CN1094730A - Peptides - Google Patents
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- CN1094730A CN1094730A CN 93105500 CN93105500A CN1094730A CN 1094730 A CN1094730 A CN 1094730A CN 93105500 CN93105500 CN 93105500 CN 93105500 A CN93105500 A CN 93105500A CN 1094730 A CN1094730 A CN 1094730A
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Abstract
Free form or salt form also have pharmacological activity for example IL-1 β discharge dipeptides, tripeptides and the tetrapeptide of inhibition, wherein last a-amino acid is based on aspartic acid, and is with a residue A
5, it is H; CF
3-Z
1-Z
2-Y
2, Z wherein
1And Z
2Respectively be direct key or a-amino acid residue, Y
2Be NH
2, C
1-4Alkylamino, two (C
1-4Alkyl) amino or via nitrogen and Z
2The heterocyclic radical that connects;-CH
2-X
1-Y
3, X wherein
1Be oxygen or sulphur, Y
3Be heteroaryl;-CH
2-Y
3Substituted-phenyl; Nuclear substituted phenoxy group methylene radical or thiophenyl methylene radical; Nuclear substituted pyridyloxy methylene radical; Or-CH
2-X
1-CO-Y
4Base, wherein X
1Be oxygen or sulphur, Y
4Phenyl or pyridyl for trialkyl methyl or replacement.
Description
Composition in the pharmacy that the present invention relates to have the peptide of pharmacy practicality, method that they produce, forms by them and the purposes in pharmacy thereof.More specifically, the invention provides a kind of compound of chemical formula I
Wherein
R is hydrogen, amino protecting group, or chooses the benzyloxy that replacement is arranged on ring wantonly;
A
1Be Xie Ansuan, leucine, L-Ala, Isoleucine or trimethyl silyl-L-Ala,
A
2Be phenylalanine or tyrosine,
N is 0 or 1,
A
3Be a direct key, Xie Ansuan, leucine, L-Ala, Isoleucine, trimethyl silyl-L-Ala, or the divalent group of a chemical formula (a)
Wherein optional available hydroxyl or C
1-4Alkoxyl group replaces A on the A ring
4It is the divalent group of a direct key or a chemical formula (b)
R wherein
1Be hydrogen or C
1-4Alkyl, and
Y
1For being connected with the alpha-carbon atom of a-amino acid and can choosing the residue of being protected ,-CH wantonly
2-CH
2-N(C
1-2Alkyl)
2, imidazoles-2-base-methyl, benzimidazolyl-2 radicals-ylmethyl, 1H-1,2,4-triazole-3-base-methyl, pyrazole-3-yl methyl, indazole-3-base-methyl or chemical formula (c) or group (d)
Wherein
R
2And R
3Be hydrogen, halogen, C independently respectively
1-4Alkyl, CF
3Or trityl, R
2And R
3In have only one to be H at most, and R
4And R
5Be hydrogen, C independently respectively
1-4Alkyl, hydroxyl, C
1-4Alkoxyl group, CF
3, phenyl or halogen, at R
4And R
5In have only one to be H at most, or A
3And A
4Form the group of a chemical formula (aa) together
Y wherein
1Defined as mentioned, and R
1And R
1aFormation-(CH together
2) m-, wherein m is 2,3,4 or 5, and
1) X is a chemical formula (e
1) divalent group
R wherein
6For H is C
1-4Alkyl,
And A
5Be hydrogen; CF
3;-Z
1-Z
2-Y
2Group, wherein Z
1And Z
2Be independently respectively a direct key or-the a-amino acid residue, and Y
2Be NH
2, C
1-4Alkylamino, two (C
1-4Alkyl) amino, or via nitrogen and Z
2The heterocyclic radical that connects;-CH
2-X
1-Y
3Group, wherein X
1Be O(oxygen) or S(sulphur) and Y
3Be assorted aromatic base;-CH
2-Y
3Group; Or chemical formula (k) arrives a group in (m)
Wherein
Y
4Be three (C
1-4Alkyl) methyl, or residue
The B ring is pyridyl,
The C ring is phenyl or pyridyl,
R
7And R
8Be C independently respectively
1-4Alkyl,
C
1-4Alkoxyl group, CF
3, halogen, nitro or cyano group, and
R
9, R
10And R
11Be nitro, cyano group, CF independently respectively
3, carbamyl, CO
2R
12,-CH=CH-CN or-CH=CHCO
2R
12,
R wherein
12Be C
1-6Alkyl,
X also can be chemical formula (e
2) divalent group
This moment A
5Be H, or
2) X is the divalent group of a chemical formula (f)
And A
5For as hereinbefore defined-Z
1-Z
2-Y
2, or a kind of group of chemical formula (k) in (o), or be OR
13Or NR
14R
15, R wherein
13For can choose wantonly with OH replace or with O(oxygen) C that interrupts
1-12Alkyl, and R
14And R
15Be hydrogen, C independently respectively
1-12Alkyl, C
6-7Cycloalkyl or phenmethyl, or
3) X is the divalent group of chemical formula (g)
And A
5For as hereinbefore defined-Z
1-Z
2-Y
2, or
4) X is chemical formula (h) or divalent group (j)
And A
5Be as hereinbefore defined chemical formula (k) group in (o),
-CH
3-Y
3Or-CH
2-X
1-Y
3,
Its collateral condition is when n is 0, A
3And A
4In only have one can be direct key, and when n is 1, A
3With A
4It not direct key;
And hydrolyzable and acceptable esters or amides and exist on the physiology of this compound with the form of free form, salt form or mixture.
The example of the protecting group such as R is: for example at " protecting group in the organic synthesis (Protective Groups in Organic Synthesis) ", T.W.Greene, J.Wiley and Sons NY(1981), disclosed among the 219-287, acyl group for example is as ethanoyl, methoxy succinyl, hydroxyl succinyl or can choose the benzoyl that replaces with for example right-methoxycarbonyl, right-methoxyl group or right-nitro wantonly on phenyl ring; Carbalkoxy is such as tertbutyloxycarbonyl; The aromatic base methoxycarbonyl, such as the 9-fluorenylmethyloxycarbonyl maybe can choose wantonly on phenyl ring with right-methoxyl group, right-nitro, right-chlorine or-benzyloxy that phenyl replaces; The aromatic base methyl is such as can choose the phenmethyl that replaces with right-methoxyl group, right-nitro or right-chlorine wantonly on ring; Or the aromatic base alkylsulfonyl, such as can choosing the phenyl sulfonyl that on ring, replaces with right-methyl, right-methoxyl group wantonly, or can choose wantonly on ring with for example amino or two (C
1-4Alkyl) the naphthyl alkylsulfonyl that replaces of amino.
When R is when on the ring benzyloxy of replacement being arranged, preferably with hydroxyl or C
1-4Benzyloxy, preferable R that alkoxyl group replaces are the benzyloxies that is unsubstituted.
Halogen is fluorine or chlorine preferably then.
Work as A
3During for the group of the chemical formula (a) that replaces, with C
1-4It is preferable that alkoxyl group replaces, and preferably the contraposition at-C=0 replaces.
The meaning of a-amino acid is meant naturally occurring or can be through a-amino acid commercial acquisition or non-natural, or its optically active isomer.Non-natural a-amino acid is a kind of amino acid that can not be incorporated under the order of mRNA in the protein, for example β-Nal, fluoro-a-amino acid, and as fluoro L-Ala, trimethyl silyl-L-Ala, or such as
And so on a-amino acid, wherein n is from 1 to 6 integer, and n
2Integer for from 1 to 12.
Can appear at Y
1On protecting group, be protection O(oxygen on the side switch amino of a-amino acid), S(sulphur) or N(nitrogen) base of functionality.The N-protected base for example is: the R that is disclosed, or the C such as sec.-propyl as mentioned
3-5Alkyl, formyl radical, the saccharide residue such as 1-deoxidation-fructosyl or alpha-glucose-based (1-4)-deoxidation-fructosyl, the dihydroxyl C such as dihydroxypropyl
3-6Alkyl, the C such as cyclohexyl or tropyl (tropinyl)
5-7Cycloalkyl.O-and S-protecting group for hydroxyl or thiol functionality are known, and for example can be: methyl, the tertiary butyl or phenmethyl.
Work as Y
2When being a heterocyclic group, can be 5 or 6 Yuans rings for example, for example: piperidino-(1-position only) or pyrrolidyl.
As Y
3The example of heterocyclic aromatic base comprise, for example: by at least one nitrogen with optionally use more heteroatoms, such as N(nitrogen), O(oxygen) or S(sulphur) 5,6 or 7 Yuans unsaturation heterocyclic groups being formed.Preferable Y
3For containing the assorted aromatic base of from 1 to 4 nitrogen-atoms, for example: pyridyl, triazolyl, tetrazyl, three azines-diketo (triazin-dionyl).
In the B of group (o) ring, nitrogen-atoms can adjacent-,-or contraposition.When the ring of the C in the group (k) was pyridyl, it can be 3-, 4-or 5-pyridyl.
Group (e
1), (e
2), (f), (g) and (j) be derived from aspartic acid and contain an asymmetric carbon atoms that group (h) then contains two asymmetric carbon atoms, and therefore causes rotational isomerism.Self-evident, unless otherwise indicated, present invention includes all indivedual isomeric form and diastereomer and mixture, for example: racemoid.
Attach to A
5Chemical formula (e for hydrogen
1) group, can annular form and the non-annularity form exist, for example:
Must understand and change form part occurring, the present invention promptly comprises lactol and two kinds of forms of oxo-carboxylic acid, that is to say, though will be chemical formula (e in the compound of chemical formula I for convenience
1) the X of group only be defined as the form of oxo-carboxylic acid, but the present invention can not be interpreted as being subjected to the restriction of any degree of employed specific named or graphic describing.Same reason be applicable to as described in hereinafter, about showing the initial substance of lactol/oxo-carboxylic acid tautomerism.
Identical reason also is applicable to the group of chemical formula (h), it can chain and two kinds of forms of cyclic exist, as follows:
And be applicable to the compound of the chemical formula I that contains chemical formula (h) group, and be applicable to corresponding initial substance.
With " hydrolyzable and acceptable esters or amides on the physiology " ester class or amides that this wording was meant, hydrolyzable under physiological condition and produce they itself can acceptance on physiology alcohols or amine, that is to say that this ester class or amides are nontoxic when the dosage content of wanting.
This ester class or amides can be that the compound of chemical formula I that has a group of carboxyl carries out esterification or amidation respectively and obtains by means of X wherein.Such ester class comprises the ester class that has aliphatics or alicyclic alcohol or have the polyvalent alcohol of 1 to 12 carbon atom.The amides of this class then comprises and has for example C of fatty amine
1-4Alkylamine, the C such as 'beta '-methoxy-ethylamine
1-4Alkoxy C
1-4Alkylamine or have the amides of aniline.
The compound of chemical formula I can be for example: free form, the form of acid salt, or exist with the form of its mixture.For example available: organic acid, polymeric acid or mineral acid form the acid salt class.The form of this acid salt comprises, for example: hydrochloride and acetate salt.Salt form can comprise also that those can obtain by the carboxylic acid group of the compound of chemical formula I, for example: the alkaline metal salt such as sodium or potassium, or replace or the ammonium salt of replacement not.The formation of mixture, for example: can make the compound of chemical formula I, carry out the addition with inorganic substance, for example: with inorganic salts or oxyhydroxide,, carry out addition, and/or make it carry out addition with polymerized organics matter as calcium and zinc salt and so on.
In the compound of chemical formula I, the following definien of tool is for independent person, or is preferable with any combination or inferior combination:
1. R is an amino protecting group or benzyloxy, preferably an amino protecting group.When n is 0 and A
3During for the group of chemical formula (a), R is preferably benzyloxy.
2. A
3And A
4It not direct key.
3. n is 0.
4. when n is 0, A
3Group for chemical formula (a).
5. A
3Be a direct key, Xie Ansuan, leucine, L-Ala, Isoleucine or trimethyl silyl L-Ala.
6. R
1Be hydrogen or methyl, hydrogen preferably.
7. Y
1Be the residue on the alpha-carbon atom that is attached at a-amino acid; amino acid is selected from L-Ala, leucine, Histidine, phenylalanine, methionine(Met), tryptophane, trimethyl silyl L-Ala; and can choose arginine, ornithine and the Methionin of protecting with side chain, perhaps Y wantonly
1Group for chemical formula (c).
8. when n is 0, A
3And A
4Also can form the group of chemical formula (aa) together.
9. m is 2 or 3.
10. X is chemical formula (e
1) group, and A
5Not hydrogen.
11. X is the group of chemical formula (g).
12. X is chemical formula (h) or group (j).
13. R
6Be hydrogen or methyl, preferably hydrogen.
14. R
5In Z
1Be the residue of a natural a-amino acid, the residue, particularly proline(Pro) of preferably aromatic/heterocyclic a-amino acid.
15. A
5In Z
2Be the residue of a natural a-amino acid, the a-amino acid of aliphatics is preferable, does not particularly have other functional groups' aliphatics a-amino acid, preferably Xie Ansuan.
16. X is for can choosing the group of in addition esterification or amidated chemical formula (e) wantonly, and A
5Be chemical formula (k), (l) or group (o).
17. X is for choosing in addition esterification or amidated chemical formula (e wantonly
1), (h) or group (j), and A
5For-CH
2-X
1-Y
3, preferably-CH
2-S-Y
3Or-CH
2-Y
3
18. X is for can choosing the group of in addition esterification or amidated chemical formula (h) wantonly, and A
5Be (k).
19. X is for can choosing the group of in addition esterification or amidated chemical formula (j) wantonly, and A
5Group for chemical formula (m).
20. the group of chemical formula (m) is a monosubstitution, is preferably in the contraposition, is preferably the 4-nitrophenyl.
21. except X, the residue of the a-amino acid that is occurred all has the L-configuration.X has D-or L-configuration.
Has configuration S 22. on (j), have the asymmetric carbon of OH base.Preferably go up it R is arranged at (j)
6Asymmetric carbon have configuration R.
In a series of specific embodiments, the present invention also provides the compound of chemical formula I, wherein
N is 0, A
3Be a direct key, Xie Ansuan, leucine, L-Ala, Isoleucine or or the trimethyl silyl L-Ala, A
4As hereinbefore defined, or A
3With A
4Form the group of chemical formula (aa) as hereinbefore defined together, and
ⅰ) X is chemical formula (e as hereinbefore defined
1) or (e
2) group, and A
5Be hydrogen, or
ⅱ) X is chemical formula (e
1) or group (f), and A
5For as hereinbefore defined-Z
1-Z
2-Y
2Or X wherein
1Be 0 chemical formula (k), (l) or group (m).
ⅲ) X is the group and the A of chemical formula (g)
5For-Z
1-Z
2-Y
2, or
ⅳ) X is the group and the A of chemical formula (j)
5Be X wherein
1Be 0 chemical formula (k), (l) or group (m).
The present invention also provides the method for the compound for preparing the chemical formula I, and its process comprises:
(a) from the compound of the chemical formula I of guard mode, remove at least one protecting group, or, add a protecting group R at the N-end group group place of the compound of chemical formula I; Or
(b) compound of a chemical formula I is transformed into the compound of another chemical formula I; Or
(c) by means of an amido linkage two peptide fragment are coupled at together, each peptide fragment contains at least one amino acid under protection or non-guard mode, and peptide fragment contains chemical formula (e as hereinbefore defined
1) a group in (j), make these protected or not protected peptide fragment have with above shown in the corresponding to sequence of compound of chemical formula I, if need, can from the compound of the chemical formula I guard mode, remove one or more protecting groups; Or
(d) X is chemical formula (e in order to prepare wherein
1) or group (h), and A
5For chemical formula (k), (l) or (o), or-CH
2-X
1-Y
3The compound of chemical formula I, with the compound of chemical formula III
R-[A
1-A
2]
n-A
3-A
4-X′-CH
2-Z
a（Ⅲ）
Wherein R, A
1To A
4And n definition as mentioned, X ' is chemical formula (e
1) or group (h), and Z
aBe a leavings group, for example: halogen,
With corresponding phenol, thiophenol or pyridone, or chemical formula HX
1Acid or its functional derivatives or the HX of-CO-Y
1-Y
3React together; Or
(e) in order to prepare the compound of chemical formula I
Wherein R, A
1To A
5And the middle as mentioned definition of n, and R
16For-C
1-12Aliphatics or alicyclic residue are with the compound oxidation of chemical formula V
R wherein, A
1To A
5, n and R
16Definition as mentioned,
Therefore reclaim the compound of chemical formula I again, obtained with free or salt form, or the product that exists with the form of mixture.
Above-mentioned method (a) to (e) can be finished according to known in the art standard technique.
In method (a), the R on the N-end group of removing the compound that also can be included in the chemical formula I of protecting group removes.For example: when R is the benzyloxy carbonyl, can remove this group with hydrogenization by means of in the presence of for example palladium catalyst.
According to method (b), for example: in order to prepare the compound that X wherein contains the chemical formula I of a carboxyl, X wherein can be contained the compound hydrolysis of chemical formula I of the carboxylic acid of an esterification or amidation.Can be by means of being handled with suitable alkali, or by the hydrolytic action of acid, for example: in the presence of trifluoroacetic acid, finish this class hydrolytic action.
Further, according to method (b), in order to prepare the compound of chemical formula I that X wherein contains the carboxyl of an esterification or amidation, X wherein can be contained compound (transfer) esterification or the amidation of chemical formula I of the carboxyl of a carboxyl or an esterification.Such ester formation effect or amidation can use known in the art any technology to finish, for example: change this carboxyl and become a functional activity base, as: the carbonylic halide of a correspondence or acid anhydride, or utilize wherein that X is the compound of the chemical formula I of the group of the chemical formula (h) of lactone form, and with this kind group and selected alcohol or amine reaction.
According to the more specific embodiments of method (b), in order to prepare the compound of chemical formula I that X wherein is the group of chemical formula (g), can be chemical formula (e with X wherein
1) or (e
2) group, and A
5For the compound of the chemical formula I of H and the compound of chemical formula II react
H
2N-NH-CO-A
5（Ⅱ）
A wherein
5Definition as above.This process can be with finishing with the known technology similar methods that is used for preparing semicarbazone (semicarbazones) class.
Can be chemical formula (e also with X wherein
1) the compound of chemical formula I of group, be chemical formula (e according to known technical change for X wherein
2) the compound of chemical formula I of group, vice versa.
Method (c) can be finished by means of known technology in the chemistry of peptides technology.Described chemical formula (the e that contains
1) peptide fragment of a group one of in (j), also mean this group this in-NR
6-be partly with a protecting group, and have a suitable end group in addition, for example: A
5Or CH
2-Za.
Use Di Si-Martin's reagent (Dess-Martin reagent) can be convenient to Method Of Accomplishment (d), for example: in the presence of the silver salt of alkali or precipitation halogen, carry out, or according to this temperature (Swern) family name oxidation program.
In these reactions, can use blocking group for functional group in reaction does not participate in reaction if need.These blocking groups can be, for example: amino protecting group, carboxyl-protecting group, acetal radical etc.After finishing the reaction of wanting, can remove these blocking groups.
Each above-mentioned method can be utilized the initial substance of any indivedual optically active isomer forms, or finishes with the initial substance of the form of mixture and [to relate to and to appear at chemical formula (e
1) in the group of (j) as X, or appear at this class group asymmetric carbon in the body before].Suitable mode is the initial substance that utilizes as S-or R-enantiomorph, and the compound of preparation chemical formula I is wherein at chemical formula (e
1) asymmetric carbon to the group of (j) has S or R configuration respectively.
Employed initial substance in method (d) or (e) availablely prepares with method (c) similar methods.This paper is not described especially to the preparation of initial substance, and these compounds method known or that know in the field whereby in this technical field prepares.
Following explanation the present invention of example system.That all temperature are is Celsius (℃).
Use following abbreviation:
The THF=tetrahydrofuran (THF)
The TFA=trifluoroacetic acid
Me OH=methyl alcohol
The EtOAc=ethyl acetate
The DCC=dicyclohexylcarbodiimide
The HOBT=hydroxybenzotriazole
Z=benzene methoxycarbonyl
The r.t.=room temperature
The Fmoc=9-fluorenylmethyloxycarbonyl
A=amorphous (amorphous)
Example 1:Z-Xie Ansuan-methionine(Met)-aspartic acid (OH)-H(Z-Val-Met-Asp(OH)-H)
Get Z-Xie Ansuan-methionine(Met)-asparagine acid anhydrides dimethylacetal-β-tert-butyl ester (1.17 gram) and place CH
2Cl
2In (150 milliliters), add the TFA(15 milliliter) and water (1 milliliter) also at room temperature stirred 2.5 hours.With solvent evaporation, add toluene twice, and evaporation once more.Crystalloid resistates is dissolved in the water (60 milliliters) of heating, from some insoluble matters, decants supernatant liquor, and under 5 °, carry out crystallization, produce first product: 117 ° of fusing points.Collect all mother liquors circumstances in which people get things ready for a trip spectrum analysis (SiO that goes forward side by side
2, acetone/hexane/EtOAc 60/40/0.5), obtain second batch of product, water development is carried out crystallization.
Embodiment 2:Z-Xie Ansuan-methionine(Met)-aspartic acid (OH)-semicarbazone
The compound (0.27 gram, 0.55 mmole) of embodiment 1 is placed the MeOH(2 milliliter), with the 1M solution of semicarbazone, HCl(0.6 milliliter) mix, add 5 pyridines then.At room temperature form crystallization: 233 to 235 ° of fusing points in 10 minutes after products.
Example 3:Z-Xie Ansuan-methionine(Met)-aspartic acid (OH)-H semicarbazone base-proline(Pro)-Xie Ansuan-N(CH)
With the compound of example 1 (0.48 gram, 1 mmole) solution in the MeOH(2 milliliter), in the mixture of water (0.5 milliliter) and 3 pyridines.And with N-(diazanyl carbonyl)-proline(Pro)-Xie Ansuan-N(CH
3)
2(0.3 gram, 1 mmole) is dissolved in the MeOH(1 milliliter), among the HCl of water (2 milliliters) and 3 2N.These two kinds of solution are merged, and under 40 ° to 50 °, heated 2 minutes.Cooling makes product form crystallization: 118 ° to 120 ° of fusing points.
Repeat the step of embodiment 1, use corresponding initial substance, can prepare following compound:
Embodiment 4:Z-Xie Ansuan-phenylalanine-asparagus fern door propylhomoserin (OH)-H
Embodiment 5:Z-Xie Ansuan-Histidine-asparagus fern door propylhomoserin (OH)-H
Repeat the step of example 2 and 3 respectively, utilize the initial substance of correspondence, can prepare the compound of following chemical formula (I A).
A wherein
3, A
4And A
5Following definition.
Example A3 A4 A5 fusing point ℃
6 val phenyl L-Ala H a
7 Xie Ansuan Histidine H 150
8 val phenyl L-Ala proline(Pro)-figured silk fabrics 126-129
Propylhomoserin-N (CH
3)
2
9 Xie Ansuan Histidine proline(Pro)-figured silk fabrics
Propylhomoserin-N (CH
3)
2
10 L-Ala-phenylalanine H 205
Tyrosine-
Xie Ansuan
Example 11:(3S)-3-(Z-valyl-phenylalanyl)-amino-5-(2,6-dimethyl benzene methanoyl)-4-oxopentanoie acid
Will (3S, 4RS)-3-(Z-Xie Ansuan-Histidine) amino-4-hydroxy-5-(2,6-dimethyl benzene methanoyl) the valeric acid tert-butyl ester (0.6 mmole) is at CH
2Cl
2In (4 milliliters), handled 45 minutes and filter it with Di Si-Martin's reagent (0.77 mmole).Add acetone and 0.5N NaOH then, again acetone evaporated is fallen.With the crystalloid material of water washing remnants, add 10% tartrate with its acidifying after, extract it with EtOAc again.The tert-butyl ester product of the EtOAc extract evaporation back output yellow crystal shape that merges.These materials are dissolved in CH
2Cl
2In (4 milliliters), add the TFA(4 milliliter), and this mixture at room temperature stirred 15 minutes.Evaporate this mixture, be evaporated to dried, the circumstances in which people get things ready for a trip of going forward side by side spectrum analysis (SiO
2, acetone/hexane/EtOAc 60/40/1), produce coloured a little crystallized product.
Example 12:(Z-valyl-alanyl)-(3R, 4S)-3-amino-4-hydroxy-5-(2,6-dichloro-benzoyl oxygen base)
With (Z-valyl-alanyl)-(3R, 4S)-3-amino-4,5-dihydroxy-acid ethyl ester and 4-Dimethylamino pyridine are dissolved in the pyridine, and dropwise add 2, the 6-dichlorobenzoyl chloride.At room temperature stir this reaction mixture and spend the night, add ice and water then, extract this mixture with AcOEt again.With the water washing organic layer, wash with NaCl solution again, use Na
2SO
4Remove moisture, after filtering, evaporating, raw product is carried out stratographic analysis, obtain title product.
Title compound (3R, 4RS) derivative can following method prepare:
With Z-Xie Ansuan-L-Ala-OH(0.26 mmole), the DCC(53 milligram, 0.26 mmole) and HOBTH
2O(39 milligram, 0.26 mmole) be dissolved in THF/DMF(2 milliliter/2 milliliter) in, and stirred 5 minutes, be added in the THF(2 milliliter then) in (3R, 4RS)-and 3-amino-4-hydroxy-5-(2,6-dimethyl benzene methanoyl) the valeric acid tert-butyl ester (87 milligrams, 0.26 mmole).Under room temperature, stir this reaction mixture and spend the night, with its evaporation circumstances in which people get things ready for a trip spectrum analysis (SiO that goes forward side by side
2, EtOAc/MeOH/NH
395/5/0.5), obtain this (3R, 4RS) title compound.
Example 13:(Z-valyl-alanyl)-(3R)-and 3-amino-4-oxo-5-(2,6-dichloro-benzoyl oxygen base) Valeric acid ethylester
Will be under-50 ℃ at CH
2Cl
2In methyl-sulphoxide dropwise add at CH
2Cl
2In oxalyl chloride solution in.After 15 minutes, dropwise be added in CH
2Cl
2In the solution of compound of example 12, and stirred these reaction mixtures 1 hour down at-40 ℃.Add triethylamine, and at room temperature continue to stir 3 hours.Add entry then, again with CH
2Cl
2Extract this reaction mixture.With NaHCO
3The solution washing organic layer is washed with NaCl solution again, uses Na
2SO
4Make its dehydration, filter and evaporate it.Make resistates carry out stratographic analysis, produced title compound.
Repeat the step of example 1 to 3 and 11 to 13, use corresponding initial substance, can prepare the compound of following chemical formula I B
A wherein
3, A
4, R
xAnd R
yAs definition hereinafter.
Example A
3A
4Ry Rx [α]
20 DC (MeOH)
Or fusing point ℃ [2]
14 val phenyl L-Ala H 2, the 6-dimethylbenzoyl
15 Xie Ansuan Histidine H 2, the 6-dimethylbenzoyl
16 Xie Ansuan Histidine H p-nitrophenyls
17 Xie Ansuan Histidine H H a[2]
(1-trityl)
18 Xie Ansuan Histidine H 2,6-dichloro-benzoyl base
19 Xie Ansuan Histidine H 2,6-two (trifluoromethyl)-benzoyl
20 Xie Ansuan Histidine H 2, the 6-dinitrobenzoyl
21 Xie Ansuan Histidine H 2,6-two (trifluoromethyl) benzoyl
(2-CF
3)
22 Xie Ansuan tryptophane H 2,6-two (trifluoromethyl) benzoyl
23 trimethylammonium Histidine H 2,6-dichloro-benzoyl base
First silicon
Oxyalkyl-
Beta Alanine
24
H 2,6-dichloro-benzoyl base
25 L-Ala-phenylalanine H H a[2]
Tyrosine-
Xie Ansuan
26 D-Xie Ansuan Histidine H 2,6-dichloro-benzoyl base-39.2 ° 1.21
27 Xie Ansuan arginine H 2,6-dichloro-benzoyl base
28 Xie Ansuan Histidine C
2H
52,6-dichloro-benzoyl base-26.7 ° 1.02
29 Xie Ansuan Histidine H
-18.0 ° 0.97
30 Xie Ansuan Histidine H
-19.0 ° 0.96
31
H 2,6-dichloro-benzoyl base
32 Xie Ansuan ornithine H 2,6-dichloro-benzoyl base
33 Xie Ansuan Methionin H 2,6-dichloro-benzoyl base
34 Xie Ansuan L-Ala H 2,6-dichloro-benzoyl base
35 Xie Ansuan Histidine H valeryls
The different C of 36 Xie Ansuan Histidines
4H
92,6-dichloro-benzoyl base * *
The positive C of 37 Xie Ansuan Histidines
10H
212,6-dichloro-benzoyl base * *
38 Xie Ansuan Histidine phenmethyls 2,6-dichloro-benzoyl base * *
39 Xie Ansuan Histidine CH
2CH
2OH 2,6-dichloro-benzoyl base * *
40 Xie Ansuan L-Ala C
2H
52,6-dichloro-benzoyl base * *
41 Xie Ansuan leucine H 2,6-dichloro-benzoyl base
42 Xie Ansuan Histidine H 2,6-dichloro-benzoyl base
43 Xie Ansuan Histidine H 2,6-dichloro-benzoyl base
(2-CF
3)
44 Xie Ansuan Histidine C
2H
5 Valeryl * *
45 Xie Ansuan Histidine H 2,6-dichloro-benzoyl base *
46 Xie Ansuan Methionin H 2,6-dichloro-benzoyl base
（N
ε-iC
3H
7)
47 Xie Ansuan Methionin C
2H
52,6-dichloro-benzoyl base * *
(N
ε-iC
3H
7)
48 Xie Ansuan L-Ala H 2,6-dichloro-benzoyl base * *
49 Xie Ansuan L-Ala uncle C
4H
92,6-dichloro-benzoyl base * *
50 Xie Ansuan L-Ala C
2H
52,6-dichloro-benzoyl base *
51 Xie Ansuan L-Ala C
2H
5 
52 trimethylammonium Histidine C
2H
52,6-dichloro-benzoyl base
Silicomethane
53
C
2H
52,6-dichloro-benzoyl base * *
The different C of 54 Xie Ansuan L-Ala
3H
7*
55 trimethylalanine uncle C
4H
92,6-dichloro-benzoyl base
Silicomethane
Base-third
Propylhomoserin
56 trimethylalanine H 2,6-dichloro-benzoyl base
Silicomethane
Base-third
Propylhomoserin
57 trimethylalanine C
2H
52,6-dichloro-benzoyl base
Silicomethane
Base-third
Propylhomoserin
* these compounds have following configuration at the asparagine acyl moiety:
These compounds of * have R at the asparagine acyl moiety, the S configuration.
Example 58:
Z-Histidine-aspartic acid
[α]
20 D=-20.3 ° of c=1 are in MeOH
Example 59:
Fmoc-Xie Ansuan-Histidine-aspartic acid
Example 60:
[α]
20 D＝-21.5° c＝1.07 MeOH
Example 61:
Example 62:
Repeat the step of example 1 to 3 and 12 to 13, and use corresponding initial substance, can prepare the compound of following chemical formula I C
Z-Xie Ansuan-A
4 
A wherein
3, R
xAnd R
yAs definition hereinafter.
Example
A
Ry
Rx
*
63 L-Ala H 2,6-dichloro-benzoyl base R, S
64 L-Ala C
2H
5 R
65 L-Ala uncle C
4H
92,6-dichloro-benzoyl base R, S
66 L-Ala-C
2H
4-OCH
32,6-dichloro-benzoyl base R, S
Example 67:(3RS)-and 3-(Z-valyl-phenylalanyl) amino-4-oxo-6-(is right-nitrophenyl-anti---5-olefin(e) acid tertiary butyl ester
With (3RS)-3-(Z-valyl-phenylalanyl) in the amino-4-oxo-valeric acid tertiary butyl ester-5-diethyl phosphonate (0.2 gram, 0.29mM) under 5 ℃, be dissolved in the THF(15 milliliter).Add the NaH(25 milligram, 0.59mM), and stirred this mixture 10 minutes.Adding THF(2 milliliter under 0 ℃) (0.18 gram 1.1mM), stirred this reaction mixture 45 minutes in this temperature to the right-nitrobenzaldehyde in again.This reaction mixture is inclined in 5% tartrate, and with ethyl acetate extraction, organic phase is purified with stratographic analysis with after Na SO dehydration, evaporating again, and produces title compound.
Example 68:Z-Xie Ansuan-phenylalanine-Radix Asparagi ammonium aldehyde dimethyl-acetal-β-methyl esters
With Z-Xie Ansuan-phenylalanine-aspartic acid (OH)-H(0.8 gram) be dissolved in the MeOH(25 milliliter that contains 8%HCl) in, to keep somewhere under room temperature and spend the night, revaporization is to doing, and with the remaining crystallization of ether washing, obtains the title compound of white crystals.168 to 171 ° of fusing points.
Initial substance can following method prepare:
Example 69:(3S)-and the 3-(fluorenylmethyloxycarbonyl) amino-5-iodo-4-ketobutyric acid tert-butyl ester
At-10 °, triethylamine (1.3 milliliters, 9.6 mmoles) is added to the milliliter at THF(60) in it (3S)-3-(fluorenylmethyloxycarbonyl) in the amino-3-carboxyl-tert-butyl acetate (3.5 gram, 8.5 mmoles), add Vinyl chloroformate (0.92 milliliter, 9.6 mmoles) subsequently again.At leisure the diazomethane solution in ether is added at 0-5 ℃ after 10 minutes, and stirred this reaction mixture 45 minutes.Under 5-10 °, be added in the HCl(2N in the ether), up to stopping to produce gas.Reaction mixture is evaporated to dried, places acetone (50 milliliters), add the NaI(4 gram), and at room temperature stirred 1 hour.Add ether (150 milliliters) again, this reaction mixture is filtered and evaporation.Resistates carries out stratographic analysis (SiO
2, the EtOAc/ hexane), produce the title compound of yellowish crystalloid.
Example 70:(3S)-and the 3-(fluorenylmethyloxycarbonyl) amino-5(2,6-dimethyl benzene methanoyl)-the 4-oxopentanoie acid tert-butyl ester
With the 3S-3-(fluorenylmethyloxycarbonyl) amino-5-iodo-4-oxo-tert-butyl acetate (1 gram, 1.8 mmole), 2,6-mesitylenic acid (0.5 gram, 3.3 mmoles) and AgOAc(0.6 gram, 3.6 mmole) be dissolved in the acetone (25 milliliters), and refluxed 1 hour.In filter and evaporation after, with crude product through stratographic analysis (SiO
2, ether/hexane 3/7), produced title compound.
Example 71:(3S)-and the 3-(fluorenylmethyloxycarbonyl) amino-5(4-nitro-phenoxy)-the 4-oxo pentyl ester tert-butyl ester
With the 3S-3-(fluorenylmethyloxycarbonyl) amino-5-iodo-4-ketobutyric acid tert-butyl ester (1 gram, 1.8 mmoles), right-nitrophenol (0.5 gram, 3.7 mmoles) and K
2CO
3(0.38 gram, 2.8 mmoles) refluxed 30 minutes in acetone (6 milliliters), added CH again
2Cl
2, and with 2N NaHCO
3Wash this organic phase.With organic phase dehydration, the evaporation that merges, and, produce the title product of yellow oil through stratographic analysis (SiO, EtOAC/ hexane 2/8).
Example 72:(Z-valyl-alanyl)-(3R, 4S)-3-amino-4,5-dihydroxy-acid ethyl ester
A) under room temperature, will (3R, 4S)-3-aminotoluene base-4,5-(isopropylidene dioxy) Valeric acid ethylester (Y.Yamada, Tetrahedron Letters 1983,24,3009) and 10% palladium (Pd) in ethanol/carbon (C), at H
2Under, vibrated 30 minutes.This reaction mixture is filtered and evaporation, obtain (3R, 4S)-3-amino-4,5-(isopropylidene dioxy) Valeric acid ethylester, do not need further purification to use.
B) Z-Xie Ansuan-L-Ala-OH is dissolved among the THF, under 5 ℃ with HOBTH
2O and DCC add.After 5 ℃ were down stirred 20 minutes, diisopropylethylamine that will be in TFH and (3R, 4S)-3-amino-4,5-(isopropylidene dioxy) Valeric acid ethylester added.At room temperature stir this reaction mixture and spend the night, with its filtration, evaporation and through stratographic analysis, produce (Z-valyl-alanyl)-(3R, 4S)-3-amino-4,5-(isopropylidene dioxy) Valeric acid ethylester.
C) with compound 74b) be dissolved in AcOH/H
2O(75/25) in, and under 40 ℃, stirred 4 hours.After evaporation, add entry, and extract this mixture with AcOEt.With water, NaHCO
3The extraction liquid that solution, NaCl solution washing merge is with Na
2SO
4Dehydration, filter and evaporate it, produce title compound.
The compound of these chemical formula I, hydrolyzable and acceptable esters and amides on their physiology, and they demonstrate the activity on the pharmacopedics at acceptable salt on the pharmacopedics (the present invention's hereinafter referred to as compound), and are being effective aspect medicine therefore.
Special as go out as shown in the in vitro test of following uses THP-1 cell reaches in the test method in vivo, The compounds of this invention has suppressed IL-1 β and has secreted.
A) with 900 microlitre THP-1 cells (0.5 * 10
6Individual cell) splashes in the culture plate in 24 holes with valinche with 100 unit gamma-interferon/0.9 milliliter RPMI RPMI-1640 (foetal calf serum that contains 2mML-glutamine and 5% heat-deactivation).Then 100 microlitre test-compounds are added.At 37 ℃, in 5%CO
2After three hours, 10 microlitre lipopolysaccharides (500 mcg/ml) are added, and continue this cultivation effect 40 hours in/95% air.Also comprise suitable control group (being and not being stimulation, solvent).Shift out nutrient solution, with 1000g centrifugal 10 minutes, make the nutrient solution clarification, 1.0 milliliters of digitonins (0.01%) are added to carry out molten born of the same parents in the hole, and use rubber policeman (rubber policeman) to scrape pine, and put 10 minutes in 4 ℃.Carry out determination of lactate dehydrogenase then at once, and sample is kept at-20 ℃, up to the mensuration that can carry out other.These are determined as: IL-1 β (nutrient solution and lysate), IL-6(nutrient solution), TNF-α (nutrient solution), PGE2(nutrient solution and lysate), the molten bubble product of serum lactic dehydrogenase (LDH) and DNA().Use can be measured IL-1 β, IL-6 and TNF-2 through the ELISA of commercial acquisition suit agent (Cistorn), uses standard RIA to measure PFE
2, and use DAPI that DNA is carried out fluorometric assay.
In this test, The compounds of this invention suppresses the release of IL-1 β selectively from about 0.01 to 100 μ M in concentration.On the contrary, IL-6, TNF-α, PGE
2Basically remain unchanged with dna content, and these compounds are nontoxic, because disengaging of LDH is constant.For example, example 40 and 50 compound have been measured the IC that has 1 and 0.1 μ M respectively
50Value (suppressing the compound concentration that 50%IL-1 β disengages).
B) LPS-heat symptom-complex
With LPS-suspension (Sigma company, numbering L-5886; 100 micrograms/5 milliliter glucose solution/kilogram, subcutaneous injection) is injected in male Tuttlingen SD mouse (150 to 160 gram).After 2 hours, utilize the thermistor rectal prob that is connected on the ELLAB telethermometer to come take temperature.After 4 hours, with the test-compound oral administration, (after 6 hours of injection LPS), take temperature again after 2 hours.According to increasing as 100% of the untreated control group temperature that obtains, the increase in temperature in treatment group is then recently represented with the percentage that this is worth.ED
50Cause 50% inhibiting dosage for the increase in temperature of measuring for the control group mouse.In this test, when dispensing dosage was in the scope of from 0.001 to 0.1 milligram of/kilogram oral administration, The compounds of this invention can suppress the caused increase in temperature of LPS.For example: the compound of having measured example 40 and 50 has the DE of 0.01 milligram of/kilogram oral administration
50Value, and the compound of example 51 has the ED of 0.05 milligram of/kilogram oral administration
50Value.
C) siliquosa Pelvetia causes foot's oedema to mouse
Every group is used the male mouse of 50FA, body weight 150 to 170 grams.The injection siliquosa Pelvetia before 1 hour, the oral test compound that is formed in the suspension in normal saline solution/0.5% tragacanth gum.Inject down in rear foot of siliquosa Pelvetia (0.1 milliliter 1% suspension in physiological saline) injection with Plantar.To measure the swelling of foot according to the anti-inflammatory instrument (antiphlogometer) of Kemper and Amel.After injection, obtain the reading of contrast at once, and after 3 and 5 hours, measure the swelling degree.Behind the reading that subtracts the t contrast, obtain the mean value of 3 and 5 hours readings.Cross the numerical value that animal obtains from treated, with to recently representing from the unprocessed percentage of crossing the numerical value of animal acquisition.ED
50For can produce 50% inhibiting dosage after 3 hours to the swelling that siliquosa Pelvetia caused.In this test method, when the dosage of oral administration was in from 0.02 to 5 milligram/kilogram scope, The compounds of this invention suppressed the swelling that caused by siliquosa Pelvetia significantly.For example, the compound that has determined example 40 and 50 has the DE of 0.2 and 1 milligram of/kilogram oral administration respectively
50Value.
Therefore, The compounds of this invention relates to for processing or comprises the etiologic imbalance that excessive IL-1 β disengages, and is effective.For example: the inflammation patient's condition and the disease of broad variety, for example: organize the degenerative process in the exhausting of calcium, os osseum and the cartilage, for example: rheumatoid arthritis and osteoarthritis, inflammatory bowel disease, irritable bowel disease, septic shock, psoriasis, asthma, adult breathe and are stranded the bone osteoporosis prolong syndrome, diabetes I type, a variety of causes, comprising: for example the osteoporosis behind climacterium or the cracked ends and with age, outage or wound, arteriosclerosis and Ah ear grow extra large Mo's disease and the bone osteoporosis that takes place.
For above-mentioned purposes, required dosage will be changed according to the mode of dispensing, pending particular condition and the effect of wanting certainly.Yet, preferably can reach gratifying result under the dose ratio 0.001 to every day of about 10 milligrams/per kilogram the weight of animals generally from about 0.001 to about 100 milligrams/per kilogram the weight of animals.For bigger Mammals, for example human, suitable dose ratio every day be according to from about 0.1 milligram to about 1 gram/sky, with dosing time, with separate doses 2 to 4 times/day, or the form of disengaging with delay.
Example 50 and 51 compound are preferable.
According to preamble, the present invention also provides:
A) a kind of processing relates to or comprises the method for the etiologic imbalance that excessive IL-1 β disengages, for example as the patient in this kind of needs treatment process who has above illustrated, these methods comprise and give hydrolyzable and acceptable esters or amides or its pharmacy acceptable salt class on the compound, its physiology of the chemical formula I of effective content to above-mentioned patient;
B) for example be used as hydrolyzable and acceptable esters and amides on the compound, its physiology of the chemical formula I of drug use with the method that is above disclosed, or its pharmacy acceptable salt class, for example: use as preparation.
The present invention's compound can be offerd medicine by the approach of any facility, and nose is specifically arranged, offer medicine through intestines, and preferably with oral administration, for example: with the form of tablet or capsule, or it is non-through the intestines dispensing, for example with Injectable solution or form of suspension, or with suppository form.Unit dosage form for example comprises the The compounds of this invention from about 25 micrograms to 500 milligram.
The compounds of this invention can free form or pharmaceutically acceptable salt form offer medicine.Such salt can traditional method prepare, and demonstrates the active grade as free cpds.
The present invention also further provides:
C) a kind of pharmaceutical composition, system is by hydrolyzable and acceptable esters or amides on the compound of chemical formula I, its physiology, or its pharmacy acceptable salt class, definition as mentioned is with pharmaceutically for this reason and acceptable diluent or carrier constitute.Such composition can traditional method be made.They can contain and be up to 99.9% activeconstituents by weight.
Claims (9)
1, a kind of compound of chemical formula I
Wherein
R is that hydrogen, amino protecting group or optional ring are gone up substituted phenmethyl.
N is 0 or 1,
A
1Be Xie Ansuan, leucine, L-Ala, Isoleucine or trimethyl silyl-L-Ala,
A
2Be phenylalanine or tyrosine,
A
3Be a direct key, Xie Ansuan, leucine, L-Ala, Isoleucine, trimethyl silyl-L-Ala, or the divalent group of chemical formula (a)
Wherein the A ring is optional can be by hydroxyl or C
1-4Alkoxyl group replaces, A
4It is the divalent group of a direct key or chemical formula (b).
R wherein
1Be hydrogen or C
1-4Alkyl, and
Y
1Be the residue on the alpha-carbon atom that is connected a-amino acid, and optional can be protected ,-CH
2-CH
2-N (C
1-2Alkyl), imidazoles-2-base-methyl, benzimidazolyl-2 radicals-ylmethyl, 1H-1,2,4-triazole-3-base-methyl, pyridin-3-yl-methyl, indazole-3-base-methyl or chemical formula (c) or group (d)
Wherein
R
2And R
3Be hydrogen, halogen, C independently respectively
1-4Alkyl, CF
3Or trityl, R
2And R
3In have one to be H at most, and R
4And R
5Be hydrogen, C independently respectively
1-4Alkyl, hydroxyl, C
1-4Alkoxyl group, CF
3, phenyl or halogen, R
4And R
5In have one to be H at most,
Or A
3And A
4Form the group of a chemical formula (aa) together
Y wherein
1Be definition as mentioned, and R
1And R
1aFormation-(CH together
2)
m-, wherein m is 2,3,4 or 5, and
I) X is a chemical formula (e
1) divalent group
R wherein
6Be H or C
1-4Alkyl,
And A
5Be hydrogen; CF
3Group-Z
1-Z
2-Y
2, Z wherein
1And Z
2Be respectively a direct key or an a-amino acid residue independently, and Y
2Be NH
2, C
1-4Alkylamino, two (C
1-4Alkyl) amino or through nitrogen-atoms and Z
2The heterocyclic radical that connects; Group-CH
2-X
1Y
3, X wherein
1Be O (oxygen) or S (sulphur), and Y
3Be assorted aromatic base; Group-CH
2-Y
3Or chemical formula (k) arrives the group in (m).
Wherein
Y
4Be three (C
1-4Alkyl) methyl or residue
The B ring is pyridyl,
The C ring is phenyl or pyridyl,
R
7And R
8C is C respectively independently
1-4Alkyl,
C
1-4Alkoxyl group, CF
3, halogen, nitro or cyano group, and R
9, R
10And R
11Be nitro, cyano group, CF independently respectively
3, carbamyl, CO
2R
12,-CH=CH=CN or-CH=CHCO
2R
12, R wherein
12Be C
1-6Alkyl,
X also can be chemical formula (e
2) divalent group
This moment A
5Be H, perhaps
Ii) X is the divalent group of chemical formula (f)
And A
5For as hereinbefore defined-Z
1-Z
2-Y
2Or the group of chemical formula (K) in (0), or OR
13Or NR
14R
15, R wherein
13Be any C that selects available OH replacement or interrupt with O (oxygen)
1-12Alkyl, and R
14And R
15Be hydrogen, C independently respectively
1-12Alkyl, C
5-7Cycloalkyl or phenmethyl, perhaps
Iii) X is the divalent group of chemical formula (g)
And A
5For definition as indicated above-Z
1-Z
2-Y
2, perhaps
Iv) X is chemical formula (h) or divalent group (j)
And A
5Be as hereinbefore defined chemization (k) group in (O) ,-CH
3-Y
3Or-CH
2-X
1-Y
3,
Collateral condition is
When n is 0, A
3With A
4In have only one to can be direct key, and when n is 1, A
3With A
4It or not direct key.
With and physiology on hydrolyzable and ester class or the amides accepted, and exist with free form, salt form or with the form of mixture.
2, according to the compound of the chemical formula I of claim 1, wherein n is 0, and A is a direct key, Xie Ansuan, leucine, L-Ala, Isoleucine or trimethyl silyl-L-Ala, A
4As the definition of claim 1, or A
3With A
4Form group together as the defined chemical formula of claim 1 (aa), and
ⅰ) X is as the defined chemical formula (e of claim 1
1) or (e
2) group, and A is H, perhaps
ⅱ) X is chemical formula (e
1) or group (f), and A
5For as claim 1 defined-Z
1-Z
2-Y
2, or as the defined chemical formula of claim 1 (k), (l) or group (m), wherein X
1Be O(oxygen),
ⅲ) as claim 1 definition, X is the group of chemical formula (g), and A
5For-Z
1-Z
2-Y
2, perhaps
ⅳ) as the definition of claim 1, X is the group of chemical formula (j), and A
5Be chemical formula (k), (l) or group (m), wherein X
1Be O(oxygen).
With and physiology on hydrolyzable and acceptable esters or amides, and
With free form, salt form, or exist with the form of mixture.
3, according to the compound of the chemical formula I of claim 1, wherein n is 0, and A
3With A
4Be not direct key, with and physiology on hydrolyzable and acceptable esters or amides, and with free form, with salt form, or exist with the form of mixture.
4, according to the compound of the chemical formula I of claim 1 or 3, Y wherein
1Be the residue on the alpha-carbon atom that is connected a-amino acid; described amino acid is selected from L-Ala, leucine, Histidine, phenylalanine, methionine(Met), tryptophane, trimethyl silyl-L-Ala; and it is optional with the shielded arginine of side chain, ornithine and the Methionin or the group of chemical formula (c); and hydrolyzable and acceptable esters or amides on the physiology; and with free form, salt form, or exist with the form of mixture.
5, according to the compound of the chemical formula I of claim 1, wherein X is chemical formula (e
1), (h) or group (j), when X is (e
1) time, A
5Be H, and hydrolyzable and acceptable esters or amides on the physiology, and with free form, salt form, or exist with the form of mixture.
6, with free form, salt form or exist: (benzene methoxycarbonyl-valyl-alanyl)-3R-3-amino-4-oxo-5-(2 with the form of mixture, 6-dichloro-benzoyl oxygen base) Valeric acid ethylester, (benzene methoxycarbonyl-valyl-alanyl)-3R, S-3-amino-4-oxo-5-(2,6-dichloro-benzoyl oxygen base) Valeric acid ethylester, (benzene methoxycarbonyl-valyl-alanyl)-3R-3-amino-4-oxo-5-(2,6-dichloropyridine base-4-ketonic oxygen base) Valeric acid ethylester, (benzene methoxycarbonyl-valyl-alanyl)-3R, S-3-amino-4-oxo-5-(2,6-dichloro-benzoyl oxygen base) valeric acid, (benzene methoxycarbonyl-valyl-alanyl)-3R, S-3-amino-4-oxo-5-(2,6-dichloro-benzoyl oxygen base) isopropyl isovalerate, (benzene methoxycarbonyl-valyl-alanyl)-3R, S-3-amino-4-oxo-5-(2,6-dichloro-benzoyl oxygen base) the valeric acid tert-butyl ester, and (benzene methoxycarbonyl-valyl-alanyl)-3S-3-amino-4-oxo-5-(2,6-dichloro-benzoyl oxygen base) valeric acid.
7, a kind of preparation is as the method for hydrolyzable on chemical formula I compound claimed in claim 1 and the physiology thereof and acceptable esters and amides, and its step comprises
(a) from the compound of the chemical formula I of guard mode, remove at least one protecting group, or, add one as the defined protecting group R of claim 1 at the N end group group place of the compound of chemical formula I; Or
(b) a kind of compound of chemical formula I is transformed into the compound of another kind of chemical formula I; Or
(c) by amido linkage two peptide fragment are coupled at together, they contain at least one amino acid under protected or not protected state respectively, and have a peptide fragment to contain as defined in claim 1 chemical formula (e
1) arrive a group in (j), and make the such peptide fragment of protected or not protected peptide that obtains have the sequence consistent with the compound of chemical formula I, if need, can remove one or more protecting groups from the compound of the chemical formula I guard mode; Or
(d) X is chemical formula (e in the claim 1 in order to prepare wherein
1) or group (h), and A
5Be chemical formula (k), (l) or group (o), or-CH
2-X
1-Y
3The compound of chemical formula I, with the compound of chemical formula III.
Wherein R, A
1To A
4And the definition of n such as claim 1, X ' is as the defined chemical formula (e of claim 1
1) or group (h), and Z
aIt is a leavings group
With a corresponding phenol, thiophenol or pyridone or chemical formula HX
1-CO-Y
4Acid or its functional derivatives or HX
1-Y
3, X wherein
1, Y
3And Y
4Be as the definition in the claim 1, react; Or
(e) in order to prepare the compound of chemical formula I
Wherein R, A
1To A
5Be as defined in claim 1, and R
16For-C
1-12Aliphatics or alicyclic residue are with the compound oxidation of chemical formula V
R wherein, A
1To A
5, n and R
16System and reclaims the compound of chemical formula I as hereinbefore defined, or hydrolyzable and acceptable esters or amides on its physiology, thereby obtains with free or salt form, or the product that exists with the form of mixture.
8, a kind of compound among the claim 1-6 is used to prepare the purposes of medicine.
9, a kind of composition pharmaceutically, the compound that comprises chemical formula I as defined in claim 1, or hydrolyzable and acceptable esters or amides on its physiology that exists with the salt form that can accept on free form or the physiology, and pharmaceutically for this reason and acceptable diluent or carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93105500 CN1094730A (en) | 1993-05-03 | 1993-05-03 | Peptides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93105500 CN1094730A (en) | 1993-05-03 | 1993-05-03 | Peptides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1094730A true CN1094730A (en) | 1994-11-09 |
Family
ID=4985751
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 93105500 Pending CN1094730A (en) | 1993-05-03 | 1993-05-03 | Peptides |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1094730A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103405768A (en) * | 2006-12-20 | 2013-11-27 | 爱克索马技术有限公司 | Methods for the treatment of IL-1[beta] related diseases |
-
1993
- 1993-05-03 CN CN 93105500 patent/CN1094730A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103405768A (en) * | 2006-12-20 | 2013-11-27 | 爱克索马技术有限公司 | Methods for the treatment of IL-1[beta] related diseases |
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