence, join in this sequence until the beta chain that structure is limited.Can will before join in the solid phase synthesis (that is, can use and not only have the N-end but also have the limited beta-chain simulative of the structure of C-end) as next " amino acid " then as the next amino acid that joins in the linear peptides by the limited beta-chain simulative structure of the suitable structure of solution synthetic technology synthetic.Be attached in the middle of the sequence by the beta-chain simulative structure that structure is limited, can add other amino acid then, to finish the peptide that is attached on the solid carrier.In addition alternatively, can on solid carrier, synthesize the linear peptides sequence of N-end and the protection of C-end, it is removed from carrier, in solution, use known solution coupling technology to be coupled on the limited beta-chain simulative structure of structure then.
In another aspect of this invention, the method that makes up the storehouse is disclosed.Traditional combinatorial chemistry technique (referring to, for example, people such as Gallop, J.Med.Chem.37:1233-1251,1994) allow to prepare a large amount of compounds rapidly dividing the sequential combination of subframe substantially by reagent.Combination technique has been used for making up by natural amino acid deutero-peptide storehouse.For example, get 20 kinds of due cares and different amino acid whose 20 kinds of mixtures, and each is all carried out coupling with one of 20 seed amino acids, created 400 (that is, 20
2) plant the storehouse of dipeptides.This program is repeated 7 times, and the result has made by about 26,000,000,000 (that is, 20
8) plant the peptide storehouse that octapeptide is formed.
In another aspect of this invention, the method for the storehouse being carried out bioactivity screening and isolating biologically active library member is disclosed.Can carry out bioactivity screening to storehouse of the present invention by multiple technologies and method.Usually, can the storehouse be contacted with the biological targets of paying close attention to of acceptor and so on by (1), make and combine between stand-in and the target spot in storehouse, (2) detect keying action by suitable check, for example by people such as Lam (Nature 354:82-84,1991) or the disclosed calorimetric check of people (Biothechnology 12:1008-1011,1994) such as Griminski (being incorporated herein the two for your guidance), screen detection.In preferred embodiment, the library member is in the solution, and target spot is fixed on the solid phase.In addition alternatively, the storehouse can be fixed on the solid phase, and can survey by it is contacted with target spot in the solution.
Can use the general scheme in preparation beta-chain simulative storehouse shown in Figure 1 to finish peptide mimics synthetic in storehouse of the present invention.The FlexChem reactor room (Reactor Block) that use has 96 orifice plates carries out selected peptide mimics synthetic of the present invention's two ring template base.In above scheme, " Pol " represents 2-chlorine trityl chloride resin (Novabiochem), and detailed process below is provided.
Step 1With 2-chlorine trityl chloride resin (1mmol/g) and Fmoc-R
1The DCE solution of-amino acid (1.5 equivalent) and DIEA (2 equivalent) places Robinson cabin, 96 hole (FlexChem).Reaction mixture was at room temperature vibrated 12 hours.With DMF, MeOH and DCM washing resin.
Step 2Before reaction, be added in the piperidines of 25% among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat this deprotection steps, and, use DCM washed product mixture then with DMF, MeOH.In resin, add 4-R
2The nmp solution of-amino-2-Fmoc-aminobutyric acid (1.5 equivalent), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
Step 3Before reaction, be added in the piperidines of 25% among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat this deprotection steps, and, use DCM washed product mixture then with DMF, MeOH.In resin, add 2-(9H-fluorenes-9-ylmethoxy carbonylamino)-5, the nmp solution of 5-dimethoxy-valeric acid (1.5 equivalent), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
Step 4Before reaction, be added in the piperidines of 25% among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat this deprotection steps, and, use DCM washed product mixture then with DMF, MeOH.In resin, add commercially available R
3The nmp solution of-acid (1.5 equivalent), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
Step 5At room temperature use formic acid (every hole 1.2mL) to handle 18 hours resin.Afterwards, remove by filter resin, under reduced pressure use SpeedVac (Servant) concentrated filtrate, obtain the oily product.These products with water/dilution in acetonitrile of 50%, are carried out freeze-drying then after freezing.
Table 2 has shown can beta-chain simulative prepared in accordance with the present invention storehouse, has provided its representational preparation process among the embodiment 9.The compound of table 2 has illustrated one aspect of the present invention, promptly following compound, wherein A be-(CH)-, B is-(CH
2)
m-and m=1, W be-(C=O)-, X is-NH (C=O)-, Y is an oxygen, Z is a hydrogen, makes C=Z represent CH
2, L is-C (=O) NHR
3, n=0, R
4Be hydrogen, R
1, R
2And R
3Can be identical or different, and be independently selected from remainder, linking group and the solid phase carrier of amino acid side chain moiety or derivatives thereof, molecule, and the steric isomer of this compound.In this each embodiment on the one hand of the present invention, R
1, R
2And R
3Be independently selected from low-molecular-weight relatively molecular moiety, promptly molecular weight at 15 (methyl) to 1, the organic group between the 000g/mol; And/or R
1, R
2And R
3In at least one represented amino acid side chain or derivatives thereof.For example, in the compound of table 2, R
3Represent aspartame.On the one hand, compound molecular weight of the present invention is within about scope of 440 to 750g/mol, and wherein the compound of table 2 provides a large amount of such examples for compounds.
Table 2
B-chain simulative storehouse
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??1 | Methyl | Phenyl | The 4-methoxy-benzyl | ??522 | ??522 |
| ??2 | Methyl | Phenyl | ??3，4-Cl 2-benzyl | ??547 | ??547 |
| ??3 | Methyl | Phenyl | The 1-naphthyl | ??528 | ??528 |
| ??4 | Methyl | Phenyl | Piperonyl | ??522 | ??522 |
| ??5 | Methyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??568 | ??568 |
| ??6 | Methyl | Phenyl | The 2-thienyl methyl | ??498 | ??498 |
| ??7 | Methyl | Phenyl | The 1-naphthyl methyl | ??542 | ??542 |
| ??8 | Methyl | Phenyl | Styroyl | ??506 | ??506 |
| ??9 | Methyl | Phenyl | The 3-p-methoxy-phenyl | ??508 | ??508 |
| ??10 | Methyl | Phenyl | N-benzoyl-amido ethyl | ??535 | ??535 |
| ??11 | Methyl | Phenyl | Benzyl | ??492 | ??492 |
| ??12 | Methyl | Phenyl | The 4-nitrobenzyl | ??537 | ??537 |
| ??13 | Sec.-propyl | Phenyl | The 4-methoxy-benzyl | ??550 | ??550 |
| ??14 | Sec.-propyl | Phenyl | ??3，4-Cl 2-benzyl | ??575 | ??575 |
| ??15 | Sec.-propyl | Phenyl | The 1-naphthyl | ??556 | ??556 |
| ??16 | Sec.-propyl | Phenyl | Piperonyl | ??550 | ??550 |
| ??17 | Sec.-propyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??596 | ??596 |
| ??18 | Sec.-propyl | Phenyl | The 2-thienyl methyl | ??526 | ??526 |
| ??19 | Sec.-propyl | Phenyl | The 1-naphthyl methyl | ??570 | ??570 |
| ??20 | Sec.-propyl | Phenyl | Styroyl | ??534 | ??534 |
| ??21 | Sec.-propyl | Phenyl | The 3-p-methoxy-phenyl | ??536 | ??536 |
| ??22 | Sec.-propyl | Phenyl | N-benzoyl-amido ethyl | ??563 | ??563 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??23 | Sec.-propyl | Phenyl | Benzyl | ??520 | ??520 |
| ??24 | Sec.-propyl | Phenyl | The 4-nitrobenzyl | ??565 | ??565 |
| ??25 | Isobutyl- | Phenyl | The 4-methoxy-benzyl | ??564 | ??564 |
| ??26 | Isobutyl- | Phenyl | ??3，4-Cl 2-benzyl | ??589 | ??589 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??27 | Isobutyl- | Phenyl | The 1-naphthyl | ??570 | ??570 |
| ??28 | Isobutyl- | Phenyl | Piperonyl | ??564 | ??564 |
| ??29 | Isobutyl- | Phenyl | 2,4, the 5-trimethoxyphenyl | ??610 | ??610 |
| ??30 | Isobutyl- | Phenyl | The 2-thienyl methyl | ??540 | ??540 |
| ??31 | Isobutyl- | Phenyl | The 1-naphthyl methyl | ??584 | ??584 |
| ??32 | Isobutyl- | Phenyl | Styroyl | ??548 | ??548 |
| ??33 | Isobutyl- | Phenyl | The 3-p-methoxy-phenyl | ??550 | ??550 |
| ??34 | Isobutyl- | Phenyl | N-benzoyl-amido ethyl | ??577 | ??577 |
| ??35 | Isobutyl- | Phenyl | Benzyl | ??534 | ??534 |
| ??36 | Isobutyl- | Phenyl | The 4-nitrobenzyl | ??579 | ??579 |
| ??37 | Benzyl | Phenyl | The 4-methoxy-benzyl | ??598 | ??598 |
| ??38 | Benzyl | Phenyl | ??3，4-Cl 2-benzyl | ??623 | ??623 |
| ??39 | Benzyl | Phenyl | The 1-naphthyl | ??604 | ??604 |
| ??40 | Benzyl | Phenyl | Piperonyl | ??598 | ??598 |
| ??41 | Benzyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??644 | ??644 |
| ??42 | Benzyl | Phenyl | The 2-thienyl methyl | ??574 | ??574 |
| ??43 | Benzyl | Phenyl | The 1-naphthyl methyl | ??618 | ??618 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??44 | Benzyl | Phenyl | Styroyl | ??582 | ??582 |
| ??45 | Benzyl | Phenyl | The 3-p-methoxy-phenyl | ??584 | ??584 |
| ??46 | Benzyl | Phenyl | N-benzoyl-amido ethyl | ??611 | ??611 |
| ??47 | Benzyl | Phenyl | Benzyl | ??568 | ??568 |
| ??48 | Benzyl | Phenyl | The 4-nitrobenzyl | ??613 | ??613 |
| ??49 | Methyl | Methoxyl group | The 4-methoxy-benzyl | ??476 | ??476 |
| ??50 | Methyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??501 | ??501 |
| ??51 | Methyl | Methoxyl group | The 1-naphthyl | ??482 | ??482 |
| ??52 | Methyl | Methoxyl group | Piperonyl | ??476 | ??476 |
| ??53 | Methyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??522 | ??522 |
| ??54 | Methyl | Methoxyl group | The 2-thienyl methyl | ??452 | ??452 |
| ??55 | Methyl | Methoxyl group | The 1-naphthyl methyl | ??496 | ??496 |
| ??56 | Methyl | Methoxyl group | Styroyl | ??460 | ??460 |
| ??57 | Methyl | Methoxyl group | The 3-p-methoxy-phenyl | ??462 | ??462 |
| ??58 | Methyl | Methoxyl group | N-benzoyl-amido ethyl | ??489 | ??489 |
| ??59 | Methyl | Methoxyl group | Benzyl | ??446 | ??446 |
| ??60 | Methyl | Methoxyl group | The 4-nitrobenzyl | ??491 | ??491 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??61 | Sec.-propyl | Methoxyl group | The 4-methoxy-benzyl | ??504 | ??504 |
| ??62 | Sec.-propyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??529 | ??529 |
| ??63 | Sec.-propyl | Methoxyl group | The 1-naphthyl | ??510 | ??510 |
| ??64 | Sec.-propyl | Methoxyl group | Piperonyl | ??504 | ??504 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??65 | Sec.-propyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??550 | ??550 |
| ??66 | Sec.-propyl | Methoxyl group | The 2-thienyl methyl | ??480 | ??480 |
| ??67 | Sec.-propyl | Methoxyl group | The 1-naphthyl methyl | ??524 | ??524 |
| ??68 | Sec.-propyl | Methoxyl group | Styroyl | ??488 | ??488 |
| ??69 | Sec.-propyl | Methoxyl group | The 3-p-methoxy-phenyl | ??490 | ??490 |
| ??70 | Sec.-propyl | Methoxyl group | N-benzoyl-amido ethyl | ??517 | ??517 |
| ??71 | Sec.-propyl | Methoxyl group | Benzyl | ??474 | ??474 |
| ??72 | Sec.-propyl | Methoxyl group | The 4-nitrobenzyl | ??519 | ??519 |
| ??73 | Isobutyl- | Methoxyl group | The 4-methoxy-benzyl | ??518 | ??518 |
| ??74 | Isobutyl- | Methoxyl group | ??3，4-Cl 2-benzyl | ??543 | ??543 |
| ??75 | Isobutyl- | Methoxyl group | The 1-naphthyl | ??524 | ??524 |
| ??76 | Isobutyl- | Methoxyl group | Piperonyl | ??518 | ??518 |
| ??77 | Isobutyl- | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??564 | ??564 |
| ??78 | Isobutyl- | Methoxyl group | The 2-thienyl methyl | ??494 | ??494 |
| ??79 | Isobutyl- | Methoxyl group | The 1-naphthyl methyl | ??538 | ??538 |
| ??80 | Isobutyl- | Methoxyl group | Styroyl | ??502 | ??502 |
| ??81 | Isobutyl- | Methoxyl group | The 3-p-methoxy-phenyl | ??504 | ??504 |
| ??82 | Isobutyl- | Methoxyl group | N-benzoyl-amido ethyl | ??531 | ??531 |
| ??83 | Isobutyl- | Methoxyl group | Benzyl | ??488 | ??488 |
| ??84 | Isobutyl- | Methoxyl group | The 4-nitrobenzyl | ??533 | ??533 |
| ??85 | Benzyl | Methoxyl group | The 4-methoxy-benzyl | ??552 | ??552 |
| ??86 | Benzyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??577 | ??577 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??87 | Benzyl | Methoxyl group | The 1-naphthyl | ??558 | ??558 |
| ??88 | Benzyl | Methoxyl group | Piperonyl | ??552 | ??552 |
| ??89 | Benzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??598 | ??598 |
| ??90 | Benzyl | Methoxyl group | The 2-thienyl methyl | ??528 | ??528 |
| ??91 | Benzyl | Methoxyl group | The 1-naphthyl methyl | ??572 | ??572 |
| ??92 | Benzyl | Methoxyl group | Styroyl | ??536 | ??536 |
| ??93 | Benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??538 | ??538 |
| ??94 | Benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??565 | ??565 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??95 | Benzyl | Methoxyl group | Benzyl | ??522 | ??522 |
| ??96 | Benzyl | Methoxyl group | The 4-nitrobenzyl | ??567 | ??567 |
| ??97 | The 2-methyl-propyl | Phenyl | The 4-methoxy-benzyl | ??564 | ??564 |
| ??98 | The 2-methyl-propyl | Phenyl | ??3，4-Cl 2-benzyl | ??589 | ??589 |
| ??99 | The 2-methyl-propyl | Phenyl | The 1-naphthyl | ??570 | ??570 |
| ??100 | The 2-methyl-propyl | Phenyl | Piperonyl | ??564 | ??564 |
| ??101 | The 2-methyl-propyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??610 | ??610 |
| ??102 | The 2-methyl-propyl | Phenyl | The 2-thienyl methyl | ??550 | ??550 |
| ??103 | The 2-methyl-propyl | Phenyl | The 1-naphthyl methyl | ??584 | ??584 |
| ??104 | The 2-methyl-propyl | Phenyl | Styroyl | ??548 | ??548 |
| ??105 | The 2-methyl-propyl | Phenyl | The 3-p-methoxy-phenyl | ??550 | ??550 |
| ??106 | The 2-methyl-propyl | Phenyl | N-benzoyl-amido ethyl | ??577 | ??577 |
| ??107 | The 2-methyl-propyl | Phenyl | Benzyl | ??534 | ??534 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??108 | The 2-methyl-propyl | Phenyl | The 4-nitrobenzyl | ??579 | ??579 |
| ??109 | The methyl thio-ethyl | Phenyl | The 4-methoxy-benzyl | ??582 | ??582 |
| ??110 | The methyl thio-ethyl | Phenyl | ??3，4-Cl 2-benzyl | ??607 | ??607 |
| ??111 | The methyl thio-ethyl | Phenyl | The 1-naphthyl | ??588 | ??588 |
| ??112 | The methyl thio-ethyl | Phenyl | Piperonyl | ??582 | ??582 |
| ??113 | The methyl thio-ethyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??628 | ??628 |
| ??114 | The methyl thio-ethyl | Phenyl | The 2-thienyl methyl | ??568 | ??568 |
| ??115 | The methyl thio-ethyl | Phenyl | The 1-naphthyl methyl | ??602 | ??602 |
| ??116 | The methyl thio-ethyl | Phenyl | Styroyl | ??566 | ??566 |
| ??117 | The methyl thio-ethyl | Phenyl | The 3-p-methoxy-phenyl | ??568 | ??568 |
| ??118 | The methyl thio-ethyl | Phenyl | N-benzoyl-amido ethyl | ??595 | ??595 |
| ??119 | The methyl thio-ethyl | Phenyl | Benzyl | ??552 | ??552 |
| ??120 | The methyl thio-ethyl | Phenyl | The 4-nitrobenzyl | ??597 | ??597 |
| ??121 | The 4-hydroxybenzyl | Phenyl | The 4-methoxy-benzyl | ??614 | ??614 |
| ??122 | The 4-hydroxybenzyl | Phenyl | ??3，4-Cl 2-benzyl | ??639 | ??639 |
| ??123 | The 4-hydroxybenzyl | Phenyl | The 1-naphthyl | ??620 | ??620 |
| ??124 | The 4-hydroxybenzyl | Phenyl | Piperonyl | ??614 | ??614 |
| ??125 | The 4-hydroxybenzyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??660 | ??660 |
| ??126 | The 4-hydroxybenzyl | Phenyl | The 2-thienyl methyl | ??600 | ??600 |
| ??127 | The 4-hydroxybenzyl | Phenyl | The 1-naphthyl methyl | ??634 | ??634 |
| ??128 | The 4-hydroxybenzyl | Phenyl | Styroyl | ??598 | ??598 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??129 | The 4-hydroxybenzyl | Phenyl | The 3-p-methoxy-phenyl | ??600 | ??600 |
| ??130 | The 4-hydroxybenzyl | Phenyl | N-benzoyl-amido ethyl | ??627 | ??627 |
| ??131 | The 4-hydroxybenzyl | Phenyl | Benzyl | ??584 | ??584 |
| ??132 | The 4-hydroxybenzyl | Phenyl | The 4-nitrobenzyl | ??629 | ??629 |
| ??133 | Cyclohexyl methyl | Phenyl | The 4-methoxy-benzyl | ??604 | ??604 |
| ??134 | Cyclohexyl methyl | Phenyl | ??3，4-Cl 2-benzyl | ??629 | ??629 |
| ??135 | Cyclohexyl methyl | Phenyl | The 1-naphthyl | ??610 | ??610 |
| ??136 | Cyclohexyl methyl | Phenyl | Piperonyl | ??604 | ??604 |
| ??137 | Cyclohexyl methyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??650 | ??650 |
| ??138 | Cyclohexyl methyl | Phenyl | The 2-thienyl methyl | ??590 | ??590 |
| ??139 | Cyclohexyl methyl | Phenyl | The 1-naphthyl methyl | ??624 | ??624 |
| ??140 | Cyclohexyl methyl | Phenyl | Styroyl | ??588 | ??588 |
| ??141 | Cyclohexyl methyl | Phenyl | The 3-p-methoxy-phenyl | ??590 | ??590 |
| ??142 | Cyclohexyl methyl | Phenyl | N-benzoyl-amido ethyl | ??617 | ??617 |
| ??143 | Cyclohexyl methyl | Phenyl | Benzyl | ??574 | ??574 |
| ??144 | Cyclohexyl methyl | Phenyl | The 4-nitrobenzyl | ??619 | ??619 |
| ??145 | The 2-methyl-propyl | Methoxyl group | The 4-methoxy-benzyl | ??518 | ??518 |
| ??146 | The 2-methyl-propyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??543 | ??543 |
| ??147 | The 2-methyl-propyl | Methoxyl group | The 1-naphthyl | ??524 | ??524 |
| ??148 | The 2-methyl-propyl | Methoxyl group | Piperonyl | ??518 | ??518 |
| ??149 | The 2-methyl-propyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??564 | ??564 |
| ??150 | The 2-methyl-propyl | Methoxyl group | The 2-thienyl methyl | ??504 | ??504 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??151 | The 2-methyl-propyl | Methoxyl group | The 1-naphthyl methyl | ??538 | ??538 |
| ??152 | The 2-methyl-propyl | Methoxyl group | Styroyl | ??502 | ??502 |
| ??153 | The 2-methyl-propyl | Methoxyl group | The 3-p-methoxy-phenyl | ??504 | ??504 |
| ??154 | The 2-methyl-propyl | Methoxyl group | N-benzoyl-amido ethyl | ??531 | ??531 |
| ??155 | The 2-methyl-propyl | Methoxyl group | Benzyl | ??488 | ??488 |
| ??156 | The 2-methyl-propyl | Methoxyl group | The 4-nitrobenzyl | ??533 | ??533 |
| ??157 | The methyl thio-ethyl | Methoxyl group | The 4-methoxy-benzyl | ??536 | ??536 |
| ??158 | The methyl thio-ethyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??561 | ??561 |
| ??159 | The methyl thio-ethyl | Methoxyl group | The 1-naphthyl | ??542 | ??542 |
| ??160 | The methyl thio-ethyl | Methoxyl group | Piperonyl | ??536 | ??536 |
| ??161 | The methyl thio-ethyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??582 | ??582 |
| ??162 | The methyl thio-ethyl | Methoxyl group | The 2-thienyl methyl | ??522 | ??522 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??163 | The methyl thio-ethyl | Methoxyl group | The 1-naphthyl methyl | ??556 | ??556 |
| ??164 | The methyl thio-ethyl | Methoxyl group | Styroyl | ??520 | ??520 |
| ??165 | The methyl thio-ethyl | Methoxyl group | The 3-p-methoxy-phenyl | ??522 | ??522 |
| ??166 | The methyl thio-ethyl | Methoxyl group | N-benzoyl-amido ethyl | ??549 | ??549 |
| ??167 | The methyl thio-ethyl | Methoxyl group | Benzyl | ??506 | ??506 |
| ??168 | The methyl thio-ethyl | Methoxyl group | The 4-nitrobenzyl | ??551 | ??551 |
| ??169 | The 4-hydroxybenzyl | Methoxyl group | The 4-methoxy-benzyl | ??568 | ??568 |
| ??170 | The 4-hydroxybenzyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??593 | ??593 |
| ??171 | The 4-hydroxybenzyl | Methoxyl group | The 1-naphthyl | ??574 | ??574 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??172 | The 4-hydroxybenzyl | Methoxyl group | Piperonyl | ??568 | ??568 |
| ??173 | The 4-hydroxybenzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??614 | ??614 |
| ??174 | The 4-hydroxybenzyl | Methoxyl group | The 2-thienyl methyl | ??554 | ??554 |
| ??175 | The 4-hydroxybenzyl | Methoxyl group | The 1-naphthyl methyl | ??588 | ??588 |
| ??176 | The 4-hydroxybenzyl | Methoxyl group | Styroyl | ??552 | ??552 |
| ??177 | The 4-hydroxybenzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??554 | ??554 |
| ??178 | The 4-hydroxybenzyl | Methoxyl group | N-benzoyl-amido ethyl | ??581 | ??581 |
| ??179 | The 4-hydroxybenzyl | Methoxyl group | Benzyl | ??538 | ??538 |
| ??180 | The 4-hydroxybenzyl | Methoxyl group | The 4-nitrobenzyl | ??583 | ??583 |
| ??181 | Cyclohexyl methyl | Methoxyl group | The 4-methoxy-benzyl | ??558 | ??558 |
| ??182 | Cyclohexyl methyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??583 | ??583 |
| ??183 | Cyclohexyl methyl | Methoxyl group | The 1-naphthyl | ??564 | ??564 |
| ??184 | Cyclohexyl methyl | Methoxyl group | Piperonyl | ??558 | ??558 |
| ??185 | Cyclohexyl methyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??604 | ??604 |
| ??186 | Cyclohexyl methyl | Methoxyl group | The 2-thienyl methyl | ??544 | ??544 |
| ??187 | Cyclohexyl methyl | Methoxyl group | The 1-naphthyl methyl | ??578 | ??578 |
| ??188 | Cyclohexyl methyl | Methoxyl group | Styroyl | ??542 | ??542 |
| ??189 | Cyclohexyl methyl | Methoxyl group | The 3-p-methoxy-phenyl | ??544 | ??544 |
| ??190 | Cyclohexyl methyl | Methoxyl group | N-benzoyl-amido ethyl | ??571 | ??571 |
| ??191 | Cyclohexyl methyl | Methoxyl group | Benzyl | ??528 | ??528 |
| ??192 | Cyclohexyl methyl | Methoxyl group | The 4-nitrobenzyl | ??573 | ??573 |
| ??193 | Methyl | Phenyl | The 4-methoxy-benzyl | ??521 | ??521 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??194 | Methyl | Phenyl | ??3，4-Cl 2-benzyl | ??546 | ??546 |
| ??195 | Methyl | Phenyl | The 1-naphthyl | ??527 | ??527 |
| ??196 | Methyl | Phenyl | Piperonyl | ??521 | ??521 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??197 | Methyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??567 | ??567 |
| ??198 | Methyl | Phenyl | The 3-hydroxybenzyl | ??507 | ??507 |
| ??199 | Methyl | Phenyl | The 1-naphthyl methyl | ??541 | ??541 |
| ??200 | Methyl | Phenyl | Styroyl | ??505 | ??505 |
| ??201 | Methyl | Phenyl | The 3-p-methoxy-phenyl | ??507 | ??507 |
| ??202 | Methyl | Phenyl | N-benzoyl-amido ethyl | ??534 | ??534 |
| ??203 | Methyl | Phenyl | Benzyl | ??491 | ??491 |
| ??204 | Methyl | Phenyl | The 4-nitrobenzyl | ??536 | ??536 |
| ??205 | Sec.-propyl | Phenyl | The 4-methoxy-benzyl | ??549 | ??549 |
| ??206 | Sec.-propyl | Phenyl | ??3，4-Cl 2-benzyl | ??574 | ??574 |
| ??207 | Sec.-propyl | Phenyl | The 1-naphthyl | ??555 | ??555 |
| ??208 | Sec.-propyl | Phenyl | Piperonyl | ??549 | ??549 |
| ??209 | Sec.-propyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??595 | ??595 |
| ??210 | Sec.-propyl | Phenyl | The 3-hydroxybenzyl | ??535 | ??535 |
| ??211 | Sec.-propyl | Phenyl | The 1-naphthyl methyl | ??569 | ??569 |
| ??212 | Sec.-propyl | Phenyl | Styroyl | ??533 | ??533 |
| ??213 | Sec.-propyl | Phenyl | The 3-p-methoxy-phenyl | ??535 | ??535 |
| ??214 | Sec.-propyl | Phenyl | N-benzoyl-amido ethyl | ??562 | ??562 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??215 | Sec.-propyl | Phenyl | Benzyl | ??519 | ??519 |
| ??216 | Sec.-propyl | Phenyl | The 4-nitrobenzyl | ??564 | ??564 |
| ??217 | Isobutyl- | Phenyl | The 4-methoxy-benzyl | ??563 | ??563 |
| ??218 | Isobutyl- | Phenyl | ??3，4-Cl 2-benzyl | ??588 | ??588 |
| ??219 | Isobutyl- | Phenyl | The 1-naphthyl | ??569 | ??569 |
| ??220 | Isobutyl- | Phenyl | Piperonyl | ??563 | ??563 |
| ??221 | Isobutyl- | Phenyl | 2,4, the 5-trimethoxyphenyl | ??609 | ??609 |
| ??222 | Isobutyl- | Phenyl | The 3-hydroxybenzyl | ??549 | ??549 |
| ??223 | Isobutyl- | Phenyl | The 1-naphthyl methyl | ??583 | ??583 |
| ??224 | Isobutyl- | Phenyl | Styroyl | ??547 | ??547 |
| ??225 | Isobutyl- | Phenyl | The 3-p-methoxy-phenyl | ??549 | ??549 |
| ??226 | Isobutyl- | Phenyl | N-benzoyl-amido ethyl | ??576 | ??576 |
| ??227 | Isobutyl- | Phenyl | Benzyl | ??533 | ??533 |
| ??228 | Isobutyl- | Phenyl | The 4-nitrobenzyl | ??578 | ??578 |
| ??229 | Benzyl | Phenyl | The 4-methoxy-benzyl | ??597 | ??597 |
| ??230 | Benzyl | Phenyl | ??3，4-Cl 2-benzyl | ??622 | ??622 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??231 | Benzyl | Phenyl | The 1-naphthyl | ??603 | ??603 |
| ??232 | Benzyl | Phenyl | Piperonyl | ??597 | ??597 |
| ??233 | Benzyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??643 | ??643 |
| ??234 | Benzyl | Phenyl | The 3-hydroxybenzyl | ??583 | ??583 |
| ??235 | Benzyl | Phenyl | The 1-naphthyl methyl | ??617 | ??617 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??236 | Benzyl | Phenyl | Styroyl | ??581 | ??581 |
| ??237 | Benzyl | Phenyl | The 3-p-methoxy-phenyl | ??583 | ??583 |
| ??238 | Benzyl | Phenyl | N-benzoyl-amido ethyl | ??610 | ??610 |
| ??239 | Benzyl | Phenyl | Benzyl | ??567 | ??567 |
| ??240 | Benzyl | Phenyl | The 4-nitrobenzyl | ??612 | ??612 |
| ??241 | The 2-methyl-propyl | Phenyl | The 4-methoxy-benzyl | ??563 | ??563 |
| ??242 | The 2-methyl-propyl | Phenyl | ??3，4-Cl 2-benzyl | ??588 | ??588 |
| ??243 | The 2-methyl-propyl | Phenyl | The 1-naphthyl | ??569 | ??569 |
| ??244 | The 2-methyl-propyl | Phenyl | Piperonyl | ??563 | ??563 |
| ??245 | The 2-methyl-propyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??609 | ??609 |
| ??246 | The 2-methyl-propyl | Phenyl | The 3-hydroxybenzyl | ??549 | ??549 |
| ??247 | The 2-methyl-propyl | Phenyl | The 1-naphthyl methyl | ??583 | ??583 |
| ??248 | The 2-methyl-propyl | Phenyl | Styroyl | ??547 | ??547 |
| ??249 | The 2-methyl-propyl | Phenyl | The 3-p-methoxy-phenyl | ??549 | ??549 |
| ??250 | The 2-methyl-propyl | Phenyl | N-benzoyl-amido ethyl | ??576 | ??576 |
| ??251 | The 2-methyl-propyl | Phenyl | Benzyl | ??533 | ??533 |
| ??252 | The 2-methyl-propyl | Phenyl | The 4-nitrobenzyl | ??578 | ??578 |
| ??253 | The methyl thio-ethyl | Phenyl | The 4-methoxy-benzyl | ??581 | ??581 |
| ??254 | The methyl thio-ethyl | Phenyl | ??3，4-Cl 2-benzyl | ??606 | ??606 |
| ??255 | The methyl thio-ethyl | Phenyl | The 1-naphthyl | ??587 | ??587 |
| ??256 | The methyl thio-ethyl | Phenyl | Piperonyl | ??581 | ??581 |
| ??257 | The methyl thio-ethyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??627 | ??627 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??258 | The methyl thio-ethyl | Phenyl | The 3-hydroxybenzyl | ??567 | ??567 |
| ??259 | The methyl thio-ethyl | Phenyl | The 1-naphthyl methyl | ??601 | ??601 |
| ??260 | The methyl thio-ethyl | Phenyl | Styroyl | ??565 | ??565 |
| ??261 | The methyl thio-ethyl | Phenyl | The 3-p-methoxy-phenyl | ??567 | ??567 |
| ??262 | The methyl thio-ethyl | Phenyl | N-benzoyl-amido ethyl | ??594 | ??594 |
| ??263 | The methyl thio-ethyl | Phenyl | Benzyl | ??551 | ??551 |
| ??264 | The methyl thio-ethyl | Phenyl | The 4-nitrobenzyl | ??596 | ??596 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??265 | The 4-hydroxybenzyl | Phenyl | The 4-methoxy-benzyl | ??613 | ??613 |
| ??266 | The 4-hydroxybenzyl | Phenyl | ??3，4-Cl 2-benzyl | ??638 | ??638 |
| ??267 | The 4-hydroxybenzyl | Phenyl | The 1-naphthyl | ??619 | ??619 |
| ??268 | The 4-hydroxybenzyl | Phenyl | Piperonyl | ??613 | ??613 |
| ??269 | The 4-hydroxybenzyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??659 | ??659 |
| ??270 | The 4-hydroxybenzyl | Phenyl | The 3-hydroxybenzyl | ??599 | ??599 |
| ??271 | The 4-hydroxybenzyl | Phenyl | The 1-naphthyl methyl | ??633 | ??633 |
| ??272 | The 4-hydroxybenzyl | Phenyl | Styroyl | ??597 | ??597 |
| ??273 | The 4-hydroxybenzyl | Phenyl | The 3-p-methoxy-phenyl | ??599 | ??599 |
| ??274 | The 4-hydroxybenzyl | Phenyl | N-benzoyl-amido ethyl | ??626 | ??626 |
| ??275 | The 4-hydroxybenzyl | Phenyl | Benzyl | ??583 | ??583 |
| ??276 | The 4-hydroxybenzyl | Phenyl | The 4-nitrobenzyl | ??628 | ??628 |
| ??277 | Cyclohexyl methyl | Phenyl | The 4-methoxy-benzyl | ??603 | ??603 |
| ??278 | Cyclohexyl methyl | Phenyl | ??3，4-Cl 2-benzyl | ??628 | ??628 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??279 | Cyclohexyl methyl | Phenyl | The 1-naphthyl | ??609 | ??609 |
| ??280 | Cyclohexyl methyl | Phenyl | Piperonyl | ??603 | ??603 |
| ??281 | Cyclohexyl methyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??649 | ??649 |
| ??282 | Cyclohexyl methyl | Phenyl | The 3-hydroxybenzyl | ??589 | ??589 |
| ??283 | Cyclohexyl methyl | Phenyl | The 1-naphthyl methyl | ??623 | ??623 |
| ??284 | Cyclohexyl methyl | Phenyl | Styroyl | ??587 | ??587 |
| ??285 | Cyclohexyl methyl | Phenyl | The 3-p-methoxy-phenyl | ??589 | ??589 |
| ??286 | Cyclohexyl methyl | Phenyl | N-benzoyl-amido ethyl | ??616 | ??616 |
| ??287 | Cyclohexyl methyl | Phenyl | Benzyl | ??573 | ??573 |
| ??288 | Cyclohexyl methyl | Phenyl | The 4-nitrobenzyl | ??618 | ??618 |
| ??289 | Methyl | Benzyloxy | The 4-methoxy-benzyl | ??553 | ??553 |
| ??290 | Methyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??577 | ??577 |
| ??291 | Methyl | Benzyloxy | The 1-naphthyl | ??559 | ??559 |
| ??292 | Methyl | Benzyloxy | Piperonyl | ??553 | ??553 |
| ??293 | Methyl | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??599 | ??599 |
| ??294 | Methyl | Benzyloxy | The 2-thienyl methyl | ??539 | ??539 |
| ??295 | Methyl | Benzyloxy | The 1-naphthyl methyl | ??573 | ??573 |
| ??296 | Methyl | Benzyloxy | Styroyl | ??537 | ??537 |
| ??297 | Methyl | Benzyloxy | The 3-p-methoxy-phenyl | ??539 | ??539 |
| ??298 | Methyl | Benzyloxy | N-benzoyl-amido ethyl | ??566 | ??566 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??299 | Methyl | Benzyloxy | Benzyl | ??523 | ??523 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??300 | Methyl | Benzyloxy | The 4-nitrobenzyl | ??568 | ??568 |
| ??301 | Sec.-propyl | Benzyloxy | The 4-methoxy-benzyl | ??581 | ??581 |
| ??302 | Sec.-propyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??605 | ??605 |
| ??303 | Sec.-propyl | Benzyloxy | The 1-naphthyl | ??587 | ??587 |
| ??304 | Sec.-propyl | Benzyloxy | Piperonyl | ??581 | ??581 |
| ??305 | Sec.-propyl | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??627 | ??627 |
| ??306 | Sec.-propyl | Benzyloxy | The 2-thienyl methyl | ??567 | ??567 |
| ??307 | Sec.-propyl | Benzyloxy | The 1-naphthyl methyl | ??601 | ??601 |
| ??308 | Sec.-propyl | Benzyloxy | Styroyl | ??565 | ??565 |
| ??309 | Sec.-propyl | Benzyloxy | The 3-p-methoxy-phenyl | ??567 | ??567 |
| ??310 | Sec.-propyl | Benzyloxy | N-benzoyl-amido ethyl | ??594 | ??594 |
| ??311 | Sec.-propyl | Benzyloxy | Benzyl | ??551 | ??551 |
| ??312 | Sec.-propyl | Benzyloxy | The 4-nitrobenzyl | ??596 | ??596 |
| ??313 | Isobutyl- | Benzyloxy | The 4-methoxy-benzyl | ??595 | ??595 |
| ??314 | Isobutyl- | Benzyloxy | ??3，4-Cl 2-benzyl | ??620 | ??620 |
| ??315 | Isobutyl- | Benzyloxy | The 1-naphthyl | ??601 | ??601 |
| ??316 | Isobutyl- | Benzyloxy | Piperonyl | ??595 | ??595 |
| ??317 | Isobutyl- | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??641 | ??641 |
| ??318 | Isobutyl- | Benzyloxy | The 2-thienyl methyl | ??581 | ??581 |
| ??319 | Isobutyl- | Benzyloxy | The 1-naphthyl methyl | ??615 | ??615 |
| ??320 | Isobutyl- | Benzyloxy | Styroyl | ??579 | ??579 |
| ??321 | Isobutyl- | Benzyloxy | The 3-p-methoxy-phenyl | ??581 | ??581 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??322 | Isobutyl- | Benzyloxy | N-benzoyl-amido ethyl | ??608 | ??608 |
| ??323 | Isobutyl- | Benzyloxy | Benzyl | ??565 | ??565 |
| ??324 | Isobutyl- | Benzyloxy | The 4-nitrobenzyl | ??610 | ??610 |
| ??325 | Benzyl | Benzyloxy | The 4-methoxy-benzyl | ??629 | ??629 |
| ??326 | Benzyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??654 | ??654 |
| ??327 | Benzyl | Benzyloxy | The 1-naphthyl | ??635 | ??635 |
| ??328 | Benzyl | Benzyloxy | Piperonyl | ??629 | ??629 |
| ??329 | Benzyl | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??675 | ??675 |
| ??330 | Benzyl | Benzyloxy | The 2-thienyl methyl | ??615 | ??615 |
| ??331 | Benzyl | Benzyloxy | The 1-naphthyl methyl | ??649 | ??649 |
| ??332 | Benzyl | Benzyloxy | Styroyl | ??613 | ??613 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??333 | Benzyl | Benzyloxy | The 3-p-methoxy-phenyl | ??615 | ??615 |
| ??334 | Benzyl | Benzyloxy | N-benzoyl-amido ethyl | ??642 | ??642 |
| ??335 | Benzyl | Benzyloxy | Benzyl | ??599 | ??599 |
| ??336 | Benzyl | Benzyloxy | The 4-nitrobenzyl | ??644 | ??644 |
| ??337 | The 2-methyl-propyl | Benzyloxy | The 4-methoxy-benzyl | ??595 | ??595 |
| ??338 | The 2-methyl-propyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??620 | ??620 |
| ??339 | The 2-methyl-propyl | Benzyloxy | The 1-naphthyl | ??601 | ??601 |
| ??340 | The 2-methyl-propyl | Benzyloxy | Piperonyl | ??595 | ??595 |
| ??341 | The 2-methyl-propyl | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??641 | ??641 |
| ??342 | The 2-methyl-propyl | Benzyloxy | The 2-thienyl methyl | ??581 | ??581 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??343 | The 2-methyl-propyl | Benzyloxy | The 1-naphthyl methyl | ??615 | ??615 |
| ??344 | The 2-methyl-propyl | Benzyloxy | Styroyl | ??579 | ??579 |
| ??345 | The 2-methyl-propyl | Benzyloxy | The 3-p-methoxy-phenyl | ??581 | ??581 |
| ??346 | The 2-methyl-propyl | Benzyloxy | N-benzoyl-amido ethyl | ??608 | ??608 |
| ??347 | The 2-methyl-propyl | Benzyloxy | Benzyl | ??565 | ??565 |
| ??348 | The 2-methyl-propyl | Benzyloxy | The 4-nitrobenzyl | ??610 | ??610 |
| ??349 | The methyl thio-ethyl | Benzyloxy | The 4-methoxy-benzyl | ??613 | ??613 |
| ??350 | The methyl thio-ethyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??638 | ??638 |
| ??351 | The methyl thio-ethyl | Benzyloxy | The 1-naphthyl | ??619 | ??619 |
| ??352 | The methyl thio-ethyl | Benzyloxy | Piperonyl | ??613 | ??613 |
| ??353 | The methyl thio-ethyl | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??659 | ??659 |
| ??354 | The methyl thio-ethyl | Benzyloxy | The 2-thienyl methyl | ??599 | ??599 |
| ??355 | The methyl thio-ethyl | Benzyloxy | The 1-naphthyl methyl | ??633 | ??633 |
| ??356 | The methyl thio-ethyl | Benzyloxy | Styroyl | ??597 | ??597 |
| ??357 | The methyl thio-ethyl | Benzyloxy | The 3-p-methoxy-phenyl | ??599 | ??599 |
| ??358 | The methyl thio-ethyl | Benzyloxy | N-benzoyl-amido ethyl | ??626 | ??626 |
| ??359 | The methyl thio-ethyl | Benzyloxy | Benzyl | ??583 | ??583 |
| ??360 | The methyl thio-ethyl | Benzyloxy | The 4-nitrobenzyl | ??628 | ??628 |
| ??361 | The 4-hydroxybenzyl | Benzyloxy | The 4-methoxy-benzyl | ??645 | ??645 |
| ??362 | The 4-hydroxybenzyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??670 | ??670 |
| ??363 | The 4-hydroxybenzyl | Benzyloxy | The 1-naphthyl | ??651 | ??651 |
| ??364 | The 4-hydroxybenzyl | Benzyloxy | Piperonyl | ??645 | ??645 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??365 | The 4-hydroxybenzyl | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??691 | ??691 |
| ??366 | The 4-hydroxybenzyl | Benzyloxy | The 2-thienyl methyl | ??631 | ??631 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??367 | The 4-hydroxybenzyl | Benzyloxy | The 1-naphthyl methyl | ??665 | ??665 |
| ??368 | The 4-hydroxybenzyl | Benzyloxy | Styroyl | ??629 | ??629 |
| ??369 | The 4-hydroxybenzyl | Benzyloxy | The 3-p-methoxy-phenyl | ??631 | ??631 |
| ??370 | The 4-hydroxybenzyl | Benzyloxy | N-benzoyl-amido ethyl | ??658 | ??658 |
| ??371 | The 4-hydroxybenzyl | Benzyloxy | Benzyl | ??615 | ??615 |
| ??372 | The 4-hydroxybenzyl | Benzyloxy | The 4-nitrobenzyl | ??660 | ??660 |
| ??373 | Cyclohexyl methyl | Benzyloxy | The 4-methoxy-benzyl | ??635 | ??635 |
| ??374 | Cyclohexyl methyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??660 | ??660 |
| ??375 | Cyclohexyl methyl | Benzyloxy | The 1-naphthyl | ??641 | ??641 |
| ??376 | Cyclohexyl methyl | Benzyloxy | Piperonyl | ??635 | ??635 |
| ??377 | Cyclohexyl methyl | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??681 | ??681 |
| ??378 | Cyclohexyl methyl | Benzyloxy | The 2-thienyl methyl | ??621 | ??621 |
| ??379 | Cyclohexyl methyl | Benzyloxy | The 1-naphthyl methyl | ??655 | ??655 |
| ??380 | Cyclohexyl methyl | Benzyloxy | Styroyl | ??619 | ??619 |
| ??381 | Cyclohexyl methyl | Benzyloxy | The 3-p-methoxy-phenyl | ??621 | ??621 |
| ??382 | Cyclohexyl methyl | Benzyloxy | N-benzoyl-amido ethyl | ??648 | ??648 |
| ??383 | Cyclohexyl methyl | Benzyloxy | Benzyl | ??605 | ??605 |
| ??384 | Cyclohexyl methyl | Benzyloxy | The 4-nitrobenzyl | ??650 | ??650 |
| ??385 | Methyl | Methoxyl group | The acetoxyl methyl | ??422 | ??422 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??386 | Methyl | Methoxyl group | 4-(2, the 5-Cl2 pyridyl) methyl | ??502 | ??502 |
| ??387 | Methyl | Methoxyl group | Chromen-2-one-3-methyl | ??500 | ??500 |
| ??388 | Methyl | Methoxyl group | Methoxymethyl | ??400 | ??400 |
| ??389 | Methyl | Methoxyl group | Pyran-2-one-5-methyl | ??450 | ??450 |
| ??390 | Methyl | Methoxyl group | Ethyl | ??384 | ??384 |
| ??391 | Methyl | Methoxyl group | 2-ethyl decyl | ??510 | ??510 |
| ??392 | Methyl | Methoxyl group | Pyrazine-2-methyl | ??434 | ??434 |
| ??393 | Methyl | Methoxyl group | The 4-pyridylmethyl | ??433 | ??433 |
| ??394 | Methyl | Methoxyl group | The 1-butylene base | ??410 | ??410 |
| ??395 | Methyl | Methoxyl group | 2-nitro-5-chloro-phenyl- | ??511 | ??511 |
| ??396 | Methyl | Methoxyl group | Cyano methyl | ??395 | ??395 |
| ??397 | Sec.-propyl | Methoxyl group | The acetoxyl methyl | ??450 | ??450 |
| ??398 | Sec.-propyl | Methoxyl group | 4-(2, the 5-Cl2 pyridyl) methyl | ??530 | ??530 |
| ??399 | Sec.-propyl | Methoxyl group | Chromen-2-one-3-methyl | ??528 | ??528 |
| ??400 | Sec.-propyl | Methoxyl group | Methoxymethyl | ??428 | ??428 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??401 | Sec.-propyl | Methoxyl group | Pyran-2-one-5-methyl | ??478 | ??478 |
| ??402 | Sec.-propyl | Methoxyl group | Ethyl | ??412 | ??412 |
| ??403 | Sec.-propyl | Methoxyl group | 2-ethyl decyl | ??538 | ??538 |
| ??404 | Sec.-propyl | Methoxyl group | Pyrazine-2-methyl | ??462 | ??462 |
| ??405 | Sec.-propyl | Methoxyl group | The 4-pyridylmethyl | ??461 | ??461 |
| ??406 | Sec.-propyl | Methoxyl group | The 1-butylene base | ??438 | ??438 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??407 | Sec.-propyl | Methoxyl group | 2-nitro-5-chloro-phenyl- | ??539 | ??539 |
| ??408 | Sec.-propyl | Methoxyl group | Cyano methyl | ??423 | ??423 |
| ??409 | Isobutyl- | Methoxyl group | The acetoxyl methyl | ??464 | ??464 |
| ??410 | Isobutyl- | Methoxyl group | 4-(2, the 5-Cl2 pyridyl) methyl | ??544 | ??544 |
| ??411 | Isobutyl- | Methoxyl group | Chromen-2-one-3-methyl | ??542 | ??542 |
| ??412 | Isobutyl- | Methoxyl group | Methoxymethyl | ??442 | ??442 |
| ??413 | Isobutyl- | Methoxyl group | Pyran-2-one-5-methyl | ??492 | ??492 |
| ??414 | Isobutyl- | Methoxyl group | Ethyl | ??426 | ??426 |
| ??415 | Isobutyl- | Methoxyl group | 2-ethyl decyl | ??552 | ??552 |
| ??416 | Isobutyl- | Methoxyl group | Pyrazine-2-methyl | ??476 | ??476 |
| ??417 | Isobutyl- | Methoxyl group | The 4-pyridylmethyl | ??475 | ??475 |
| ??418 | Isobutyl- | Methoxyl group | The 1-butylene base | ??452 | ??452 |
| ??419 | Isobutyl- | Methoxyl group | 2-nitro-5-chloro-phenyl- | ??553 | ??553 |
| ??420 | Isobutyl- | Methoxyl group | Cyano methyl | ??437 | ??437 |
| ??421 | Benzyl | Methoxyl group | The acetoxyl methyl | ??498 | ??498 |
| ??422 | Benzyl | Methoxyl group | 4-(2, the 5-Cl2 pyridyl) methyl | ??578 | ??578 |
| ??423 | Benzyl | Methoxyl group | Chromen-2-one-3-methyl | ??576 | ??576 |
| ??424 | Benzyl | Methoxyl group | Methoxymethyl | ??476 | ??476 |
| ??425 | Benzyl | Methoxyl group | Pyran-2-one-5-methyl | ??526 | ??526 |
| ??426 | Benzyl | Methoxyl group | Ethyl | ??460 | ??460 |
| ??427 | Benzyl | Methoxyl group | 2-ethyl decyl | ??586 | ??586 |
| ??428 | Benzyl | Methoxyl group | Pyrazine-2-methyl | ??510 | ??510 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??429 | Benzyl | Methoxyl group | The 4-pyridylmethyl | ??509 | ??509 |
| ??430 | Benzyl | Methoxyl group | The 1-butylene base | ??486 | ??486 |
| ??431 | Benzyl | Methoxyl group | 2-nitro-5-chloro-phenyl- | ??587 | ??587 |
| ??432 | Benzyl | Methoxyl group | Cyano methyl | ??471 | ??471 |
| ??433 | The 2-methyl-propyl | Methoxyl group | The acetoxyl methyl | ??464 | ??464 |
| ??434 | The 2-methyl-propyl | Methoxyl group | 4-(2, the 5-Cl2 pyridyl) methyl | ??544 | ??544 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??435 | The 2-methyl-propyl | Methoxyl group | Chromen-2-one-3-methyl | ??542 | ??542 |
| ??436 | The 2-methyl-propyl | Methoxyl group | Methoxymethyl | ??442 | ??442 |
| ??437 | The 2-methyl-propyl | Methoxyl group | Pyran-2-one-5-methyl | ??492 | ??492 |
| ??438 | The 2-methyl-propyl | Methoxyl group | Ethyl | ??426 | ??426 |
| ??439 | The 2-methyl-propyl | Methoxyl group | 2-ethyl decyl | ??552 | ??552 |
| ??440 | The 2-methyl-propyl | Methoxyl group | Pyrazine-2-methyl | ??476 | ??476 |
| ??441 | The 2-methyl-propyl | Methoxyl group | The 4-pyridylmethyl | ??475 | ??475 |
| ??442 | The 2-methyl-propyl | Methoxyl group | The 1-butylene base | ??452 | ??452 |
| ??443 | The 2-methyl-propyl | Methoxyl group | 2-nitro-5-chloro-phenyl- | ??553 | ??553 |
| ??444 | The 2-methyl-propyl | Methoxyl group | Cyano methyl | ??437 | ??437 |
| ??445 | The methyl thio-ethyl | Methoxyl group | The acetoxyl methyl | ??482 | ??482 |
| ??446 | The methyl thio-ethyl | Methoxyl group | 4-(2, the 5-Cl2 pyridyl) methyl | ??562 | ??562 |
| ??447 | The methyl thio-ethyl | Methoxyl group | Chromen-2-one-3-methyl | ??560 | ??560 |
| ??448 | The methyl thio-ethyl | Methoxyl group | Methoxymethyl | ??460 | ??460 |
| ??449 | The methyl thio-ethyl | Methoxyl group | Pyran-2-one-5-methyl | ??510 | ??510 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??450 | The methyl thio-ethyl | Methoxyl group | Ethyl | ??444 | ??444 |
| ??451 | The methyl thio-ethyl | Methoxyl group | 2-ethyl decyl | ??570 | ??570 |
| ??452 | The methyl thio-ethyl | Methoxyl group | Pyrazine-2-methyl | ??494 | ??494 |
| ??453 | The methyl thio-ethyl | Methoxyl group | The 4-pyridylmethyl | ??493 | ??493 |
| ??454 | The methyl thio-ethyl | Methoxyl group | The 1-butylene base | ??470 | ??470 |
| ??455 | The methyl thio-ethyl | Methoxyl group | 2-nitro-5-chloro-phenyl- | ??571 | ??571 |
| ??456 | The methyl thio-ethyl | Methoxyl group | Cyano methyl | ??455 | ??455 |
| ??457 | The 4-hydroxybenzyl | Methoxyl group | The acetoxyl methyl | ??514 | ??514 |
| ??458 | The 4-hydroxybenzyl | Methoxyl group | 4-(2, the 5-Cl2 pyridyl) methyl | ??594 | ??594 |
| ??459 | The 4-hydroxybenzyl | Methoxyl group | Chromen-2-one-3-methyl | ??592 | ??592 |
| ??460 | The 4-hydroxybenzyl | Methoxyl group | Methoxymethyl | ??492 | ??492 |
| ??461 | The 4-hydroxybenzyl | Methoxyl group | Pyran-2-one-5-methyl | ??542 | ??542 |
| ??462 | The 4-hydroxybenzyl | Methoxyl group | Ethyl | ??476 | ??476 |
| ??463 | The 4-hydroxybenzyl | Methoxyl group | 2-ethyl decyl | ??602 | ??602 |
| ??464 | The 4-hydroxybenzyl | Methoxyl group | Pyrazine-2-methyl | ??526 | ??526 |
| ??465 | The 4-hydroxybenzyl | Methoxyl group | The 4-pyridylmethyl | ??525 | ??525 |
| ??466 | The 4-hydroxybenzyl | Methoxyl group | The 1-butylene base | ??502 | ??502 |
| ??467 | The 4-hydroxybenzyl | Methoxyl group | 2-nitro-5-chloro-phenyl- | ??603 | ??603 |
| ??468 | The 4-hydroxybenzyl | Methoxyl group | Cyano methyl | ??487 | ??487 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??469 | The 2-hydroxyethyl | Methoxyl group | The acetoxyl methyl | ??452 | ??452 |
| ??470 | The 2-hydroxyethyl | Methoxyl group | 4-(2, the 5-Cl2 pyridyl) methyl | ??532 | ??532 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??471 | The 2-hydroxyethyl | Methoxyl group | Chromen-2-one-3-methyl | ??530 | ??530 |
| ??472 | The 2-hydroxyethyl | Methoxyl group | Methoxymethyl | ??430 | ??430 |
| ??473 | The 2-hydroxyethyl | Methoxyl group | Pyran-2-one-5-methyl | ??480 | ??480 |
| ??474 | The 2-hydroxyethyl | Methoxyl group | Ethyl | ??414 | ??414 |
| ??475 | The 2-hydroxyethyl | Methoxyl group | 2-ethyl decyl | ??540 | ??540 |
| ??476 | The 2-hydroxyethyl | Methoxyl group | Pyrazine-2-methyl | ??464 | ??464 |
| ??477 | The 2-hydroxyethyl | Methoxyl group | The 4-pyridylmethyl | ??463 | ??463 |
| ??478 | The 2-hydroxyethyl | Methoxyl group | The 1-butylene base | ??440 | ??440 |
| ??479 | The 2-hydroxyethyl | Methoxyl group | 2-nitro-5-chloro-phenyl- | ??541 | ??541 |
| ??480 | The 2-hydroxyethyl | Methoxyl group | Cyano methyl | ??425 | ??425 |
| ??481 | Methyl | Phenyl | 2, the 4-pentadienyl | ??469 | ??469 |
| ??482 | Methyl | Phenyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??548 | ??548 |
| ??483 | Methyl | Phenyl | Chromen-2-one-3-methyl | ??547 | ??547 |
| ??484 | Methyl | Phenyl | Methoxymethyl | ??446 | ??446 |
| ??485 | Methyl | Phenyl | Pyran-2-one-5-methyl | ??496 | ??496 |
| ??486 | Methyl | Phenyl | Ethyl | ??430 | ??430 |
| ??487 | Methyl | Phenyl | 2-ethyl decyl | ??501 | ??501 |
| ??488 | Methyl | Phenyl | Pyrazine-2-methyl | ??480 | ??480 |
| ??489 | Methyl | Phenyl | The 4-pyridylmethyl | ??479 | ??479 |
| ??490 | Methyl | Phenyl | The 1-butylene base | ??457 | ??457 |
| ??491 | Methyl | Phenyl | 2-nitro-5-chloro-phenyl- | ??558 | ??558 |
| ??492 | Methyl | Phenyl | Cyano methyl | ??441 | ??441 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??493 | Sec.-propyl | Phenyl | 2, the 4-pentadienyl | ??497 | ??497 |
| ??494 | Sec.-propyl | Phenyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??576 | ??576 |
| ??495 | Sec.-propyl | Phenyl | Chromen-2-one-3-methyl | ??575 | ??575 |
| ??496 | Sec.-propyl | Phenyl | Methoxymethyl | ??475 | ??475 |
| ??497 | Sec.-propyl | Phenyl | Pyran-2-one-5-methyl | ??525 | ??525 |
| ??498 | Sec.-propyl | Phenyl | Ethyl | ??459 | ??459 |
| ??499 | Sec.-propyl | Phenyl | 2-ethyl decyl | ??529 | ??529 |
| ??500 | Sec.-propyl | Phenyl | Pyrazine-2-methyl | ??509 | ??509 |
| ??501 | Sec.-propyl | Phenyl | The 4-pyridylmethyl | ??508 | ??508 |
| ??502 | Sec.-propyl | Phenyl | The 1-butylene base | ??485 | ??485 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??503 | Sec.-propyl | Phenyl | 2-nitro-5-chloro-phenyl- | ??586 | ??586 |
| ??504 | Sec.-propyl | Phenyl | Cyano methyl | ??470 | ??470 |
| ??505 | Isobutyl- | Phenyl | 2, the 4-pentadienyl | ??511 | ??511 |
| ??506 | Isobutyl- | Phenyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??590 | ??590 |
| ??507 | Isobutyl- | Phenyl | Chromen-2-one-3-methyl | ??589 | ??589 |
| ??508 | Isobutyl- | Phenyl | Methoxymethyl | ??489 | ??489 |
| ??509 | Isobutyl- | Phenyl | Pyran-2-one-5-methyl | ??539 | ??539 |
| ??510 | Isobutyl- | Phenyl | Ethyl | ??473 | ??473 |
| ??511 | Isobutyl- | Phenyl | 2-ethyl decyl | ??543 | ??543 |
| ??512 | Isobutyl- | Phenyl | Pyrazine-2-methyl | ??523 | ??523 |
| ??513 | Isobutyl- | Phenyl | The 4-pyridylmethyl | ??522 | ??522 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??514 | Isobutyl- | Phenyl | The 1-butylene base | ??499 | ??499 |
| ??515 | Isobutyl- | Phenyl | 2-nitro-5-chloro-phenyl- | ??600 | ??600 |
| ??516 | Isobutyl- | Phenyl | Cyano methyl | ??484 | ??484 |
| ??517 | Benzyl | Phenyl | 2, the 4-pentadienyl | ??545 | ??545 |
| ??518 | Benzyl | Phenyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??624 | ??624 |
| ??519 | Benzyl | Phenyl | Chromen-2-one-3-methyl | ??623 | ??623 |
| ??520 | Benzyl | Phenyl | Methoxymethyl | ??523 | ??523 |
| ??521 | Benzyl | Phenyl | Pyran-2-one-5-methyl | ??573 | ??573 |
| ??522 | Benzyl | Phenyl | Ethyl | ??507 | ??507 |
| ??523 | Benzyl | Phenyl | 2-ethyl decyl | ??577 | ??577 |
| ??524 | Benzyl | Phenyl | Pyrazine-2-methyl | ??557 | ??557 |
| ??525 | Benzyl | Phenyl | The 4-pyridylmethyl | ??556 | ??556 |
| ??526 | Benzyl | Phenyl | The 1-butylene base | ??533 | ??533 |
| ??527 | Benzyl | Phenyl | 2-nitro-5-chloro-phenyl- | ??634 | ??634 |
| ??528 | Benzyl | Phenyl | Cyano methyl | ??518 | ??518 |
| ??529 | The 2-methyl-propyl | Phenyl | 2, the 4-pentadienyl | ??511 | ??511 |
| ??530 | The 2-methyl-propyl | Phenyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??590 | ??590 |
| ??531 | The 2-methyl-propyl | Phenyl | Chromen-2-one-3-methyl | ??589 | ??589 |
| ??532 | The 2-methyl-propyl | Phenyl | Methoxymethyl | ??489 | ??489 |
| ??533 | The 2-methyl-propyl | Phenyl | Pyran-2-one-5-methyl | ??539 | ??539 |
| ??534 | The 2-methyl-propyl | Phenyl | Ethyl | ??473 | ??473 |
| ??535 | The 2-methyl-propyl | Phenyl | 2-ethyl decyl | ??543 | ??543 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??536 | The 2-methyl-propyl | Phenyl | Pyrazine-2-methyl | ??523 | ??523 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??537 | The 2-methyl-propyl | Phenyl | The 4-pyridylmethyl | ??522 | ??522 |
| ??538 | The 2-methyl-propyl | Phenyl | The 1-butylene base | ??499 | ??499 |
| ??539 | The 2-methyl-propyl | Phenyl | 2-nitro-5-chloro-phenyl- | ??600 | ??600 |
| ??540 | The 2-methyl-propyl | Phenyl | Cyano methyl | ??484 | ??484 |
| ??541 | The methyl thio-ethyl | Phenyl | 2, the 4-pentadienyl | ??529 | ??529 |
| ??542 | The methyl thio-ethyl | Phenyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??609 | ??609 |
| ??543 | The methyl thio-ethyl | Phenyl | Chromen-2-one-3-methyl | ??607 | ??607 |
| ??544 | The methyl thio-ethyl | Phenyl | Methoxymethyl | ??507 | ??507 |
| ??545 | The methyl thio-ethyl | Phenyl | Pyran-2-one-5-methyl | ??557 | ??557 |
| ??546 | The methyl thio-ethyl | Phenyl | Ethyl | ??491 | ??491 |
| ??547 | The methyl thio-ethyl | Phenyl | 2-ethyl decyl | ??561 | ??561 |
| ??548 | The methyl thio-ethyl | Phenyl | Pyrazine-2-methyl | ??541 | ??541 |
| ??549 | The methyl thio-ethyl | Phenyl | The 4-pyridylmethyl | ??540 | ??540 |
| ??550 | The methyl thio-ethyl | Phenyl | The 1-butylene base | ??517 | ??517 |
| ??551 | The methyl thio-ethyl | Phenyl | 2-nitro-5-chloro-phenyl- | ??618 | ??618 |
| ??552 | The methyl thio-ethyl | Phenyl | Cyano methyl | ??502 | ??502 |
| ??553 | The 4-hydroxybenzyl | Phenyl | 2, the 4-pentadienyl | ??561 | ??561 |
| ??554 | The 4-hydroxybenzyl | Phenyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??640 | ??640 |
| ??555 | The 4-hydroxybenzyl | Phenyl | Chromen-2-one-3-methyl | ??639 | ??639 |
| ??556 | The 4-hydroxybenzyl | Phenyl | Methoxymethyl | ??539 | ??539 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??557 | The 4-hydroxybenzyl | Phenyl | Pyran-2-one-5-methyl | ??589 | ??589 |
| ??558 | The 4-hydroxybenzyl | Phenyl | Ethyl | ??523 | ??523 |
| ??559 | The 4-hydroxybenzyl | Phenyl | 2-ethyl decyl | ??593 | ??593 |
| ??560 | The 4-hydroxybenzyl | Phenyl | Pyrazine-2-methyl | ??573 | ??573 |
| ??561 | The 4-hydroxybenzyl | Phenyl | The 4-pyridylmethyl | ??572 | ??572 |
| ??562 | The 4-hydroxybenzyl | Phenyl | The 1-butylene base | ??549 | ??549 |
| ??563 | The 4-hydroxybenzyl | Phenyl | 2-nitro-5-chloro-phenyl- | ??650 | ??650 |
| ??564 | The 4-hydroxybenzyl | Phenyl | Cyano methyl | ??534 | ??534 |
| ??565 | The 2-hydroxyethyl | Phenyl | 2, the 4-pentadienyl | ??499 | ??499 |
| ??566 | The 2-hydroxyethyl | Phenyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??578 | ??578 |
| ??567 | The 2-hydroxyethyl | Phenyl | Chromen-2-one-3-methyl | ??577 | ??577 |
| ??568 | The 2-hydroxyethyl | Phenyl | Methoxymethyl | ??476 | ??476 |
| ??569 | The 2-hydroxyethyl | Phenyl | Pyran-2-one-5-methyl | ??527 | ??527 |
| ??570 | The 2-hydroxyethyl | Phenyl | Ethyl | ??460 | ??460 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??571 | The 2-hydroxyethyl | Phenyl | 2-ethyl decyl | ??531 | ??531 |
| ??572 | The 2-hydroxyethyl | Phenyl | Pyrazine-2-methyl | ??511 | ??511 |
| ??573 | The 2-hydroxyethyl | Phenyl | The 4-pyridylmethyl | ??510 | ??510 |
| ??574 | The 2-hydroxyethyl | Phenyl | The 1-butylene base | ??487 | ??487 |
| ??575 | The 2-hydroxyethyl | Phenyl | 2-nitro-5-chloro-phenyl- | ??588 | ??588 |
| ??576 | The 2-hydroxyethyl | Phenyl | Cyano methyl | ??471 | ??471 |
| ??577 | Methyl | Methyl | 2, the 4-pentadienyl | ??406 | ??406 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??578 | Methyl | Methyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??486 | ??486 |
| ??579 | Methyl | Methyl | Chromen-2-one-3-methyl | ??484 | ??484 |
| ??580 | Methyl | Methyl | Methoxymethyl | ??384 | ??384 |
| ??581 | Methyl | Methyl | Pyran-2-one-5-methyl | ??434 | ??434 |
| ??582 | Methyl | Methyl | Ethyl | ??368 | ??368 |
| ??583 | Methyl | Methyl | 2-ethyl decyl | ??438 | ??438 |
| ??584 | Methyl | Methyl | Pyrazine-2-methyl | ??418 | ??418 |
| ??585 | Methyl | Methyl | The 4-pyridylmethyl | ??417 | ??417 |
| ??586 | Methyl | Methyl | The 1-butylene base | ??394 | ??394 |
| ??587 | Methyl | Methyl | 2-nitro-5-chloro-phenyl- | ??495 | ??495 |
| ??588 | Methyl | Methyl | Cyano methyl | ??434 | ??434 |
| ??589 | Sec.-propyl | Methyl | 2, the 4-pentadienyl | ??434 | ??434 |
| ??590 | Sec.-propyl | Methyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??514 | ??514 |
| ??591 | Sec.-propyl | Methyl | Chromen-2-one-3-methyl | ??512 | ??512 |
| ??592 | Sec.-propyl | Methyl | Methoxymethyl | ??412 | ??412 |
| ??593 | Sec.-propyl | Methyl | Pyran-2-one-5-methyl | ??462 | ??462 |
| ??594 | Sec.-propyl | Methyl | Ethyl | ??396 | ??396 |
| ??595 | Sec.-propyl | Methyl | 2-ethyl decyl | ??466 | ??466 |
| ??596 | Sec.-propyl | Methyl | Pyrazine-2-methyl | ??446 | ??446 |
| ??597 | Sec.-propyl | Methyl | The 4-pyridylmethyl | ??445 | ??445 |
| ??598 | Sec.-propyl | Methyl | The 1-butylene base | ??422 | ??422 |
| ??599 | Sec.-propyl | Methyl | 2-nitro-5-chloro-phenyl- | ??523 | ??523 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??600 | Sec.-propyl | Methyl | Cyano methyl | ??462 | ??462 |
| ??601 | Isobutyl- | Methyl | 2, the 4-pentadienyl | ??448 | ??448 |
| ??602 | Isobutyl- | Methyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??528 | ??528 |
| ??603 | Isobutyl- | Methyl | Chromen-2-one-3-methyl | ??526 | ??526 |
| ??604 | Isobutyl- | Methyl | Methoxymethyl | ??426 | ??426 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??605 | Isobutyl- | Methyl | Pyran-2-one-5-methyl | ??476 | ??476 |
| ??606 | Isobutyl- | Methyl | Ethyl | ??410 | ??410 |
| ??607 | Isobutyl- | Methyl | 2-ethyl decyl | ??480 | ??480 |
| ??608 | Isobutyl- | Methyl | Pyrazine-2-methyl | ??460 | ??460 |
| ??609 | Isobutyl- | Methyl | The 4-pyridylmethyl | ??459 | ??459 |
| ??610 | Isobutyl- | Methyl | The 1-butylene base | ??436 | ??436 |
| ??611 | Isobutyl- | Methyl | 2-nitro-5-chloro-phenyl- | ??537 | ??537 |
| ??612 | Isobutyl- | Methyl | Cyano methyl | ??476 | ??476 |
| ??613 | Benzyl | Methyl | 2, the 4-pentadienyl | ??482 | ??482 |
| ??614 | Benzyl | Methyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??562 | ??562 |
| ??615 | Benzyl | Methyl | Chromen-2-one-3-methyl | ??560 | ??560 |
| ??616 | Benzyl | Methyl | Methoxymethyl | ??460 | ??460 |
| ??617 | Benzyl | Methyl | Pyran-2-one-5-methyl | ??510 | ??510 |
| ??618 | Benzyl | Methyl | Ethyl | ??444 | ??444 |
| ??619 | Benzyl | Methyl | 2-ethyl decyl | ??514 | ??514 |
| ??620 | Benzyl | Methyl | Pyrazine-2-methyl | ??494 | ??494 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??621 | Benzyl | Methyl | The 4-pyridylmethyl | ??493 | ??493 |
| ??622 | Benzyl | Methyl | The 1-butylene base | ??470 | ??470 |
| ??623 | Benzyl | Methyl | 2-nitro-5-chloro-phenyl- | ??571 | ??571 |
| ??624 | Benzyl | Methyl | Cyano methyl | ??510 | ??510 |
| ??625 | The 2-methyl-propyl | Methyl | 2, the 4-pentadienyl | ??448 | ??448 |
| ??626 | The 2-methyl-propyl | Methyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??528 | ??528 |
| ??627 | The 2-methyl-propyl | Methyl | Chromen-2-one-3-methyl | ??526 | ??526 |
| ??628 | The 2-methyl-propyl | Methyl | Methoxymethyl | ??426 | ??426 |
| ??629 | The 2-methyl-propyl | Methyl | Pyran-2-one-5-methyl | ??476 | ??476 |
| ??630 | The 2-methyl-propyl | Methyl | Ethyl | ??410 | ??410 |
| ??631 | The 2-methyl-propyl | Methyl | 2-ethyl decyl | ??480 | ??480 |
| ??632 | The 2-methyl-propyl | Methyl | Pyrazine-2-methyl | ??460 | ??460 |
| ??633 | The 2-methyl-propyl | Methyl | The 4-pyridylmethyl | ??459 | ??459 |
| ??634 | The 2-methyl-propyl | Methyl | The 1-butylene base | ??436 | ??436 |
| ??635 | The 2-methyl-propyl | Methyl | 2-nitro-5-chloro-phenyl- | ??537 | ??537 |
| ??636 | The 2-methyl-propyl | Methyl | Cyano methyl | ??476 | ??476 |
| ??637 | The methyl thio-ethyl | Methyl | 2, the 4-pentadienyl | ??466 | ??466 |
| ??638 | The methyl thio-ethyl | Methyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??546 | ??546 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??639 | The methyl thio-ethyl | Methyl | Chromen-2-one-3-methyl | ??544 | ??544 |
| ??640 | The methyl thio-ethyl | Methyl | Methoxymethyl | ??444 | ??444 |
| ??641 | The methyl thio-ethyl | Methyl | Pyran-2-one-5-methyl | ??494 | ??494 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??642 | The methyl thio-ethyl | Methyl | Ethyl | ??428 | ??428 |
| ??643 | The methyl thio-ethyl | Methyl | 2-ethyl decyl | ??498 | ??498 |
| ??644 | The methyl thio-ethyl | Methyl | Pyrazine-2-methyl | ??478 | ??478 |
| ??645 | The methyl thio-ethyl | Methyl | The 4-pyridylmethyl | ??477 | ??477 |
| ??646 | The methyl thio-ethyl | Methyl | The 1-butylene base | ??454 | ??454 |
| ??647 | The methyl thio-ethyl | Methyl | 2-nitro-5-chloro-phenyl- | ??555 | ??555 |
| ??648 | The methyl thio-ethyl | Methyl | Cyano methyl | ??494 | ??494 |
| ??649 | The 4-hydroxybenzyl | Methyl | 2, the 4-pentadienyl | ??498 | ??498 |
| ??650 | The 4-hydroxybenzyl | Methyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??578 | ??578 |
| ??651 | The 4-hydroxybenzyl | Methyl | Chromen-2-one-3-methyl | ??576 | ??576 |
| ??652 | The 4-hydroxybenzyl | Methyl | Methoxymethyl | ??476 | ??476 |
| ??653 | The 4-hydroxybenzyl | Methyl | Pyran-2-one-5-methyl | ??526 | ??526 |
| ??654 | The 4-hydroxybenzyl | Methyl | Ethyl | ??460 | ??460 |
| ??655 | The 4-hydroxybenzyl | Methyl | 2-ethyl decyl | ??530 | ??530 |
| ??656 | The 4-hydroxybenzyl | Methyl | Pyrazine-2-methyl | ??510 | ??510 |
| ??657 | The 4-hydroxybenzyl | Methyl | The 4-pyridylmethyl | ??509 | ??509 |
| ??658 | The 4-hydroxybenzyl | Methyl | The 1-butylene base | ??486 | ??486 |
| ??659 | The 4-hydroxybenzyl | Methyl | 2-nitro-5-chloro-phenyl- | ??587 | ??587 |
| ??660 | The 4-hydroxybenzyl | Methyl | Cyano methyl | ??526 | ??526 |
| ??661 | The 2-hydroxyethyl | Methyl | 2, the 4-pentadienyl | ??436 | ??436 |
| ??662 | The 2-hydroxyethyl | Methyl | 4-(2, the 5-Cl2 pyridyl) methyl | ??516 | ??516 |
| ??663 | The 2-hydroxyethyl | Methyl | Chromen-2-one-3-methyl | ??514 | ??514 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??664 | The 2-hydroxyethyl | Methyl | Methoxymethyl | ??414 | ??414 |
| ??665 | The 2-hydroxyethyl | Methyl | Pyran-2-one-5-methyl | ??464 | ??464 |
| ??666 | The 2-hydroxyethyl | Methyl | Ethyl | ??398 | ??398 |
| ??667 | The 2-hydroxyethyl | Methyl | 2-ethyl decyl | ??468 | ??468 |
| ??668 | The 2-hydroxyethyl | Methyl | Pyrazine-2-methyl | ??448 | ??448 |
| ??669 | The 2-hydroxyethyl | Methyl | The 4-pyridylmethyl | ??447 | ??447 |
| ??670 | The 2-hydroxyethyl | Methyl | The 1-butylene base | ??424 | ??424 |
| ??671 | The 2-hydroxyethyl | Methyl | 2-nitro-5-chloro-phenyl- | ??525 | ??525 |
| ??672 | The 2-hydroxyethyl | Methyl | Cyano methyl | ??464 | ??464 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??673 | Cyclohexyl methyl | Methoxyl group | The 4-methoxy-benzyl | ??559 | ??559 |
| ??674 | The 4-phenylbenzyl | Methoxyl group | The 4-methoxy-benzyl | ??629 | ??629 |
| ??675 | ??4-NO 2-benzyl | Methoxyl group | The 4-methoxy-benzyl | ??598 | ??598 |
| ??676 | ??3，4-Cl 2-benzyl | Methoxyl group | The 4-methoxy-benzyl | ??621 | ??621 |
| ??677 | Cyclopentyl (spiral shell) | Methoxyl group | The 4-methoxy-benzyl | ??531 | ??531 |
| ??678 | The 4-methyl-benzyl | Methoxyl group | The 4-methoxy-benzyl | ??567 | ??567 |
| ??679 | The 1-naphthyl methyl | Methoxyl group | The 4-methoxy-benzyl | ??603 | ??603 |
| ??680 | The 4-F-benzyl | Methoxyl group | The 4-methoxy-benzyl | ??571 | ??571 |
| ??681 | ??3，4-F 2-benzyl | Methoxyl group | The 4-methoxy-benzyl | ??589 | ??589 |
| ??682 | Cyclohexyl | Methoxyl group | The 4-methoxy-benzyl | ??545 | ??545 |
| ??683 | The 2-Cl-benzyl | Methoxyl group | The 4-methoxy-benzyl | ??587 | ??587 |
| ??684 | The 4-Cl-benzyl | Methoxyl group | The 4-methoxy-benzyl | ??587 | ??587 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??685 | Cyclohexyl methyl | Methoxyl group | ??3，4-Cl 2-phenyl | ??583 | ??583 |
| ??686 | The 4-phenylbenzyl | Methoxyl group | ??3，4-Cl 2-phenyl | ??654 | ??654 |
| ??687 | ??4-NO 2-benzyl | Methoxyl group | ??3，4-Cl 2-phenyl | ??622 | ??622 |
| ??688 | ??3，4-Cl 2-benzyl | Methoxyl group | ??3，4-Cl 2-phenyl | ??646 | ??646 |
| ??689 | Cyclopentyl (spiral shell) | Methoxyl group | ??3，4-Cl 2-phenyl | ??555 | ??555 |
| ??690 | The 4-methyl-benzyl | Methoxyl group | ??3，4-Cl 2-phenyl | ??591 | ??591 |
| ??691 | The 1-naphthyl methyl | Methoxyl group | ??3，4-Cl 2-phenyl | ??627 | ??627 |
| ??692 | The 4-F-benzyl | Methoxyl group | ??3，4-Cl 2-phenyl | ??595 | ??595 |
| ??693 | ??3，4-F 2-benzyl | Methoxyl group | ??3，4-Cl 2-phenyl | ??613 | ??613 |
| ??694 | Cyclohexyl | Methoxyl group | ??3，4-Cl 2-phenyl | ??569 | ??569 |
| ??695 | The 2-Cl-benzyl | Methoxyl group | ??3，4-Cl 2-phenyl | ??612 | ??612 |
| ??696 | The 4-Cl-benzyl | Methoxyl group | ??3，4-Cl 2-phenyl | ??612 | ??612 |
| ??697 | Cyclohexyl methyl | Methoxyl group | The 1-naphthyl | ??565 | ??565 |
| ??698 | The 4-phenylbenzyl | Methoxyl group | The 1-naphthyl | ??635 | ??635 |
| ??699 | ??4-NO 2-benzyl | Methoxyl group | The 1-naphthyl | ??604 | ??604 |
| ??700 | ??3，4-Cl 2-benzyl | Methoxyl group | The 1-naphthyl | ??627 | ??627 |
| ??701 | Cyclopentyl (spiral shell) | Methoxyl group | The 1-naphthyl | ??537 | ??537 |
| ??702 | The 4-methyl-benzyl | Methoxyl group | The 1-naphthyl | ??573 | ??573 |
| ??703 | The 1-naphthyl methyl | Methoxyl group | The 1-naphthyl | ??609 | ??609 |
| ??704 | The 4-F-benzyl | Methoxyl group | The 1-naphthyl | ??577 | ??577 |
| ??705 | ??3，4-F 2-benzyl | Methoxyl group | The 1-naphthyl | ??595 | ??595 |
| ??706 | Cyclohexyl | Methoxyl group | The 1-naphthyl | ??551 | ??551 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??707 | The 2-Cl-benzyl | Methoxyl group | The 1-naphthyl | ??593 | ??593 |
| ??708 | The 4-Cl-benzyl | Methoxyl group | The 1-naphthyl | ??593 | ??593 |
| ??709 | Cyclohexyl methyl | Methoxyl group | Piperonyl | ??559 | ??559 |
| ??710 | The 4-phenylbenzyl | Methoxyl group | Piperonyl | ??629 | ??629 |
| ??711 | ??4-NO 2-benzyl | Methoxyl group | Piperonyl | ??598 | ??598 |
| ??712 | ??3，4-Cl 2-benzyl | Methoxyl group | Piperonyl | ??621 | ??621 |
| ??713 | Cyclopentyl (spiral shell) | Methoxyl group | Piperonyl | ??531 | ??531 |
| ??714 | The 4-methyl-benzyl | Methoxyl group | Piperonyl | ??567 | ??567 |
| ??715 | The 1-naphthyl methyl | Methoxyl group | Piperonyl | ??603 | ??603 |
| ??716 | The 4-F-benzyl | Methoxyl group | Piperonyl | ??571 | ??571 |
| ??717 | ??3，4-F 2-benzyl | Methoxyl group | Piperonyl | ??589 | ??589 |
| ??718 | Cyclohexyl | Methoxyl group | Piperonyl | ??545 | ??545 |
| ??719 | The 2-Cl-benzyl | Methoxyl group | Piperonyl | ??587 | ??587 |
| ??720 | The 4-Cl-benzyl | Methoxyl group | Piperonyl | ??587 | ??587 |
| ??721 | Cyclohexyl methyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??605 | ??605 |
| ??722 | The 4-phenylbenzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??675 | ??675 |
| ??723 | ??4-NO 2-benzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??644 | ??644 |
| ??724 | ??3，4-Cl 2-benzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??668 | ??668 |
| ??725 | Cyclopentyl (spiral shell) | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??577 | ??577 |
| ??726 | The 4-methyl-benzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??613 | ??613 |
| ??727 | The 1-naphthyl methyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??649 | ??649 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??728 | The 4-F-benzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??617 | ??617 |
| ??729 | ??3，4-F 2-benzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??635 | ??635 |
| ??730 | Cyclohexyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??591 | ??591 |
| ??731 | The 2-Cl-benzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??633 | ??633 |
| ??732 | The 4-Cl-benzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??633 | ??633 |
| ??733 | Cyclohexyl methyl | Methoxyl group | The 3-hydroxybenzyl | ??545 | ??545 |
| ??734 | The 4-phenylbenzyl | Methoxyl group | The 3-hydroxybenzyl | ??615 | ??615 |
| ??735 | ??4-NO 2-benzyl | Methoxyl group | The 3-hydroxybenzyl | ??584 | ??584 |
| ??736 | ??3，4-Cl 2-benzyl | Methoxyl group | The 3-hydroxybenzyl | ??607 | ??607 |
| ??737 | Cyclopentyl (spiral shell) | Methoxyl group | The 3-hydroxybenzyl | ??517 | ??517 |
| ??738 | The 4-methyl-benzyl | Methoxyl group | The 3-hydroxybenzyl | ??553 | ??553 |
| ??739 | The 1-naphthyl methyl | Methoxyl group | The 3-hydroxybenzyl | ??589 | ??589 |
| ??740 | The 4-F-benzyl | Methoxyl group | The 3-hydroxybenzyl | ??557 | ??557 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??741 | 3, the 4-F2-benzyl | Methoxyl group | The 3-hydroxybenzyl | ??575 | ??575 |
| ??742 | Cyclohexyl | Methoxyl group | The 3-hydroxybenzyl | ??531 | ??531 |
| ??743 | The 2-Cl-benzyl | Methoxyl group | The 3-hydroxybenzyl | ??573 | ??573 |
| ??744 | The 4-Cl-benzyl | Methoxyl group | The 3-hydroxybenzyl | ??573 | ??573 |
| ??745 | Cyclohexyl methyl | Methoxyl group | The 1-naphthyl methyl | ??579 | ??579 |
| ??746 | The 4-phenylbenzyl | Methoxyl group | The 1-naphthyl methyl | ??649 | ??649 |
| ??747 | ??4-NO 2-benzyl | Methoxyl group | The 1-naphthyl methyl | ??618 | ??618 |
| ??748 | ??3，4-Cl 2-benzyl | Methoxyl group | The 1-naphthyl methyl | ??642 | ??642 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??749 | Cyclopentyl (spiral shell) | Methoxyl group | The 1-naphthyl methyl | ??551 | ??551 |
| ??750 | The 4-methyl-benzyl | Methoxyl group | The 1-naphthyl methyl | ??587 | ??587 |
| ??751 | The 1-naphthyl methyl | Methoxyl group | The 1-naphthyl methyl | ??623 | ??623 |
| ??752 | The 4-F-benzyl | Methoxyl group | The 1-naphthyl methyl | ??591 | ??591 |
| ??753 | ??3，4-F 2-benzyl | Methoxyl group | The 1-naphthyl methyl | ??609 | ??609 |
| ??754 | Cyclohexyl | Methoxyl group | The 1-naphthyl methyl | ??565 | ??565 |
| ??755 | The 2-Cl-benzyl | Methoxyl group | The 1-naphthyl methyl | ??607 | ??607 |
| ??756 | The 4-Cl-benzyl | Methoxyl group | The 1-naphthyl methyl | ??607 | ??607 |
| ??757 | Cyclohexyl methyl | Methoxyl group | Styroyl | ??543 | ??543 |
| ??758 | The 4-phenylbenzyl | Methoxyl group | Styroyl | ??613 | ??613 |
| ??759 | ??4-NO 2-benzyl | Methoxyl group | Styroyl | ??582 | ??582 |
| ??760 | ??3，4-Cl 2-benzyl | Methoxyl group | Styroyl | ??605 | ??605 |
| ??761 | Cyclopentyl (spiral shell) | Methoxyl group | Styroyl | ??515 | ??515 |
| ??762 | The 4-methyl-benzyl | Methoxyl group | Styroyl | ??551 | ??551 |
| ??763 | The 1-naphthyl methyl | Methoxyl group | Styroyl | ??587 | ??587 |
| ??764 | The 4-F-benzyl | Methoxyl group | Styroyl | ??555 | ??555 |
| ??765 | ??3，4-F 2-benzyl | Methoxyl group | Styroyl | ??573 | ??573 |
| ??766 | Cyclohexyl | Methoxyl group | Styroyl | ??529 | ??529 |
| ??767 | The 2-Cl-benzyl | Methoxyl group | Styroyl | ??571 | ??571 |
| ??768 | The 4-Cl-benzyl | Methoxyl group | Styroyl | ??571 | ??571 |
| ??769 | Cyclohexyl methyl | Methoxyl group | The 3-p-methoxy-phenyl | ??545 | ??545 |
| ??770 | The 4-phenylbenzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??615 | ??615 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??771 | ??4-NO 2-benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??584 | ??584 |
| ??772 | ??3，4-Cl 2-benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??607 | ??607 |
| ??773 | Cyclopentyl (spiral shell) | Methoxyl group | The 3-p-methoxy-phenyl | ??517 | ??517 |
| ??774 | The 4-methyl-benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??553 | ??553 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??775 | The 1-naphthyl methyl | Methoxyl group | The 3-p-methoxy-phenyl | ??589 | ??589 |
| ??776 | The 4-F-benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??557 | ??557 |
| ??777 | ??3，4-F 2-benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??575 | ??575 |
| ??778 | Cyclohexyl | Methoxyl group | The 3-p-methoxy-phenyl | ??531 | ??531 |
| ??779 | The 2-Cl-benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??573 | ??573 |
| ??780 | The 4-Cl-benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??573 | ??573 |
| ??781 | Cyclohexyl methyl | Methoxyl group | N-benzoyl-amido ethyl | ??572 | ??572 |
| ??782 | The 4-phenylbenzyl | Methoxyl group | N-benzoyl-amido ethyl | ??642 | ??642 |
| ??783 | ??4-NO 2-benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??611 | ??611 |
| ??784 | ??3，4-Cl 2-benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??634 | ??634 |
| ??785 | Cyclopentyl (spiral shell) | Methoxyl group | N-benzoyl-amido ethyl | ??544 | ??544 |
| ??786 | The 4-methyl-benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??580 | ??580 |
| ??787 | The 1-naphthyl methyl | Methoxyl group | N-benzoyl-amido ethyl | ??616 | ??616 |
| ??788 | The 4-F-benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??584 | ??584 |
| ??789 | ??3，4-F 2-benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??602 | ??602 |
| ??790 | Cyclohexyl | Methoxyl group | N-benzoyl-amido ethyl | ??558 | ??558 |
| ??791 | The 2-Cl-benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??600 | ??600 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??792 | The 4-Cl-benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??600 | ??600 |
| ??793 | Cyclohexyl methyl | Methoxyl group | Benzyl | ??529 | ??529 |
| ??794 | The 4-phenylbenzyl | Methoxyl group | Benzyl | ??599 | ??599 |
| ??795 | ??4-NO 2-benzyl | Methoxyl group | Benzyl | ??568 | ??568 |
| ??796 | ??3，4-Cl 2-benzyl | Methoxyl group | Benzyl | ??591 | ??591 |
| ??797 | Cyclopentyl (spiral shell) | Methoxyl group | Benzyl | ??501 | ??501 |
| ??798 | The 4-methyl-benzyl | Methoxyl group | Benzyl | ??537 | ??537 |
| ??799 | The 1-naphthyl methyl | Methoxyl group | Benzyl | ??573 | ??573 |
| ??800 | The 4-F-benzyl | Methoxyl group | Benzyl | ??541 | ??541 |
| ??801 | ??3，4-F 2-benzyl | Methoxyl group | Benzyl | ??559 | ??559 |
| ??802 | Cyclohexyl | Methoxyl group | Benzyl | ??515 | ??515 |
| ??803 | The 2-Cl-benzyl | Methoxyl group | Benzyl | ??557 | ??557 |
| ??804 | The 4-Cl-benzyl | Methoxyl group | Benzyl | ??557 | ??557 |
| ??805 | Cyclohexyl methyl | Methoxyl group | ??4-NO 2-benzyl | ??574 | ??574 |
| ??806 | The 4-phenylbenzyl | Methoxyl group | ??4-NO 2-benzyl | ??644 | ??644 |
| ??807 | ??4-NO 2-benzyl | Methoxyl group | ??4-NO 2-benzyl | ??613 | ??613 |
| ??808 | ??3，4-Cl 2-benzyl | Methoxyl group | ??4-NO 2-benzyl | ??636 | ??636 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??809 | Cyclopentyl (spiral shell) | Methoxyl group | ??4-NO 2-benzyl | ??546 | ??546 |
| ??810 | The 4-methyl-benzyl | Methoxyl group | ??4-NO 2-benzyl | ??582 | ??582 |
| ??811 | The 1-naphthyl methyl | Methoxyl group | ??4-NO 2-benzyl | ??618 | ??618 |
| ??812 | The 4-F-benzyl | Methoxyl group | ??4-NO 2-benzyl | ??586 | ??586 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??813 | ??3，4-F 2-benzyl | Methoxyl group | ??4-NO 2-benzyl | ??604 | ??604 |
| ??814 | Cyclohexyl | Methoxyl group | ??4-NO 2-benzyl | ??560 | ??560 |
| ??815 | The 2-Cl-benzyl | Methoxyl group | ??4-NO 2-benzyl | ??602 | ??602 |
| ??816 | The 4-Cl-benzyl | Methoxyl group | ??4-NO 2-benzyl | ??602 | ??602 |
| ??817 | Cyclohexyl methyl | Methoxyl group | 2, the 4-pentadienyl | ??505 | ??505 |
| ??818 | The 4-phenylbenzyl | Methoxyl group | 2, the 4-pentadienyl | ??575 | ??575 |
| ??819 | ??4-NO 2-benzyl | Methoxyl group | 2, the 4-pentadienyl | ??544 | ??544 |
| ??820 | ??3，4-Cl 2-benzyl | Methoxyl group | 2, the 4-pentadienyl | ??567 | ??567 |
| ??821 | Cyclopentyl (spiral shell) | Methoxyl group | 2, the 4-pentadienyl | ??477 | ??477 |
| ??822 | The 4-methyl-benzyl | Methoxyl group | 2, the 4-pentadienyl | ??513 | ??513 |
| ??823 | The 1-naphthyl methyl | Methoxyl group | 2, the 4-pentadienyl | ??549 | ??549 |
| ??824 | The 4-F-benzyl | Methoxyl group | 2, the 4-pentadienyl | ??517 | ??517 |
| ??825 | ??3，4-F 2-benzyl | Methoxyl group | 2, the 4-pentadienyl | ??535 | ??535 |
| ??826 | Cyclohexyl | Methoxyl group | 2, the 4-pentadienyl | ??491 | ??491 |
| ??827 | The 2-Cl-benzyl | Methoxyl group | 2, the 4-pentadienyl | ??533 | ??533 |
| ??828 | The 4-Cl-benzyl | Methoxyl group | 2, the 4-pentadienyl | ??533 | ??533 |
| ??829 | Cyclohexyl methyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??584 | ??584 |
| ??830 | The 4-phenylbenzyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??655 | ??655 |
| ??831 | ??4-NO 2-benzyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??623 | ??623 |
| ??832 | ??3，4-Cl 2-benzyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??647 | ??647 |
| ??833 | Cyclopentyl (spiral shell) | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??556 | ??556 |
| ??834 | The 4-methyl-benzyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??592 | ??592 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??835 | The 1-naphthyl methyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??628 | ??628 |
| ??836 | The 4-F-benzyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??596 | ??596 |
| ??837 | ??3，4-F 2-benzyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??614 | ??614 |
| ??838 | Cyclohexyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??570 | ??570 |
| ??839 | The 2-Cl-benzyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??613 | ??613 |
| ??840 | The 4-Cl-benzyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??613 | ??613 |
| ??841 | Cyclohexyl methyl | Methoxyl group | Chromen-2-one-3-methyl | ??583 | ??583 |
| ??842 | The 4-phenylbenzyl | Methoxyl group | Chromen-2-one-3-methyl | ??653 | ??653 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??843 | ??4-NO 2-benzyl | Methoxyl group | Chromen-2-one-3-methyl | ??622 | ??622 |
| ??844 | ??3，4-Cl 2-benzyl | Methoxyl group | Chromen-2-one-3-methyl | ??645 | ??645 |
| ??845 | Cyclopentyl (spiral shell) | Methoxyl group | Chromen-2-one-3-methyl | ??555 | ??555 |
| ??846 | The 4-methyl-benzyl | Methoxyl group | Chromen-2-one-3-methyl | ??591 | ??591 |
| ??847 | The 1-naphthyl methyl | Methoxyl group | Chromen-2-one-3-methyl | ??627 | ??627 |
| ??848 | The 4-F-benzyl | Methoxyl group | Chromen-2-one-3-methyl | ??595 | ??595 |
| ??849 | ??3，4-F 2-benzyl | Methoxyl group | Chromen-2-one-3-methyl | ??613 | ??613 |
| ??850 | Cyclohexyl | Methoxyl group | Chromen-2-one-3-methyl | ??569 | ??569 |
| ??851 | The 2-Cl-benzyl | Methoxyl group | Chromen-2-one-3-methyl | ??611 | ??611 |
| ??852 | The 4-Cl-benzyl | Methoxyl group | Chromen-2-one-3-methyl | ??611 | ??611 |
| ??853 | Cyclohexyl methyl | Methoxyl group | Methoxymethyl | ??483 | ??483 |
| ??854 | The 4-phenylbenzyl | Methoxyl group | Methoxymethyl | ??553 | ??553 |
| ??855 | ??4-NO 2-benzyl | Methoxyl group | Methoxymethyl | ??521 | ??521 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??856 | ??3，4-Cl 2-benzyl | Methoxyl group | Methoxymethyl | ??545 | ??545 |
| ??857 | Cyclopentyl (spiral shell) | Methoxyl group | Methoxymethyl | ??454 | ??454 |
| ??858 | The 4-methyl-benzyl | Methoxyl group | Methoxymethyl | ??491 | ??491 |
| ??859 | The 1-naphthyl methyl | Methoxyl group | Methoxymethyl | ??527 | ??527 |
| ??860 | The 4-F-benzyl | Methoxyl group | Methoxymethyl | ??494 | ??494 |
| ??861 | ??3，4-F 2-benzyl | Methoxyl group | Methoxymethyl | ??512 | ??512 |
| ??862 | Cyclohexyl | Methoxyl group | Methoxymethyl | ??469 | ??469 |
| ??863 | The 2-Cl-benzyl | Methoxyl group | Methoxymethyl | ??511 | ??511 |
| ??864 | The 4-Cl-benzyl | Methoxyl group | Methoxymethyl | ??511 | ??511 |
Can use the general scheme in beta-chain simulative storehouse shown in Figure 2 to carry out peptide mimics synthetic in storehouse of the present invention.The FlexChem reactor room that use has 96 orifice plates is finished selected peptide mimics synthetic of the present invention's two ring template base.In above scheme, " Pol " represents 2-chlorine trityl chloride resin (Novabiochem), and detailed process below is provided.
Step 1With 2-chlorine trityl chloride resin (1mmol/g) and Fmoc-R
1The DCE solution of-beta-amino acids (1.5 equivalent) and DIEA (2 equivalent) places Robinson cabin, 96 hole (FlexChem).Reaction mixture was at room temperature vibrated 12 hours.With DMF, MeOH and DCM washing resin.
Step 2Before reaction, be added in the piperidines of 25% among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat this deprotection steps, with product mixtures DMF, MeOH, wash with DCM then then.In resin, add 4-R
2The nmp solution of-amino-2-Fmoc-aminobutyric acid (1.5 equivalent), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
Step 3Before reaction, be added in the piperidines of 25% among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat this deprotection steps, and, use DCM washed product mixture then with DMF, MeOH.In resin, add 2-(9H-fluorenes-9-ylmethoxy carbonylamino)-5, the nmp solution of 5-dimethoxy-valeric acid (1.5 equivalent), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
Step 4Before reaction, be added in the piperidines of 25% among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat this deprotection steps, with product mixtures DMF, MeOH, wash with DCM then then.In resin, add commercially available R
3The nmp solution of-acid (1.5 equivalent), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
Step 5At room temperature use formic acid (every hole 1.2mL) to handle 18 hours resin.Afterwards, remove by filter resin, under reduced pressure use SpeedVac (Servant) concentrated filtrate, obtain the oily product.These products with water/dilution in acetonitrile of 50%, are carried out freeze-drying then after freezing.
Table 3 has shown can beta-chain simulative prepared in accordance with the present invention storehouse, has provided its representational preparation process among the embodiment 10.The compound of table 3 has illustrated one aspect of the present invention, promptly following compound, wherein A be-(CH)-, B is-(CH
2)
m-and m=1, W does not exist, i.e. R
bAnd between the heterocyclic N direct key, X is-NH (C=O)-, Y is an oxygen, Z is a hydrogen, makes C=Z represent CH
2, L is-C (=O) NHR
3, n=0, R
4Be hydrogen, R
1, R
2And R
3Can be identical or different, and be independently selected from remainder, linking group and the solid phase carrier of amino acid side chain moiety or derivatives thereof, molecule, and the steric isomer of this compound.In this each embodiment on the one hand of the present invention, R
1, R
2And R
3Be independently selected from low-molecular-weight relatively molecular moiety, promptly molecular weight at 15 (methyl) to 1, the organic group between the 000g/mol; And/or R
1, R
2And R
3In at least one represented amino acid side chain or derivatives thereof.For example, in the compound of table 3, R
3Represent glutaric acid derivatives.On the one hand, compound molecular weight of the present invention is within about scope of 450 to 800g/mol, and wherein the compound of table 3 provides a large amount of such examples for compounds.
Table 3
B-chain simulative storehouse
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??865 | Propyl group | Phenyl | The 4-methoxy-benzyl | ??565 | ??565 |
| ??866 | Propyl group | Phenyl | ??3，4-Cl 2-benzyl | ??585 | ??585 |
| ??867 | Propyl group | Phenyl | The 1-naphthyl | ??589 | ??589 |
| ??868 | Propyl group | Phenyl | Piperonyl | ??549 | ??549 |
| ??869 | Propyl group | Phenyl | 2,4, the 5-trimethoxyphenyl | ??571 | ??571 |
| ??870 | Propyl group | Phenyl | The 3-hydroxybenzyl | ??551 | ??551 |
| ??871 | Propyl group | Phenyl | The 1-naphthyl methyl | ??565 | ??565 |
| ??872 | Propyl group | Phenyl | Styroyl | ??578 | ??578 |
| ??873 | Propyl group | Phenyl | The 3-p-methoxy-phenyl | ??611 | ??611 |
| ??874 | Propyl group | Phenyl | N-benzoyl-amido ethyl | ??535 | ??535 |
| ??875 | Propyl group | Phenyl | Benzyl | ??551 | ??551 |
| ??876 | Propyl group | Phenyl | ??4-NO 2-benzyl | ??580 | ??580 |
| ??877 | Propyl group | Methoxyl group | The 4-methoxy-benzyl | ??519 | ??519 |
| ??878 | Propyl group | Methoxyl group | ??3，4-Cl 2-benzyl | ??539 | ??539 |
| ??879 | Propyl group | Methoxyl group | The 1-naphthyl | ??543 | ??543 |
| ??880 | Propyl group | Methoxyl group | Piperonyl | ??503 | ??503 |
| ??881 | Propyl group | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??525 | ??525 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??882 | Propyl group | Methoxyl group | The 3-hydroxybenzyl | ??505 | ??505 |
| ??883 | Propyl group | Methoxyl group | The 1-naphthyl methyl | ??519 | ??519 |
| ??884 | Propyl group | Methoxyl group | Styroyl | ??532 | ??532 |
| ??885 | Propyl group | Methoxyl group | The 3-p-methoxy-phenyl | ??565 | ??565 |
| ??886 | Propyl group | Methoxyl group | N-benzoyl-amido ethyl | ??489 | ??489 |
| ??887 | Propyl group | Methoxyl group | Benzyl | ??505 | ??505 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??888 | Propyl group | Methoxyl group | ??4-NO 2-benzyl | ??534 | ??534 |
| ??889 | Isobutyl- | Phenyl | The 4-methoxy-benzyl | ??593 | ??593 |
| ??890 | Isobutyl- | Phenyl | ??3，4-Cl 2-benzyl | ??613 | ??613 |
| ??891 | Isobutyl- | Phenyl | The 1-naphthyl | ??618 | ??618 |
| ??892 | Isobutyl- | Phenyl | Piperonyl | ??577 | ??577 |
| ??893 | Isobutyl- | Phenyl | 2,4, the 5-trimethoxyphenyl | ??599 | ??599 |
| ??894 | Isobutyl- | Phenyl | The 3-hydroxybenzyl | ??579 | ??579 |
| ??895 | Isobutyl- | Phenyl | The 1-naphthyl methyl | ??593 | ??593 |
| ??896 | Isobutyl- | Phenyl | Styroyl | ??606 | ??606 |
| ??897 | Isobutyl- | Phenyl | The 3-p-methoxy-phenyl | ??639 | ??639 |
| ??898 | Isobutyl- | Phenyl | N-benzoyl-amido ethyl | ??563 | ??563 |
| ??899 | Isobutyl- | Phenyl | Benzyl | ??579 | ??579 |
| ??900 | Isobutyl- | Phenyl | ??4-NO 2-benzyl | ??608 | ??608 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??901 | Isobutyl- | Methoxyl group | The 4-methoxy-benzyl | ??547 | ??547 |
| ??902 | Isobutyl- | Methoxyl group | ??3，4-Cl 2-benzyl | ??567 | ??567 |
| ??903 | Isobutyl- | Methoxyl group | The 1-naphthyl | ??571 | ??571 |
| ??904 | Isobutyl- | Methoxyl group | Piperonyl | ??531 | ??531 |
| ??905 | Isobutyl- | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??553 | ??553 |
| ??906 | Isobutyl- | Methoxyl group | The 3-hydroxybenzyl | ??533 | ??533 |
| ??907 | Isobutyl- | Methoxyl group | The 1-naphthyl methyl | ??547 | ??547 |
| ??908 | Isobutyl- | Methoxyl group | Styroyl | ??560 | ??560 |
| ??909 | Isobutyl- | Methoxyl group | The 3-p-methoxy-phenyl | ??593 | ??593 |
| ??910 | Isobutyl- | Methoxyl group | N-benzoyl-amido ethyl | ??517 | ??517 |
| ??911 | Isobutyl- | Methoxyl group | Benzyl | ??533 | ??533 |
| ??912 | Isobutyl- | Methoxyl group | ??4-NO 2-benzyl | ??562 | ??562 |
| ??913 | 4-bromo-benzyl | Phenyl | The 4-methoxy-benzyl | ??692 | ??692 |
| ??914 | 4-bromo-benzyl | Phenyl | ??3，4-Cl 2-benzyl | ??712 | ??712 |
| ??915 | 4-bromo-benzyl | Phenyl | The 1-naphthyl | ??716 | ??716 |
| ??916 | 4-bromo-benzyl | Phenyl | Piperonyl | ??676 | ??676 |
| ??917 | 4-bromo-benzyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??698 | ??698 |
| ??918 | 4-bromo-benzyl | Phenyl | The 3-hydroxybenzyl | ??678 | ??678 |
| ??919 | 4-bromo-benzyl | Phenyl | The 1-naphthyl methyl | ??692 | ??692 |
| ??920 | 4-bromo-benzyl | Phenyl | Styroyl | ??705 | ??705 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??921 | 4-bromo-benzyl | Phenyl | The 3-p-methoxy-phenyl | ??738 | ??738 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??922 | 4-bromo-benzyl | Phenyl | N-benzoyl-amido ethyl | ??662 | ??662 |
| ??923 | 4-bromo-benzyl | Phenyl | Benzyl | ??678 | ??678 |
| ??924 | 4-bromo-benzyl | Phenyl | ??4-NO 2-benzyl | ??707 | ??707 |
| ??925 | 4-bromo-benzyl | Methoxyl group | The 4-methoxy-benzyl | ??646 | ??646 |
| ??926 | 4-bromo-benzyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??666 | ??666 |
| ??927 | 4-bromo-benzyl | Methoxyl group | The 1-naphthyl | ??670 | ??670 |
| ??928 | 4-bromo-benzyl | Methoxyl group | Piperonyl | ??630 | ??630 |
| ??929 | 4-bromo-benzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??652 | ??652 |
| ??930 | 4-bromo-benzyl | Methoxyl group | The 3-hydroxybenzyl | ??631 | ??631 |
| ??931 | 4-bromo-benzyl | Methoxyl group | The 1-naphthyl methyl | ??645 | ??645 |
| ??932 | 4-bromo-benzyl | Methoxyl group | Styroyl | ??659 | ??659 |
| ??933 | 4-bromo-benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??692 | ??692 |
| ??934 | 4-bromo-benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??615 | ??615 |
| ??935 | 4-bromo-benzyl | Methoxyl group | Benzyl | ??631 | ??631 |
| ??936 | 4-bromo-benzyl | Methoxyl group | ??4-NO 2-benzyl | ??660 | ??660 |
| ??937 | Benzyl | Phenyl | The 4-methoxy-benzyl | ??613 | ??613 |
| ??938 | Benzyl | Phenyl | ??3，4-Cl 2-benzyl | ??633 | ??633 |
| ??939 | Benzyl | Phenyl | The 1-naphthyl | ??638 | ??638 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??940 | Benzyl | Phenyl | Piperonyl | ??597 | ??597 |
| ??941 | Benzyl | Phenyl | 2,4, the 5-trimethoxyphenyl | ??619 | ??619 |
| ??942 | Benzyl | Phenyl | The 3-hydroxybenzyl | ??599 | ??599 |
| ??943 | Benzyl | Phenyl | The 1-naphthyl methyl | ??613 | ??613 |
| ??944 | Benzyl | Phenyl | Styroyl | ??626 | ??626 |
| ??945 | Benzyl | Phenyl | The 3-p-methoxy-phenyl | ??659 | ??659 |
| ??946 | Benzyl | Phenyl | N-benzoyl-amido ethyl | ??583 | ??583 |
| ??947 | Benzyl | Phenyl | Benzyl | ??599 | ??599 |
| ??948 | Benzyl | Phenyl | ??4-NO 2-benzyl | ??628 | ??628 |
| ??949 | Benzyl | Methoxyl group | The 4-methoxy-benzyl | ??567 | ??567 |
| ??950 | Benzyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??587 | ??587 |
| ??951 | Benzyl | Methoxyl group | The 1-naphthyl | ??591 | ??591 |
| ??952 | Benzyl | Methoxyl group | Piperonyl | ??551 | ??551 |
| ??953 | Benzyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??573 | ??573 |
| ??954 | Benzyl | Methoxyl group | The 3-hydroxybenzyl | ??553 | ??553 |
| ??955 | Benzyl | Methoxyl group | The 1-naphthyl methyl | ??567 | ??567 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??956 | Benzyl | Methoxyl group | Styroyl | ??580 | ??580 |
| ??957 | Benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??613 | ??613 |
| ??958 | Benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??537 | ??537 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??959 | Benzyl | Methoxyl group | Benzyl | ??553 | ??553 |
| ??960 | Benzyl | Methoxyl group | ??4-NO 2-benzyl | ??582 | ??582 |
| ??961 | Propyl group | Benzyloxy | 2, the 4-pentadienyl | ??541 | ??541 |
| ??962 | Propyl group | Benzyloxy | ??3-(2，6-Cl 2-pyridyl) methyl | ??620 | ??620 |
| ??963 | Propyl group | Benzyloxy | Chromen-2-one-3-methyl | ??619 | ??619 |
| ??964 | Propyl group | Benzyloxy | Methoxymethyl | ??519 | ??519 |
| ??965 | Propyl group | Benzyloxy | Pyran-2-one-4-methyl | ??569 | ??569 |
| ??966 | Propyl group | Benzyloxy | Ethyl | ??503 | ??503 |
| ??967 | Propyl group | Benzyloxy | 2-ethyl decyl | ??629 | ??629 |
| ??968 | Propyl group | Benzyloxy | Pyrazine-2-methyl | ??553 | ??553 |
| ??969 | Propyl group | Benzyloxy | The 4-pyridylmethyl | ??552 | ??552 |
| ??970 | Propyl group | Benzyloxy | The 4-butenyl | ??529 | ??529 |
| ??971 | Propyl group | Benzyloxy | ??2-NO 2-5-Cl-phenyl | ??630 | ??630 |
| ??972 | Propyl group | Benzyloxy | Cyano methyl | ??514 | ??514 |
| ??973 | Propyl group | Methoxyl group | 2, the 4-pentadienyl | ??465 | ??465 |
| ??974 | Propyl group | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??544 | ??544 |
| ??975 | Propyl group | Methoxyl group | Chromen-2-one-3-methyl | ??543 | ??543 |
| ??976 | Propyl group | Methoxyl group | Methoxymethyl | ??442 | ??442 |
| ??977 | Propyl group | Methoxyl group | Pyran-2-one-4-methyl | ??492 | ??492 |
| ??978 | Propyl group | Methoxyl group | Ethyl | ??426 | ??426 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??979 | Propyl group | Methoxyl group | 2-ethyl decyl | ??553 | ??553 |
| ??980 | Propyl group | Methoxyl group | Pyrazine-2-methyl | ??476 | ??476 |
| ??981 | Propyl group | Methoxyl group | The 4-pyridylmethyl | ??476 | ??476 |
| ??982 | Propyl group | Methoxyl group | The 4-butenyl | ??453 | ??453 |
| ??983 | Propyl group | Methoxyl group | ??2-NO 2-5-Cl-phenyl | ??554 | ??554 |
| ??984 | Propyl group | Methoxyl group | Cyano methyl | ??437 | ??437 |
| ??985 | Isobutyl- | |
2, the 4-pentadienyl | ??569 | ??569 |
| ??986 | Isobutyl- | Benzyloxy | ??3-(2，6-Cl 2-pyridyl) methyl | ??649 | ??649 |
| ??987 | Isobutyl- | Benzyloxy | Chromen-2-one-3-methyl | ??647 | ??647 |
| ??988 | Isobutyl- | Benzyloxy | Methoxymethyl | ??547 | ??547 |
| ??989 | Isobutyl- | Benzyloxy | Pyran-2-one-4-methyl | ??597 | ??597 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??990 | Isobutyl- | Benzyloxy | Ethyl | ??531 | ??531 |
| ??991 | Isobutyl- | Benzyloxy | 2-ethyl decyl | ??657 | ??657 |
| ??992 | Isobutyl- | Benzyloxy | Pyrazine-2-methyl | ??581 | ??581 |
| ??993 | Isobutyl- | Benzyloxy | The 4-pyridylmethyl | ??580 | ??580 |
| ??994 | Isobutyl- | Benzyloxy | The 4-butenyl | ??557 | ??557 |
| ??995 | Isobutyl- | Benzyloxy | ??2-NO 2-5-Cl-phenyl | ??658 | ??658 |
| ??996 | Isobutyl- | Benzyloxy | Cyano methyl | ??542 | ??542 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??997 | Isobutyl- | |
2, the 4-pentadienyl | ??493 | ??493 |
| ??998 | Isobutyl- | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??572 | ??572 |
| ??999 | Isobutyl- | Methoxyl group | Chromen-2-one-3-methyl | ??571 | ??571 |
| ??1000 | Isobutyl- | Methoxyl group | Methoxymethyl | ??471 | ??471 |
| ??1001 | Isobutyl- | Methoxyl group | Pyran-2-one-4-methyl | ??521 | ??521 |
| ??1002 | Isobutyl- | Methoxyl group | Ethyl | ??455 | ??455 |
| ??1003 | Isobutyl- | Methoxyl group | 2-ethyl decyl | ??581 | ??581 |
| ??1004 | Isobutyl- | Methoxyl group | Pyrazine-2-methyl | ??505 | ??505 |
| ??1005 | Isobutyl- | Methoxyl group | The 4-pyridylmethyl | ??504 | ??504 |
| ??1006 | Isobutyl- | Methoxyl group | The 4-butenyl | ??481 | ??481 |
| ??1007 | Isobutyl- | Methoxyl group | ??2-NO 2-5-Cl-phenyl | ??582 | ??582 |
| ??1008 | Isobutyl- | Methoxyl group | Cyano methyl | ??466 | ??466 |
| ??1009 | Benzyl | Benzyloxy | 2, the 4-pentadienyl | ??589 | ??589 |
| ??1010 | Benzyl | Benzyloxy | ??3-(2，6-Cl 2-pyridyl) methyl | ??669 | ??669 |
| ??1011 | Benzyl | Benzyloxy | Chromen-2-one-3-methyl | ??667 | ??667 |
| ??1012 | Benzyl | Benzyloxy | Methoxymethyl | ??567 | ??567 |
| ??1013 | Benzyl | Benzyloxy | Pyran-2-one-4-methyl | ??617 | ??617 |
| ??1014 | Benzyl | Benzyloxy | Ethyl | ??551 | ??551 |
| ??1015 | Benzyl | Benzyloxy | 2-ethyl decyl | ??677 | ??677 |
| ??1016 | Benzyl | Benzyloxy | Pyrazine-2-methyl | ??601 | ??601 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??1017 | Benzyl | Benzyloxy | The 4-pyridylmethyl | ??600 | ??600 |
| ??1018 | Benzyl | Benzyloxy | The 4-butenyl | ??577 | ??577 |
| ??1019 | Benzyl | Benzyloxy | ??2-NO 2-5-Cl-phenyl | ??678 | ??678 |
| ??1020 | Benzyl | Benzyloxy | Cyano methyl | ??562 | ??562 |
| ??1021 | Benzyl | Methoxyl |
2, the 4-pentadienyl | ??513 | ??513 |
| ??1022 | Benzyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??592 | ??592 |
| ??1023 | Benzyl | Methoxyl group | Chromen-2-one-3-methyl | ??591 | ??591 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??1024 | Benzyl | Methoxyl group | Methoxymethyl | ??491 | ??491 |
| ??1025 | Benzyl | Methoxyl group | Pyran-2-one-4-methyl | ??541 | ??541 |
| ??1026 | Benzyl | Methoxyl group | Ethyl | ??475 | ??475 |
| ??1027 | Benzyl | Methoxyl group | 2-ethyl decyl | ??601 | ??601 |
| ??1028 | Benzyl | Methoxyl group | Pyrazine-2-methyl | ??525 | ??525 |
| ??1029 | Benzyl | Methoxyl group | The 4-pyridylmethyl | ??524 | ??524 |
| ??1030 | Benzyl | Methoxyl group | The 4-butenyl | ??501 | ??501 |
| ??1031 | Benzyl | Methoxyl group | ??2-NO 2-5-Cl-phenyl | ??602 | ??602 |
| ??1032 | Benzyl | Methoxyl group | Cyano methyl | ??486 | ??486 |
| ??1033 | Phenyl propyl | Benzyloxy | 2, the 4-pentadienyl | ??617 | ??617 |
| ??1034 | Phenyl propyl | Benzyloxy | ??3-(2，6-Cl 2-pyridyl) methyl | ??697 | ??697 |
| ??1035 | Phenyl propyl | Benzyloxy | Chromen-2-one-3-methyl | ??695 | ??695 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H | |
| ??1036 | Phenyl propyl | Benzyloxy | Methoxymethyl | ??595 | ??595 | |
| ??1037 | Phenyl propyl | Benzyloxy | Pyran-2-one-4-methyl | ??645 | ??645 | |
| ??1038 | Phenyl propyl | Benzyloxy | Ethyl | ??579 | ??579 | |
| ??1039 | Phenyl propyl | Benzyloxy | 2-ethyl decyl | ??705 | ??705 | |
| ??1040 | Phenyl propyl | Benzyloxy | Pyrazine-2-methyl | ??629 | ??629 | |
| ??1041 | Phenyl propyl | Benzyloxy | The 4-pyridylmethyl | ??628 | ??628 | |
| ??1042 | Phenyl propyl | Benzyloxy | The 4-butenyl | ??605 | ??605 | |
| ??1043 | Phenyl propyl | Benzyloxy | ??2-NO 2-5-Cl-phenyl | ??706 | ??706 | |
| ??1044 | Phenyl propyl | Benzyloxy | Cyano methyl | ??590 | ??590 | |
| ??1045 | Phenyl | Methoxyl group | 2, the 4-pentadienyl | ??541 | ??541 | |
| ??1046 | Phenyl propyl | Methoxyl group | ??3-(2，6-Cl 2-pyridyl) methyl | ??620 | ??620 | |
| ??1047 | Phenyl propyl | Methoxyl group | Chromen-2-one-3-methyl | ??619 | ??619 | |
| ??1048 | Phenyl propyl | Methoxyl group | Methoxymethyl | ??519 | ??519 | |
| ??1049 | Phenyl propyl | Methoxyl group | Pyran-2-one-4-methyl | ??569 | ??569 | |
| ??1050 | Phenyl propyl | Methoxyl group | Ethyl | ??503 | ??503 | |
| ??1051 | Phenyl propyl | Methoxyl group | 2-ethyl decyl | ??629 | ??629 | |
| ??1052 | Phenyl propyl | Methoxyl group | Pyrazine-2-methyl | ??553 | ??553 | |
| ??1053 | Phenyl propyl | Methoxyl group | The 4-pyridylmethyl | ??552 | ??552 | |
| ??1054 | Phenyl propyl | Methoxyl group | The 4-butenyl | ??529 | ??529 | |
| ??1055 | Phenyl propyl | Methoxyl group | ??2-NO 2-5-Cl-phenyl | ??630 | ??630 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H | ||
| ??1056 | Phenyl propyl | Methoxyl group | Cyano methyl | ??514 | ??514 | ||
| ??1057 | Methyl | Methoxyl group | The 4-methoxy-benzyl | ??491 | ??491 | ||
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H | ||
| ??1058 | Methyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??515 | ??515 | ||
| ??1059 | Methyl | Methoxyl group | The 1-naphthyl | ??497 | ??497 | ||
| ??1060 | Methyl | Methoxyl group | Piperonyl | ??490 | ??490 | ||
| ??1061 | | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??537 | ??537 | ||
| ??1062 | Methyl | Methoxyl group | The 3-hydroxybenzyl | ??476 | ??476 | ||
| ??1063 | Methyl | Methoxyl group | The 1-naphthyl methyl | ??511 | ??511 | ||
| ??1064 | Methyl | Methoxyl group | Styroyl | ??475 | ??475 | ||
| ??1065 | Methyl | Methoxyl group | The 3-p-methoxy-phenyl | ??476 | ??476 | ||
| ??1066 | Methyl | Methoxyl group | N-benzoyl-amido ethyl | ??504 | ??504 | ||
| ??1067 | Methyl | Methoxyl group | Benzyl | ??460 | ??460 | ||
| ??1068 | Methyl | Methoxyl group | ??4-NO 2-benzyl | ??505 | ??505 | ||
| ??1069 | Amino | Methoxyl group | The 4-methoxy-benzyl | ??492 | ??492 | ||
| ??1070 | Amino | Methoxyl group | ??3，4-Cl 2-benzyl | ??516 | ??516 | ||
| ??1071 | Amino | Methoxyl group | The 1-naphthyl | ??498 | ??498 | ||
| ??1072 | Amino | Methoxyl group | Piperonyl | ??491 | ??491 | ||
| ??1073 | Amino | Methoxyl |
2,4, the 5-trimethoxyphenyl | ??538 | ??538 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H | ||
| ??1074 | Amino | Methoxyl group | The 3-hydroxybenzyl | ??477 | ??477 | ||
| ??1075 | Amino | Methoxyl group | The 1-naphthyl methyl | ??512 | ??512 | ||
| ??1076 | Amino | Methoxyl group | Styroyl | ??476 | ??476 | ||
| ??1077 | Amino | Methoxyl group | The 3-p-methoxy-phenyl | ??477 | ??477 | ||
| ??1078 | Amino | Methoxyl group | N-benzoyl-amido ethyl | ??505 | ??505 | ||
| ??1079 | Amino | Methoxyl group | Benzyl | ??461 | ??461 | ||
| ??1080 | Amino | Methoxyl group | ??4-NO 2-benzyl | ??506 | ??506 | ||
| ??1081 | The 3-propenyl | Methoxyl group | The 4-methoxy-benzyl | ??517 | ??517 | ||
| ??1082 | The 3-propenyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??541 | ??541 | ||
| ??1083 | The 3-propenyl | Methoxyl group | The 1-naphthyl | ??523 | ??523 | ||
| ??1084 | The 3-propenyl | Methoxyl group | Piperonyl | ??517 | ??517 | ||
| ??1085 | The 3- | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??563 | ??563 | ||
| ??1086 | The 3-propenyl | Methoxyl group | The 3-hydroxybenzyl | ??503 | ??503 | ||
| ??1087 | The 3-propenyl | Methoxyl group | The 1-naphthyl methyl | ??537 | ??537 | ||
| ??1088 | The 3-propenyl | Methoxyl group | Styroyl | ??501 | ??501 | ||
| ??1089 | The 3-propenyl | Methoxyl group | The 3-p-methoxy-phenyl | ??503 | ??503 | ||
| ??1090 | The 3-propenyl | Methoxyl group | N-benzoyl-amido ethyl | ??530 | ??530 | ||
| ??1091 | The 3-propenyl | Methoxyl group | Benzyl | ??487 | ??487 | ||
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H | ||
| ??1092 | The 3-propenyl | Methoxyl group | ??4-NO 2-benzyl | ??532 | ??532 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??1093 | Acetate | Methoxyl group | The 4-methoxy-benzyl | ??535 | ??535 |
| ??1094 | Acetate | Methoxyl group | ??3，4-Cl 2-benzyl | ??559 | ??559 |
| ??1095 | Acetate | Methoxyl group | The 1-naphthyl | ??541 | ??541 |
| ??1096 | Acetate | Methoxyl group | Piperonyl | ??534 | ??534 |
| ??1097 | Acetate | Methoxyl |
2,4, the 5-trimethoxyphenyl | ??581 | ??581 |
| ??1098 | Acetate | Methoxyl group | The 3-hydroxybenzyl | ??521 | ??521 |
| ??1099 | Acetate | Methoxyl group | The 1-naphthyl methyl | ??555 | ??555 |
| ??1100 | Acetate | Methoxyl group | Styroyl | ??519 | ??519 |
| ??1101 | Acetate | Methoxyl group | The 3-p-methoxy-phenyl | ??521 | ??521 |
| ??1102 | Acetate | Methoxyl group | N-benzoyl-amido ethyl | ??548 | ??548 |
| ??1103 | Acetate | Methoxyl group | Benzyl | ??505 | ??505 |
| ??1104 | Acetate | Methoxyl group | ??4-NO 2-benzyl | ??549 | ??549 |
| ??1105 | Propionic acid | Methoxyl group | The 4-methoxy-benzyl | ??549 | ??549 |
| ??1106 | Propionic acid | Methoxyl group | ??3，4-Cl 2-benzyl | ??573 | ??573 |
| ??1107 | Propionic acid | Methoxyl group | The 1-naphthyl | ??555 | ??555 |
| ??1108 | Propionic acid | Methoxyl group | Piperonyl | ??549 | ??549 |
| ??1109 | Propionic acid | Methoxyl |
2,4, the 5-trimethoxyphenyl | ??595 | ??595 |
| ??1110 | Propionic acid | Methoxyl group | The 3-hydroxybenzyl | ??535 | ??535 |
| ??1111 | Propionic acid | Methoxyl group | The 1-naphthyl methyl | ??569 | ??569 |
| ??1112 | Propionic acid | Methoxyl group | Styroyl | ??533 | ??533 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??1113 | Propionic acid | Methoxyl group | The 3-p-methoxy-phenyl | ??535 | ??535 |
| ??1114 | Propionic acid | Methoxyl group | N-benzoyl-amido ethyl | ??562 | ??562 |
| ??1115 | Propionic acid | Methoxyl group | Benzyl | ??519 | ??519 |
| ??1116 | Propionic acid | Methoxyl group | ??4-NO 2-benzyl | ??564 | ??564 |
| ??1117 | The 4-vinyl benzyl | Methoxyl group | The 4-methoxy-benzyl | ??593 | ??593 |
| ??1118 | The 4-vinyl benzyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??617 | ??617 |
| ??1119 | The 4-vinyl benzyl | Methoxyl group | The 1-naphthyl | ??599 | ??599 |
| ??1120 | The 4-vinyl benzyl | Methoxyl group | Piperonyl | ??593 | ??593 |
| ??1121 | The 4-vinyl benzyl | Methoxyl |
2,4, the 5-trimethoxyphenyl | ??639 | ??639 |
| ??1122 | The 4-vinyl benzyl | Methoxyl group | The 3-hydroxybenzyl | ??579 | ??579 |
| ??1123 | The 4-vinyl benzyl | Methoxyl group | The 1-naphthyl methyl | ??613 | ??613 |
| ??1124 | The 4-vinyl benzyl | Methoxyl group | Styroyl | ??577 | ??577 |
| ??1125 | The 4-vinyl benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??579 | ??579 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??1126 | The 4-vinyl benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??606 | ??606 |
| ??1127 | The 4-vinyl benzyl | Methoxyl group | Benzyl | ??563 | ??563 |
| ??1128 | The 4-vinyl benzyl | Methoxyl group | ??4-NO 2-benzyl | ??608 | ??608 |
| ??1129 | The piperonyl methyl | Methoxyl group | The 4-methoxy-benzyl | ??611 | ??611 |
| ??1130 | The piperonyl methyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??635 | ??635 |
| ??1131 | The piperonyl methyl | Methoxyl group | The 1-naphthyl | ??617 | ??617 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H | ||
| ??1132 | The piperonyl methyl | Methoxyl group | Piperonyl | ??611 | ??611 | ||
| ??1133 | The piperonyl | Methoxyl group | 2,4, the 5-trimethoxyphenyl | ??657 | ??657 | ||
| ??1134 | The piperonyl methyl | Methoxyl group | The 3-hydroxybenzyl | ??597 | ??597 | ||
| ??1135 | The piperonyl methyl | Methoxyl group | The 1-naphthyl methyl | ??631 | ??631 | ||
| ??1136 | The piperonyl methyl | Methoxyl group | Styroyl | ??595 | ??595 | ||
| ??1137 | The piperonyl methyl | Methoxyl group | The 3-p-methoxy-phenyl | ??597 | ??597 | ||
| ??1138 | The piperonyl methyl | Methoxyl group | N-benzoyl-amido ethyl | ??624 | ??624 | ||
| ??1139 | The piperonyl methyl | Methoxyl group | Benzyl | ??581 | ??581 | ||
| ??1140 | The piperonyl methyl | Methoxyl group | ??4-NO 2-benzyl | ??626 | ??626 | ||
| ??1141 | The 4-F-benzyl | Methoxyl group | The 4-methoxy-benzyl | ??585 | ??585 | ||
| ??1142 | The 4-F-benzyl | Methoxyl group | ??3，4-Cl 2-benzyl | ??609 | ??609 | ||
| ??1143 | The 4-F-benzyl | Methoxyl group | The 1-naphthyl | ??591 | ??591 | ||
| ??1144 | The 4-F-benzyl | Methoxyl group | Piperonyl | ??585 | ??585 | ||
| ??1145 | The 4-F-benzyl | Methoxyl |
2,4, the 5-trimethoxyphenyl | ??631 | ??631 | ||
| ??1146 | The 4-F-benzyl | Methoxyl group | The 3-hydroxybenzyl | ??571 | ??571 | ||
| ??1147 | The 4-F-benzyl | Methoxyl group | The 1-naphthyl methyl | ??605 | ??605 | ||
| ??1148 | The 4-F-benzyl | Methoxyl group | Styroyl | ??569 | ??569 | ||
| ??1149 | The 4-F-benzyl | Methoxyl group | The 3-p-methoxy-phenyl | ??571 | ??571 | ||
| ??1150 | The 4-F-benzyl | Methoxyl group | N-benzoyl-amido ethyl | ??598 | ??598 | ||
| ??1151 | The 4-F-benzyl | Methoxyl group | Benzyl | ??555 | ??555 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??1152 | The 4-F-benzyl | Methoxyl group | ??4-NO 2-benzyl | ??600 | ??600 |
| ??1153 | Methyl | Benzyloxy | The 4-methoxy-benzyl | ??567 | ??567 |
| ??1154 | Methyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??591 | ??591 |
| ??1155 | Methyl | Benzyloxy | The 1-naphthyl | ??573 | ??573 |
| ??1156 | Methyl | Benzyloxy | Piperonyl | ??567 | ??567 |
| ??1157 | Methyl | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??613 | ??613 |
| ??1158 | Methyl | Benzyloxy | The 3-hydroxybenzyl | ??553 | ??553 |
| ??1159 | Methyl | Benzyloxy | The 1-naphthyl methyl | ??587 | ??587 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| ??1160 | Methyl | Benzyloxy | Styroyl | ??551 | ??551 |
| ??1161 | Methyl | Benzyloxy | The 3-p-methoxy-phenyl | ??553 | ??553 |
| ??1162 | Methyl | Benzyloxy | N-benzoyl-amido ethyl | ??580 | ??580 |
| ??1163 | Methyl | Benzyloxy | Benzyl | ??537 | ??537 |
| ??1164 | Methyl | Benzyloxy | ??4-NO 2-benzyl | ??582 | ??582 |
| ??1165 | Amino | Benzyloxy | The 4-methoxy-benzyl | ??568 | ??568 |
| ??1166 | Amino | Benzyloxy | ??3，4-Cl 2-benzyl | ??592 | ??592 |
| ??1167 | Amino | Benzyloxy | The 1-naphthyl | ??574 | ??574 |
| ??1168 | Amino | Benzyloxy | Piperonyl | ??568 | ??568 |
| ??1169 | Amino | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??614 | ??614 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H | ||
| ??1170 | Amino | Benzyloxy | The 3-hydroxybenzyl | ??554 | ??554 | ||
| ??1171 | Amino | Benzyloxy | The 1-naphthyl methyl | ??588 | ??588 | ||
| ??1172 | Amino | Benzyloxy | Styroyl | ??552 | ??552 | ||
| ??1173 | Amino | Benzyloxy | The 3-p-methoxy-phenyl | ??554 | ??554 | ||
| ??1174 | Amino | Benzyloxy | N-benzoyl-amido ethyl | ??581 | ??581 | ||
| ??1175 | Amino | Benzyloxy | Benzyl | ??538 | ??538 | ||
| ??1176 | Amino | Benzyloxy | ??4-NO 2-benzyl | ??583 | ??583 | ||
| ??1177 | The 3-propenyl | Benzyloxy | The 4-methoxy-benzyl | ??593 | ??593 | ||
| ??1178 | The 3-propenyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??617 | ??617 | ||
| ??1179 | The 3-propenyl | Benzyloxy | The 1-naphthyl | ??599 | ??599 | ||
| ??1180 | The 3-propenyl | Benzyloxy | Piperonyl | ??593 | ??593 | ||
| ??1181 | The 3- | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??639 | ??639 | ||
| ??1182 | The 3-propenyl | Benzyloxy | The 3-hydroxybenzyl | ??579 | ??579 | ||
| ??1183 | The 3-propenyl | Benzyloxy | The 1-naphthyl methyl | ??613 | ??613 | ||
| ??1184 | The 3-propenyl | Benzyloxy | Styroyl | ??577 | ??577 | ||
| ??1185 | The 3-propenyl | Benzyloxy | The 3-p-methoxy-phenyl | ??579 | ??579 | ||
| ??1186 | The 3-propenyl | Benzyloxy | N-benzoyl-amido ethyl | ??606 | ??606 | ||
| ??1187 | The 3-propenyl | Benzyloxy | Benzyl | ??563 | ??563 | ||
| ??1188 | The 3-propenyl | Benzyloxy | ??4-NO 2-benzyl | ??608 | ??608 | ||
| ??1189 | Acetate | Benzyloxy | The 4-methoxy-benzyl | ??611 | ??611 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H | ||
| ??1190 | Acetate | Benzyloxy | ??3，4-Cl 2-benzyl | ??635 | ??635 | ||
| ??1191 | Acetate | Benzyloxy | The 1-naphthyl | ??617 | ??617 | ||
| ??1192 | Acetate | Benzyloxy | Piperonyl | ??611 | ??611 | ||
| ??1193 | | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??657 | ??657 | ||
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H | ||
| ??1194 | Acetate | Benzyloxy | The 3-hydroxybenzyl | ??597 | ??597 | ||
| ??1195 | Acetate | Benzyloxy | The 1-naphthyl methyl | ??631 | ??631 | ||
| ??1196 | Acetate | Benzyloxy | Styroyl | ??595 | ??595 | ||
| ??1197 | Acetate | Benzyloxy | The 3-p-methoxy-phenyl | ??597 | ??597 | ||
| ??1198 | Acetate | Benzyloxy | N-benzoyl-amido ethyl | ??624 | ??624 | ||
| ??1199 | Acetate | Benzyloxy | Benzyl | ??581 | ??581 | ||
| ??1200 | Acetate | Benzyloxy | ??4-NO 2-benzyl | ??626 | ??626 | ||
| ??1201 | Propionic acid | Benzyloxy | The 4-methoxy-benzyl | ??625 | ??625 | ||
| ??1202 | Propionic acid | Benzyloxy | ??3，4-Cl 2-benzyl | ??649 | ??649 | ||
| ??1203 | Propionic acid | Benzyloxy | The 1-naphthyl | ??631 | ??631 | ||
| ??1204 | Propionic acid | Benzyloxy | Piperonyl | ??625 | ??625 | ||
| ??1205 | Propionic acid | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??671 | ??671 | ||
| ??1206 | Propionic acid | Benzyloxy | The 3-hydroxybenzyl | ??611 | ??611 | ||
| ??1207 | Propionic acid | Benzyloxy | The 1-naphthyl methyl | ??645 | ??645 | ||
| ??1208 | Propionic acid | Benzyloxy | Styroyl | ??609 | ??609 |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H | ||
| ??1209 | Propionic acid | Benzyloxy | The 3-p-methoxy-phenyl | ??611 | ??611 | ||
| ??1210 | Propionic acid | Benzyloxy | N-benzoyl-amido ethyl | ??638 | ??638 | ||
| ??1211 | Propionic acid | Benzyloxy | Benzyl | ??595 | ??595 | ||
| ??1212 | Propionic acid | Benzyloxy | ??4-NO 2-benzyl | ??640 | ??640 | ||
| ??1213 | The 4-vinyl benzyl | Benzyloxy | The 4-methoxy-benzyl | ??669 | ??669 | ||
| ??1214 | The 4-vinyl benzyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??694 | ??694 | ||
| ??1215 | The 4-vinyl benzyl | Benzyloxy | The 1-naphthyl | ??675 | ??675 | ||
| ??1216 | The 4-vinyl benzyl | Benzyloxy | Piperonyl | ??669 | ??669 | ||
| ??1217 | The 4- | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??715 | ??715 | ||
| ??1218 | The 4-vinyl benzyl | Benzyloxy | The 3-hydroxybenzyl | ??655 | ??655 | ||
| ??1219 | The 4-vinyl benzyl | Benzyloxy | The 1-naphthyl methyl | ??689 | ??689 | ||
| ??1220 | The 4-vinyl benzyl | Benzyloxy | Styroyl | ??653 | ??653 | ||
| ??1221 | The 4-vinyl benzyl | Benzyloxy | The 3-p-methoxy-phenyl | ??655 | ??655 | ||
| ??1222 | The 4-vinyl benzyl | Benzyloxy | N-benzoyl-amido ethyl | ??682 | ??682 | ||
| ??1223 | The 4-vinyl benzyl | Benzyloxy | Benzyl | ??639 | ??639 | ||
| ??1224 | The 4-vinyl benzyl | Benzyloxy | ??4-NO 2-benzyl | ??684 | ??684 | ||
| ??1225 | The piperonyl methyl | Benzyloxy | The 4-methoxy-benzyl | ??687 | ??687 | ||
| ??1226 | The piperonyl methyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??712 | ??712 | ||
| ??1227 | The piperonyl methyl | Benzyloxy | The 1-naphthyl | ??693 | ??693 | ||
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H |
| Numbering | ??R a | ??R b | ??R c | Molecular weight | ??M+H | ||
| ??1228 | The piperonyl methyl | Benzyloxy | Piperonyl | ??687 | ??687 | ||
| ??1229 | The | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??733 | ??733 | ||
| ??1230 | The piperonyl methyl | Benzyloxy | The 3-hydroxybenzyl | ??673 | ??673 | ||
| ??1231 | The piperonyl methyl | Benzyloxy | The 1-naphthyl methyl | ??707 | ??707 | ||
| ??1232 | The piperonyl methyl | Benzyloxy | Styroyl | ??671 | ??671 | ||
| ??1233 | The piperonyl methyl | Benzyloxy | The 3-p-methoxy-phenyl | ??673 | ??673 | ||
| ??1234 | The piperonyl methyl | Benzyloxy | N-benzoyl-amido ethyl | ??700 | ??700 | ||
| ??1235 | The piperonyl methyl | Benzyloxy | Benzyl | ??657 | ??657 | ||
| ??1236 | The piperonyl methyl | Benzyloxy | ??4-NO 2-benzyl | ??702 | ??702 | ||
| ??1237 | The 4-F-benzyl | Benzyloxy | The 4-methoxy-benzyl | ??661 | ??661 | ||
| ??1238 | The 4-F-benzyl | Benzyloxy | ??3，4-Cl 2-benzyl | ??686 | ??686 | ||
| ??1239 | The 4-F-benzyl | Benzyloxy | The 1-naphthyl | ??667 | ??667 | ||
| ??1240 | The 4-F-benzyl | Benzyloxy | Piperonyl | ??661 | ??661 | ||
| ??1241 | The 4-F-benzyl | Benzyloxy | 2,4, the 5-trimethoxyphenyl | ??707 | ??707 |
Beta-chain simulative structure of the present invention can be used as bioactive agents, as diagnostic reagent, preventive and therapeutical agent.Preferably, compound is formulated as the acceptable form of medicine, then useful beta-chain simulative structure of the present invention is treated patient's administration of demand.
Therefore, the invention provides and contain the pharmaceutical composition of structure (I ") to the compound of (I ' ").For the preparation of drug combination that contains this compound, those skilled in the art can use known common practise of association area and technology.Common known variety carrier and other additive can be used for preparing composition of the present invention.Pharmaceutical composition of the present invention can be with the mode administration of standard for the disease condition of needs treatments, for example by oral, rectum or administered parenterally.
For these purposes, compound of the present invention can be formulated as by means commonly known in the art form such as tablet, capsule, water-based or oily solution or suspension, (lipid) emulsion, dispersible powder, suppository, ointment, emulsifiable paste, drops and sterile injectable water-based or oily solution or suspension.
Suitable pharmaceutical compositions of the present invention is a kind of composition that is suitable for the unit dosage form of oral administration, for example contains tablet or the capsule of about 1mg to about 1g compound of the present invention.
On the other hand, pharmaceutical composition of the present invention is a kind of composition that is suitable for intravenous injection, subcutaneous injection or intramuscular injection.For instance, the patient can accept vein, the subcutaneous or intramuscular dosage of about 1 μ g/kg to about 1g/kg The compounds of this invention.Can give vein, subcutaneous and intramuscular dosage by the mode of bullet formula injection (bolus injection).In addition alternatively, can give vein dosage by the continuous transfusion of for some time.
In addition alternatively, the patient accepts to approximate greatly the day oral dosage of day parenteral dosage, and every day is with this compound administration 1 to 4 time.
Following table has illustrated the representational compound that is useful on human treatment or prevention or the pharmaceutical dosage forms of its drug acceptable salt of containing:
| |
The mg/ sheet |
| Compound | ??100 |
| Lactose Ph.Eur. | ??179 |
| Croscarmellose sodium | ??12.0 |
| Polyvinylpyrolidone (PVP) | ??6 |
| Magnesium Stearate | ??3.0 |
| |
The mg/ sheet |
| Compound | ??50 |
| Lactose Ph.Eur. | ??229 |
| |
The mg/ sheet |
| Croscarmellose sodium | ??12.0 |
| Polyvinylpyrolidone (PVP) | ??6 |
| Magnesium Stearate | ??3.0 |
| |
The mg/ sheet |
| Compound | ??1.0 |
| Lactose Ph.Eur. | ??92 |
| Croscarmellose sodium | ??4.0 |
| Polyvinylpyrolidone (PVP) | ??2.0 |
| Magnesium Stearate | ??1.0 |
| Capsule | The mg/ capsule |
| Compound | ?10 |
| Lactose Ph.Eur. | ?389 |
| Croscarmellose sodium | ?100 |
| Magnesium Stearate | ?1.0 |
| Injection I | ??(50mg/ml) |
| Compound | ??0.5％w/v |
| Isotonic aqueous solution | To 100% |
The pharmaceutical composition that contains general formula (I) compound can be used for effect required on the multiple biology, comprises the proteolytic enzyme that suppresses in the warm-blooded animal, regulates in the warm-blooded animal with the factor-related peptide of cell signalling and is used for suppressing the kinases of warm-blooded animal.By comprising that the method for compound that the animal that needs are arranged is used the structural formula (I) of significant quantity can reach these effects.
And as hereinafter going through, beta-chain simulative structure of the present invention can also be used for coming across in the TXi Baoshouti at the MHC-I of warm-blooded animal inhibiting peptide and/or MHC-II effectively; Inhibiting peptide is attached on the SH2 structural domain in warm-blooded animal; Inhibiting peptide is attached on the SH3 structural domain in warm-blooded animal; Inhibiting peptide is attached on the PTB structural domain in warm-blooded animal; Regulate G protein coupled receptor (GPCR) and ionic channel in the warm-blooded animal; With the cytokine of regulating in the warm-blooded animal.
Kinase inhibition (comprising that SH2 and SH3 structural domain suppress)
On the one hand, the invention provides the kinase whose method of inhibition in warm-blooded animal.This method comprises uses a certain amount of compound of the present invention to animal, and wherein this consumption is effective for suppressing kinases.Kinases (being also referred to as protein kinase) is a class catalyzed reaction and makes biomolecules (typically being another kind of enzyme) that the enzyme of phosphorylation takes place thus.It is believed that the nearly 1000 kinds of kinases (Hunter, Cell 50:823-829,1987) of having encoded in the mammalian genes group.A large amount of kinases allows fast signal to amplify and a plurality of check point.
Phosphorylation is a covalent modification very common in the signal transduction process, and those activity of proteins that cause phosphorylation takes place change.Kinases thereby be key ingredient in the signal pathway.Kinases marshalling is usually gone in several functions of modules districts or " structural domain " (Cohen, people such as G.B., Cell 80:237-248,1995).The structural domain of a kind of being called " SH3 " is 55-70 amino acid whose zone on the peptide that is attached to proline rich, the especially extended chain.The structural domain that another is called " SH2 " is about 100 the amino acid whose Tyrosine O-phosphate calmodulin binding domain CaMs of length.It is believed that these two kinds of structural domains are with the identification of protein substrate with in conjunction with relevant.These and other structural domain comprises the structural domain in myristoylation and palmitoylation site, is responsible for having assembled the multiprotein complex (people such as Mayer, Mol.Cell.Biol.12:609-618,1992 that catalyst structure domain are directed to correct target spot; With Mayer and Baltimore, Mol.Cell.Biol.14:2883-2894,1994).Although known SH2 and SH3 structural domain are present in some kinases, these structural domains also are present in other protein.Compound of the present invention can be used for suppressing the combination of kinases or other protein SH2-or SH3-mediation.
Health a large amount of different, but use kinases in the intramolecularly signal transduction mechanism that often is mutually related.For example, the cell instrumentality of somatomedin, transduced element, hormone, cell cycle regulating protein and many other types, in their signal cascade (signaling cascade), utilize Tyrosylprotein kinase (referring to, for example, people such as Bolen, FASEB J.6:3403-3409,1992; With Ullrich and Schlessinger, Cell 61:203-212,1990).Serine/threonine kinase has remedied the residuum in the most of kinases family.
With the effect of external test enzyme and understand a kind of important method of its function, be to use specific enzyme inhibitors in vivo.If find that one or more compounds can inhibitory enzyme, this inhibitor can be used for the activity of regulatory enzyme, and can observe the effect of reduction.Such method helps to explain the approach of multiple intermediary metabolism, and also is crucial for understanding enzyme kinetics and definite catalyst mechanism.The invention provides such compound.
The regulation and control of many immunne responses are by transmitting the receptor-mediated of signal via the Tyrosylprotein kinase that contains the SH2 structural domain.T-cell-stimulating by antigen specific T-cell receptor (TCR) has started the signal transduction cascade system, and it has caused lymphokine secretion and hyperplasia.It is the increase of tyrosine kinase activity that TCR activates one of biochemical reaction of back very early time.Especially, T-cell-stimulating and hyperplasia are by containing the p56 of SH2 structural domain
LckAnd p59
FynThe activation of the T-cell receptors mediation of Tyrosylprotein kinase and ZAP-70 and Syk (Weiss and Litman, Cell 76:263-274,1994) is controlled.Other evidence shows that several src-family's kinases (lck, blk, fyn) have participated in therefore can being used in conjunction with the stimulation that receives from several independently receptor structures from the signal transduction pathway of B-cell antigen receptor guiding.Therefore, block interactional inhibitor between these SH2 structural domain kinases and their homoreceptor, can in autoimmune disease, transplant rejection reaction, be used as immunosuppressor,, and under the situation of Lymphocytic leukemia, be used as cancer therapy drug perhaps as anti-inflammatory agent.
In addition, the non-film PTP enzyme of striding of the known SH2 of containing structural domain, with them called after SH-PTP1 and SH-PTP2 (Neel, Cell Biology 4:419-432,1993), SH-PTP1 is equal to PTP1C, HCP or SHP, and SH-PTP2 is also referred to as PTP1D or PTP2C.SH-PTP1 all is being able to high level expression in pedigree and the hematopoietic cell of whole differential periods.Be responsible for motheaten (me) mouse phenotype owing to confirm the SH-PTP1 gene, this just provides the basis of prediction blocking-up with the inhibitor effect of its cell substrate interaction.Therefore, can expect that the inhibition of SH-PTP1 causes the T-cell response to the mitogenesis stimulation that damages, the NK cell function of reduction, and the disappearance of the B-cell precursors with potential treatment application as indicated above.
Compound of the present invention is combined in the ability on the SH2 structural domain of STAT6, or be combined in ability on the SH2 structural domain of Protein-tyrosine-phosphatase SH-PTP1, can be with people such as Payne, P.N.A.S.USA 90:4902-4906, disclosed program certification in 1993.Can be by people such as Songyang, Cell 72:767-778,1993 program is screened in conjunction with the stand-in storehouse SH2.In addition referring to people such as Songyang, Current Biology 4:973-982,1994 program, the ability of serving as the substrate or the inhibitor of protein kinase with test compounds.
Therefore, on the one hand, the invention provides the method that suppresses Phosphoric acid esterase in warm-blooded animal, this method comprises that with a certain amount of compound of the present invention be animals administer, and wherein this consumption is effective for suppressing Phosphoric acid esterase.
In II type (non-insulin-depending type) diabetes, the contended with effect of activated insulin receptor kinase of tyrosine phosphatase (PTP-1b) may have been represented important drug target.Experiment in vitro shows that injection PTP enzyme has been blocked the phosphorylation of the insulin stimulating of tyrosyl residue on the endogenous protein.Therefore, compound of the present invention can be used for regulating in diabetes the effect of Regular Insulin.
On the other hand, the invention provides the Tyrosine O-phosphate residue and the second proteinic SH2 structural domain bonded method that suppresses in first protein.This method comprises to be made a certain amount of compound of the present invention and contains the first and second proteinic compositions and contact.The combination by the second proteinic SH2 structural domain and the first proteinic Tyrosine O-phosphate residue is effective to this consumption between first and second protein for alleviating.
Proteolytic enzyme suppresses
On the other hand, the invention provides the method for arrestin enzyme in warm-blooded animal.This method comprises that with a certain amount of compound of the present invention as herein described be animals administer.This consumption is effective for the proteolytic enzyme that suppresses in the animal.In different embodiments: proteolytic enzyme is serine protease; Proteolytic enzyme is the serine protease that is selected from zymoplasm, the X factor, the IX factor, the VII factor, the XI factor, urokinase, HCV proteolytic enzyme, chymase trypsinase and kallikrein; Proteolytic enzyme is zymoplasm; Proteolytic enzyme is the VII factor; Proteolytic enzyme is selected from aspartic acid, halfcystine and metalloprotease.
Suppress about proteolytic enzyme, cathepsin B is usually the lysosome L-Cysteine HCL Anhydrous relevant with the protein conversion with proenzyme processing.Activity level raises and to relate to metastases people such as (, Cancer Metastasis Rev.9:333-352,1990) SloaneB.F., rheumatoid arthritis (Werb, Z.Textbook of Rheumatology, Keller, W.N.; Harris, W.D.; Ruddy, S.; Sledge, C.S., Eds., 1989, W.B.Saunder Co., Philadelphia, Pa., pp.300-321) and muscular dystrophy (Katunuma and Kominami, Rev.Physiol.Biochem.Pharmacol.108:1-20,1987).
Calpain is that kytoplasm or film are in conjunction with Ca
++-activated proteolytic enzyme, its response intracellular Ca2+ level change and cause the degraded of cytoskeletal protein.They help the tissue degradation (referring to Wang and Yuen Trends Pharmacol.Sci.15:412-419,1994) in sacroiliitis and the muscular dystrophy.
Interleukin-saccharase (ICE) is cut into pro-IL-1 β a kind of mediator of inflammation IL-1 β of key, therefore the inhibition of ICE proof can be used for arthritic treatment (referring to, for example, people such as Miller B.E., J.Immunol.154:1331-1338,1995).ICE or class ICE proteolytic enzyme can also work in apoptosis (apoptosis), therefore in lacking of proper care diseases associated with apoptosis, cancer, AIDS, alzheimer's disease and other play a role (referring to Barr and Tomei, Biotechnol.12:487-493,1994).
Hiv protease is brought into play keying action in the life cycle of AIDS virus HIV.In the final step of virus maturation, it is cut into the polyprotein precursor functional enzyme and the structural protein of virosome nuclear.The hiv protease inhibitor is confirmed as a kind of fabulous AIDS treatment target spot very soon (referring to Huff, J.R., J.Med.Chem.34:2305-2314), and verifiedly can be used for its treatment, ritonavir (ritonavir), Crixivan and saquinavir (saquinavir) obtain checking and approving of FDA and have then confirmed this point recently.
Hepatitis C virus (HCV) is the major cause of non-first type in the world today and non-hepatitis B.Estimate to have infected nearly 5,000 ten thousand people.Current, there is not satisfied treatment can stop this debilitating advancing of disease.During this viral life cycle, produced about 3000 amino acid whose polyproteins, it is sheared by the proteolytic enzyme of virus and host protein enzyme, produces sophisticated virogene product.The serine protease that is positioned at HCV NS3 albumen ruptures on four specific sites, produces to be considered to for the vital unstructuredness albumen of virus replication.Therefore, the HCV proteinase inhibitor is noticeable medicinal design target spot, may have great treatment benefit (people such as Neddermann, Bio.Chem.378:469-476,1997).
Angiotensin-converting enzyme (ACE) is the part of renin-angiotensin system, and it plays central role in the adjusting of blood pressure.ACE is cut into the octapeptide Angiotensin II with angiotensin I, and it is because vasoconstrictor activity is a kind of effective hypertensor.Proved that being suppressed at of ACE can be used for hypertensive treatment (William, G.H., N.Engl.J.Med.319:1517-1525,1989) in the treatment
The main component collagen protein of collagenase incising cell epimatrix (as reticular tissue, skin, blood vessel).Collagenase activities raises and to impel sacroiliitis (people such as Krane, Ann.N.Y.Acad.Sci.580:340-354,1990), metastases (Flug and Kopf-Maier, Acta Anat.Basel 152:69-84,1995) and other and connective tissue degradation diseases associated.
The serine protease of tryptase forms a big class of high selectivity and hemostasis/solidify (Davie and Fujikawa, Ann.Rev.799-829,1975) and the relevant enzyme of complement activation (Muller-Eberhard, Ann.Rev.Biochem.44:697-724,1975).These proteolytic enzyme are checked order, shown the existence of homology tryptase nuclear, it has the aminoacid insertion of modified specificity, and causes usually and the interaction of other macromolecular components (people such as Magnusson, Miami Winter Symposia 11:203-239,1976).
Zymoplasm is a kind of serine protease of tryptase, its effect is producing the process of fibrin from fibrinogen, with in the activation process of platelet receptor, limited proteolysis is provided, therefore in thrombosis and hemostasis, play crucial effects (Mann, K.G., Trends Biochem.Sci.12:229-233,1987).By only two the Arg-Gly keys in 181 Arg-in the selectivity cutting fibrinogen or the Lys-Xaa sequence, zymoplasm shows significant specificity (Blomback in fibrinopeptide A that removes fibrinogen and B, Blood Clotting Enzymology, Seeger, W.H. (ed.), Academic Press, New York, 1967, pp.143-215).
Many important morbid states are relevant with abnormal hemostasis, comprise the acute coronary syndromes.Acetylsalicylic acid and heparin are widely used in treatment patient's acute coronary syndromes.But these medicaments have some intrinsic limitation.For example, concurrent atherosclerotic plaque disruptive thrombosis, tend to be a thrombin-mediated, rely on hematoblastic process, it relatively has resistibility (people such as Fuster for the inhibition of acetylsalicylic acid and heparin, N.Engl.J.Med.326:242-50,1992).
Thrombin inhibitors prevents that the blood vessel injury site forms thrombus in vivo.And because zymoplasm still is effective somatomedin, it starts the smooth muscle cell proliferation on the coronary artery physical abuse site, and inhibitor is blocked this hyperplasia smooth muscle cell reaction, and reduces restenosis.Thrombin inhibitors can also reduce the inflammatory reaction (people such as Harker, Am.J.Cardiol.75:122-16B, 1995) in the cells of vascular wall.
And, at least two kinds of clear and definite transcription factors of definition, nf (NF) κ B and activated protein (AP)-the 1st, by intracellular redox (redox) status adjustment.Redox state has brought treatment conclusion likely to the adjusting of genetic expression.For example, the transcription factor NF-KB of redox modulating and the binding site of AP-1 are positioned at the promoter region of many kinds gene directly related with disease pathogenesis, AIDS, cancer, atherosclerosis and diabetic complication (Sen and Packer for example, FASEB Journal 10:709-720,1996).More particularly, for example the combination of the transcription factor of NF-κ B and AP-1 on DNA consensus site is by oxidation antioxidation running balance, and especially mercaptan-disulphide balance drives.
Under the situation of NF-κ B, in the adjusting of NF-κ B function, bringing into play the mercaptan of being correlated with on the physiology of crucial effects, be the protein of reductive Trx or reductive similar thioredoxin.Trx is the important protein oxydo-reductase with anti-oxidant function.Therefore have been found that the DNA combination of Trx incremental adjustments (upregulate) activated NF-κ B, and increase expression of gene people such as (, Proc.Natl.Acad.Sci.USA 91:1672-1676,1994) Schenk.Trx relates to the kytoplasm NF-κ B (the especially reduction of cys-62) of reduction activation, so it helps to examine transposition and DNA in conjunction with people such as (, J.Biol.Chem.268:11380-11388,1993) Hayashi.
Have been found that Fos and the Jun dna binding activity in the AP-1 mixture regulates people such as (, Science 249:1157-1162,1990) Abate by redox state.Each albumen contains single conservative halfcystine (both sides are Methionin and arginine) in its DNA binding domains.As if this mercaptan is not the part of disulfide linkage, can exist as sulfenic acid or-sulfinic acid with its oxidised form.Ref-1 is a kind of difunctional nuclear protein that also has endonuclease enzyme dna repairing activity, and it is by the also original stimulation AP-1DNA combination of this adjusting halfcystine.Wherein with the halfcystine of key with the Fos mutant that Serine replaces, caused AP-1DNA in conjunction with active 3 times increase, and no longer oxidated reduction control people such as (, Oncogene 8:695-701,1993) Okuno.Therefore and since in the transcription factor fos family at least four members, the jun family in 3 members and the ATF/CREB family at least 4 members all contain this conservative halfcystine, the redox control of transcription factor is seemingly general.
As mentioned above, for example the adjusting of the transcription factor of NF-κ B and AP-1 has important treatment conclusion.For example, AP-1 is the important amboceptor that produces of tumour people such as (, Proc.Natl.Acad.Sci.USA 92:4972-4976,1995) Yoshioka.Therefore, prevent the compound of AP-1 transcriptional activity in treatment for cancer, to have applicability.And because it is being regulated the direct effect in inflammatory cytokine and the endotoxic response, the activation of NF-κ B has been brought into play important effect in the development of the acute disease of the chronic disease of for example rheumatoid arthritis and for example septic shock.It is believed that for example the autoimmune disease of systemic lupus erythematous (SLE) and alzheimer's disease is also relevant with the activation of NF-κ B.Similarly, NF-κ B is bringing into play important effect in the activation of HIV genetic expression.Other thinks that the illness relevant with NF-κ B comprises that influenza, atherosclerosis, tumour take place and ataxia telangiectasia (AT).
Oxydo-reductase suppresses
About the adjusting of transcription factor, compound of the present invention is regulated transcription factor, and this transcription factor is controlled by the also original of cellular oxidation reductase enzyme by cysteine residues in conjunction with the ability of DNA.In one embodiment, transcription factor is NF-κ B.In this embodiment, compound of the present invention has the activity of immunity and/or inflammatory reaction amboceptor, perhaps is used to control the growth of cell.In another embodiment, transcription factor is AP-1, and the cellular oxidation reductase enzyme is Ref-1.In this embodiment, compound of the present invention has the activity of anti-inflammatory agent and/or carcinostatic agent.In other another embodiment, transcription factor is selected from Myb and glucocorticoid acceptor.Other transcription factor that can be regulated in the context of the present invention also comprises: NF-κ B family transcription factor, for example Rel-A, c-Rel, Rel-B, p50 and p52; AP-1 family transcription factor, for example Fos, FosB, Fra-1, Fra-2, Jun, JunB and JunD; ATF; CREB; STAT-1 ,-2 ,-3 ,-4 ,-5 and-6; NFAT-1 ,-2 and-4; MAF; The Tiroidina factor; IRF; Oct-1 and-2; NF-Y; Egr-1; And USF-43.
Therefore, one aspect of the present invention provides the method for inhibited oxidation reductase enzyme in warm-blooded animal, and it comprises that with a certain amount of compound of the present invention be animals administer, and wherein this consumption is effective for the inhibited oxidation reductase enzyme.The inhibition of oxidoreductase activity can be as regulating the method for transcribing.
CAAX suppresses
On the other hand, the invention provides the method that CAAX suppresses in the warm-blooded animal body.This method comprises that with a certain amount of compound of the present invention as herein described be animals administer.This consumption is effective for providing CAAX to suppress in animal body.
Ras is a kind of protein product of ras oncogene, and it is and the relevant embrane-associated protein of signal transduction of regulating cell fission and growth.The sudden change of Ras gene is one of modal gene unconventionality relevant with human cancer (Barbacid, M.Annu Rev Biochem 56:779-827,1987).These sudden changes cause all the time the growth signals of " unlatching ", produce cancer cells.In order to be positioned on the cytolemma, Ras need pass through the isoprenylation that halfcystine takes place farnesyl transferase (FT enzyme) in its C-end CAAX sequence, wherein, and in the CAAX sequence, " a " is defined as the amino acid with hydrophobic side chain, and " X " is another amino acid.This posttranslational modification is vital to its activity.Shown the peptidyl inhibitor blocking-up of FT enzyme or slowed down the growth of tumour in cell cultures and whole animal (people such as Kohl, Science260:1934-1937,1993 with sequence C aaX; Buss and Marsters, Chemistry and Biology 2:787-791,1995).
The method that screening suppresses the active compound activity of CAAX is being known in the art.Referring to, for example United States Patent (USP) the 6th, 391, and No. 574, it has described the method for the compound that the proteolysis of CAAX albumin A AX tripeptides is removed in the identification of suppressor cell.Referring to United States Patent (USP) the 5th, 990, No. 277, it discloses several suitable checks again, and reference (people such as Gibbs, Cell 77:175,1994; Gibbs, Cell 65:1,1991; Maltese, FASEB J.4:3319,1990; People such as Moores, J.Biol.Chem.266:14603,1991; People such as Goldstein, J.Biol.Chem.266:15575,1991; European patent 0 461 869A2; Casey, J.LipidRes.33:1731-1740,1992; People such as Cox, Curr.Opin.Cell.Biol.4:1008-1016,1992; People such as Garcia, J.Biol.Chem.268:18415-18418,1993; People such as Vogt, J.Biol.Chem.270:660-664,1995; People such as Kohl, Science, 260:1934-1937,1993; People such as Garcia, J.Biol.Chem., 268:18415-18418,1993; With people such as Vogt, J.Biol.Chem.270:660-664,1995).
The MHC molecule
On the other hand, the invention provides inhibition antigen peptide bonded method on the first kind or the second class MHC molecule.This method comprises makes compound according to the present invention contact with the composition that comprises the antigen peptide and the first kind or the second class MHC molecule.So that the effective consumption of binding affinity contacts compound between two species with antigen/molecule for reducing.
An immune importance is a t cell responses.This reaction needed T cell recognition is called cell surface molecule complex body or the major histocompatibility complex (" MHC ") and the peptide of human leucocyte antigen (" HLA "), and interact with it (referring to, for example, people such as Male, Advanced Immunology (J.P.Lipincott Company, 1987).By being ingested by antigen presenting cell (APC), antigen has shifted immune response at least in part, and APC is at the second class glycoprotein that contains the genes encoding in major histocompatibility complex (MHC) on its surface.Then, antigen is under the situation of surface bonding MHC glycoprotein, and by the interaction between T cells with antigenic specificity acceptor and the antigen-MHC complex body, present to special helper T cell (T helper cell), stimulate helper T cell with the reaction of mediation antigen specific immune, comprise the importing of cytotoxin T cell function, importing and some secretions of assisting and encouraging the factor of this reaction of B cell function.In one aspect of the invention, the MHC molecule is HLA-A2.1, HLA-A1 or HLA-A3.1, and perhaps any other is present in HLA allelotrope in the melanoma patient.
Compound of the present invention and MHC I molecule bonded ability basically can be as people such as Elliot, and Nature 351:402-406 proves described in 1991.Similarly, compound of the present invention and MHC II molecule bonded ability can be by people such as Kwok, J.Immunol.155:2468-2467, and the method in 1995 proves.
Albumen with 14-3-3 structural domain
On the other hand, the invention provides and suppress first peptide and second the peptide bonded method that contains the 14-3-3 structural domain, wherein first peptide has the binding affinity with the 14-3-3 structural domain of second peptide.This method comprises makes compound of the present invention contact with the composition that contains (first) peptide, and this peptide has the binding affinity with the 14-3-3 structural domain of second peptide.
Albumen and binding partners thereof with 14-3-3 structural domain have been described in the document.These peptides can be used for method of the present invention.Referring to, for example Dai and Murakami, J Neurochem2003 Jan.84 (1): 23-24; People such as Lim, J Biol Chem 2002 Oct.25,277 (43): 40997-1008; People such as Parvaresch, FEBS Lett 2002 Dec.18,532 (3): 357-62; People such as Eilers, Mol Cell Biol 2002Dec., 22 (24): 8514-26; People such as Liu, CancerRes 2002 Nov.15,62 (22): 6475-80; People such as Truong, Proteins 2002 Nov.15,49 (3): 321-5; People such as Birkenfeld, Biochem J 2003 Jan.1,369 (Pt 1): 45-54; People such as Espejo, Biochem J 2002 Nov.1,367 (Pt 3): 697-702; With people such as Benzing, J Biol Chem 2002 Sep.6,277 (36): 32954-62.
In the practical application of the inventive method, be that it is had the warm-blooded animal administration that needs with the compound of the present invention for the treatment of significant quantity.For example, can be with compound of the present invention for being diagnosed as following illness or the warm-blooded animal administration of its developing risk arranged, described illness is selected from any or multiple Ke Langshi disease (Chrohn ' s disease), asthma, rheumatoid arthritis, local asphyxia, reperfusion injury, graft versus host disease (GVHD), amyotrophic lateral sclerosis (ALS), alzheimer's disease, allograft rejection and adult T cell leukemia.
The compound disease of epiloia
The patient who suffers from the compound disease of epiloia (TSC) in brain, heart, kidney and other tissue, developed usually multiple culprit lesion (referring to, for example, Gomez, M.R.Brain Dev.17 (suppl): 55-57,1995).The research of mammalian cell shown the overexpression negative regulation hyperplasia of TSC1 (it expresses TSC1) and TSC2 (it expresses antituberculin) and induce G1/S suppress (arrest) (referring to, for example, Miloloza, A. wait the people, Hum.Mol.Genet.9:1721-1727,2000).Other studies show that, TSC1 and resistive connection close rhzomorph and bring into play function on beta-catenin degraded complex body levels, more particularly, these albumen by participate in beta-catenin degraded complex body come the stability of negative regulation beta-catenin and activity (referring to, for example, Mak, people such as B.C., J.Biol.Chem.278 (8): 5947-5951,2003).Beta-catenin is the protein of a kind of 95-kDa, it is by its related participation cell adhesion with membrane-bound cadherin family member, and as the key component of Wnt/Wingless approach participate in hyperplasia and differentiation (referring to, for example, Daniels, D.L. wait the people, Trends Biochem.Sci.26:672-678,2001).The destruction that has shown this approach is carcinogenic in human and rodent.The invention provides regulation and control beta-catenin active compound, especially regulate it and the compound of other protein interactions, so can be used for the treatment of TSC.
In order to describe not is to limit, and following embodiment is provided.
Embodiment
In preparation embodiment and embodiment, used following abbreviation:
BMS; The boron dimethyl thioether
CbzOSu: carbobenzoxy-(Cbz) N-hydroxy-succinamide
DIC:1, the 3-DIC
DIEA:N, the N-diisopropyl ethyl amine
DIPEA:N, the N-diisopropyl ethyl amine
DMAP:N, the N-dimethyl aminopyridine
DMF: dimethyl formamide
DMSO: methyl-sulphoxide
EA: ethyl acetate
EDC:1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
EDCl:1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
FmocOsu:9-fluorenylmethoxycarbonyl N-hydroxy-succinamide
HATU:[2-(1H-9-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate
Hex.: hexane
The HOBT:N-hydroxybenzotriazole
MC: methylene dichloride
MeOH: methyl alcohol
-OBn:-O-benzyl
PPTS: tosic acid pyridine
PyBOP: benzotriazole-1-base-oxo-three-pyrrolidyl-phosphorus hexafluorophosphate
P-TsOH: tosic acid
THF: tetrahydrofuran (THF)
TLC: thin-layer chromatography
(1) preparation of naphthalene-2-carboxylic acid amide
(25g, (38ml 0.4356mol) and the DMF of catalytic amount, and at room temperature stirred 2 hours to add oxalyl chloride in MC 0.145mol) (200ml) solution to the 2-naphthoic acid.After the solvent evaporation, with thick acyl chlorides with MC (200ml) dilution, under the ice bath temperature to the aqueous solution that wherein drips ammonium hydroxide (160ml).Stir after 1 hour, by the product of suction filtration collecting precipitation, development and dry obtains inscribing the compound of stating in hexane, and it uses in next step without further purifying.
(2) preparation of naphthalene-2-base-methylamine
In THF (100ml) solution of the crude amide that under 0 ℃, in previous step (1), obtains, slowly add BMS (27.5ml, 0.2904mol).The reaction mixture that generates is heated to 60 ℃, heated 3 hours,, extract 0 ℃ of following cancellation with 5%HCl, and wash with 5%HCl with EA.Combining water layer, and with its usefulness 1N NaOH alkalization, extract with EA once more.Merge organic layer and it is concentrated, obtain the titled reference compound (13g) of white solid.
TLC system 1:MC/MeOH=90: 10v/v Rf=0.23
1H-NMR(300MHz，CDCl
3)δppm：4.07(s，2H)，7.48(m，3H)，7.79(m，4H)
(1) preparation of 1H-Indoline-2-carboxylic acid acid amides
(1g, (1.64ml 18.62mmol) and the DMF of catalytic amount, and at room temperature stirred 2 hours to add oxalyl chloride in MC 6.21mmol) (30ml) solution to Indoline-2-carboxylic acid.After the solvent evaporation, with thick acyl chlorides with MC (20ml) dilution, under the ice bath temperature to the aqueous solution (7ml) that wherein dropwise adds ammonium hydroxide.Stir after 1 hour, by the product of suction filtration collecting precipitation, development and dry obtains inscribing the compound of stating in hexane, and it uses in next step without further purifying.
(2) preparation of (1H-indoles-2-yl)-methylamine
In THF (30ml) solution of the crude amide that under 0 ℃, in previous step (1), obtains, slowly add BMS (1.18ml, 12.42mmol).The reaction mixture that generates is heated to 60 ℃, heated 3 hours,, extract 0 ℃ of following cancellation with 5%HCl, and wash with 5%HCl with EA.Combining water layer, and with its usefulness 1N NaOH alkalization, extract with EA once more.Merge organic layer and it is concentrated, obtain the titled reference compound (0.28g) of yellow oily.
TLC system 1:MC/MeOH=90: 10v/v Rf=0.15
1H-NMR(300MHz，CDCl
3)δppm：3.98(s，2H)，7.08(m，3H)，7.26(m，1H)，7.58(d，1H)，9.10(br?s，1H)
(1) preparation of 2-benzyloxycarbonyl amino-4-oxo-benzyl butyrate
(10g, (2.93ml 0.0336mol) and the DMF of catalytic amount, and at room temperature stirred 2 hours to add oxalyl chloride in MC 0.028mol) (200ml) solution to Z-Asp-OBn under 0 ℃.After the solvent evaporation, thick acyl chlorides is dissolved in the benzene (400ml), (15.1ml 0.056mol) and the Pd (0) of catalytic amount, at room temperature stirs and spends the night to add down slowly tri-butyl tin hydride at 0 ℃.After the solvent evaporation, add ether (100ml)/10%KF aqueous solution (100ml), and at room temperature stirred 2 hours, filter then, obtain two phase liquid.Separate organic layer and it is concentrated, obtain thick product, it is purified by column chromatography, obtain the titled reference compound Z-Asp-OBn aldehyde (6g) of faint yellow oily.
Among Rf: hexane/EA (2/1) 0.29
(2) 2-benzyloxycarbonyl amino-4, the preparation of 4-dimethoxy-benzyl butyrate
(6g, the p-TsOH of adding catalytic amount at room temperature stirred 5 hours the Z-Asp-OBn aldehyde that obtains in previous step (1) in methyl alcohol 17.58mmol) (100ml) solution.After reaction is finished, solvent evaporation is obtained thick product, it is purified by column chromatography, obtain the titled reference compound Z-Asp-OBn acetal (5g) of faint yellow oily.
Among the Rf:Hex./EA (2/1) 0.32
(3) 2-benzyloxycarbonyl amino-4,4-dimethoxy-butyro-preparation
(0.5g, (0.11g in aqueous solution 2.1mmol) (20ml), at room temperature stirred 30 minutes 1.29mmol) to be dissolved in THF (20ml)/NaOH with the Z-Asp-OBn acetal that obtains in the previous step (2).After the starting raw material completely dissolve, evaporation concentration reaction mixture, water/EA dilution then.Separate water layer, and under 0 ℃, it is acidified to pH 4-5 very carefully with 1N HCl, extract with EA once more.Merge organic layer and it is concentrated, obtain the titled reference compound Z-Asp-OBn acetal (0.27g) of faint yellow oily.
TLC system 1: hexane/EA=20: 10v/v Rf=0.10
1H-NMR(300MHz，CDCl
3)δppm：2.20(s，2H)，3.35(d，6H)，4.52(m，2H)，5.19(t，2H)，5.80(d，1H)，7.37(br?s，5H)
(4) 2-amino-4,4-dimethoxy-butyro-preparation
In the reaction vessel of hydrogen balloon is housed, the Z-Asp-OBn acetal that obtains in the adding previous step (3) (2.22g, (20ml) solution of acetate 5.73mmol) and Joseph Pearman (Pearlman ' s) catalyzer, and at room temperature stir and spend the night.The reaction mixture that generates is filtered, concentrates and freeze-drying, obtain thick product, it uses in next step without further purifying.
(5) 2-(9H-fluorenes-9-ylmethoxy carbonylamino)-4,4-dimethoxy-butyro-preparation
In the THF (100ml) of the thick Asp-OH acetal that in previous step (4), obtains/water (100ml) solution, and adding FmocOsu (2.13g, 6.3mmol)/(1.93g 22.92mmol), at room temperature stirs and spends the night sodium bicarbonate.The reaction mixture that generates is concentrated, and water/EA dilution.The water phase separated layer, and under 0 ℃, it is acidified to pH 4-5 very carefully with 1N HCl, extract with EA once more.Merge organic layer and it is concentrated, obtain thick product, it is purified by column chromatography, obtain the titled reference compound (1.5g) of foam solid shape.
Among the Rf:Hex./EA (2/1) 0.15
(1) preparation of 2-benzyloxycarbonyl amino-valeric acid
(20g, (1/1, (45.7g 544mmol), is cooled to 0 ℃ to water/THF 136mmol) in ice bath 400ml) to add sodium bicarbonate in the solution to L-L-glutamic acid.(37.3g 150mmol), and at room temperature stirs and spends the night to add CbzOSu in reaction mixture.After reaction is finished, the reaction mixture that generates is extracted with EA.Separate water layer, it is acidified to pH 2 with dense HCl down at 0 ℃, and once more with EA extraction (4 times).Concentrate organic layer, obtain thick product, it is purified with column chromatography, obtain the titled reference compound (16g) of colorless oil.
Among the Rf:MC/MeOH (9/1) 0.2
(2) preparation of 4-(2-carboxyl-ethyl)-5-oxo-oxazolidines-3-benzyl carboxylate
With the N-Cbz-L-L-glutamic acid (4g that obtains in the previous step (1), 14.22mmol), pTsOH, molecular sieve (5g) and the toluene (100ml) of Paraformaldehyde 96 (5g), catalytic amount places Dean-Rodney Stark (Dean-Stark) device, and reflux and disappear until starting raw material.The reaction mixture that generates is cooled to room temperature, filters and concentrate, obtain thick product, it is purified by column chromatography, obtain the titled reference compound (2g) of colorless oil.
Rf: among the pure EA 0.45
(3) preparation of 5-oxo-5-(3-oxo-propyl group)-oxazolidines-3-benzyl carboxylate
(2g, (0.7ml 7.5mmol) and the DMF of catalytic amount, and at room temperature stirred 2 hours to add oxalyl chloride in MC 6.82mmol) (200ml) solution at the L-glutamic acid of two protections that obtain in previous step (2) under 0 ℃.After the solvent evaporation, the thick acyl chlorides that generates is dissolved among the THF (400ml), (3.86ml 14.34mmol) and the Pd (0) of catalytic amount, and at room temperature stirs and spends the night to wherein slowly adding tri-butyl tin hydride under 0 ℃.After the solvent evaporation, add ether (100ml)/10%KF aqueous solution (100ml), at room temperature stirred 2 hours, filter then, obtain two phase liquid.Separate organic layer and it is concentrated, obtain thick product, it is purified by column chromatography, obtain the titled reference compound (0.7g) of colorless oil.
Among Rf: hexane/EA (4/1) 0.23
(4) preparation of 4-(3,3-dimethoxy-propyl group) 5-oxo-oxazolidines-3-benzyl carboxylate
(0.7g, the pTsOH of adding catalytic amount at room temperature stirred 7 hours the two protection aldehyde that obtain in previous step (3) in MeOH 2.53mmol) (30ml) solution.After reaction is finished, come concentrated reaction mixture, obtain thick product, it is purified by column chromatography, obtain the titled reference compound (0.5g) of colorless oil by evaporating solvent.
Among Rf: hexane/EA (4/1) 0.33
(5) 2-benzyloxycarbonyl amino-5, the preparation of 5-dimethoxy-valeric acid
(0.456g 1.411mmol) is dissolved among MeOH (20ml)/1N NaOH (10ml), at room temperature stirs and spends the night with the two protection acetals that obtain in the previous step (4).After the starting raw material completely dissolve, by the evaporating solvent concentrated reaction mixture, and with its water/EA dilution.Separate water layer, and under 0 ℃, it is acidified to pH 4-5 very carefully with 1N HCl, extract with EA once more.Merge organic layer and it is concentrated, obtain the titled reference compound (0.35g) of colorless oil.
Among the Rf:Hex./EA (1/1) 0.1
(6) 2-amino-5, the preparation of 5-dimethoxy-valeric acid
In the reaction vessel of hydrogen balloon was housed, (0.35g, the 10%Pd/C of (10ml) solution of MeOH 1.13mmol) and catalytic amount at room temperature stirred and spend the night to add the Cbz-acetal that obtains in the previous step (5).The reaction mixture that generates is filtered and concentrates, obtain the thick product (0.2g) of colorless oil, it uses in next step without further purifying.
Among the Rf:Hex./EA (1/1) 0.01
(7) 2-(9H-fluorenes-9-ylmethoxy carbonylamino)-5, the preparation of 5-dimethoxy-valeric acid
In the THF (10ml) of the thick Glu-OH acetal that in previous step (6), obtains/water (10ml) solution, and adding FmocOsu (0.42g, 1.24mmol)/(0.5g 5.9mmol), and at room temperature stirs and spends the night sodium bicarbonate.After the solvent evaporation, with the reaction mixture water/EA dilution that generates.Separate water layer, and under 0 ℃, it is acidified to pH 4-5 very carefully with 1N HCl, and extract with EA once more.Merge organic layer and it is concentrated, obtain the titled reference compound (0.19g) of colorless oil.
TLC system 1: pure EA Rf=0.25
1H-NMR(300MHz，CDCl
3)δppm：1.75(br?m，4H)，3.28(d，6H)，3.43(q，1H)，4.20(t，1H)，4.38(m，3H)，5.62(d，1H)，7.31(m，4H)，7.65(d，2H)，7.75(d，2H)
Preparation embodiment 5
(1) preparation of 2-t-butoxycarbonyl amino-4-methoxycarbonyl-amino-butyric acid
(3g slowly adds NaOH (2.75g, 68.75mmol, 5 equivalents) until pH＞11, the methyl chlorocarbonate in wherein adding toluene (50mL) (2.6g, 27.5mmol, 2 equivalents) in water 13.75mmol) (50mL) solution to Boc-Dab-OH.The reaction mixture that generates was stirred 2 hours.In order to carry out the TLC check, take out small amount of aqueous phase and use the 1NHCl acidifying.After confirming that by TLC reaction is finished, separate organic phase, and with water with the acidifying of 10%HCl solution, with EA extraction (5mL * 2).Merge organic phase, it is used anhydrous Na
2SO
4Drying is vacuum concentration also, obtains the thick product (3.277g, 11.86mmol, 86%) of colorless oil.
TLC system: EA R
f=0.2
1H-NMR(300MHz，CDCl
3)δppm：1.30～1.50(bs，9H)，2.00～2.30(m，2H)，3.10～3.30(m，2H)，3.70(bs，3H)，4.35(m，1H)，5.40(m，1H)，5.65(bs，1H)。
(2) preparation of (1-benzylamino formyl radical-3-methoxycarbonyl amino-propyl group)-t-butyl carbamate
At the 2-t-butoxycarbonyl amino that in previous step (1), obtains under 5 ℃-4-methoxycarbonyl amino-butyric acid (1.1g, 3.98mmol) DMF (20mL) solution in add EDCI (763mg, 3.98mmol, 1 equivalent), HOBT (538mg, 3.98mmol, 1 equivalent) and DIEA (1.4mL, 7.96mmol, and stirred 1 day 2 equivalents).After confirming that by TLC check reaction is finished, under 5 ℃ with reaction soln with 10%HCl acidifying (until pH～4), and extract with EA (20mL).Merge organic phase, it is used saturated NaHCO
3With the salt water washing, use anhydrous Na
2SO
4Dry also vacuum concentration obtains resistates, adds EA and normal hexane and makes its curing, and purify by column chromatography, obtains the titled reference compound (620mg, 1.7mmol, 43%) of white solid.
R
f＝0.7(EA)
1H-NMR(300MHz，CDCl
3)δppm：1.45(bs，9H)，1.75～2.10(m，2H)，3.05(m，1H)，3.45(m，1H)，3.65(s，3H)，4.25(m，H)，4.45(d，2H，J＝5.7Hz)，5.45(m，1H)，7.05(m，1H)，7.20～7.45(m，5H)。
(3) preparation of (3-amino-3-benzyloxycarbonyl group-propyl group)-t-butyl carbamate hydrochloride
(the 1-benzylamino formyl radical-3-methoxycarbonyl amino-propyl group)-t-butyl carbamate (1g that in previous step (2), obtains; 2.7mmol) 1, add 1 in 4-diox (10mL) solution, 4-diox (6.8mL; 4N HCl 27mmol), and stirred 2 hours.After confirming that by TLC check reaction is finished, reaction soln is concentrated and vacuum-drying, obtain the titled reference compound of white solid.
1-benzyl-7-methyl-6-sulfo--six hydrogen-Mi Dingbing [1,6-A] pyrimid-2-one
(A) N-benzyl-3-[3-(2-[1,3] dioxolane-2-base-ethyl)-3 methyl-thioureido]-propionic acid amide
Preparation
Under 0 ℃, the methylene dichloride suspension of Beta-alanine benzyl amido hydrochloride (1.0 equivalent) and N-methylmorpholine (2.2 equivalent) was handled 10 minutes with thiophosgene (1.2 equivalent).Make reaction mixture be warming up to room temperature, and continue to stir 2 hours.Clear soln is diluted with ethyl acetate, and use 10%KHSO
4Solution, distilled water and saturated NaCl solution washing.With organic layer Na
2SO
4Dry and concentrated, obtain the oily resistates.
This product is dissolved in the methylene dichloride, and uses 2-(N-methyl-2-amino-ethyl)-1 down at 0 ℃, 3-dioxolane (0.9 equivalent) was handled 10 minutes.Make reaction mixture be warming up to room temperature, and continue to stir 4 hours.Reactant is diluted with ethyl acetate, and use 10%KHSO
4Solution, distilled water, saturated NaHCO
3Solution, distilled water and saturated NaCl solution washing.With organic layer Na
2SO
4Dry and concentrated, obtain the oily resistates.By this thick product of column chromatography (silica gel, ethyl acetate/hexane=5/2) purification, obtain pure product.
1H-NMR(500MHz，CDCl
3)δppm：2.02(m，2H)，2.60(m，2H)，3.18(s，3H)，3.82(m，2H)，3.88(m，2H)，4.03(m，4H)，4.44(m，2H)，4.91(m，1H)，6.84(br.s，1H)，7.25-7.38(m，5H)；
MS(m/z，ESI)，352(MH
+)
(B) preparation of 1-benzyl-7-methyl-6-sulfo--six hydrogen-Mi Dingbing [1,6-a] pyrimid-2-one
The acid amides that obtains in the previous step (A) was handled 4 days with formic acid under 60 ℃.Decompression, obtains pure topic and states product by preparation TLC (silica gel, ethyl acetate/methanol=5/1) purification resistates down with after the formic acid evaporation.
1H-NMR(500MHz，CDCl
3)δppm：2.05(m，1H)，2.36(m，1H)，2.64(d，1H)，2.96(m，1H)，3.30(m，3H)，3.44(s，3H)，4.42(d，1H)，4.86(br.s，1H)，5.08(d，1H)，5.49(m，1H)，7.25-7.38(m，5H)；
MS(m/z，ESI)，290(MH
+)，311(M
+Na)
1,7-dibenzyl-6-sulfo--six hydrogen-Mi Dingbing [1,6-A] pyrimid-2-one
(A) N-benzyl-3-[3-benzyl-(3,3-diethoxy-propyl group)-thioureido]-preparation of propionic acid amide
Under 0 ℃, the methylene dichloride suspension of Beta-alanine benzyl amido hydrochloride (1.0 equivalent) and N-methylmorpholine (2.2 equivalent) was handled 10 minutes with thiophosgene (1.2 equivalent).Make reaction mixture be warming up to room temperature, and continue to stir 2 hours.Clear soln is diluted with ethyl acetate, and use 10%KHSO
4Solution, distilled water and saturated NaCl solution washing.With organic layer Na
2SO
4Dry and concentrated, obtain the oily resistates.This product is dissolved in the methylene dichloride, and (N-benzyl-1-amino-3,3-di ethyl propyl ether (0.9 equivalent) was handled 10 minutes with 2-down at 0 ℃.Make reaction mixture be warming up to room temperature, and continue to stir 6 hours.The reaction mixture that generates is diluted with ethyl acetate, and use 10%KHSO
4Solution, distilled water, saturated NaHCO
3Solution, distilled water and saturated NaCl solution washing.With organic layer Na
2SO
4Dry and concentrated, obtain the oily resistates.By this thick product of column chromatography (silica gel, ethyl acetate/hexane=2/1) purification, obtain pure topic and state product.
1H-NMR(400MHz，CDCl
3)δppm：1.22(t，6H)，1.95(m，2H)，2.60(m，2H)，3.46(m，2H)，3.60(br.t，2H)，3.63(m，2H)，3.97(m，2H)，4.38(m，2H)，4.52(m，1H)，5.07(br.s，2H)，6.16(br.s，1H)，6.98(br.s，1H)，7.25-7.38(m，10H)；
MS(m/z，ESI)，458(MH
+)
(B) 1, the preparation of 7-dibenzyl-6-sulfo--six hydrogen-Mi Dingbing [1,6-a] pyrimid-2-one
The acid amides that obtains in the previous step (A) was handled 4 days with formic acid under 60 ℃.Decompression by preparation TLC (silica gel, ethyl acetate/methanol=5/1) purification resistates, obtains pure product down with after the formic acid evaporation.
1H-NMR(500MHz，CDCl
3)δppm：1.94(m，1H)，2.24(m，1H)，2.62(m，1H)，3.01(m，1H)，3.18(m，1H)，3.43(m，1H)，3.62(m，1H)，4.39(d，1H)，4.51(m，1H)，4.91(m，1H)，5.02(d，1H)，5.26(d，1H)，5.53(m，1H)，7.25-7.40(m，10H)；
MS(m/z，APCI)，366(MH
+)
1,7-dibenzyl-six hydrogen-Mi Dingbing [1,6-A] pyrimidine-2,6-diketone
(A) N-benzyl-3-[3-benzyl-(3,3-diethoxy-propyl group)-thioureido]-preparation of propionic acid amide
Under 0 ℃, the methylene dichloride suspension of Beta-alanine benzyl amido hydrochloride (1.0 equivalent) and N-methylmorpholine (3.2 equivalent) was handled 10 minutes with thiophosgene (0.7 equivalent).Make reaction mixture be warming up to room temperature, and continue to stir 2 hours.Clear soln is diluted with ethyl acetate, and use 10%KHSO
4Solution, distilled water and saturated NaCl solution washing.With organic layer Na
2SO
4Dry and concentrated, obtain the oily resistates.This product is dissolved in the methylene dichloride, and (N-benzyl-1-amino 3,3-di ethyl propyl ether (0.9 equivalent) was handled 10 minutes with 2-down at 0 ℃.Make reaction mixture be warming up to room temperature, and continue to stir 4 hours.The reaction mixture that generates is diluted with ethyl acetate, and use 10%KHSO
4Solution, distilled water, saturated NaHCO
3Solution, distilled water and saturated NaCl solution washing.With organic layer Na
2SO
4Dry and concentrated, obtain the oily resistates.By this thick product of column chromatography (silica gel, ethyl acetate/hexane=2/1) purification, obtain pure topic and state product.
1H-NMR(400MHz，CDCl
3)δppm：1.23(t，6H)，1.87(m，2H)，2.55(m，2H)，3.24(m，2H)，3.49(m，2H)，3.59(m，2H)，3.65(m，2H)，4.45-4.58(m，5H)，5.62(br.s，1H)，6.57(br.s，1H)，7.25-7.48(m，10H)；
MS(m/z，ESI)，442(MH
+)
(B) 1,7-dibenzyl-six hydrogen-Mi Dingbing [1,6-a] pyrimidine-2, the preparation of 6-diketone
The acid amides that obtains in the previous step (A) was handled 4 days with formic acid under 60 ℃.Decompression by preparation TLC (silica gel, ethyl acetate) purification resistates, obtains inscribing the compound of stating down with after the formic acid evaporation.
1H-NMR(400MHz，CDCl
3)δppm：1.89(m，1H)，2.19(m，1H)，2.58(m，1H)，2.75(m，1H)，3.02(m，3H)，4.42(d，J＝12.4Hz，1H)，4.55(d，J＝2.4Hz，2H)，4.65(m，1H)，4.78(m，1H)，4.98(d，J＝12.4Hz，1H)，7.25-7.38(m，10H)；
MS(m/z，ESI)，350(MH
+)
1,7-dibenzyl-6-oxo-octahydro-Mi Dingbing [1,6-a] pyrimid-2-one
The preparation of the ArgoGel resin of (A) (3-bromo-1-methoxy propane-1-oxo)-connection
With dry ArgoGel resin and tosic acid pyridine (pyridiniumpara-toluensulphonate) (240mg, 0.96mmol) 1,2-ethylene dichloride (15mL) suspension is heated to backflow, removes the water of solvent and trace simultaneously continuously.After removing the cut of about 5mL, add 3-bromo-1,1-Propanal dimethyl acetal (700mg, 3.84mmol) 1,2-ethylene dichloride (5mL) solution, mixture keep to reflux 4 hours, remove continuously EtOH/EDC, use DMF afterwards with the diox washing resin, then the freeze-drying product that obtains requiring.
The preparation of the ArgoGel resin of (B) (3-benzylamino-1-methoxy propane-1-oxo)-connection
With benzyl amine (520mg, DMSO 4.85mmol) (4mL) solution join the bromoacetal resin (1g, 0.48mmol) in, with suspension 60 ℃ of down vibrations 15 hours.With the resin filter that generates, and wash with DMSO, MeOH and MC, vacuum-drying is spent the night.Detect secondary amine by the chloranil test.
(C) preparation of Beta-alanine benzyl amine urea
At room temperature (80mg adds triphosgene (0.72mmol) in N-methylmorpholine 0.36mmol) (120 μ l) and MC (2mL) solution to Beta-alanine benzyl acid amides HCl salt.After 10 minutes, the isocyanate solution that generates is joined the secondary amine resin that obtains in the previous step (2), and (100mg is in suspension 0.048mmol), and sustained oscillation at room temperature 3 hours.With DMF, MeOH and MC washing resin, and finishing by chloranil test detection reaction.
(D) 1, the preparation of 7-dibenzyl-6-oxo-octahydro-Mi Dingbing [1,6-a] pyrimid-2-one
The resin that contains thiourea group in the step (C) is handled with formic acid, and sustained oscillation 15 minutes.The elimination resin concentrates filtrate and purifies by chromatography (silica gel), obtains inscribing the compound of stating.
1H-NMR(500MHz，CDCl
3)δppm：1.94(m，1H)，2.24(m，1H)，2.62(m，1H)，3.01(m，1H)，3.18(m，1H)，3.43(m，1H)，3.62(m，1H)，4.39(d，1H)，4.51(m，1H)，4.91(m，1H)，5.02(d，1H)，5.26(d，1H)，5.53(m，1H)，7.25-7.40(m，10H)；
MS(m/z，APCI)，366(MH
+)
Embodiment 5
1,7-dibenzyl-2-oxo-6-sulfo--octahydro-Mi Dingbing [1,6-a] pyrimidine-4-benzyl carboxylate
(A) preparation of 2-isothiocyanato-succsinic acid 1-benzyl ester 4-(9H-fluorenes-9-ylmethyl) ester
(1g adds DIC (532 μ l, 1.1 equivalents), DMAP (188mg, 0.5 equivalent) and fluorenyl methyl alcohol (635mg, 1.05 equivalents) in MC solution 3.09mmol) to 2-t-butoxycarbonyl amino-succsinic acid 1-benzyl ester.After reaction is finished, with reaction mixture 1N hydrochloric acid and the saturated NaHCO that generates
3Solution washing, and, obtain fluorenyl methyl esters (400mg) by column chromatography (silica gel) purification.
This ester is diluted in the diox (10ml), and adds the 4NHCl solution of diox, and continue to stir 2 hours, to remove the Boc protecting group.After reaction is finished, with the solution evaporate to dryness.The HCl salt of amine is diluted with MC and N-methylmorpholine, add thiophosgene (1.2 equivalent) down at about 0 ℃.After reaction is finished, with mixture 10%KHSO
4Solution, distilled water, saturated NaHCO
3Solution, distilled water and saturated NaCl solution washing.With organic layer Na
2SO
4Dry and concentrated, obtain the oily resistates.By this thick product of column chromatography (silica gel, ethyl acetate/hexane=1/1) purification, obtain pure topic and state product.
(B) aspartic acid benzyl, fluorenyl ester thiocarbamide
With the MC solution and the N-methylmorpholine of the isocyanic ester (0.5mmol) that obtains in the previous step (A), join that (200mg is in suspension 0.04mmol), and sustained oscillation at room temperature 3 hours as resulting secondary amine resin in embodiment 4 steps (B).The resin that generates is washed with DMF, MeOH and MC, and finishing by chloranil test detection reaction.
(C) aspartic acid thiocarbamide benzyl acid amides
With the resin that obtains in the previous step (B) swelling 30 minutes in DMF (4mL), and add 25% piperidine solution, to cut off the protection of fluorenyl methyl.The resin that generates is washed with DMF, MeOH and MC.With the resin drying under reduced pressure, and swelling once more, to wherein add DIC (8 μ L, 0.05mmol), HOBt (8mg, 0.05mmol) and DIEA (18 μ L, 0.1mmol), so that acid is activated.Vibrate after 30 minutes, add benzyl amine and sustained oscillation and spend the night, obtain required benzyl amide resins.
(D) 1, the system of 7-dibenzyl-2-oxo-6-sulfo--octahydro-Mi Dingbing [1,6-a] pyrimidine-4-benzyl carboxylate
Be equipped with
With the resin swelling in MC (4mL) that obtains in the previous step (C), to wherein adding PPTS (10mg), and, obtain inscribing the compound of stating 60 ℃ of heating 4 hours down.MS(m/z，ESI)，500(MH
+)。
Embodiment 6
7-benzyl-6-sulfo--six hydrogen-Mi Dingbing [1,6-a] pyrimidine-1-benzyl carboxylate
(A) 3-[3-benzyl-3-(3,3-diethoxy-propyl group)-thioureido]-propyl group }-benzyl carbamate
Preparation
Under 0 ℃, the MC suspension of Cbz-diaminopropanes HCl salt (1.0 equivalent) and N-methylmorpholine (2.2 equivalent) was handled 10 minutes with thiophosgene (1.2 equivalent).Make the solution that generates be warming up to room temperature, and continue to stir 2 hours.The settled solution that generates is diluted with ethyl acetate, and use 10%KHSO
4, water and saturated NaCl washing.With organic layer Na
2SO
4Drying is also concentrated, obtains the oily resistates, it is dissolved among the MC, and uses N-benzyl-1-amino-3 down at 0 ℃, and 3-di ethyl propyl ether (0.9 equivalent) processing 10 minutes makes it be warming up to room temperature then and continuation was stirred 6 hours.The reaction mixture that generates is diluted with ethyl acetate, and use 10%KHSO
4Solution, water, saturated NaHCO
3, water and saturated NaCl washing.With organic layer Na
2SO
4Dry and concentrated, obtain the oily resistates, make it pass through column chromatography (silica gel, ethyl acetate/hexane, 2/1) subsequently and purify, obtain inscribing the compound of stating.
1H-NMR(400MHz，CDCl
3)δppm：1.17(t，6H)，1.5(bs，2H)，1.75(t，2H)，1.92(m，2H)，3.20(q，2H)，3.45(m，2H)，3.60(m，4H)，3.75(q，2H)，4.51(t，1H)，5.06(s，4H)，6.75(br.s，1H)，7.25-7.38(m，10H)；
MS(m/z，ESI)，442(M-OEt
+)。
(B) preparation of 7-benzyl-6-sulfo--six hydrogen-Mi Dingbing [1,6-a] pyrimidine-1-benzyl carboxylate
Add PPTS in the MC solution of the acid amides that in previous step (A), obtains, and under 70 ℃, stir and spend the night.The reaction mixture that generates is under reduced pressure concentrated, obtain resistates, it is purified by preparation TLC (pure ethyl acetate), obtain inscribing the compound of stating.
1H-NMR(400MHz，CDCl
3)δppm：1.89(m，2H)，1.95(m，1H)，2.63(m，1H)，2.80(m，1H)，3.10(m，1H)，3.45(m，1H)，3.89(m，1H)，4.01(m，1H)，4.39(d，1H)，4.51(m，1H)，4.92(m，2H)，5.10(m，2H)，7.16-7.4(m，10H)；
MS(m/z，ESI)，396(MH
+)
Embodiment 7
8-ethanoyl-6-oxo-six hydrogen-pyrazine is [1,2-a] pyrimidine-1-benzyl carboxylate also
(A) preparation of [ethanoyl-(2,2-dimethoxy-ethyl)-amino]-acetate
At room temperature in the MeOH solution of benzyl glycine HCl salt (1 equivalent), add dimethoxy acetaldehyde (1.05 equivalent), add NaCNBH then
3(1.2 equivalent) stirred 5 hours.The reaction mixture that generates is under reduced pressure concentrated, obtain the oily resistates, it is dissolved among the MC, and uses saturated NaHCO
3Solution, water and saturated NaCl solution washing.With organic layer Na
2SO
4Dry and concentrated, obtain the oily resistates, it is dissolved among the MC, and handles with triethylamine (3 equivalent) and Acetyl Chloride 98Min. (1.1 equivalent) down at 0 ℃.
After reaction is finished, with the saturated NaHCO of reaction mixture that generates
3Solution, water and saturated NaCl solution washing.With organic layer Na
2SO
4Dry and concentrated, obtain the oily resistates, it is purified by column chromatography (silica gel, ethyl acetate), obtain pure product.With this product with 10%Pd/C with contain H
2Balloon hydrogenation, obtain inscribing the compound of stating, it is used for next step without further purifying.
1H-NMR(400MHz，CDCl
3)δppm：2.09(s，1H)，2.20(s，2H)，3.40(d，6H)，3.48(d，2H)，4.16(s，2H)，4.44(m，1H)
(B) (3-{2-[ethanoyl-(2,2-dimethoxy-ethyl)-amino]-acetylamino }-propyl group)-amino
The preparation of benzyl formate
Add HATU (1 equivalent), DIPEA (3 equivalent) and Cbz-diaminopropanes HCl salt (1.0 equivalent) in the MC solution of the acid that in previous step (A), obtains (1 equivalent), and at room temperature stirred 3 hours.Reaction mixture is under reduced pressure concentrated, obtain the oily resistates, it is purified by preparation TLC, obtain inscribing the compound of stating.
1H-NMR(400MHz，CDCl
3)δppm：1.60(m，2H)，2.01(s，1H)，2.20(s，2H)，3.20(d，2H)，3.24(m，2H)，3.40(d，6H)，3.50(d，2H)，4.06(s，2H)，4.44(m，1H)，5.08(s，2H)，5.18(d，1H)，6.91(br?d，1H)，7.16(br?s，5H)；
MS(m/z，ESI)，396(MH
+)
(C) the also preparation of [1,2-a] pyrimidine-1-benzyl carboxylate of 8-ethanoyl-6-oxo-six hydrogen-pyrazine
In the MC solution of the amide precursor of the Cbz protection that under room temperature, in previous step (B), obtains, add PPTS (1 equivalent), and be heated to 70 ℃, heated 5 hours.Concentrate the reaction mixture that generates, obtain resistates, its sign is as follows.
1H-NMR(400MHz，CDCl
3)δppm：1.90(m，2H)，2.10(s，1H)，2.30(s，2H)，2.61(m，1H)，2.82(m，1H)，3.15(m，1H)，3.50(m，1H)，3.9(m，1H)，4.0(m，1H)，4.2(m，1H)，4.3(s，1H)，4.47(m，1H)，5.08-5.18(m，2H)，5.28(br?s，1H)，7.16(br?s，5H)；
MS(m/z，ESI)，332(MH
+)
Embodiment 8
7-benzyloxy amino-4-benzylamino formyl radical-6-oxo-six hydrogen-pyrrolo-[1,2-a] pyrimidine-1-carboxylate methyl ester
(A) [1-(1-benzylamino formyl radical-3-methoxycarbonyl amino-propyl group formamyl)-3,3-two
Methoxyl group-propyl group]-preparation of benzyl carbamate
In the MC solution of the amino acid acetal (100mg, 1.3 equivalents) of the Cbz protection that in preparation embodiment 3 (3), obtains, add PyBOP (1 equivalent of acid), DIPEA (6 equivalents of acid) and HOBt (1.3 equivalent), and stirred 30 minutes.(71mg 0.27mmol), stirred 7 hours to add aminobenzyl acid amides HCl salt in reaction mixture.With the saturated NaHCO of reaction mixture that generates
3, water and saturated NaCl washing.With organic layer MgSO
4Dry and concentrated, obtain the oily resistates, it is purified by column chromatography (silica gel, ethyl acetate), obtain inscribing compound (50mg, the productive rate: 35%) stated.
1H-NMR(300MHz，CDCl
3)δppm：2.1(t，2H)，3.05(m，1H)，3.50(ss，6H)，3.45(m，1H)，3.75(s，3H)，4.25(q，1H)，4.41(m，2H)，4.55(m，1H)，5.0(q，2H)，5.3(m，1H)，5.95(m，1H)，7.2-7.4(m，10H)
(B) 4-benzylamino formyl radical-7-benzyloxy formamyl-6-oxo-six hydrogen-pyrrolo-[1,2-a]
The preparation of pyrimidine-1-carboxylate methyl ester
(5mg 0.009mmol) is dissolved in the formic acid (1mL), and stirring is spent the night with the acetal acid amides cyclisation precursor that obtains in the previous step (A).The reaction mixture that generates is concentrated into drying, and it is used for next step without further purifying.
1H-NMR(300MHz，CDCl
3)δppm：2.25(m，2H)，2.61(t，2H)，3.24(m，1H)，3.50(s.3H)，3.55(m，1H)，3.95(m，1H)，4.45(m，2H)，4.65(d，1H)，4.8(m，2H)，5.3(m，1H)，5.7(d，1H)，7.15-7.4(m，10H)，7.85(m，1H)
(C) 7-benzyloxy amino-4-benzylamino formyl radical-6-oxo-six hydrogen-pyrrolo-[1,2-a] pyrimidine-1-
The preparation of carboxylate methyl ester
At room temperature MeOH solution and the Pd/C (1mg) with the Cbz dicyclic compound that obtains in the previous step (B) places the reaction vessel that hydrogen balloon is housed, and stirs 2 hours.After reaction is finished, reaction mixture is removed by filter Pd/C with kieselguhr filter, and the vapourisation under reduced pressure solvent.The oily resistates that generates is dissolved among the MC,, stirred 30 minutes to the MC solution that wherein adds phenylformic acid (1.1 equivalent) and PyBOP (1.1 equivalent), HOBt (1.1 equivalent) and DIPEA (3 equivalent).In the solution of the activated acids that generates, add amine aqueous solution, continue to stir 3 hours.The reaction mixture that generates is under reduced pressure concentrated, obtain the oily resistates, it is purified by preparation TLC, obtain inscribing the compound of stating.
1H-NMR(300MHz，CDCl
3)δppm：2.25(m，2H)，2.65(m，2H)，3.27(m，1H)，3.70(s，3H)，3.6(m，1H)，4.10(m，1H)，4.54(m，2H)，4.8(t，1H)，5.45(m，1H)，7.15-7.42(m，10H)，7.9(d，1H)，8.31(t，1H)
Embodiment 9
7-benzyloxy amino-4-(1-carboxyl-ethylamino formyl radical)-6-oxo-six hydrogen-pyrrolo-[1,2-a] pyrimidine-1-carboxylate methyl ester
Fig. 3 has shown the methodological synthetic schemes that is used to illustrate embodiment 9.
With 2-chlorine trityl chloride resin (200mg, 1mmol/g) and DCE (2mL) solution of Fmoc-L-Ala (1.5 equivalents, commercially available) and DIEA (2 equivalent) place the bottle of tool nut.Reaction mixture was at room temperature vibrated 12 hours.Collect resin by filtering, and it is used DMF, MeOH, with the DCM washing, obtain first and form fragment then.
Before reaction, be added in 25% piperidines among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat this deprotection steps, with product mixtures DMF, MeOH, wash with DCM then then.The nmp solution that in resin, adds 2-(9H-fluorenes-9-ylmethoxy carbonylamino)-4-methoxycarbonyl amino-butyric acid (1.5 equivalents, second forms fragment), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
Before reaction, be added in 25% piperidines among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat this deprotection steps, and, use DCM washed product mixture then with DMF, MeOH.In resin, add 2-(9H-fluorenes-9-ylmethoxy carbonylamino)-5, the nmp solution of 5-dimethoxy-valeric acid (1.5 equivalent), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
Before reaction, be added in 25% piperidines among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat this deprotection steps, with product mixtures DMF, MeOH, wash with DCM then then.The nmp solution that in resin, adds commercially available phenylformic acid (1.5 equivalent), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
At room temperature use formic acid (every hole 1.2mL) to handle 18 hours resin.Afterwards, remove by filter resin, filtrate is under reduced pressure concentrated, obtain the oily product.
1H-NMR(300MHz，MeOH-d
4)δ1.40(d，3H)，1.90(m，1H)，2.20(m，1H)，2.30～2.25(m，2H)，3.15(m，1H)，3.20(m，1H)，3.45(s，3H)，3.40～3.60(m，1H)，4.20～4.40(m，2H)，4.70(t，1H)，5.40(t，1H)，7.25～7.45(m，3H)，7.75(d，2H)；
MS(m/z，ESI)：433(MH
+)，455(MNa
+)
Embodiment 10
7-benzyloxy amino-4-(2-carboxyl-propyl group formamyl)-6-oxo-six hydrogen-pyrrolo-[1,2-a] pyrimidine-1-carboxylate methyl ester
Fig. 4 has shown the methodological synthetic schemes that is used to illustrate embodiment 10.
With 2-chlorine trityl chloride resin (200mg, 1mmol/g) and DCE (2mL) solution of Fmoc-Beta-alanine (1.5 equivalent) and DIEA (2 equivalent) place the bottle of tool nut.At room temperature with reaction mixture vibration 12 hours.Collect resin by filtering, and it is used DMF, MeOH, with the DCM washing, obtain first and form fragment then.
Before reaction, be added in 25% piperidines among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat this deprotection steps, product mixtures with DMF, MeOH, is washed with DCM then.The nmp solution that in resin, adds 2-(9H-fluorenes-9-ylmethoxy carbonylamino)-4-methoxycarbonyl amino-butyric acid (1.5 equivalents, second forms fragment), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
Before reaction, be added in 25% piperidines among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat deprotection steps, with product mixtures DMF, MeOH, wash with DCM then then.In resin, add 2-(9H-fluorenes-9-ylmethoxy carbonylamino)-5, the nmp solution of 5-dimethoxy-valeric acid (1.5 equivalent), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
Before reaction, be added in 25% piperidines among the DMF in DMF swollen resin.Afterwards, reaction mixture was at room temperature vibrated 30 minutes.Repeat this deprotection steps, with product mixtures DMF, MeOH, wash with DCM then then.The nmp solution that in resin, adds commercially available phenylformic acid (1.5 equivalent), DIC (1.5 equivalent) and HOBT (1.5 equivalent).After reaction mixture at room temperature vibrated 12 hours,, use the DCM washing resin then with DMF, MeOH.
At room temperature use formic acid (every hole 1.2mL) to handle 18 hours resin.After removing by filter resin, filtrate is under reduced pressure concentrated, obtain the oily product.
1H-NMR(300MHz，MeOH-d
4)δ1.40(d，3H)，1.90(m，1H)，2.20(m，1H)，2.30～2.50(m，2H)，3.15(m，2H)，3.35(s，3H)，3.40～3.60(m，3H)，4.20～4.40(m，2H)，4.70(t，1H)，5.40(t，1H)，7.25～7.45(m，3H)，7.75(d，2H)。
MS(m/z，ESI)：447(MH
+)，469(MNa
+)
This paper has listed the reference of some process of various detailed descriptions, compound and/or composition, and is incorporated herein its full content as a reference.
Should recognize,, can carry out various modifications without departing from the spirit and scope of the present invention although described the specific embodiment of the present invention at this for illustrative purposes.Therefore, the present invention is not limited by other except being subjected to the appended claims restriction.
Claims (5)
1. one kind is selected from following compound:
1-benzyl-7-methyl-6-sulfo--six hydrogen-Mi Dingbing [1,6-a] pyrimid-2-one;
1,7-dibenzyl-6-sulfo--six hydrogen-Mi Dingbing [1,6-a] pyrimid-2-one;
1,7-dibenzyl-six hydrogen-Mi Dingbing [1,6-a] pyrimidine-2,6-diketone;
1,7-dibenzyl-6-oxo-octahydro-Mi Dingbing [1,6-a] pyrimid-2-one;
1,7-dibenzyl-2-oxo-6-sulfo--octahydro-Mi Dingbing [1,6-a] pyrimidine-4-benzyl carboxylate;
7-benzyl-6-sulfo--six hydrogen-Mi Dingbing [1,6-a] pyrimidine-1-benzyl carboxylate;
8-ethanoyl-6-oxo-six hydrogen-pyrazine is [1,2-a] pyrimidine-1-benzyl carboxylate also;
7-benzyloxy amino-4-benzylamino formyl radical-6-oxo-six hydrogen-pyrrolo-[1,2-a] pyrimidine-1-carboxylate methyl ester;
7-benzyloxy amino-4-(1-carboxyl-ethylamino formyl radical)-6-oxo-six hydrogen-pyrrolo-[1,2-a] pyrimidine-1-carboxylate methyl ester; With
7-benzyloxy amino-4-(2-carboxyl-propyl group formamyl)-6-oxo-six hydrogen-pyrrolo-[1,2-a] pyrimidine-1-carboxylate methyl ester.
2. pharmaceutical composition, it comprises compound according to claim 1 and pharmaceutically acceptable carrier.
3. the application of compound according to claim 1 in the medicine of preparation discriminating bioactive compounds.
4. compound according to claim 1 is in preparation application in the kinase whose medicine of inhibition in warm-blooded animal.
5. the application of compound according to claim 1 in the medicine of preparation inhibition CAAX in warm-blooded animal.
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