CN101111513A - Glycopeptide antibiotic monomer derivative - Google Patents
Glycopeptide antibiotic monomer derivative Download PDFInfo
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- CN101111513A CN101111513A CNA2005800474219A CN200580047421A CN101111513A CN 101111513 A CN101111513 A CN 101111513A CN A2005800474219 A CNA2005800474219 A CN A2005800474219A CN 200580047421 A CN200580047421 A CN 200580047421A CN 101111513 A CN101111513 A CN 101111513A
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Abstract
Novel glycopeptide antibiotic derivatives. These derivatives are represented by the formula (aglycon part of glycopeptide antibiotic derivative)-(Sac-NH)-R A [wherein (aglycon part of glycopeptide antibiotic derivative) is the part formed by removing the sugar part from a known glycopeptide antibiotic derivative; (Sac-NH) part is an amino sugar part or a sugar chain part containing an amino sugar; and R A represents, e.g., the formula -X 1 -Ar 1 -X 2 -Y-X 3 -Ar 2 (wherein X 1 , X 2 , and X 3 each represents 1) a single bond or 2] a heteroatom or heteroatom-containing group selected from the group consisting of -N=, =N-, -NR 1 -, -O-, etc.; Y represents -NR 2 CO- or -CONR 2 - (wherein R 2 represents hydrogen or lower alkyl), etc.]]. These derivatives have antibacterial activity against vancomycin-resistant bacteria.
Description
Technical field
The medical composition that the present invention relates to glycopeptide antibiotic derivatives and contain it.
Background technology
Glycopeptide antibiotic is the microbiotic with complicated many cyclic peptide structures by various microorganisms, and effective to most of Pueraria lobota Lan Shi positive bacteria.In recent years, occurred for example penicillin, cynnematin being had chemical sproof bacterial strain, the streptococcus aureus of multidrug resistant and methicillin-resistance (MRSA) infects and caused serious problem in clinical practice.Glycopeptide antibiotic as vancomycin is typically effective to these patience bacterial strains, and therefore, vancomycin becomes the last tool drug of MRSA and the infection of other endurance strain.
But for example the specific bacterial strain of vancomycin-resistant enterococcus (VRE) etc. begins vancomycin is produced patience.The mechanism of the patience of VRE, degree are different because of the difference of the gene type that had, and it depends on for example genes relevant with patience such as Van A, B, C, D, E, G.Wherein, for example to be all the Teicoplanin Targocin of glycopeptide antibiotics effective to Van Type B VRE with vancomycin.On the other hand, the VRE of Van A type is the bacterial classification that will treat especially clinically, to the also not listing of the effective glycopeptide antibiotic of this patience strain.In addition, recently, also found to obtain the streptococcus aureus (VRSA) of VRE patience.Therefore, be necessary to develop and have the active of improvement and/or glycopeptide derivatives optionally.Most derivatives of vancomycin and other glycopeptide are known.For example can be with reference to following document.
Patent documentation 1: Japanese kokai publication sho 61-251699 communique
Patent documentation 2: Japanese kokai publication hei 7-258289 communique
Patent documentation 3: international open WO96/30401 brochure
Patent documentation 4: international open WO00/39156 brochure
Patent documentation 5: TOHKEMY 2000-302687 communique
Patent documentation 6: international open WO2004/44222 brochure
Patent documentation 7: international open WO2001/81372 brochure
Summary of the invention
The present invention relates to the derivative of novel glycopeptide derivatives matter, it is compared with glycopeptide antibiotic in the past has characteristic raising, that improve.Specific glycopeptide derivatives, particularly vancomycin derivatives of the present invention are compared the anti-microbial activity with increase with vancomycin itself.
That is, the present invention relates to:
(1) compound, its pharmaceutically useful salt or their solvate represented of following formula:
(glycopeptide antibiotic derivatives aglycon part)-(Sac-NH)-R
A
In the formula,
" (glycopeptide antibiotic derivatives aglycon part) " is for removing the part behind the sugar moieties from known glycopeptide antibiotic derivatives;
" (Sac-NH) " is aminosugar or the sugar chain that contains aminosugar;
R
AFor being expressed from the next:
-X
1-Ar
1-X
2-Y-X
3-Ar
2，
In the formula, X
1, X
2, X
3Be independently respectively
1) singly-bound
2) be selected from-N=,=N-,-NR
1-(wherein, R
1Be hydrogen or low alkyl group) ,-O-,-S-,-SO-and-SO
2-in contain heteroatom group or their linking group, perhaps
3) randomly be mingled with the optional substituted alkylidene group or the alkenylene (alkenylene) of heteroatom group identical or different more than 1 or 1;
Y is-NR
2CO-,-CONR
2-(at this, R
2Be hydrogen or low alkyl group) or the group represented of following formula:
[formula 1]
(in the formula, R
3Be alkylidene group)
And
Ar
1And Ar
2Be optional carbocyclic ring or the heterocycle that is substituted and can has unsaturated link(age) respectively independently).
Preferred formula:
[formula 2]
Or
[formula 3]
The compound of expression
More preferably formula:
[formula 4]
In the formula, R
AIdentical with above-mentioned definition;
R
BFor-OH ,-NR
5R
5' (at this, R
5And R
5' respectively be independently hydrogen, optional substituted alkyl ,-NH-R ,-NH-COR ,-NH-CONHR ,-OR (wherein each R respectively independently for hydrogen or choose substituted alkyl wantonly) or the aminosugar residue) or-OR
6(R wherein
6Be optional substituted alkyl (this alkyl can include heteroatom group);
R
C(this alkyl can include heteroatom group (preferred-NH-)) for hydrogen or optional substituted alkyl; With
R
DBe hydrogen or low alkyl group,
R is optional substituted alkyl,
Its condition is that (glycopeptide antibiotic derivatives aglycon part)-(Sac-NH) part is not expressed from the next:
[formula 5]
In the formula, R is a saccharide residue.
(2) contain the medical composition of compound, its pharmaceutically useful salt or their solvate of the invention described above, preferably relate to antibiotic compound.
The invention still further relates to the medical composition of compound, its pharmaceutically useful salt or their solvate and above-mentioned (2) of above-mentioned (1), wherein, do not comprise R
ASituation for 4-(single fluorobenzoyl amino) benzyl.
The invention still further relates to the medical composition of compound, its pharmaceutically useful salt or their solvate and (2) of above-mentioned (1), wherein, do not comprise Ar
1Be phenylene, Y is-NR
2CO-and Ar
2Situation for single fluorophenyl.
The invention still further relates to the medical composition of compound, its pharmaceutically useful salt or their solvate and (2) of above-mentioned (1), wherein, do not comprise Ar
2Situation for single fluorophenyl.
The invention still further relates to compound, its pharmaceutically useful salt or their solvate of following (3)～(18); And the medical composition that contains them, the preferred antibiotics composition.
(3) compound of above-mentioned (1), wherein, Y is-NR
2CO-or-CONR
2-(at this, R
2Be hydrogen or low alkyl group).
(4) compound of above-mentioned (1), wherein, Ar
1And Ar
2Be optional substituted aryl or optional substituted heteroaryl, optional substituted heterocyclic radical or optional substituted cycloalkyl.
(5) compound of above-mentioned (1), wherein, Ar
1And Ar
2Be optional substituted aryl, optional substituted heteroaryl, optional substituted heterocyclic radical or optional substituted cycloalkyl, and Y be-NHCO-or-CONH-.
(6) compound of above-mentioned (1), wherein, X
1It is low-grade alkylidene;
(7) compound of above-mentioned (1), wherein, X
2Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group;
(8) compound of above-mentioned (1), wherein, X
3Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group;
(9) compound of above-mentioned (1), wherein, X
1It is low-grade alkylidene; X
2Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group; X
3Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group; Y is-NHCO-or-CONH-; Ar
1Be optional substituted phenyl, optional substituted heteroaryl, optional substituted heterocyclic radical or optional substituted cycloalkyl; Ar
2Be optional substituted phenyl, optional substituted heterocyclic radical or optional substituted cycloalkyl.
(10) compound of above-mentioned (1), wherein, X
1It is low-grade alkylidene; X
2And X
3Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group independently of one another; Y is the group that following formula is represented:
[formula 6]
R in the formula
3It is alkylidene group;
Ar
1Be optional substituted phenyl, optional substituted heteroaryl, optional substituted heterocyclic radical or optional substituted cycloalkyl; And Ar
2Be optional substituted aryl, optional substituted heterocyclic radical or optional substituted cycloalkyl;
(11) any one compound in above-mentioned (1)～(10), wherein, Ar
2Be any one in aryl, heterocyclic radical or the following formula fused rings:
[formula 7]
With
Optional 1 or 1 above substituting group replacement that is selected from the following substituting group of described aryl, heterocyclic radical or above-mentioned fused rings: low alkyl group, lower alkoxy, cycloalkyl, aryloxy, aralkoxy, optional substituted aryloxy low alkyl group, optional substituted aryloxycarbonyl, elementary alkoxy carbonyl, nitro, hydroxyl, carboxyl, cyano group, oxo base, SO
2NH
2, SO
2Me, SO
2-cyclic amino; optional substituted amino; optional substituted formamyl; optional substituted carbamoyloxy; halogen; junior alkyl halides; halogenated lower alkoxy; halogenated lower alkylthio; the junior alkyl halides carbonyl; the heterocycle low alkyl group; the heterocycle lower alkoxy; the cycloalkyl lower alkoxy; aralkoxy; optional substituted heteroaryl; optional substituted heteroaryl-low alkyl group; optional substituted heteroaryl-lower alkoxy; heterocyclic radical; the heterocyclic radical lower alkoxy; optional substituted aryl and optional substituted heteroaryl.
(12) any one compound in above-mentioned (1)～(10), wherein, Ar
2It is optional 1 or 1 aryl that above substituting group replaces that is selected from the following radicals: halogen; Single, two or three junior alkyl halides; Single, two or three halogenated lower alkoxies; Single, two or three halogenated lower alkylthios; List or two elementary alkyl amido; The cycloalkyl methoxyl group; Benzyloxy; Elementary alkoxy carbonyl amino; Nitro.
(13) any one compound in above-mentioned (1)～(12), wherein, Ar
1Be optional by the amino phenyl that replaces, described amino is optional to be substituted.
(14) any one compound in above-mentioned (1)～(12), wherein, Ar
1It is optional substituted heteroaryl.
(15) any one compound in above-mentioned (1)～(12), wherein, X
1It is low-grade alkylidene; X
2Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group; X
3Be singly-bound, low-grade alkylidene or heteroatom group; Y is-NHCO-or-CONH-; Ar
1It is optional substituted heteroaryl; And Ar
2Be optional substituted phenyl, optional substituted heterocyclic radical or optional substituted cycloalkyl.
(16) any one compound in preferred compound in above-mentioned (1) or above-mentioned (3)～(15), wherein, R
BBe-OH; R
CBe hydrogen; And R
DBe hydrogen.
(17) any one compound in preferred compound in above-mentioned (1) or above-mentioned (3)～(15), wherein, R
BBe-NR
5R
5' (at this, R
5And R
5' be independently of one another hydrogen, optional substituted alkyl ,-NH-R ,-NH-COR ,-NH-CONHR ,-O-R (wherein, R be hydrogen independently of one another or chooses substituted alkyl wantonly) or aminosugar residue); R
CBe hydrogen; R
DBe hydrogen.
(18) any one compound in preferred compound in above-mentioned (1) or above-mentioned (3)～(15), wherein, R
BBe-NR
5R
5' (at this, R
5Be hydrogen, R
5' be alkyl-NH-R ,-NH-COR ,-NH-CONHR ,-O-R (wherein, each R is hydrogen or optional substituted alkyl independently of one another) or aminosugar residue, it is replaced by the wetting ability substituting group); R
CBe hydrogen; R
DBe hydrogen.
The invention still further relates to compound and the pharmaceutically useful salt or their solvate of above-mentioned (1) that following formula represents:
[formula 8]
In the formula,
R
ABe formula-X
1-Ar
1-X
2-Y-X
3-Ar
2,
In the formula, X
1, X
2And X
3Be independently of one another
1) singly-bound;
2) be selected from-N=,=N-,-NR
1-(R wherein
1Be hydrogen or low alkyl group) ,-O-,-S-,-SO-and-SO
2-in heteroatoms or heteroatom group; Perhaps
3) optional heteroatoms identical or different more than 1 or 1 and optional substituted alkylidene group or the alkenylene of being mingled with;
Y is-NR
2CO-,-CONR
2-(at this R
2Be hydrogen or low alkyl group) or the group represented of following formula:
[formula 9]
R in the formula
3It is alkylidene group;
Ar
1And Ar
2Be optional carbocyclic ring or the heterocycle that is substituted and can has unsaturated link(age) independently of one another;
R
BBe-OH or-NR
5R
5', wherein, R
5And R
5' be hydrogen or optional substituted alkyl independently;
R
CBe hydrogen or optional substituted alkyl (this alkyl can include heteroatom group); With
R
DBe hydrogen or low alkyl group.
The invention still further relates to compound and pharmaceutically useful salt or their solvate that the structural formula of above-mentioned formula 7 is represented, wherein, X
1It is low-grade alkylidene; X
2It is the low-grade alkylidene that singly-bound maybe can contain heteroatom group; X
3It is singly-bound; Y is-NHCO-or-CONH-; Ar
1It is optional substituted phenyl; And Ar
2Be optional substituted phenyl, R
BBe OH, R
CAnd R
DBe hydrogen.
Glycopeptide antibiotic derivatives of the present invention, its pharmaceutically useful salt or their solvate demonstrate anti-microbial activity to the various microorganisms such as staphylococcus, suis, streptococcus pneumoniae and faecalis that comprise MRSA.Particularly, described compound is also effective to vancomycin patience bacterial strain, and is especially also effective to resistance of vancomycin enteritis coccus (VRE), vancomycin patience streptococcus aureus (VRSA).Therefore, described compound is in treatment or for example prevent aspect the various microbisms such as meningitis, septicemia, pneumonia, sacroiliitis, peritonitis etc., bronchitis, pyothorax useful.Preferred compound water soluble height of the present invention, and demonstrate the excellent drug dynamic metabolism and/or safety aspect toxicity.
Embodiment
(1) compound
For compound of the present invention is described, the term that uses in this specification sheets is described below.When each term uses separately or with other term, has identical implication.
Term " glycopeptide antibiotic derivatives aglycon part " is meant from being that the known glycopeptide antibiotic derivatives of feature is removed remaining part behind the following stated sugar moieties with the many cyclic peptide nuclear that is randomly replaced by glycosyl." sugar moieties " can be removed more than 1 or 1, preferably removes 1.For example, when glycopeptide antibiotic derivatives was vancomycin, aglycon partly was to remove sugar chain (disaccharides) part that contains aminosugar, the i.e. part that α-L-vancosaminyl-β-the D-Glucopyranose obtains.In addition, having the vancomycin derivatives of modifying body, for example remove N-methyl D-leucine and acidylate form thereof at the peptide chain N-terminal is that known (Expert Opin.Ther.Patents (2004) 14,141-173).Therefore, aglycon partly comprises by these vancomycin derivatives and removes the part that " sugar moieties " obtains as mentioned above.As known glycopeptide antibiotic derivatives, can enumerate disclosed compound in the following document: Japanese kokai publication sho 61-251699 communique, Japanese kokai publication hei 7-258289 communique, international open WO96/30401 brochure, international open WO00/39156 brochure, TOHKEMY 2000-302687 communique, international open WO2004/44222 brochure, United States Patent (USP) the 4th, 639, No. 433, United States Patent (USP) the 4th, 643, No. 987, United States Patent (USP) the 4th, 497, No. 802, United States Patent (USP) the 4th, 698, No. 327, United States Patent (USP) the 5th, 591, No. 714, United States Patent (USP) the 5th, 840, No. 684, with United States Patent (USP) the 5th, 843, No. 889; EP0802199; EP0801075; EP0667353; WO97/28812; WO97/38702; WO98/52589; WO98/52592; J.Am.Chem.Soc., 1996,118,13107-13108; J.Am.Chem.Soc., 1997,119,12041-12047; J.Am.Chem.Soc., 1994,116,4573-4590.
Particularly, can from following compound, select.
Formula:
[formula 10]
Compound or its pharmaceutically useful salt of expression:
In the formula,
R and R
1Be hydrogen or methyl independently;
R
2And R
3Be hydrogen or formula R independently
6R
7The group that CH-represents is at this R
6And R
7Be R independently
5, R
5-(C
1-C
5)-alkyl or R
5-(C
2-C
5-thiazolinyl), R wherein
5Be hydrogen, C
1-C
10-alkyl, C
2-C
10-thiazolinyl, C
1-C
4-alkoxyl group, C
3-C
10-cycloalkyl, C
5-C
12-cycloalkenyl group, phenyl, naphthyl, indenyl, 1,2,3,4-tetrahydro naphthyl, naphthalane base, adamantyl, ring contain 3～8 heteroatomic monocyclic type heteroaromatics or contain 6～11 heteroatomic dicyclic heterocyclic radicals that (its condition is at least 1 of these atoms and is carbon, these heteroatomic at least one be selected from O, N and S), R
5Optional quilt is selected from hydroxyl, nitro, C
1-C
10-alkoxyl group, C
1-C
10-alkyl, phenyl, C
1-C
6-alkylthio, cyano group, halogen, C
2-C
4-amido, amino, C
1-C
4The one or more of-dialkyl amido replace;
R
4Be hydrogen, perhaps R
1And R
2, and/or R
3And R
4Represent the group that following formula is represented together:
[formula 11]
In the formula, R
6And R
7Be R
5, R
5-(C
1-C
5-alkyl) or R
5-(C
2-C
5-thiazolinyl);
N is 1 or 2,
Its condition is: (i) R
2And R
3In at least one be not hydrogen, (ii) when n was 2, R was a hydrogen, (iii) when R be methyl and R
3When being hydrogen, R then
2Not methyl, (iv) as R and R
1When all being hydrogen, R then
2Be hydrogen or methyl, and n is 1;
(spy opens clear 61-251699 communique)
Formula:
[formula 12]
Compound or its pharmaceutically useful salt of expression,
In the formula,
X and Y are hydrogen or chlorine independently;
R is hydrogen, 4-table-vancosaminyl, actinosaminyl or ristosaminyl;
R
1Be hydrogen or seminose;
R
2Be-NH
2,-NHCH
3Perhaps-N (CH
3)
2
R
3Be-CH
2CH (CH
3)
2, [right-OH ,-Cl] phenyl, right-rhamnosyl-phenyl, [right-rhamnosyl-semi-lactosi] phenyl, [right-semi-lactosi-semi-lactosi] phenyl or [right-CH
3The O-rhamnosyl] phenyl;
R
4Be-CH
2(CO) NH
2, benzyl, [right-OH] phenyl or [right-OH ,-Cl] phenyl;
R
5Be hydrogen or seminose;
R
6Be 4-table-vancosaminyl, L-acosaminyl, L-ristosaminyl or L-actinosaminyl;
R
7Be (C
2-C
16) thiazolinyl, (C
2-C
12) alkynyl, (C
1-C
12) alkyl-R
8, (C
1-C
12-alkyl)-halogen, (C
2-C
6-thiazolinyl)-R
8, (C
2-C
6-alkynyl)-R
8, (C
1-C
12-alkyl)-O-R
8, and R
7With R
6Amino connect;
R
8Be:
A) unsubstituted polyaromatic or be independently selected from the following radicals 1 or 1 polyaromatic that above substituting group replaces: (i) hydroxyl, (ii) halogen, (iii) nitro, (iv) (C
1-C
6)-alkyl, (v) (C
1-C
6)-thiazolinyl, (vi) (C
1-C
6)-alkynyl, (vii) (C
1-C
6)-alkyl, (C
1-C
6)-alkoxyl group, (viii) halogen-(C
1-C
6)-alkyl, (ix) halogen-(C
1-C
6)-alkoxyl group, (x) carbonyl (carbo)-(C
1-C
6(the C that)-alkoxyl group, (xi) carbobenzoxy (carbobenzyloxy), (xii) alkoxy, halogen or nitro replace
1-C
6)-alkyl, (C
1-C
6)-carbobenzoxy, (xiii) formula :-S (O) n ' R
9The group of expression, wherein n ' is 0-2, R
9Be (C
1-C
6)-alkyl, phenyl or quilt (C
1-C
6)-alkyl, (C
1-C
6The phenyl that)-alkoxyl group, halogen or nitro replace, and (xiv) formula :-C (O) N (R
10)
2The group of expression, in the formula, R
10Be hydrogen, (C independently
1-C
6)-alkyl, (C
1-C
6)-alkoxyl group, phenyl or quilt (C
1-C
6)-alkyl, (C
1-C
6The phenyl that)-alkoxyl group, halogen or nitro replace;
B) unsubstituted heteroaryl or be independently selected from the following radicals 1 or 1 heteroaryl that above substituting group replaces: (i) halogen, (ii) (C
1-C
6)-alkyl, (iii) (C
1-C
6)-alkoxyl group, (iv) halogen-(C
1-C
6)-alkyl, (v) halogen-(C
1-C
6)-alkoxyl group, (vi) phenyl, (vii) thiophenyl is (viii) by halogen, (C
1-C
6)-alkyl, (C
1-C
6)-thiazolinyl, (C
1-C
6)-alkynyl, (C
1-C
6The phenyl that)-alkoxyl group or nitro replace, (ix) carbonyl-(C
1-C
6) alkoxyl group, (x) carbobenzoxy is (xi) by (C
1-C
6)-alkyl, (C
1-C
6The carbobenzoxy that)-alkoxyl group, halogen or nitre replace, (xii) formula of above-mentioned definition :-S (O) n ' R
9The group of expression, (xiii) formula of above-mentioned definition :-C (O) N (R
10)
2The group of expression and (xiv) thienyl;
C) group represented of following formula:
[formula 13]
In the formula,
A
1Be-OC (A
2)
2-C (A
2)
2-O-,-O-C (A
2)
2-O-,-C (A
2)
2-O-or-C (A
2)
2-C (A
2)
2-C (A
2)
2-C (A
2)
2-, each A wherein
2Be independently selected from hydrogen, (C
1-C
6)-alkyl, (C
1-C
6) alkoxyl group and (C
4-C
10)-cycloalkyl;
D) group represented of following formula:
[formula 14]
In the formula,
P is 1～5, R
11Be independently selected from: (i) hydrogen, (ii) nitro, (iii) hydroxyl, (iv) halogen, (v) (C
1-C
8)-alkyl, (vi) (C
1-C
6)-alkoxyl group, (vii) (C
9-C
12)-alkyl, (viii) (C
2-C
9)-alkynyl, (ix) (C
9-C
12)-alkoxyl group is (x) by (C
1-C
3)-alkoxyl group, hydroxyl, halogen-(C
1-C
3)-alkoxyl group or (C
1-C
4) (the C that replaces of alkylthio
1-C
3)-alkoxyl group, (xi) (C
2-C
5)-alkene oxygen base, (xii) (C
1-C
13)-alkynyloxy group, (xiii) halogen-(C
1-C
6)-alkyl, (xiv) halogen-(C
1-C
6)-alkoxyl group, (xv) (C
2-C
6)-alkylthio, (xvi) (C
2-C
10)-alkanoyloxy, (xvii) carboxyl-(C
2-C
4)-thiazolinyl, (xviii) (C
1-C
3)-alkylsulfonyloxy, (xix) carboxyl-(C
1-C
3)-alkyl, (xx) N-[two (C
1-C
3) alkyl] amino-(C
1-C
3) alkoxyl group, (xxi) cyano group-(C
1-C
6)-alkoxyl group and (xxii) phenylbenzene-(C
1-C
6)-alkyl,
Its condition is to work as R
11Be (C
1-C
8)-alkyl, (C
1-C
8During)-alkoxy or halogen, then p is more than 2 or 2.In addition, work as R
7Be (C
1-C
3-alkyl)-R
8The time, R then
11Not hydrogen, (C
1-C
8)-alkyl, (C
1-C
8)-alkoxy or halogen;
E) formula:
[formula 15]
The group of expression,
In the formula,
Q is 0～4,
R
12Be independently selected from (i) halogen, (ii) nitro, (iii) (C
1-C
6)-alkyl, (iv) (C
1-C
6)-alkoxyl group, (v) halogen-(C
1-C
6)-alkyl, (vi) halogen-(C
1-C
6)-alkoxyl group and (vii) hydroxyl and (vii) (C
1-C
6)-alkylthio,
R is 1～5, and its condition is that q+r is not more than 5,
Z is the group that is independently selected from the following radicals: (i) singly-bound does not (ii) replace or by hydroxyl, (C
1-C
6)-alkyl or (C
1-C
6Divalence (the C that)-alkoxyl group replaces
1-C
6)-alkyl, (iii) divalence (C
2-C
6)-thiazolinyl, (iv) divalence (C
2-C
6)-alkynyl, perhaps (v) formula :-(C (R
14)
2) s-R
15-or-R
15-(C (R
14)
2) group represented of s-
In the formula, s is 0-6, R
14Be independently selected from hydrogen, (C
1-C
6)-alkyl or (C
4-C
10)-cycloalkyl, R
15Be selected from-O-,-S-,-SO-,-SO
2-,-SO
2-O-,-C (O)-,-OC (O)-,-C (O) O-,-NH-,-N (C
1-C
6-alkyl)-and-C (O) NH-,-NHC (O)-,-N=N-,
R
13Be independently selected from (i) (C
4-C
10)-heterocyclic radical, (ii) heteroaryl does not (iii) replace or quilt (C
1-C
6(the C that)-alkyl replaces
4-C
10)-cycloalkyl or (iv) do not replace or be independently selected from halogen, hydroxyl, nitro, (C
1-C
10)-alkyl, (C
1-C
10)-alkoxyl group, halogen-(C
1-C
3)-alkoxyl group, halogen-(C
1-C
3)-alkyl, (C
1-C
3)-alkoxyl phenyl, phenyl, phenyl-(C
1-C
3)-alkyl, (C
1-C
6)-alkoxyl phenyl, phenyl-(C
1-C
3)-alkynyl and (C
1-C
6The phenyl that 1～5 substituting group in the)-alkyl phenyl replaces;
F) do not replace or be independently selected from the following radicals 1 or 1 (C that above substituting group replaces
4-C
10)-cycloalkyl: (i) (C
1-C
6)-alkyl, (ii) (C
1-C
6)-alkoxyl group, (iii) (C
1-C
6)-thiazolinyl, (iv) (C
1-C
6)-alkynyl, (v) (C
4-C
10)-cycloalkyl, (vi) phenyl, (vii) thiophenyl is (viii) by nitro, halogen, (C
1-C
6The phenyl that)-alkanoyloxy or carbocyclic ring alkoxyl group replace, and (ix) formula :-Z-R
13(in the formula, Z and R
13Identical with above-mentioned definition) expression group; And
G) formula:
[formula 16]
The group of expression,
In the formula,
A
3And A
4Be (i) key, (ii)-O-, (iii)-S (O) t-(in the formula, t is 0～2), (iv)-C (R
17)
2-(in the formula, R
17Be independently selected from hydrogen, (C
1-C
6)-alkyl, hydroxyl, (C
1-C
6)-alkyl, (C
1-C
6)-alkoxyl group, perhaps two R
17Represent O together), (v)-N (R
18)
2-(in the formula, R
18Be independently selected from hydrogen, (C
1-C
6)-alkyl, (C
1-C
6)-thiazolinyl, (C
1-C
6)-alkynyl, (C
4-C
10)-cycloalkyl, phenyl or by nitro, halogen or (C
1-C
6The phenyl that)-alkanoyloxy replaces, perhaps two R
18Represent (C together
4-C
10)-cycloalkyl), R
16Be the R of above-mentioned definition
12Or R
13, and
U is 0～4.
The compound of formula (1) and (2) expression:
[formula 17]
In the formula,
N is 0～10 integer,
N ' be 1～12 integer and
M is 2～60 integer];
(TOHKEMY 2000-302687 communique); Perhaps
Formula I:
[formula 18]
Compound with and pharmaceutically useful salt, steric isomer and prodrug,
In the formula,
R
1Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl, heterocycle and-R
a-Y-R
b-(Z)
xPerhaps optional quilt-R
a-Y-R
b-(Z)
xThe glycosyl that replaces;
R
2Be hydrogen, perhaps optional quilt-R
a-Y-R
b-(Z)
xThe glycosyl that replaces;
R
3Be-OR
cOr-NR
cR
c
R
4Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl ,-R
a-Y-R
b-(Z)
x,-C (O) R
dAnd optional quilt-R
a-Y-R
b-(Z)
xThe glycosyl that replaces;
R
5Be selected from hydrogen, halogen ,-CH (R
c)-NR
cR
c,-CH (R
c)-NR
cR
eAnd-CH (R
c)-NR
c-R
a-Y-R
b-(Z)
x
R
6Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl ,-R
a-Y-R
b-(Z)
x,-C (O) R
dAnd optional quilt-NR
c-R
a-Y-R
b-(Z)
xThe glycosyl that replaces, perhaps R
5And R
6Form optional quilt-NR with the atom that is connected with them
c-R
a-Y-R
b-(Z)
xThe heterocycle that replaces;
R
7Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl ,-R
a-Y-R
b-(Z)
xWith-C (O) R
d
R
8Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl and heterocycle;
R
9Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl and heterocycle;
R
10Be selected from alkyl and substituted alkyl;
R
11Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl and heterocycle, perhaps R
10And R
11With form heterocycle with their bonding ground carbon and nitrogen-atoms;
R
12Be selected from hydrogen, alkyl, substituted alkyl and-C (O) OR
d
R
13Be selected from hydrogen or-OR
14
R
14Be selected from hydrogen ,-C (O) R
dAnd glycosyl;
R
aBe independently selected from alkylidene group, substituted alkylene, alkenylene, replacement alkenylene, alkynylene and replacement alkynylene;
R
bBe independently selected from alkylidene group, substituted alkylene, alkenylene, replacement alkenylene, alkynylene and replacement alkynylene;
R
cBe independently selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl, heterocycle and-C (O) R
d
R
dBe independently selected from alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl and heterocycle;
R
eIt is glycosyl;
X
1, X
2And X
3Be independently selected from hydrogen or chlorine;
Y be independently selected from oxygen, sulphur ,-S-S-,-NR
c,-S (O)-,-SO
2-,-NR
cC (O)-,-OSO
2-,-OC (O)-,-NR
cSO
2-,-C (O) NR
c,-C (O) O-,-SO
2NR
c,-SO
2O-,-P (O) (OR
c) O-,-P (O) (OR
c) NR
c,-OP (O) (OR
c) O-,-OP (O) (OR
c) NR
c,-OC (O) O-,-NR
cC (O) O-,-NR
cC (O) NR
c,-OC (O) NR
c-and-NR
cSO
2NR
c-;
Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl group, heteroaryl and heterocycle;
N is 0,1 or 2; With
X is 1 or 2,
Its condition is R
1, R
2, R
4, R
5, R
6Or R
7In at least one be formula-R
a-Y-R
b-(Z)
xGroup; And
(i) as Y be-NR
c, R
cBe the alkyl of 1～4 carbon atom, Z is a hydrogen, and R
bWhen being alkylidene group, R then
bAt least contain 5 carbon atoms;
(ii) working as Y is-C (O) NR
c-, Z is a hydrogen, and R
bWhen being alkylidene group, R then
bAt least contain 5 carbon atoms;
(iii) working as Y is sulphur, and Z is a hydrogen, R
bWhen being alkylidene group, R then
bAt least contain 7 carbon atoms; And
(iv) working as Y is oxygen, and Z is a hydrogen, R
bWhen being alkylidene group, R then
bAt least contain 11 carbon atoms];
(Japanese Unexamined Patent Application Publication 2002-533472 communique).
Formula I:
[formula 19]
Compound and pharmaceutically useful salt, steric isomer and prodrug thereof,
In the formula,
R
1Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl, heterocycle and-R
a-Y-R
b-(Z)
x, perhaps R
1Be optional quilt-R
a-Y-R
b-(Z)
x, R
f,-C (O) R
fOr-C (O)-R
a-Y-R
b-(Z)
xThe glycosyl that replaces;
R
2Be hydrogen or optional quilt-R
a-Y-R
b-(Z)
x, R
f,-C (O) R
fOr-C (O)-R
a-Y-R
b-(Z)
xThe glycosyl that replaces;
R
3Be-OR
c,-NR
cR
c,-O-R
a-Y-R
b-(Z)
x,-NR
c-R
a-Y-R
b-(Z)
x,-NR
cR
eOr-O-R
e, perhaps R
3Be to comprise connection N-, the O-of 1 or 1 above phosphono or the group of S-;
R
4Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl ,-R
a-Y-R
b-(Z)
x,-C (O) R
d,-R
a-Y-R
b-(Z)
x, R
f,-C (O) R
fPerhaps optional quilt-C (O)-R
a-Y-R
b-(Z)
xThe glycosyl that replaces;
R
5Be selected from hydrogen, halogen ,-CH (R
c)-NR
cR
c,-CH (R
c)-NR
cR
e,-CH (R
c)-NR
c-R
a-Y-R
b-(Z)
x,-CH (R
c)-Rx ,-CH (R
c)-NR
c-R
a-C (=O)-R
xWith the group that contains 1 or 1 above phosphono;
R
6Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl ,-R
a-Y-R
b-(Z)
x,-C (O) R
dWith optional quilt-NR
c-R
a-Y-R
b-(Z)
xThe glycosyl that replaces, perhaps R
5And R
6Form optional quilt-NR together with atom with their bondings
c-R
a-Y-R
b-(Z)
xThe heterocycle that replaces;
R
7Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl ,-R
a-Y-R
b-(Z)
xWith-C (O) R
d
R
8Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl and heterocycle;
R
9Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl and heterocycle;
R
10Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl and heterocycle; Perhaps R
8And R
10Formation-Ar together
1-O-Ar
2-, Ar wherein
1And Ar
2Be arylidene or inferior heteroaryl independently;
R
11Be independently selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl and heterocycle, perhaps R
10And R
11Carbon atom and nitrogen-atoms with their institute's bondings form heterocycle;
R
12Be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl, heterocycle ,-C (O) R
d,-C (NH) R
d,-C (O) NR
cR
c,-C (O) OR
d,-C (NH) NR
cR
cWith-R
a-Y-R
b-(Z)
x, perhaps R
11And R
12Nitrogen-atoms with their institute's bondings forms heterocycle;
R
13Be selected from hydrogen or-OR
14
R
14Be selected from hydrogen ,-C (O) R
dAnd glycosyl;
R
aBe independently selected from alkylidene group, substituted alkylene, alkenylene, replacement alkenylene, alkynylene and replacement alkynylene;
R
bBe independently selected from covalent linkage, alkylidene group, substituted alkylene, alkenylene, replacement alkenylene, alkynylene and replacement alkynylene, condition is when Z is hydrogen, R
bIt or not covalent linkage;
R
cBe independently selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl, heterocycle and-C (O) R
d
R
dBe independently selected from alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl and heterocycle;
R
eIt is glycosyl;
R
fBe alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl group, substituted cycloalkenyl, aryl, heteroaryl or heterocycle independently;
R
XThe aminosugar of the N that is bonding or bonding the heterocycle of N, and X
1, X
2And X
3Be independently selected from hydrogen or chlorine;
Y be independently selected from oxygen, sulphur ,-S-S-,-NR
c-,-S (O)-,-SO
2-,-NR
cC (O)-,-OSO
2-,-OC (O)-,-NR
cSO
2-,-C (O) NR
c,-C (O) O-, ,-SO
2NR
c,-SO
2O-,-P (O) (OR
c) O-,-P (O) (OR
c) NR
c,-OP (O) (OR
c) O-,-OP (O) (OR
c) NR
c-,-OC (O) O-,-NR
cC (O) O-, NR
cC (O) NR
c,-OC (O) NR
c,-C (=O)-and-NR
cSO
2NR
c-;
Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl group, heteroaryl and heterocycle;
N is 0,1 or 2;
X is 1 or 2;
(TOHKEMY 2003-531869 communique).
Formula
A
1-A
2-A
3-A
4-A
5-A
6-A
7
The glycopeptide of expression, and pharmaceutically useful salt:
In the formula,
Each horizontal line is represented covalent linkage;
A
1Base comprises a-amino acid residue, alkyl, aryl, aralkyl, alkyloyl, aroyl, aralkanoyl, heterocycle, heterocycle-carbonyl, heterocycle-alkyl, heterocycle-alkyl-carbonyl, alkyl sulphonyl, aryl sulfonyl, guanidine radicals, formamyl or cluck the ton base of modification or unmodified;
Each A
2～A
7Base comprises the a-amino acid residue of modification or unmodified, thus, and (i) A
1Base and A
2Amino bonded on the base, (ii) each A
2, A
4And A
6Base has the aromatic series side chain respectively, and this aromatic series side chain is by covalently cross-linked more than 2 or 2, and (iii) A
7Base has terminal carboxyl(group), ester, acid amides or N substituted amide base; And
A
1～A
7Being bonded on one or more glycosyls that have 1 or 1 above saccharide residue respectively by glycosidic link more than 1 or 1 of base; At this at least 1 described saccharide residue is to be modified to have formula: YXR, N
+(R
1)=CR
2R
3, N=PR
1R
2R
3, N
+R
1R
2R
3Or P
+R
1R
2R
3In substituent disaccharides more than 1 or 1, in the formula, the Y base is singly-bound, O, NR
1Perhaps S; The X group is O, NR
1, S, SO
2, C (O) O, C (O) S, C (S) O, C (S) S, C (NR
1) O, C (O) NR
1Perhaps halogen (this moment do not exist Y and R); And R, R
1, R
2And R
3Be hydrogen, alkyl, aryl, aralkyl, alkyloyl, aroyl, aralkanoyl, heterocyclic radical, heterocycle-carbonyl, heterocycle-alkyl, heterocycle-alkyl-carbonyl, alkyl sulphonyl or aryl sulfonyl independently
Its condition is that at least 1 substituting group of formula YXR is not a hydroxyl; X and Y not all are O; X and Y are not respectively S and O, perhaps O and S; And if had this substituting group more than 2 or 2, then they can be the same or different; And condition is to work as A
4Fashionable with the disaccharide bond of the glucosyl residue with the amino hexose residue that contains the N-replacement, then this glucosyl residue is modified to and has at least 1 following substituting group: YXR, N
+(R
1)=CR
2R
3, N=PR
1R
2R
3, N
+R
1R
2R
3Or P
+R
1R
2R
3
(TOHKEMY 2002-520422 communique).
Formula:
[formula 20]
The compound or its salt of expression,
In the formula,
X is hydrogen or chlorine;
R is 4-table-vancosaminyl or formula-R
a-R
7aThe group of expression, wherein R
aBe 4-table-vancosaminyl, R
7aTo define itself and R hereinafter
aAmino bonded;
R
2Be-NHCH
3Or-N (CH
3) R
7b, R wherein
7bTo define hereinafter;
R
6Be 4-table-vancosaminyl;
R
7To define hereinafter, with R
aAmino bonded; With
R
7, R
7aAnd R
7bBe independently selected from hydrogen, C
2-16Thiazolinyl, C
2-12Alkynyl, (C
1-12Alkyl)-R
8, (C
1-12Alkyl)-halogen, (C
2-6Thiazolinyl)-R
8, (C
2-6Alkynyl)-R
8(C
1-12Alkyl)-O-R
8, its condition is R
7, R
7aAnd R
7bNot hydrogen entirely, and R
8Be selected from:
A) do not replace or be independently selected from 1 or 1 polyaromatic that above substituting group replaces in following:
(i) hydroxyl,
(ii) halogen,
(iii) nitro,
(iv) C
1-6Alkyl,
(v) C
1-6Thiazolinyl,
(vi) C
1-6Alkynyl,
(vii) C
1-6Alkoxyl group,
(viii) halogen-(C
1-6Alkyl),
(ix) halogen-(C
1-6Alkoxyl group),
(x) carbonyl-(C
1-6Alkoxyl group),
(xi) carbobenzoxy,
(xii) by C
1-6Alkyl, C
1-6The carbobenzoxy that alkoxyl group, halogen or nitro replace,
(xiii) formula-S (O) n '-R
9The group of expression, wherein n ' is 0-2, R
9Be C
1-6Alkyl, phenyl or by C
1-6Alkyl, C
1-6The phenyl that alkoxyl group, halogen or nitro replace and (xiv) formula-C (O) N (R
10)
2The group of expression, wherein each R
10Substituting group is hydrogen, C independently
1-6Alkyl, C
1-6Alkoxyl group, phenyl or by C
1-6Alkyl, C
1-6The phenyl that alkoxyl group, halogen or nitro replace;
B) do not replace or independently be selected from the heteroaryl of 1 or 1 above substituting group replacement in following:
(i) halogen,
(ii) C
1-6Alkyl,
(iii) C
1-6Alkoxyl group,
(iv) halogen-(C
1-6Alkyl),
(v) halogen-(C
1-6Alkoxyl group),
(vi) phenyl,
(vii) thiophenyl,
(viii) by halogen, C
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, C
1-6The phenyl that alkoxyl group or nitro replace,
(ix) carbonyl-(C
1-6Alkoxyl group),
(x) carbobenzoxy,
(xi) by C
1-6Alkyl, C
1-6The carbobenzoxy that alkoxyl group, halogen or nitro replace,
(xii) formula-S (O) n '-R of above definition
9The group of expression,
(xiii) formula-C (O) N (R of above definition
10)
2The expression group and
(xiv) thienyl;
C) group represented of following formula:
[formula 21]
Wherein, A
1Be-OC (A
2)
2C (A
2)
2O-,-OC (A
2)
2O-,-C (A
2)
2O-or-C (A
2)
2C (A
2)
2C (A
2)
2C (A
2)
2-, and each A
2Substituting group is independently selected from hydrogen, C
1-6Alkyl, C
1-6Alkoxyl group and C
4-10Cycloalkyl;
D) group represented of following formula:
[formula 22]
Wherein,
P is 1～5; With
R
11Be independently selected from:
(i) hydrogen,
(ii) nitro,
(iii) hydroxyl,
(iv) halogen,
(v) C
1-8Alkyl,
(vi) C
1-8Alkoxyl group,
(vii) C
9-12Alkyl,
(viii) C
2-9Alkynyl,
(ix) C
9-12Alkoxyl group,
(x) by C
1-3Alkoxyl group, hydroxyl, halogen-C
1-3Alkoxyl group or C
1-4The C that alkylthio replaces
1-3Alkoxyl group,
(xi) C
2-5Alkene oxygen base,
(xii) C
1-13Alkynyloxy group,
(xiii) halogen-C
1-6Alkyl,
(xiv) halogen-C
1-6Alkoxyl group,
(xv) C
2-6Alkylthio,
(xvi) C
2-10Alkanoyloxy,
(xvii) carboxyl-(C
2-4Thiazolinyl),
(xviii) C
1-3Alkylsulfonyloxy,
(xix) carboxyl-(C
1-3Alkyl),
(xx) N-[two (C
1-3Alkyl] amino-(C
1-3Alkoxyl group),
(xxi) cyano group-(C
1-6Alkoxyl group) and
(xxii) phenylbenzene-(C
1-6Alkyl),
Its condition is to work as R
11Be C
1-9Alkyl, C
1-8During alkoxy or halogen, p must perhaps work as R more than or equal to 2
7Be C
1-3Alkyl-R
8The time, R
11Not hydrogen, C
1-9Alkyl, C
1-8Alkoxy or halogen;
E) group represented of following formula:
[formula 23]
Wherein,
Q is 0～4;
R
12Be independently selected from:
(i) halogen,
(ii) nitro,
(iii) C
1-6Alkyl,
(iv) C
1-6Alkoxyl group,
(v) halogen-(C
1-6Alkyl),
(vi) halogen-(C
1-6Alkoxyl group),
(vii) hydroxyl and
(viii) C
1-6Alkylthio,
R is 1～5; Its condition is that the summation of q+r is not more than 5;
Z is selected from:
(i) singly-bound,
(ii) do not replace or by hydroxyl, C
1-6Alkyl or C
1-6The divalence C that alkoxyl group replaces
1-6Alkyl,
(iii) divalence C
2-6Thiazolinyl,
(iv) divalence C
2-6Alkynyl, or
(v) formula-(C (R
14)
2) sR
15-or-R
15(C (R
14)
2) group that s-represents, wherein s is 0-6, each R
14Substituting group is independently selected from hydrogen, C
1-6Alkyl or C
4-10Cycloalkyl, and R
15Be selected from-O-,-S-,-SO-,-SO
2-,-SO
2O-,-C (O)-,-OC (O)-,-C (O) O-,-NH-,-N (C
1-6Alkyl)-,-C (O) NH-,-NHC (O)-and-N=N-;
R
13Be independently selected from:
(i) C
4-10Heterocyclic radical,
(ii) heteroaryl,
(iii) do not replace or by C
1-6The C that alkyl replaces
4-10Cycloalkyl
(iv) do not replace or be independently selected from the phenyl of 1～5 substituting group replacement in the following radicals: halogen, hydroxyl, nitro, C
1-10Alkyl, C
1-10Alkoxyl group, halogen-C
1-3Alkoxyl group, halogen-C
1-3Alkyl, C
1-3Alkoxyl phenyl, phenyl, phenyl-(C
1-3Alkyl), C
1-6Alkoxyl phenyl, phenyl-(C
1-3Alkynyl) and C
1-6Alkyl phenyl;
F) do not replace or be selected from the C of 1 or 1 above substituting group replacement in the following radicals
4-10Cycloalkyl:
(i) C
1-6Alkyl,
(ii) C
1-6Alkoxyl group,
(iii) C
1-6Thiazolinyl,
(iv) C
1-6Alkynyl,
(v) C
4-10Cycloalkyl,
(vi) phenyl,
(vii) thiophenyl,
(viii) by nitro, halogen, C
1-6The phenyl that alkanoyloxy or carbocyclic ring alkoxyl group replace and
(ix) formula-ZR
13The group of expression, wherein Z and R
13Identical with above-mentioned definition; And
G) group represented of following formula:
[formula 24]
Wherein,
A
3And A
4Be selected from independently of one another:
(i) key,
(ii)-O-，
(iii)-and S (O) t-, wherein t is 0～2,
(iv)-C (R
17)
2-, each R wherein
17Substituting group is independently selected from hydrogen, C
1-6Alkyl, hydroxyl and C
1-6Alkoxyl group, perhaps two R
17Represent O together,
(v)-N (R
18)
2-, each R wherein
18Be hydrogen, C independently
1-6Alkyl, C
1-6Thiazolinyl, C
1-6Alkynyl, C
4-10Cycloalkyl, phenyl and by nitro, halogen, C
1-6The phenyl that alkanoyloxy replaces, or two R
18Represent C together
4-10Cycloalkyl;
R
16Be the R of above-mentioned definition
12Or R
13And
U is 0-4,
R is 4-table-vancosaminyl and R in the same compound but be not included in
2Be-NH (CH
3) compound].
(Japanese kokai publication hei 11-502534 communique)
As the object lesson of glycopeptide antibiotic derivatives, can enumerate vancomycin, Teicoplanin Targocin, ristomycin, ristocetin, aclacinomycin, actinoidin, aridicin, avotan, azureomycin, balhimycin, chloroorienticin A, chloroorienticin B, chloropolysporin, decaplanin, N-demethyl vancomycin, eremomycin, galacardin, helvecardin, izupeptin, kibdelin, mannopeptin, orienticin, parvodicin, synmonicin, oritavancin, telavancin, dalbavancin, A-40926 etc.
Term " sugar moieties " is meant monose or polysaccharide (for example disaccharides) part, and comprises aminosugar, contains sugar chain or other sugar or the sugar chain part of aminosugar.Preferably refer to the aminosugar part or contain aminosugar sugar chain (preferred disaccharides) partly, for example, when being vancomycin, be meant the disaccharides that is connected phenol moieties, i.e. α-L-vancosaminyl-β-D-Glucopyranose part.Described sugar moieties typically comprises for example D-glucose; the D-seminose; the D-wood sugar; the D-semi-lactosi; vancosamin; 3-removes first vancosamin; 3-table-vancosamin; 4-table-vancosamin; acosamin; actinosamin; daunosamin; 3-table-daunosamin; ristosamin; N-methyl D-glycosamine; the D-glucuronic acid; N-ethanoyl-D-glycosamine; N-ethanoyl-D-galactosamine; sialic acid; 2-O-(α-L-vancosaminyl)-β-D-Glucopyranose; (3-removes first-α-L-vancosaminyl)-β-D-Glucopyranose to 2-O-; sucrose; lactose or maltose.
Term " saccharide residue " is meant from above-mentioned " sugar moieties " removes 1 nubbin behind the OH.
Term " aminosugar residue " is meant from " aminosugar " or contains " the sugar chain part that aminosugar is arranged " removes 1 nubbin behind the amino.
Term " Sac-NH " part is meant known aminosugar part in the glycopeptide antibiotic derivatives or contains the sugar chain part of aminosugar.Term " aminosugar part " expression has the monosaccharide groups of amino or substituted-amino.Representational aminosugar partly comprises: L-vancosaminyl, 3-demethyl-vancosaminyl, 3-table-vancosaminyl, 4-table-vancosaminyl, 4-ketone-vancosaminyl, acosaminyl, actinosaminyl, daunosaminyl, 3-table-daunosaminyl, ristosaminyl, N-methyl D-glucaminyl, N-ethanoyl-D-glucosamyl or N-acyl group-D-glucosamyl etc.Preferred actinosaminyl, acosaminyl, 4-table-vancosaminyl, 4-ketone-vancosaminyl, ristosaminyl or vancosaminyl.Especially preferred L-vancosaminyl.As the sugar chain part that contains aminosugar, can enumerate α-L-vancosaminyl-β-D-Glucopyranose, 3-demethyl-α-L-vancosaminyl-β-D-Glucopyranose.
As mentioned above, " (glycopeptide antibiotic derivatives aglycon part)-(Sac-NH) " is the glycopeptide antibiotic derivatives with terminal amino group sugar moieties.
Therefore, glycopeptide antibiotic derivatives of the present invention has R for bonding on the amino of aminosugar endways
AThe compound of group.
R
AUse formula :-X
1-Ar
1-X
2-Y-X
3-Ar
2Expression.
R
AGroup is characterised in that, partly contains amido linkage at Y.
Term " low alkyl group " is meant that carbonatoms is the univalent perssad of 1～6 straight or branched stable hydrocarbon, comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, n-hexyl, isohexyl.
X
1, X
2And X
3Definition in " connect base " be meant and contain heteroatomic linking group, described heteroatoms is selected from-N=,=N-,-NR
1-(R wherein
1Be hydrogen or low alkyl group) ,-O-,-S-,-SO-and-SO
2-, for example refer to-S-S-,-NR
1CO-,-NR
1O-,-NR
1S-,-OSO
2-,-OCO-,-SO
2NR
1-etc.
Term " alkylidene group " is meant that carbonatoms is the divalent group of 1～6 straight or branched stable hydrocarbon, comprises for example methylene radical, ethylidene, trimethylene, propylidene, butylidene, tetramethylene, ethyl ethylidene, pentamethylene or hexa-methylene etc.Preferred carbonatoms is 1～4 the saturated alkylidene group of straight or branched, for example methylene radical, ethylidene, trimethylene or tetramethylene.Preferred methylene radical.
Term " alkenylene " is meant that the carbonatoms that has more than 1 or 1 two keys in above-mentioned " alkylidene group " is the divalent group of 2～6 straight or branched aliphatic unsaturated hydrocarbon, for example can enumerate vinylidene, propenylidene or crotonylidene.Preferred carbonatoms is 2～3 straight chain alkenylene, for example vinylidene or propenylidene.
Term " optional substituted alkylidene group or alkenylene " is meant to have 1～5 substituting group; preferably have 1～3 substituent alkylidene group or alkenylene; at this; described substituting group is selected from: optional substituted alkyl (methyl for example; ethyl; sec.-propyl; benzyl; formamyl alkyl (for example carbamyl ylmethyl); list or dialkyl amido formyl radical alkyl (for example formyl-dimethylamino ethyl); hydroxyalkyl; heterocyclic radical alkyl (morpholino ethyl for example; the THP trtrahydropyranyl ethyl); alkoxy carbonyl alkyl (ethoxy carbonyl methyl for example; the ethoxy carbonyl ethyl); list or dialkyl aminoalkyl (for example dimethyl aminoethyl) etc.); alkoxyalkyl (methoxy ethyl for example; ethoxyl methyl; ethoxyethyl group; isopropoxy ethyl etc.); acyl group (formyl radical for example; optional substituted alkyl-carbonyl (ethanoyl for example; propionyl; butyryl radicals; isobutyryl; pentanoyl; isovaleryl; valeryl; caproyl; capryloyl; the methoxy ethyl carbonyl; 2; 2; 2-trifluoroethyl carbonyl; ethoxy carbonyl methyl carbonyl; alkoxyalkyl carbonyl (for example methoxy ethyl carbonyl); alkyl-carbamoyl alkyl-carbonyl (for example methylamino formyl radical ethyl carbonyl); alkoxy carbonyl ethanoyl etc.); optional substituted aryl carbonyl (benzoyl for example; toluyl etc.)); optional substituted aralkyl (benzyl for example; 4-F-benzyl etc.); hydroxyl; optional substituted alkyl sulphonyl (methylsulfonyl for example; ethylsulfonyl; different third alkylsulfonyl; 2; 2; 2-trifluoro ethylsulfonyl; the benzyl alkylsulfonyl; methoxy ethyl alkylsulfonyl etc.); the optional aryl sulfonyl that is replaced by alkyl or halogen (benzenesulfonyl for example; tosyl group; the 4-fluorosulfonyl); cycloalkyl (for example; cyclopropyl etc.); the optional aryl that is replaced by alkyl (for example 4-aminomethyl phenyl etc.); alkyl amino sulfonyl (methylamino alkylsulfonyl for example; dimethylamino alkylsulfonyl etc.); alkyl amino-carbonyl (for example; dimethylamino carbonyl etc.); alkoxy carbonyl (for example; ethoxy carbonyl etc.); naphthene base carbonyl (for example; cyclopropyl carbonyl; cyclohexyl-carbonyl etc.); optional substituted sulfamyl (for example; sulfamyl; the methyl sulfamyl; diformazan sulfamyl etc.); alkyl-carbonyl-amino (for example; the methyl carbonylamino); heterocyclic radical (for example; the morpholino base; THP trtrahydropyranyl); optional substituted amino (for example, list or dialkyl amido (for example dimethylamino); formyl radical amino).
Therefore, " optional heteroatom group identical or different more than 1 or 1 and optional substituted alkylidene group or the alkenylene of being mingled with " be meant optional be mingled be selected from-N=,=N-,-NR
1-(wherein, R
1Be hydrogen or low alkyl group) ,-O-,-S-,-SO-and-SO
2-in more than 1 or 1 identical or different heteroatom group and optional substituted alkylidene group or alkenylene.At this, " being mingled with " is meant that heteroatom group is present in the situation between the carbon atom that constitutes above-mentioned alkylidene group or alkenylene, or is present in described carbon atom and Ar
1, Y or Ar
2Between situation.For example, can enumerate-O-CH
2-,-CH
2-O-,-CH
2-O-CH
2-, CH
2-NH-CH
2-,-O-CH
2-O-,-CH
2-O-CH
2-NH-CH
2-, CH
2-N=CH-,-CH
2-O-CH=N-CH
2-and-O-CH=CH-,-CH=CH-O-,-CH=CH-O-CH
2-, CH
2-NH-CH=CH-,-O-CH=CH-O-or-(CH
2-O)-Ar
1-(O-CH
2-O)-Y-(O-CH
2)-Ar
2Deng.In addition, as the situation that alkylidene group is replaced by the oxo base, can preferably enumerate-CO-.
X
1Be preferably C
1-C
3Alkylidene group.
X
2Be preferably singly-bound, C
1-C
3Alkylidene group, O or NH, more preferably singly-bound or NH.
Y is preferably-NHCO-,-CONH-,-NMeCO-,-CONMe-or following radicals:
[formula 25]
In addition, Y can be the piperazine cyclic group, and more preferably-NHCO-or-CONH-.
X
3Be preferably singly-bound, C
1-C
3Alkylidene group, O or NH, more preferably singly-bound.
In addition ,-Y-X
3-and-X
2-Y-can form following structure:
[formula 26]
Ar
1And Ar
2Independently of one another for being substituted or can being undersaturated carbocyclic ring or heterocycle.
Ar
1And Ar
2Definition in term " optional undersaturated carbocyclic ring " be meant that carbonatoms is that 3～10 cycloalkyl or carbonatoms are 3～10 cycloalkenyl group or aryl.
Term " cycloalkyl " comprises for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.Preferred carbonatoms is 3～6 cycloalkyl, for example cyclopentyl, cyclohexyl.
Term " cycloalkenyl group " comprises for example having cyclopropenyl radical (for example, the 1-cyclopropenyl radical), the cyclobutene base (for example, 1-cyclobutene base), cyclopentenyl (for example, 1-cyclopentenes-1-base, 2-cyclopentenes-1-base, 3-cyclopentenes-1-yl), tetrahydrobenzene (for example, 1-tetrahydrobenzene-1-base, 2-tetrahydrobenzene-1-base, 3-tetrahydrobenzene-1-yl), cycloheptenyl (for example, the 1-cycloheptenyl), cyclooctene base (for example, 1-cyclooctene base).Preferred especially 1-tetrahydrobenzene-1-base, 2-tetrahydrobenzene-1-base, 3-tetrahydrobenzene-1-base.
Term " aryl " is meant mononuclear aromatics base (phenyl) and polynuclear aromatics base (for example, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl etc.).Preferred phenyl or naphthyl (for example, 1-naphthyl, 2-naphthyl).
Ar
1And Ar
2Term in the definition " optional undersaturated heterocycle " is meant heterocyclic radical or heteroaryl.
Term " heterocyclic radical " be have in the finger ring at least 1 nitrogen-atoms, Sauerstoffatom or sulphur atom, in commutable optional position optional substituted non-aromatic heterocyclic radical.1-pyrrolinyl for example, the 2-pyrrolinyl, the 3-pyrrolinyl, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, the 1-imidazolinyl, the 2-imidazolinyl, the 4-imidazolinyl, the 1-imidazolidyl, the 2-imidazolidyl, the 4-imidazolidyl, the 1-pyrazolinyl, the 3-pyrazolinyl, the 4-pyrazolinyl, the 1-pyrazolidyl, the 3-pyrazolidyl, the 4-pyrazolidyl, piperidino-(1-position only), the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 1-piperazinyl, the 2-piperazinyl, the 2-morpholinyl, morpholinyl, morpholino, THP trtrahydropyranyl etc." non-aromatic heterocyclic radical " also can be undersaturated so long as non-aromatic then can be saturated.
Term " heteroaryl " is meant the monocyclic aromatic heterocycle base and condenses aromatic heterocycle.The monocyclic aromatic heterocycle base is meant by 5～8 Yuans aromatic nucleus deutero-that can have 1～4 Sauerstoffatom, sulphur atom and/or nitrogen-atoms in the ring chooses substituted group wantonly in commutable position.Condense aromatic heterocycle and be 5～8 Yuans aromatic nucleus that can have 1～4 Sauerstoffatom, sulphur atom and/or nitrogen-atoms in the finger ring and 1～4 5～8 yuan of aromatic carbon ring or other 5～8 yuan of heteroaromatic condensed in commutable position optional substituted group.
Term " heteroaryl " comprises, furyl (2-furyl is for example for example arranged, the 3-furyl), thienyl (2-thienyl for example, the 3-thienyl), pyrryl (1-pyrryl for example, the 2-pyrryl, the 3-pyrryl), imidazolyl (1-imidazolyl for example, the 2-imidazolyl, the 4-imidazolyl), pyrazolyl (1-pyrazolyl for example, the 3-pyrazolyl, the 4-pyrazolyl), triazolyl (for example 1,2, the 4-triazol-1-yl, 1,2,4-triazole-3-base, 1,2,4-triazole-4-yl), tetrazyl (1-tetrazyl for example, the 2-tetrazyl, the 5-tetrazyl), azoles base (for example, 2- azoles base, 4- azoles base, 5- azoles base), different azoles base (the different azoles of 3-base for example, the different azoles of 4-base, the different azoles of 5-base), thiazolyl (2-thiazolyl for example, the 4-thiazolyl, the 5-thiazolyl), thiadiazolyl group, isothiazolyl (3-isothiazolyl for example, the 4-isothiazolyl, the 5-isothiazolyl), pyridyl (2-pyridyl for example, the 3-pyridyl, the 4-pyridyl), pyridazinyl (3-pyridazinyl for example, the 4-pyridazinyl), pyrimidyl (2-pyrimidyl for example, the 4-pyrimidyl, the 5-pyrimidyl), furazan base (for example 3-furazan base), pyrazinyl (for example, the 2-pyrazinyl), the di azoly (for example, 1,3,4- diazole-2-yl), benzofuryl (for example, 2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] furyl, 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl), benzothienyl (for example, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] thienyl), benzimidazolyl-(1-benzimidazolyl-for example, the 2-benzimidazolyl-, the 4-benzimidazolyl-, the 5-benzimidazolyl-), dibenzofuran group, the benzoxazol base, quinoxalinyl (2-quinoxalinyl for example, the 5-quinoxalinyl, the 6-quinoxalinyl), cinnolines base (3-cinnolines base for example, 4-cinnolines base, 5-cinnolines base, 6-cinnolines base, 7-cinnolines base, 8-cinnolines base), quinazolyl (2-quinazolyl for example, the 4-quinazolyl, the 5-quinazolyl, the 6-quinazolyl, the 7-quinazolyl, the 8-quinazolyl), quinolyl (2-quinolyl for example, the 3-quinolyl, the 4-quinolyl, the 5-quinolyl, the 6-quinolyl, the 7-quinolyl, the 8-quinolyl), phthalazinyl (for example, the 1-phthalazinyl, the 5-phthalazinyl, the 6-phthalazinyl), isoquinolyl (1-isoquinolyl for example, the 3-isoquinolyl, the 4-isoquinolyl, the 5-isoquinolyl, the 6-isoquinolyl, the 7-isoquinolyl, the 8-isoquinolyl), puryl, pteridyl (2-pteridyl for example, the 4-pteridyl, the 6-pteridyl, the 7-pteridyl), carbazyl, phenanthridinyl, acridyl (for example, the 1-acridyl, the 2-acridyl, the 3-acridyl, the 4-acridyl, the 9-acridyl), indyl (for example, 1-indyl, the 2-indyl, the 3-indyl, the 4-indyl, the 5-indyl, the 6-indyl, the 7-indyl), pseudoindoyl, phenazinyl (1-phenazinyl for example, the 2-phenazinyl) or phenanthridinyl (1-phenanthridinyl for example, the 2-phenanthridinyl, the 3-phenanthridinyl, the 4-phenanthridinyl) etc.
Ar
1And Ar
2In carbocyclic ring and/or heterocycle also comprise wherein aromatic nucleus and non-aromatic ring condensed those.
By R
ADefinition obviously as can be known, it is a divalent group, as above-mentioned R
AIn the above-mentioned carbocyclic ring of univalent perssad or the carbon atom in the heterocycle or heteroatoms should with other group bondings.
R
ABe preferably down and show divalent group:
[formula 27]
[formula 28]
Wherein, especially preferred phenylene (for example 1,2-, 1,3-and 1,4-phenylene).The optimal way of heterocyclic radical also comprises 5 or 6 Yuans cyclic groups that contain 1～2 N atom.
Ar
2Can be selected from following radicals:
[formula 29]
Ar
2Be preferably optional substituted aryl, be preferably optional substituted phenyl especially.
As Ar
1And Ar
2The substituting group of " optional carbocyclic ring or the heterocycle that is substituted and can has unsaturated link(age) " in the definition comprises low alkyl group, hydroxyl low-grade alkyl, optional substituted lower alkoxy (hydroxyl for example, phenoxy group, optional substituted heterocyclic radical (preferred 5-6 person's ring), lower alkoxy, optional substituted amino (low alkyl group for example, low-grade alkenyl, cyano group, phenyl), optional substituted lower alkoxy low alkyl group (hydroxyl for example, lower alkoxy, optional substituted heterocyclic radical (preferred 5-6 person's ring)), cycloalkyl, optional substituted aryloxy, optional substituted aralkoxy, optional substituted aryloxy low alkyl group, optional substituted aryloxycarbonyl, elementary alkoxy carbonyl, nitro, hydroxyl, carboxyl, elementary alkoxy carbonyl, cyano group, the oxo base, the carboxyl low-grade alkenyl, SO
2-cyclic amino (preferred 5-6 person's ring); the low alkyl group sulfuryl amino; optional substituted amino (low alkyl group for example; lower alkoxy; acyl group (lower alkylcarbonyl for example; amino lower alkylcarbonyl; the low-grade alkyl amino lower alkylcarbonyl); heterocyclic radical (preferred 5-6 person's ring)); optional substituted amino low alkyl group; optional substituted formamyl (low alkyl group for example; CN; OH); optional substituted carbamoyloxy; halogen; junior alkyl halides; halogenated lower alkoxy; halogenated lower alkylthio; the junior alkyl halides carbonyl; the heterocycle low alkyl group; the heterocycle lower alkoxy; the cycloalkyl lower alkoxy; optional substituted aralkoxy; optional substituted heteroaryl (preferred 5-6 person's ring); optional substituted heteroaryl-low alkyl group; optional substituted heteroaryl-lower alkoxy; optional substituted heterocyclic radical; optional substituted heterocyclic radical low alkyl group; optional substituted heterocyclic radical lower alkoxy; optional substituted heterocyclic radical carbonyl low-grade alkenyl; optional substituted heterocyclic radical amino; optional substituted aryl; and optional substituted heterocyclic radical carbonyl low-grade alkenyl; SCO
2R, OC (=S) OR, OC (=O) SR, C (=S) OR, SC (=O) SR, SC (=S) SR, OC (=S) NH
2, SC (=O) NH
2, SC (=S) NH
2, OC (=S) NHR, SC (=O) NHR, SC (=S) NHR, OSO
2NHR, OSO
2NHPh, OC (=S) NR
2, SC (=O) NR
2, SC (=S) NR
2, C (=S) NH
2, C (=S) NHR, C (=S) NR
2(R is a low alkyl group), CONHCN, CONHOH etc.
As above-mentioned optional substituted amino amino, list or two elementary alkyl amido, phenyl amino, N-alkyl-n-phenyl amino, list or two lower alkoxy low-grade alkyl aminos, list or dihydroxyl low-grade alkyl amino elementary alkoxy carbonyl amino, elementary alkyl amido methanoyl amino, lower alkylcarbonyl amino, NHC (=O) SR, NHC (=S) OR, NHC (=S) SR, NHC (=S) R, NH (CH for example arranged
2)
2OH, N[(CH
2)
2OH]
2Low alkyl group), optional substituted kharophen (for example optional substituted heterocyclic radical (substituting group: for example low alkyl group), amino, alkylamino) etc. (R is a low alkyl group), optional substituted heterocyclic radical amino (substituting group:.The substituting group of above-mentioned optional substituted aryl, aralkyl, heteroaryl, heterocyclic radical comprises: low alkyl group, lower alkoxy, lower alkoxy low alkyl group, heterocyclic radical (preferred 5-6 person's ring), cyano group etc.
As Ar
1And Ar
2The substituting group of " carbocyclic ring or the heterocycle that can have unsaturated link(age) " in the definition, more specifically, be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, vinyl, allyl group, propargyl, OH, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, vinyloxy group, allyloxy, the alkynes propoxy-, benzyloxy, 2,3,4-picolyl oxygen base, furfuryl group oxygen base, thiophene methoxy, the imidazolyl methoxyl group, the pyrazolyl methoxyl group, the triazolyl methoxyl group, the thiazolyl methoxyl group, azoles ylmethoxy, different azoles ylmethoxy, phenyl ethoxy, 2,3,4-pyridyl oxyethyl group, the furyl oxyethyl group, the thiophene oxyethyl group, the imidazolyl oxyethyl group, the pyrazolyl oxyethyl group, the triazolyl oxyethyl group, the thiazolyl oxyethyl group, azoles base oxethyl, different azoles base oxethyl, cyclo propyl methoxy, the cyclopentyl methoxyl group, the cyclohexyl methoxyl group, the tetrahydropyran-4-base methoxyl group, [1,3] dioxolane-2-ylmethoxy, OCO
2Me, NHCO
2Me, OCONHMe, NHCONHMe, NHCOMe, CONH
2, CONHMe, CONMe
2, OCONHPh, SCO
2Me, OC (=S) OMe, OC (=O) SMe, C (=S) OMe, SC (=O) SMe, SC (=S) SMe, NHC (=O) SMe, NHC (=S) OMe, NHC (=S) SMe, OC (=S) NH
2, SO
2NH
2, SO
2Me, SC (=O) NH
2, SC (=S) NH
2, OC (=S) NHMe, SC (=O) NHMe, SC (=S) NHMe, OSO
2NHMe, OSO
2NHPh, OC (=S) NMe
2, SC (=O) NMe
2, SC (=S) NMe
2, NHC (=S) Me, C (=S) NH
2, C (=S) NHMe, C (=S) NMe
2, NO
2, NH
2, NHMe, NMe
2, NHEt, NEt
2, NH (CH
2)
2OH), N[(CH
2)
2OH]
2, piperazinyl, 4-Alkylpiperidine subbase (for example 4-methyl piperidine subbase), piperidyl, morpholino, F, Cl, Br, CF
3, OCF
3, OCH
2CF
3, CN, oxo base etc.Ar
1Or Ar
2Can preferably contain 1～3 above-mentioned substituting group.
Example as the combination of more preferred substituents can comprise 1) low alkyl group, aralkoxy and nitro, 2) low alkyl group, aralkoxy and amino, 3) low alkyl group, hydroxyl and nitro, and 4) low alkyl group, hydroxyl and amino etc.
Ar
1One of optimal way be optional substituted phenylene.Preferred substituents as on the phenylene comprises halogen; hydroxyl; hydroxyl low-grade alkyl; optional substituted lower alkoxy; optional substituted amino (substituting group: low alkyl group for example; heterocyclic radical; the heterocyclic radical low alkyl group; the lower alkoxy low alkyl group; hydroxyl low-grade alkyl; the low alkyl group alkylsulfonyl); optional substituted amino low alkyl group; optional substituted heterocyclic radical; optional substituted heterocyclic radical low alkyl group; the phenylene that is replaced by the heterocycle low alkyl group (wherein heterocycle low alkyl group optional is substituted) randomly; optional substituted formamyl (substituting group: for example low alkyl group); optional substituted formamyl low-grade alkenyl.Preferred heterocyclic radical is the optional heterocyclic radical that is replaced by low alkyl group separately, for example morpholino base, piperidino-(1-position only), piperidino-(1-position only)), pyridyl etc.
Ar
1One of optimal way be optional substituted 5～7 element heterocycle bases.Substituting group on the heterocycle preferably includes low alkyl group, oxo base, halogen, amino low alkyl group, list or two elementary alkyl amido low alkyl group, lower alkoxy low alkyl group.
Ar
2Be preferably 1 or 1 aryl or heterocycle that above substituting group replaces that can be selected from the following radicals: halogen; Single, two or three junior alkyl halides; Single, two, three or four halogenated lower alkoxies; Single, two, three or four halogenated lower alkylthios; List or two elementary alkyl amido; The cycloalkyl methoxyl group; Optional substituted benzyloxy; Elementary alkoxy carbonyl amino; Nitro; Heterocycle (for example optional morpholino that is replaced by low alkyl group independently, piperidino-(1-position only), piperidino-(1-position only), pyrrolidyl (pyrrolidino) etc.); Optional substituted kharophen, optional substituted lower alkoxy, ethanoyl (for example optional substituted lower alkylcarbonyl) and optional substituted elementary alkoxy carbonyl.
Term " aralkoxy " is meant the group that above-mentioned " alkyl " of replacement above-mentioned " aryl " replaced by Sauerstoffatom, for example can enumerate benzyloxy, phenylbenzene methoxy base, triphenyl methoxyl group, benzene oxyethyl group, 1-naphthyl methoxyl group, 2-naphthyl methoxyl group etc.
Term " lower alkoxy " is meant the group that above-mentioned " low alkyl group " replaced by Sauerstoffatom, for example can enumerate methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy etc.Especially preferred methoxyl group, oxyethyl group.
Term " aryloxy " is meant the group that above-mentioned " aryl " replaced by Sauerstoffatom.
Term " optional substituted amino " is meant and replaces or unsubstituted amino.
Term " optional substituted formamyl " is meant substituted or unsubstituted formamyl.
The substituting group that is used for " optional substituted amino " and " optional substituted formamyl " comprises: choose substituted alkyl (methyl for example wantonly; ethyl; sec.-propyl; benzyl; formamyl alkyl (for example carbamyl ylmethyl); list or dialkyl amido formyl radical alkyl (for example formyl-dimethylamino ethyl); hydroxyalkyl; heterocyclic radical alkyl (morpholino ethyl for example; the THP trtrahydropyranyl ethyl); alkoxy carbonyl alkyl (ethoxy carbonyl methyl for example; the ethoxy carbonyl ethyl); list or dialkyl aminoalkyl are (for example; dimethyl aminoethyl) etc.); alkoxyalkyl (methoxy ethyl for example; ethoxyl methyl; ethoxyethyl group; isopropoxy ethyl etc.); acyl group (formyl radical for example; optional substituted alkyl-carbonyl (ethanoyl for example; propionyl; butyryl radicals; isobutyryl; pentanoyl; isovaleryl; valeryl; caproyl; capryloyl; the methoxy ethyl carbonyl; 2; 2; 2-trifluoroethyl carbonyl; ethoxy carbonyl methyl carbonyl; alkoxyalkyl carbonyl (for example methoxy ethyl carbonyl); alkyl-carbamoyl alkyl-carbonyl (for example methylamino formyl radical ethyl carbonyl); alkoxy carbonyl ethanoyl etc.); optional substituted aryl carbonyl (benzoyl for example; toluyl etc.)); optional substituted aralkyl (for example; benzyl; 4-F-benzyl etc.); hydroxyl; optional substituted alkyl sulphonyl (methylsulfonyl for example; ethylsulfonyl; different third alkylsulfonyl; 2; 2; 2-trifluoro ethylsulfonyl; the benzyl alkylsulfonyl; methoxyl group ethylsulfonyl etc.); optional by aryl sulfonyl (for example, the benzenesulfonyl of alkyl or halogen replacement; tosyl group; 4-fluorobenzene alkylsulfonyl); cycloalkyl (for example cyclopropyl etc.); the optional aryl that is replaced by alkyl (for example 4-aminomethyl phenyl etc.); alkyl amino sulfonyl (methylamino alkylsulfonyl for example; dimethylamino alkylsulfonyl etc.); alkyl amino-carbonyl (for example dimethylamino carbonyl etc.); alkoxy carbonyl (for example ethoxy carbonyl etc.); naphthene base carbonyl (cyclopropyl carbonyl for example; cyclohexyl-carbonyl etc.); optional substituted sulfamyl (sulfamyl for example; the methyl sulfamyl; dimethylamino alkylsulfonyl etc.); alkyl-carbonyl-amino (for example methyl carbonylamino); heterocyclic radical (morpholino for example; THP trtrahydropyranyl); optional substituted amino (for example list or dialkyl amido (for example dimethylamino); formyl radical amino) etc.It can be replaced by above-mentioned substituting group list or two replacements.
The amino of " optional substituted amino " and " optional substituted formamyl " can be by alkylidene group replacements such as (for example trimethylene, tetramethylene, pentamethylenes), and perhaps An Ji nitrogen-atoms forms the ring that contains O, S together.
Amino for " optional substituted amino " and " optional substituted formamyl "; 2 amino substituting groups form nitrogen heterocycle (preferred 5～7 Yuans rings that ring contains sulphur atom and/or Sauerstoffatom together with the nitrogen-atoms that is adjacent; and preferably saturated), and described ring can be by replacements such as oxo base, low alkyl group or hydroxyls.This ring can be replaced by the oxo base at the S atom site.
For example, preferred piperidino-(1-position only), piperidino-(1-position only), morpholino, pyrrolidyl, thiazine-2-base, 2-oxo-piperidine subbase, 2-oxo-pyrrolidine base, 1,5～6 Yuans rings such as 1-dioxy-1,2-thiazines-2-base, 4-hydroxymorpholine generation.
The substituting group of " optional substituted aryl " and " optional substituted heteroaryl " is identical with the situation of above-mentioned " optional substituted amino ".
R
AFormula-X
1-Ar
1-X
2-Y-X
3-Ar
2The optimal way of the group of expression is as follows:
(1)-CH
2-(replacement) Ph-CONR-(Ph of replacement)
(2)-CH
2-(replacement) Ph-NRCO-(Ph of replacement)
(3)-CH
2-(replacement) Ph-CH
2-CONR-(Ph of replacement)
(4)-CH
2-(replacement) Ph-CH
2-NRCO-(Ph of replacement)
(5)-CH
2-(replacement) Ph-X-CONR-(Ph of replacement)
(6)-CH
2-(replacement) Ph-X-NRCO-(Ph of replacement)
(7)-CH
2-(replacement) Ph-Q-(Ph of replacement)
(8)-CH
2-(replacement) Het-CONR-(Ph of replacement)
(9)-CH
2-(replacement) Het-NRCO-(Ph of replacement)
(10)-CH
2-(replacement) Ph-CONR-CH
2-(Ph of replacement)
(11)-CH
2-(replacement) Ph-NRCO-CH
2-(Ph of replacement)
(12)-CH
2-(replacement) Ph-CH
2-CONR-CH
2-(Ph of replacement)
(13)-CH
2-(replacement) Ph-CH
2-NRCO-CH
2-(Ph of replacement)
(14)-CH
2-(replacement) Ph-X-CONR-CH
2-(Ph of replacement)
(15)-CH
2-(replacement) Ph-X-NRCO-CH
2-(Ph of replacement)
(16)-CH
2-(replacement) Ph-Q-CH
2-(Ph of replacement)
(17)-CH
2-(replacement) Het-CONR-CH
2-(Ph of replacement)
(18)-CH
2-(replacement) Het-NRCO-CH
2-(Ph of replacement)
(19)-(CH
2) m-(replacement) Ph-CONR-(Ph of replacement)
(20)-(CH
2) m-(replacement) Ph-NRCO-(Ph of replacement)
(21)-(CH
2) m-(replacement) Ph-CH
2-CONR-(Ph of replacement)
(22)-(CH
2) m-(replacement) Ph-CH
2-NRCO-(Ph of replacement)
(23)-(CH
2) m-(replacement) Ph-X-CONR-(Ph of replacement)
(24)-(CH
2) m-(replacement) Ph-X-NRCO-(Ph of replacement)
(25)-(CH
2) m-(replacement) Ph-Q-(Ph of replacement)
(26)-(CH
2) m-(replacement) Het-CONR-(Ph of replacement)
(27)-(CH
2) m-(replacement) Het-NRCO-(Ph of replacement)
Wherein, Ph=phenyl; R=hydrogen or low alkyl group; X=O or NH; Q is Q1 as defined above or Q2; Het is heteroaryl or heterocyclic radical (preferred 5 or 6 members); M is 2 or 3; " replacement " expression is optional substituted.
As R
B, R
C, R
DIn the chemically modified group can enumerate for example substituting group described in the TOHKEMY 2001-163898.Shown in these substituent examples are specific as follows.
R
BCan be selected from following (2-1)～(2-7):
(2-1) hydroxyl:
(2-2) optional substituted list or dialkyl amido (not comprising the group described in (2-4)); at this; the common bondings of 2 moieties form ring, and wherein said substituting group be that amino, alkyl monosubstituted amino, dialkyl amido, trialkyl ammonium, hydroxyl, guanidine radicals (guanidino), carboxyl, alkoxy carbonyl, optional formamyl, list or dialkyl amido formyl radical, list or ammonia diaryl base formyl radical, aryl, alkyl amido or aryl amido, alkyl urea base or the aryl that is replaced by cyano group are urinated basic ,-(C=O) N
--N
+(R
X)
3,-N
+(R
X)
2(CH
2)
mCOOR
Y,-N
+(R
X)
2(CH
2)
mN
+(R
X)
3,-SO
2-OR
YPerhaps-P=O (OR
Y)
2(wherein, m is 1～3, R
XBe C
1-C
3Alkyl, and R
YBe hydrogen or C
1-C
3Alkyl) or these substituent combinations, and the alkyl in the described substituting group is alkoxy carbonyl or aryloxycarbonyl replacement further, and the aromatic ring in the described substituting group can further be replaced by following substituting group: optional by halogen, nitro, amino, hydroxyl, carboxyl, alkoxy carbonyl, the amino alkyl that replaces; Optional by the hydroxyalkyl of acidylate or alkylthio; Perhaps their combination;
(2-3) optional by the cycloalkyl amino of amino or hydroxyl replacement;
(2-4) disubstituted methyl amino-NHCHR
6R
7, wherein, R
6Be selected from carboxyl, optional substituted alkoxy carbonyl, formamyl, optional substituted alkyl monosubstituted amino formyl radical or optional substituted cycloalkyl amino formyl radical; at this, described substituting group be amino, alkyl monosubstituted amino, dialkyl amido, trialkyl ammonium, carboxyl, hydroxyl ,-(C=O) N
--N
+(R
X)
3, optional quilt-(CH
2)
mCOOR
X(at this m is 1～3, R
XBe C
1-C
3Alkyl) aryl of Qu Daiing ,-N
+(R
X)
2(CH
2)
mCOOR
Y(wherein, R
YBe hydrogen or C
1-C
3Alkyl) or-N
+(R
X)
2(CH
2)
mN
+(R
X)
3, or their combination, and R wherein
7Be that wherein nitrogen-atoms is optional by C
1-C
3Indoles, sulfo-indoles or imidazolyl that alkyl replaces;
(2-5) tripeptides R-A
1-A
2-A
3-: A wherein
1, A
2And A
3Be amino acid unit arbitrarily independently of one another, R is hydroxyl, amino or the optional substituted list or the dialkyl amido of described tripeptides C-terminal, and wherein said substituting group is amino, alkyl monosubstituted amino, dialkyl amido, trialkyl ammonium, guanidine radicals or aryl;
(2-6) can be by the diazanyl or the hydroxamic acid of alkyl or arylalkyl replacement, wherein said arylalkyl is optional further to be replaced by alkyl; With
(2-7) alkoxyl group that can be replaced by aryl carbonyl, described aryl carbonyl is optional to be replaced by nitro, hydroxamic acid or alkyl;
Its condition is, in (2-2)-(2-7), any heterocycle of existence can contain heteroatoms, and the carbon-to-carbon singly-bound that exists can be mingled with heteroatoms or is selected from-O (P=O) (OR
F) O-(R
FBe hydrogen, alkoxy carbonyl or aryloxycarbonyl) and imino-in heteroatom group;
R
BBe preferably-OH ,-NHR
5Or-NHR
5R
5' (at this, R
5And R
5' be hydrogen, optional substituted alkyl ,-NH-R ,-NH-COR ,-NH-CONHR ,-O-R (each R is hydrogen or optional substituted alkyl independently) or aminosugar residue.Preferred R
5And R
5' any one party be hydrogen.
Substituting group as optional substituted alkyl, the preferred hydrophilic substituting group, for example for being selected from 1～10 in the following substituting group, preferred 1～6 identical or different substituting group: amino, list or two elementary alkyl amido, trialkylamine, amino low-grade alkyl amino, hydroxyl low-grade alkyl amino, hydroxyl, carboxyl, elementary alkoxy carbonyl, SO
3H, PO
3H
2, optional substituted formamyl, quaternary ammonium group (for example trialkyl amino (for example ,-N
+(CH
3)
3)), optional substituted heterocyclic radical (heterocyclic radical or heteroaryl), optional substituted heterocycle sulfenyl, guanidine radicals, NHSO
2NH
2, the hydroxyl lower alkoxy.Assorted intra-annular N atom can be by quaternized to form salt.Substituting group as optional substituted heterocyclic radical comprises hydroxyl, amino, carboxyl, amino low alkyl group, quaternary ammonium low alkyl group.Low alkyl group on the quaternary ammonium group can further be substituted alkyl (substituting group: carboxyl, hydroxyl, quaternary ammonium group) and replace.
R
CBe selected from down following (3-1)-(3-4):
(3-1) hydrogen;
(3-2) the optional amino methyl that is replaced by alkyl, cycloalkyl or alkylidene group, wherein said alkyl, cycloalkyl and alkylidene group can have substituting group respectively, the amino that described substituting group replaces for optional alkoxy carbonyl or aryloxycarbonyl, alkyl monosubstituted amino, dialkyl amido, trialkyl ammonium, the optional aryl that is substituted by cycloalkyl, hydroxyl, guanidine radicals ,-O-(P=O) is (OH)
2, carboxyl ,-N
+(R
X)
2(CH
2)
mN
+(R
X)
3Or-(C=O)-N
--N
+(R
X)
3, wherein m is 1～3, R
XBe C
1-C
3Alkyl, or their combination, and the alkyl in wherein said alkyl monosubstituted amino or the dialkyl amido is optional is further replaced by amino;
(3-3) for can have substituent alkynyl, wherein said substituting group is the amino of optional alkoxy carbonyl or aryloxycarbonyl replacement, perhaps aryl;
(3-4) halogen;
Its condition is, at (3-2) with (3-3), any aromatic ring of existence can contain heteroatoms, and any carbon-to-carbon singly-bound that exists can be mingled with heteroatoms or is selected from-O (P=O) (OR
F) O-(R
FBe hydrogen, alkoxy carbonyl or aryloxycarbonyl), the heteroatom group in amido and the imino-;
R
CBe preferably hydrogen or optional substituted alkyl.The substituting group that is used for the substituted alkyl of examples of such optional is preferably above-mentioned-NHR
5, the perhaps above-mentioned R that is used for
5In the substituting group of optional substituted alkyl.
As preferred R
BAnd R
CCombination comprise, for example: R
BFor hydrogen ,-NHR
5(R
5Be list or two elementary alkyl amido low alkyl group, three low alkyl group ammonium low alkyl groups or aminosugar residue) ,-NR
5R
5' (R
5And R
5' be hydroxyl low-grade alkyl together) or-NHCH
2CON-N
+(Me)
3And R
CBe hydrogen, list or disubstituted amido low alkyl group (substituent example: low alkyl group, list or two elementary alkyl amido low alkyl group, three low alkyl group ammonium low alkyl groups, hydroxyl low-grade alkyl, hydroxyl lower alkoxy low alkyl group ,-CH
2CON-N+ (Me)
3, replaced by 1～6 hydroxyl low alkyl group, carboxyl, hydroxyl, oxo base, optional substituted formamyl, guanidine radicals, sulfonic group, phosphate, by NHSO
2NH
2And/or the amino low alkyl group that replaces, optional substituted heterocycle low alkyl group (substituting group: amino low alkyl group), optional substituted quaternary ammonium low alkyl group (substituting group: carboxyl, hydroxyl, quaternary ammonium group)).Concrete combination is provided among aftermentioned table 1-6～1-8.As preferred mode, can enumerate the situation of following table 47～53,99～108 in addition.
R
DBe selected from following (4-1)-(4-6):
(4-1) hydrogen;
(4-2) can have substituent alkyl, wherein, described substituting group is alkoxy carbonyl, amino, optional by alkylating aryl, aryl carbonyl, formamyl, list or dialkyl amido formyl radical or list or alkyl diaryl formamyl, perhaps their combination, at this, the alkyl or aryl in the described substituting group can further be replaced by following substituting group: amino or hydroxyl that optional alkoxy carbonyl or aryloxycarbonyl replace;
(4-3) can be by the alkoxy carbonyl of choosing wantonly by alkylating aryl replaced;
(4-4) aryl amido or aryl sulfonyl amino;
(4-5) optional by alkylating amino or amidino groups; And
(4-6) nitroso-group;
Its condition is that in (4-2)～(4-5), any aromatic ring of existence can contain heteroatoms, and any carbon-to-carbon singly-bound can be mingled with heteroatoms.
R
DPreferably hydrogen or optional substituted alkyl.
(for example Expert Opin.Ther.Patents (2004) 14, and 141-173) described method can partly be taken off leucine residue with N-terminal, is converted into-NH according to document in addition
2, further optional with its acidylate (for example, table 110).
Preferred compound of the present invention is divided into following a few class:
1) R wherein
ABe formula :-X
1-Ar
1-X
2-Y-X
3-Ar
2Compound or its pharmaceutically useful salt or their solvate of expression;
In the formula, each symbol definition is same as described above.
2) Ar wherein
1And Ar
2Compound, its pharmaceutically useful salt or their solvate for optional substituted aryl, optional substituted heteroaryl or optional substituted cycloalkyl;
3) Ar wherein
1And Ar
2Be optional substituted phenyl ring, and Y be-NHCO-or-compound, its pharmaceutically useful salt or their solvate of CONH-;
4) X wherein
1Be compound, its pharmaceutically useful salt or their solvate of low-grade alkylidene;
5) X wherein
2Be compound, its pharmaceutically useful salt or their solvate of singly-bound, low-grade alkylidene or above-mentioned heteroatom group;
6) X wherein
3Be compound, its pharmaceutically useful salt or their solvate of singly-bound, low-grade alkylidene or above-mentioned heteroatom group;
7) R wherein
ABe formula :-X
1-Ar
1-X
2-Y-X
3-Ar
2Compound, its pharmaceutically useful salt or their solvate of the group of expression,
Wherein, X
1It is low-grade alkylidene; X
2Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group; X
3Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group; Y is-NHCO-or-CONH-; Ar
1It is optional substituted phenyl ring; Ar
2Be optional substituted phenyl ring, optional substituted heterocyclic radical or optional substituted cycloalkyl;
8) R wherein
ABy formula :-X
1-Ar
1-X
2-Q-Ar
2Or-X
1-Ar
1-Q-X
3-Ar
2Compound, its pharmaceutically useful salt or their solvate of expression,
Wherein, X
1It is low-grade alkylidene; X
2And X
3Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group; Ar
1It is optional substituted phenyl ring; Ar
2Be optional substituted phenyl ring, optional substituted heterocyclic radical or optional substituted cycloalkyl;
9) R wherein
ABe phenyl ring or heterocyclic compound, its pharmaceutically useful salt or their solvate, optional 1 or 1 above substituting group replacement that is selected from the following radicals of described phenyl ring or heterocycle: low alkyl group, nitro, aralkoxy, optional substituted amino, hydroxyl, halogen, oxo base, lower alkoxy, aryloxy, formamyl, optional substituted carbamoyloxy and heterocyclic radical; Ar
2The another one optimal way be the optional aryl that is selected from 1 or 1 above substituting group replacement in the following radicals, described substituting group is: halogen; Single, two or three junior alkyl halides; Single, two or three halogenated lower alkoxies; Single, two or three halogenated lower alkylthios; List or two elementary alkyl amido, cycloalkyl methoxyl group, benzyloxy, elementary alkoxy carbonyl amino and nitro; And
10) wherein aminosugar partly is L-vancosaminyl; 3-demethyl-vancosaminyl; 3-table-vancosaminyl; 4-table-vancosaminyl; 4-ketone-vancosaminyl; acosaminyl; actinosaminyl; daunosaminyl; 3-table-daunosaminyl; ristosaminyl; N-methyl D-glucaminyl; N-ethanoyl-D-glucosamyl or N-acyl group-D-glucosamyl; the compound of L-vancosaminyl more preferably; its pharmaceutically useful salt; or their solvate.
Available above-mentioned 1) any in～10) all kinds of constitutes compound more than 2 or 2.
11) preferred The compounds of this invention is:
R wherein
ABe formula:
-X
1-Ar
1-X
2-Y-X
3-Ar
2
The group of expression,
Wherein, X
1It is low-grade alkylidene; X
2It is singly-bound; X
3It is singly-bound; Y is-NHCO-or-CONH-; Ar
1It is optional substituted phenyl ring; Ar
2Be optional substituted phenyl ring, optional substituted heterocyclic radical or optional substituted cycloalkyl, be preferably optional substituted phenyl ring.As Ar
1On substituting group comprise optional substituted amino and/or Ar
2On substituting group be preferably and be selected from following one or more: halogen; Single, two or three junior alkyl halides; Single, two or three halogenated lower alkoxies; Single, two or three halogenated lower alkylthios; List or two elementary alkyl amido; The cycloalkyl methoxyl group; Benzyloxy; Elementary alkoxy carbonyl amino and nitro; R
BBe-NR
5R
5'; R
CIt is the group (preferably optional substituted alkyl) beyond the hydrogen; And/or R
DIt is the group (for example, optional substituted alkyl) beyond the hydrogen.
Preferred R
BAnd R
CChemically modified as mentioned above.
Further, the compound of other optimal way of the present invention is as follows:
12) Ar
1It is optional substituted heteroaryl;
13) X
1It is low-grade alkylidene; X
2Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group; X
3Be singly-bound, low-grade alkylidene or heteroatom group; Y is-NHCO-or-CONH-; Ar
1It is optional substituted heteroaryl; Ar
2Be optional substituted phenyl, optional substituted heterocyclic radical or optional substituted cycloalkyl;
14) R
BBe-OH; R
CBe hydrogen; R
DBe hydrogen;
15) R
BBe-NR
5R
5' (wherein, R
5And R
5' be hydrogen, optional substituted alkyl or aminosugar residue independently of one another); R
CBe hydrogen; R
DBe hydrogen;
16) R
BBe-NR
5R
5' (R wherein
5Be hydrogen; R
5' the alkyl or the aminosugar residue that are replaced by the wetting ability substituting group); R
CBe hydrogen; R
DBe hydrogen;
17) R
BBe-OH; R
CIt is optional substituted alkyl (wherein moieties can contain heteroatom group); R
DBe hydrogen;
18) R
BBe-OH; R
CThe alkyl (wherein moieties can contain heteroatom group) that is replaced by the wetting ability substituting group; R
DBe hydrogen;
19) X
1It is low-grade alkylidene; X
2Be singly-bound, low-grade alkylidene or heteroatom group; X
3Be singly-bound, low-grade alkylidene or heteroatom group; Y is-NHCO-or-CONH-; Ar
1Be optional substituted phenyl or optional substituted heteroaryl; Ar
2Be optional substituted phenyl, optional substituted heterocyclic radical or optional substituted cycloalkyl; And R
B, R
CAnd R
DSatisfy following condition 1)-3) at least one compound:
1) R
BBe-NR
5R
5', wherein, R
5And R
5' be hydrogen, optional substituted alkyl or aminosugar residue independently of one another;
2) R
CBe optional substituted alkyl, wherein moieties can contain heteroatom group;
3) R
DIt is low alkyl group;
(20) X
1Be low-grade alkylidene, be preferably C
1-C
3Alkylidene group; X
2Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group (for example, NH), preferred singly-bound; X
3Be singly-bound, low-grade alkylidene or heteroatom group (for example, NH), preferred singly-bound; Y is-NHCO-or-CONH-; Ar
1Be optional substituted heteroaryl or optional substituted heterocyclic radical (preferred 5～6 Yuans rings); And Ar
2Be optional substituted phenyl, optional substituted heterocyclic radical (preferred 5～6 Yuans rings) or optional substituted cycloalkyl (preferred 3～7 Yuans rings).One of such embodiment comprises R
B, R
CAnd R
DFurther satisfy following condition 1)-4) at least one compound:
1) R
BBe-OH ,-NR
5R
5' (wherein, R
5And R
5' be independently of one another hydrogen, optional substituted alkyl ,-NH-R ,-NH-COR ,-NH-CONHR ,-O-R (each R is hydrogen and optional substituted alkyl independently) or aminosugar residue) or-OR
6(R
6Be optional substituted alkyl, wherein moieties can contain heteroatom group (for example, preferred 1～2 NH, O etc.));
2) R
CIt is optional substituted alkyl (wherein moieties can contain heteroatom group);
3) R
DIt is low alkyl group;
4) sloughed the situation of leucine residue at the N-end.
The compounds of this invention is as follows more specifically:
[table 1-1]
[table 1-2]
[table 1-3]
[table 1-4]
[table 1-5]
[table 1-6]
[table 1-7]
[table 1-8]
[table 2-1]
[table 2-2]
[table 2-3]
[table 2-4]
[table 2-5]
[table 2-6]
[table 2-7]
[table 2-8]
[table 2-9]
[table 2-10]
[table 2-11]
[table 2-12]
[table 2-13]
[table 2-14]
[table 2-15]
[table 2-16]
In above-mentioned table, Me: methyl, Et: ethyl, Pr: n-propyl, iPr: sec.-propyl, iBu: isobutyl-, tBu: the tertiary butyl, key: singly-bound
Table 1 is for two kinds of R
ATo R
B, R
CAnd R
DLaunch, table 2 is for two kinds of R
B, R
CAnd R
DTo R
ALaunch.As compound of the present invention, comprise the arbitrary combination of the described group of table 1 and table 2.
The present invention includes above-claimed cpd, its pharmaceutically useful salt and their solvate.The possible tautomer of the theoretic institute of compound of the present invention, geometrical isomer etc. are also within the scope of the invention.
Term " pharmaceutically useful " etc. is meant on preventing or is not deleterious in the treatment.
Pharmaceutically useful salt as The compounds of this invention comprises for basic salt, an alkali metal salts such as sodium salt, sylvite for example being arranged; Alkaline earth salt such as calcium salt, magnesium salts; Ammonium salt; The aliphatics amine salt of trismethylamine salt, triethyl amine salt, dicyclohexyl amine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, meglumin salt, diethanolamine salt or ethylenediamine salt etc. for example; N for example, the aralkyl amine salt of N-dibenzyl-ethylenediamin, benzylamine (benethamine) salt etc.; The heteroaromatic amine salt of pyridinium salt, picoline salt, isoquinoline 99.9 etc. for example; The quaternary ammonium salt of tetramethyl ammonium, tetraethyl-ammonium salt, benzyl trimethyl ammonium salt, benzyl triethyl ammonium ammonium salt, benzyl tributyl ammonium salt, methyl trioctylphosphine ammonium salt, 4-butyl ammonium etc. for example; Alkaline amino acid salt of arginic acid salt, lysine salt etc. etc. for example.As acid-salt, comprise for example inorganic acid salt of hydrochloride, vitriol, nitrate, phosphoric acid salt, carbonate, supercarbonate, perchlorate etc.; The organic acid salt of acetate, propionic salt, lactic acid salt, maleate, fumarate, tartrate, malate, Citrate trianion, ascorbate salt etc. for example; And the sulfonate of mesylate, isethionate, benzene sulfonate, tosilate etc. for example; Acidic amino acid salt of aspartate, glutaminate etc. etc. for example.
In addition, various solvates of the present invention for example can be enumerated a solvate, two solvates, monohydrate, dihydrate etc. also within the scope of the invention.
(2) general step
It below is representational preparation compound step of the present invention.The preparation of described compound is not limited to these steps, can prepare The compounds of this invention by other step yet.
Compound of the present invention is as raw material, with the amino part (R of aminosugar with vancomycin or its known derivative
A) or C-terminal (R
B), resorcinol moiety (R
C) or the methylamino of N-terminal part (R
D) carry out the chemically modified synthetic.Described chemically modified can be carried out according to described methods such as for example Japanese kokai publication hei 7-258289 numbers, WO00/39156, Japanese kokai publication hei 2001-163898 number.Particularly, it can carry out in such a way.
1) R
AThe modification of part
Generally, be with vancomycin as raw material, it is chosen wantonly in the presence of alkali, and corresponding to formula-X
1-Ar
1-X
2-Y-X
3-Ar
2The R of expression
AThe different aldehyde reactions of part form the intermediate schiff bases, then with its reduction, carry out the N-alkylation, form target secondary amine.
Particularly, the formation of schiff bases is following to be carried out: choose wantonly in inert gas atmosphere such as nitrogen or argon for example, in for example dimethyl formamide or methyl alcohol isopolarity solvent or their mixed solvent, choose wantonly in the presence of alkali, under about 25 ℃～about 100 ℃ temperature, implement.This reaction usually in room temperature～100 ℃, preferred about 60 ℃～80 ℃ temperature carried out about 30 minutes～2 hours.As the alkali that reaction is used, (for example: diisopropyl ethyl amine etc.) can enumerate alkylamine.
Then, preferably purify intermediates schiff bases not gets final product with reduction of metal hydride complex compound or catalytic reduction.As the metal hydride complex compound, can use hydroboration metals such as sodium borohydride or sodium cyanoborohydride.Catalytic reduction can be bent at Ke Lebo for example in the presence of homogeneous phase such as sharp (Crabtree) catalyzer, Wilkinson catalyzer, palladium carbon, platinum carbon or rhodium carbon or the heterogeneous catalyst and be carried out with hydrogen.Reduction reaction was carried out about 1～24 hour under about 25 ℃～about 100 ℃ temperature.Preferably use excessive sodium cyanoborohydride (for example 3～5 equivalents) in above-mentioned solvent about 60 ℃～about 80 ℃ of enforcements.
2) R
BThe modification of part
Typically, be to use vancomycin as raw material, by the carboxylic moiety amidation of ordinary method, be converted into R with C-terminal
B=-NR
5R
5' various amide derivatives.
3) R
CThe modification of part
Typically, be to use vancomycin as raw material, by ordinary method the resorcinol moiety alkylation is got final product.
4) R
DThe modification of part
Typically, be with vancomycin as raw material, by ordinary method with the methylamino of N-terminal part for example the N-alkylation get final product.
(3) medical composition
The present invention also comprises the medical composition that contains novel glycopeptide derivatives of the present invention.Therefore, the glycopeptide compound of the form of preferred pharmaceutically useful salt can be prepared metacheirisis that is preferred for infectation of bacteria and per os or the enteron aisle external administration that prevents disposal.
During oral administration, compound of the present invention can use with any formulation in the following common preparation, for example solid preparations such as tablet, powder, granule, capsule; Aqua; The oiliness clouding agent; Or liquid preparations such as syrup or elixir.During the enteron aisle external administration, compound of the present invention can be used as water-based or oiliness is hanged turbid injection, nasal drop uses.When preparing such preparation, can use habitual vehicle, tackiness agent, lubricant, aqueous solvent, oil-based solvent, emulsifying agent, clouding agent, preservatives, stablizer etc. arbitrarily.As antimicrobial drug, preferred oral preparation, intravenous injection etc.
Preparation of the present invention can prepare with pharmaceutically useful carrier or thinner combination (for example mixing) by the The compounds of this invention that will treat significant quantity.The preparation of compound of the present invention can prepare by known method with the composition of known easy acquisition.
When preparing the medical composition of The compounds of this invention, activeconstituents can be mixed with carrier or, perhaps add in the carrier of the form of making capsule, anther sac (sacheier), paper or other container with the carrier dilution.When carrier uses as thinner, solid, semisolid or the fluent material of carrier for playing a role as medium.Therefore, preparation of the present invention can be made tablet, pill, powder agent, suck agent, elixir, suspension agent, emulsion, solution, syrup, aerosol (solid in the liquid medium) and ointment form.Such preparation can contain 10% active compound at the most.The compounds of this invention preferably makes preparation before using.
Well known to a person skilled in the art that any suitable carrier all can be used for described preparation.Carrier is solid, liquid or solid and mixtures of liquids in this preparation.For example, for intravenous injection, The compounds of this invention is dissolved in 4% dextrose/0.5% sodium citrate aqueous solution.Solid preparation comprises powder, tablet and capsule.Gu the shape carrier is for being made of the material more than a kind or a kind of the material of spices, lubricant, solvating agent, suspension agent, tackiness agent, tablet disintegrant, capsule.Be used for oral tablet and contain for example appropriate excipients such as lime carbonate, yellow soda ash, lactose, calcium phosphate, together with for example disintegrating agent such as W-Gum, Lalgine; And/or tackiness agent such as gelatin, gum arabic for example; Lubricants such as Magnesium Stearate, stearic acid, talcum for example.
In powder agent, carrier for the activeconstituents blended of pulverizing very carefully pulverize very thin solid.In tablet, activeconstituents mixes with the fusible carrier with necessity in the proper ratio, and is cured as required size and shape.Powder agent and tablet contain the activeconstituents of 1～about 99 weight % new compound of the present invention of having an appointment.The example of suitable solid carrier comprises magnesiumcarbonate, Magnesium Stearate, talcum, granulated sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil.
Liquid preparation comprises suspension agent, emulsion, syrup and elixir.Activeconstituents solubilized or for example be dispersed in aqua sterilisa, sterilization organic solvent or both the medicinal carriers such as mixture.Activeconstituents usually may be dissolved in the suitable organic solvent, for example in the aqueous solution of propylene glycol.Be dispersed in water-based starch, carboxymethylcellulose sodium solution or the suitable oil by the activeconstituents that will pulverize and can prepare other composition.
The dosage of The compounds of this invention is different because of the kind of medication, patient age, body weight, state and disease, and common when oral, per day for adults is about 0.1～7000mg, is preferably 0.5～2000mg.Metering in described day can be divided into multiple dosing.In addition, during the enteron aisle external administration, the about 0.1～1000mg of per day for adults is preferably about 0.5～500mg.
Embodiment
Illustrate in greater detail the present invention by the following examples, but the present invention is not subjected to any restriction of these embodiment.
All MS data shown in following preparation example and the embodiment are all calculated by molar average weight
(C＝12.0107，H＝1.0079，O＝15.9994，N＝14.0067，Cl＝35.4527，P＝30.9738，Na＝22.9898).
Preparation example 1
The preparation of carboxylic acid derivative 3
[formula 30]
Carboxylic acid derivative 3 is prepared as follows.
In the dry DMF40ml solution of 4-methyl-3-hydroxyl-2-nitrobenzoic acid 1 (Aldrich) 3.943g (20.0mmol), add bromotoluene 4.98ml (42mmol) and fine powder salt of wormwood 5.8g (42mmol).This mixture was stirred 40 hours at 65 ℃ in argon atmospher.The solution that obtains is injected water and ethyl acetate, reaction is stopped.With resultant ethyl acetate extraction (3 * 40ml).Collect ethyl acetate layer, dried over mgso is used in water and salt water washing.Filter, solution is heated up in a steamer in decompression, obtains viscous yellow oil matter 2.R
f=0.87 (ethyl acetate: ethanol=4: 1).
1H NMR(CDCl
3)：7.76(d，J＝8.00，1H)，7.42(m，11H)，5.33(s，2H)，4.96(s，2H)，2.40(s，3H).
With crude ester 2 usefulness potassium hydroxide 5.6g (100mmol), THF 20mL, water 20mL and methyl alcohol 30mL hydrolysis.Reaction stirred is until analyzing initial substance completely dissolve (about 16 hours) with TLC.Reactant is transferred to acidity, with chloroform extraction (3 * 30mL).Collect chloroform layer, wash with water, use dried over mgso.Filter, decompression is heated up in a steamer and is desolvated, and obtains pale yellow powder.It is used the ethyl acetate/hexane recrystallization, obtain white crystals 4.984g (86%).R
f=0.60 (ethyl acetate: ethanol=4: 1).
1H NMR(CDCl
3)：7.82(d，1H，J＝8.04Hz)，7.38-7.43(m，6H)，4.98(s,2H)，2.43(s,3H).
Embodiment 1
[formula 31]
By carboxylic acid derivative 3 preparation aldehyde derivatives 5, make itself and vancomycin reaction obtain target compound.
[formula 32]
Compound 4
With acid 3 (0.574g, 2mmol), the mixture heating up of oxalyl chloride 0.226mL (2.6mmol, 1.3 equivalents), 20mL methylene dichloride and 2 DMF refluxed 40 minutes.Distilled dichloromethane and excessive oxalyl chloride obtain viscous yellow oil matter.The residue that obtains is dissolved among the THF, is transferred to rapidly and contains in ice bath, being cooled in 0 ℃ the round-bottomed flask (100ml) of 4-aminobenzyl alcohol (Wako) 0.246g (2mmol), triethylamine 0.348mL (2.5mmol) and THF10ml.After adding acyl chlorides, solution was stirred 30 minutes at 0 ℃.By this solution being injected the flask that contains ethyl acetate and sodium bicarbonate aqueous solution reaction is stopped.With resultant ethyl acetate extraction (3 * 30mL).Collect acetic acid ethyl ester extract, dried over mgso is used in water and salt water washing.Filter, decompression is heated up in a steamer and is desolvated, and obtains the resultant of pale yellow colored solid volume morphing.It is used the ethyl acetate/hexane recrystallization, obtain white crystals 0.588g (75%).
1H NMR(CDCl
3)：7.74(s，1H，)，7.55(d，2H，J＝7.60Hz)，7.34(d，2H，J＝7.60Hz)，7.36-7.45(m，7H)，5.02(s，2H)，4.67(s，2H)，2.40(s，3H).
Compound 5
With compound 4 (0.588g), Manganse Dioxide (MnO
2) mixture of 3g and methylene dichloride 20ml is stirring at room 3 hours, until being consumed fully by TLC analysis confirmation initial substance.Decompression is heated up in a steamer and is desolvated, and obtains faint yellow solid 0.46g (77%).
1H NMR(CDCl
3)：9.95(s，1H，)，7.89(d，2H，J＝8.32Hz)，7.76(d，2H，J＝8.32Hz)，7.39-7.45(m，7H)，5.03(s，2H)，2.43(s，3H).
Compound 6
With 0.114mL (2 equivalent) diisopropyl ethyl amine (DIEA) add vancomycin 0.495g (0.333mmol, 1 equivalent) DMF/MeOH (1: 1,20mL) and in the solution of aldehyde 5 (0.13g, 0.333mmol, 1 equivalent).Solution after 2 hours, is cooled to room temperature 70 ℃ of heating.After adding sodium cyanoborohydride 0.0836g (1.332mmol, 4 equivalents), 70 ℃ of restir 24 hours, cool overnight was to normal temperature with reaction mixture.Then inject ether 400ml.The centrifugation white depositions.Throw out by the reversed-phase column chromatography purifying, is obtained the compound 6 (0.376g, 62%) of white solid form.R
f=0.45 (CH
3CN: H
2O: TFA=1: 1: 0.01), and MS (MALDI-TOF, CHCA), for C
88H
93Cl
2N
11NaO
28[M+Na]
+Calculated value 1846.63, measured value 1846.15.
Embodiment 2
[formula 33]
Prepare compound 10 similarly to Example 1.
[formula 34]
Compound 8
With acid 3 (0.574g, 2mmol), the mixture heating up of 2 of oxalyl chloride 0.226mL (2.6mmol, 1.3 equivalents), methylene dichloride 20mL and DMF refluxed 40 minutes.Distilled dichloromethane and excessive oxalyl chloride obtain viscous yellow oil.The residue that obtains is dissolved among the THF, is transferred to rapidly and contains in ice bath, being cooled in 0 ℃ the round-bottomed flask (100ml) of 3-aminobenzyl alcohol (Wako) 0.246g (2mmol), triethylamine 0.348mL (2.5mmol) and THF10ml.After adding acyl chlorides, solution was stirred 30 minutes at 0 ℃.By this solution being injected the flask that contains ethyl acetate and sodium bicarbonate aqueous solution reaction is stopped.With resultant ethyl acetate extraction (3 * 30mL).Collect acetic acid ethyl ester extract, dried over mgso is used in water and salt water washing.Filter, decompression is heated up in a steamer and is desolvated, and obtains the resultant of pale yellow colored solid volume morphing.It with column chromatography purifying (ethyl acetate), is obtained compound 8 (0.678g, 86%).R
f＝0.62(EtoAc)。
1H NMR(CDCl
3)：7.78(s，1H，)，7.63(s，1H)，7.36-7.45(m，9H)，7.19(d，1H，J＝7.60Hz)，5.03(s，2H)，4.72(s，2H)，2.42(s，3H).
Compound 9
With compound 8 (0.678g), Manganse Dioxide (MnO
2) mixture of 3.07g and methylene dichloride 20ml is stirring at room 2 hours, until being consumed fully by TLC analysis confirmation initial substance.Decompression is heated up in a steamer and is desolvated, and obtains crude product (0.554g), with column chromatography (ethyl acetate) purifying, obtains compound 9 (0.491g, 73%).
1H NMR(CDCl
3)：10.01(s，1H，)，7.92(d，1H，J＝7.60Hz)，7.85(s，1H)，7.71(d，1H，J＝8.00Hz)，7.54(t，1H，J＝8.00Hz)，7.37-7.45(m，7H)，5.03(s，2H)，2.42(s，3H).
Compound 10
With 0.114mL (2 equivalent) diisopropyl ethyl amine (DIEA) add vancomycin 0.495g (0.333mmol, 1 equivalent) DMF/MeOH (1: 1,20mL) and in the solution of aldehyde 9 (0.13g, 0.333mmol, 1 equivalent).After 2 hours, make it be cooled to room temperature 70 ℃ of heating then solution.After adding sodium cyanoborohydride 0.0836g (1.332mmol, 4 equivalents), reaction mixture 70 ℃ of restir 24 hours, is cooled to normal temperature and spends the night.Then inject ether 400ml.The centrifugation white depositions.Throw out by the reversed-phase column chromatography purifying, is obtained the compound 10 (0.565g, 93%) of white solid form.R
f=0.51 (CH
3CN: H
2O: TFA=1: 1: 0.01), and MS (MALDI-TOF, CHCA), to C
88H
93Cl
2N
11NaO
28[M+Na]
+Calculated value 1846.63, measured value 1846.37.
Embodiment 3
[formula 35]
Compound 11
(51.8mg, methyl alcohol 3ml solution 0.028mmol) is catalytic reduction (about 3 hours) under the condition that 10% palladium-carbon catalyst 50mg exists, and obtains corresponding aminophenol compound 11 with the compound 10 of embodiment 2 preparation.(MALDI-TOF is CHCA) to C for MS
81H
89Cl
2N
11NaO
26[M+Na]
+Calculated value 1726.53, measured value 1726.67.
Embodiment 4
[formula 36]
Prepare compound 16 similarly to Example 1.
[formula 37]
Compound 13
With the acid 3 of preparation example 1 preparation (2.87g, 10.0mmol), oxalyl chloride 1.13ml (1.3 equivalent), methylene dichloride 80ml and the DMF2 mixture heating up of dripping refluxed 40 minutes.Distilled dichloromethane and excessive oxalyl chloride obtain viscous yellow oil matter.The residue that obtains is dissolved among the THF, be transferred to rapidly and contain 3-amino-1-propyl alcohol 0.92ml (12mmol, 1.2 equivalent), triethylamine 0.348mL (25mmol, 2.5 equivalents) and THF 80ml's is cooled in ice bath in 0 ℃ the round-bottomed flask (250ml).After adding acyl chlorides, solution was stirred 30 minutes at 0 ℃.By this solution being injected the flask that contains ethyl acetate and sodium bicarbonate aqueous solution reaction is stopped.With resultant ethyl acetate extraction (3 * 40mL).Collect acetic acid ethyl ester extract, dried over mgso is used in water and salt water washing.Filter, decompression is heated up in a steamer and is desolvated, and obtains the resultant of the faint yellow oily thing of viscosity form.This crude product is further purified, is used for the next step.R
f=0.65 (ethyl acetate: ethanol=4: 1).
1H NMR 7.28-7.42(m，7H，)，4.98(s，2H)，3.73(t，2H，J＝5.60Hz)，3.55(q，2H，J＝5.60Hz)，2.36(s，3H)，1.77(m，2H).
Compound 14
(2.04ml adds potassiumiodide (24.5g, 0.15mol among the DMF70ml) and alcohol 13 (10mmol among the DMF30ml) at 0 ℃ with syringe in DMF10ml solution 28mmol) in argon atmospher to the thionyl chloride that stirs.Reaction mixture after 3 hours, is used water quenching 50 ℃ of stirrings, with ether extraction (3 * 100mL).With ether the extract sodium thiosulfate solution and the water washing of collecting.With the organic solution anhydrous magnesium sulfate drying.Filter, decompression is heated up in a steamer and is desolvated, and obtains the product of pale yellow colored solid volume morphing.It is used the ethyl acetate/hexane recrystallization, obtain faint yellow crystallization 2.41g (53.1%, 2 step).
1HNMR 7.36-7.43(m，6H，)，7.28(d，1H，J＝8.40Hz)，4.99(s，2H)，3.51(q，2H，J＝6.40Hz)，3.24(t，2H，J＝6.40Hz)，2.38(s，3H)，2.12(m，2H).
Compound 15
Adding Anhydrous potassium carbonate 0.345g (2.5mmol) and compound 14 in the acetone 10ml of 4-hydroxy benzaldehyde 0.336g (2.75mmol) solution (1.135g, 2.5mmol).With reactant reflux 20 hours.After mixture is cooled to room temperature, inject water 200ml.Filter, obtain the product of white solid form,, obtain compound 15 (0.504g, 45%) by column chromatography (5% methyl alcohol/chloroform) purifying.
R
f＝0.50(CHCl
3∶MeOH＝95∶5)，
1H NMR(CD(Cl
3)：9.89(s，1H，)，7.84(d，2H，J＝8.40Hz)，7.27-7.41(m，7H)，7.27(s，1H)，7.01(d，2H，J＝8.40Hz)，4.99(s，2H)，4.17(t，2H，J＝6.00Hz)，3.64(t，2H，J＝6.00Hz)，2.38(s，3H)，2.15(m，3H).
Compound 16
With 0.114mL (2 equivalent) diisopropyl ethyl amine (DIEA) add vancomycin 0.495g (0.333mmol, 1 equivalent) DMF/MeOH (1: 1,20mL) in the solution of aldehyde 15 (0.149g, 0.333mmol, 1 equivalent).Solution after 2 hours, is cooled to room temperature 70 ℃ of heating.After adding sodium cyanoborohydride 0.0836g (1.332mmol, 4 equivalents), reaction mixture 70 ℃ of restir 24 hours, is cooled to normal temperature and spends the night.Then inject ether 400ml.The centrifugation white depositions.Throw out by the reversed-phase column chromatography purifying, is obtained the compound 16 (0.396g, 63%) of white solid form.R
f=0.34 (acetonitrile: water: TFA=1: 1: 0.01).(MALDI is CHCA) to C for MS
91H
99Cl
2N
11NaO
29[M+Na]
+Calculated value 1904.71, measured value 1905.04.
Compound 5
[formula 38]
Compound 24
(364.2mg 0.2mmol) is dissolved among dry dimethyl sulfoxide (DMSO) (DMSO) 4ml compound 10 that embodiment 2 is prepared.To wherein adding dry dimethyl formamide (DMF) 4ml and 3-(dimethylamino) propyl group amine (Nacalai) 50.4 μ L (0.4mmol, 2 equivalents).Mixture is cooled to 0 ℃, add in the DMF0.5ml solution of HBTU (TCI) 113.6mg (0.3mmol, 1.5 equivalents) and HOBT (Wako) 40.5mg (0.3mmol, 1.5 equivalents), then add diisopropyl ethyl amine (DIEA) 171 μ L (1mmol, 5.0 equivalents).Then reactant is risen to room temperature, stir spend the night (about 12 hours).Reaction mixture is injected methylene dichloride 200ml.The throw out that filtration obtains is used washed with dichloromethane, drying under reduced pressure.Throw out is passed through reversed-phase HPLC (Develos1l ODS-HG-5, Ф 20mm * 250mm, CH
3CN: H
2O: TFA=1: 2: 0.1%, flow velocity 2mL/min, UV:215nm, t
R=18.63 minutes) purifying, obtain the compound 24 (45.5mg, 45%) of light color solid form.(MALDI-TOF is CHCA) to C for MS
93H
105Cl
2N
13NaO
27[M+Na]
+Calculated value 1930.80, measured value 1931.59.
Embodiment 6
[formula 39]
Compound 26
With (amino methyl) phosphonic acids (Aldrich) (155.4mg, 1.4mmol) and diisopropyl ethyl amine (DIEA) 0.24mL (1.4mmol) in water 1.5mL, mix, be stirred to evenly.Add then acetonitrile 5ml and methane amide (37% aqueous solution, 16.5 μ L, 0.22mmol), then add compound 10 (364.2mg, 0.2mmol) and diisopropylethylamine (DIEA) 0.24mL (1.4mmol).Mixture, is neutralized solution after 20 hours in stirring at room with the 20%TFA aqueous solution.Acetonitrile is removed in decompression, with the suspension lyophilize that obtains.With solid reversed-phase HPLC (Develosil ODS-HG-5, Ф 20mm * 250mm, the CH that reclaims
3CN: H
2O: TFA=1: 1: 0.1%, flow velocity 3mL/min, UV:215nm, t
R=13.58 minutes) purifying, obtain compound 26 (66.1mg, 17%).MS(MALDI-TOF，
CHCA) to C
90H
99Cl
2N
12NaO
31P[M+Na]
+Calculated value 1969.68, measured value 1967.77.
Embodiment 7
Compound 27
[formula 40]
0.114mL (2 equivalent) diisopropyl ethyl amine (DIEA) is added chloroorienticinB (0.495g, 0.333mmol, 1 equivalent) and the dimethyl formamide (DMF) of aldehyde 19 (0.0857g, 0.333mmol, 1 equivalent)/1: 1 (20ml) solution of methyl alcohol (MeOH) in.Solution after 3 hours, is cooled to room temperature 70 ℃ of heating.Add sodium cyanoborohydride (NaBH
3CN) behind the 0.084g (1.332mmol, 4 equivalents), reaction mixture 70 ℃ of restir 24 hours, is made it be cooled to normal temperature and spends the night.Then inject ether (Et
2O) among the 300ml.The centrifugation white depositions.(acetonitrile: water: trifluoracetic acid (TFA)=1: 2: 0.1%, flow velocity 3mL/ minute, UV:215nm) purifying obtained compound 27 (110.2mg, 36%), is faint yellow solid for Develosil ODS-HG-5, Ф 20mm * 250mm by HPLC with throw out.
(MALDI-TOF is CHCA) to C for MS
80H
86Cl
2N
10NaO
27[M+Na]
+Calculated value 1713.49, measured value 1713.94.
Embodiment 8
Compound 29
[formula 41]
With DIEA0.114mL (2 equivalent) add chloroorienticin B (0.495g, 0.333mmol, 1 equivalent) and aldehyde 15 (0.149g, 0.333mmol, 1 equivalent) DMF/MeOH (1: 1,20mL) in the solution.Solution after 2 hours, is cooled to room temperature 70 ℃ of heating.Add NaBH
3Behind the CN 0.0836g (1.332mmol, 4 equivalents), reaction mixture 70 ℃ of restir 24 hours, is cooled to normal temperature.Then inject 400mL Et
2Among the O.With the white depositions centrifugation.Throw out by the reversed-phase column chromatography purifying, is obtained compound 29 (0.135g, 22%), be white solid.
(MALDI is CHCA) to C for MS
91H
99Cl
2N
11NaO
29[M+Na]
+Calculated value 1904.71, measured value 1904.95.
Embodiment 9
Compound 31
[formula 42]
With DIEA0.114mL (2 equivalent) add chloroorienticin B 0.495g (0.333mmol, 1 equivalent) and aldehyde 9 (0.13g, 0.333mmol, 1 equivalent) DMF/MeOH (1: 1,20mL) in the solution.Solution after 2 hours, is cooled to room temperature 70 ℃ of heating.Add NaBH
3Behind the CN 0.0836g (1.332mmol, 4 equivalents), reaction mixture 70 ℃ of restir 24 hours, is cooled to room temperature.Then inject 400mL Et
2Among the O.The centrifugation white depositions.Throw out by the reversed-phase column chromatography purifying, is obtained compound 31 (0.205g, 34%), be white solid.(MALDI-TOF is CHCA) to C for MS
88H
93Cl
2N
11NaO
28[M+Na]
+Calculated value 1846.63, measured value 1846.64.
Embodiment 10
Prepare compound 37 by carboxylic acid 32 according to following step.
[formula 43]
Compound 33
With 5-nitro-3-trifluoromethylbenzoic acid 32 (34.2g, 145.5mmol) add the oxalyl chloride be suspended in the methylene dichloride (500ml) (16.5mL, 189mmol) in.In the suspension that obtains, add dimethyl formamide (0.5ml), stirred 1 hour at 45 ℃.The concentrating under reduced pressure reaction solution is dissolved among the THF (300ml).With this solution in nitrogen gas stream, drop under ice-cooled 3-aminophenyl alcohol (18.5g, 150mmol) and triethylamine (20.3mL, 182mmol) in.
With mixing solutions in stirring at room after 2 hours, the insolubles that leaching is separated out, concentrating under reduced pressure filtrate.Add entry and Di Iso Propyl Ether in the residue that obtains, the crystallization that leaching is subsequently separated out obtains the compound 33 of pale yellow powder form.Receipts amount 49.9g (100%)
1H-NMR(DMSO-d6)δ：10.72(1H，s)，9.06(1H，s)，8.76(1H，s)，8.69(1H，s)，7.75(1H，s)，7.70(1H，d，J＝8.1Hz)，7.34(1H，t，J＝7.8Hz)，7.11(1H，d，J＝7.6Hz)，5.27(1H，t，J＝5.8Hz)，4.54(2H，d，J＝6.1Hz).
Compound 34
15M aqueous ammonium chloride solution (30ml) is added compound 33, and (49.9g in ethanol 145.5mmol) (600mL) suspension, and 90 ℃ of stirrings, makes its dissolving.(73g 1310mmol), stirred 20 hours at 90 ℃ to add iron with 1 hour in reaction solution.Use the diatomite filtration reaction solution, decompression concentrated solution.Add entry in the residue that obtains, the crystallization that leaching is separated out after the Di Iso Propyl Ether washing, obtains the compound 34 of pale yellow powder form.Receipts amount: 39.9g (88%).
1H-NMR(DMSO-d6)δ：10.26(1H，s)，7.75(1H，s)，7.66(1H，d，J＝8.1Hz)，7.38(2H，d，J＝5.6Hz)，7.30(1H，t，J＝7.8Hz)，7.06(2H，d，J＝9.1Hz)，5.84(2H，s)，5.22(1H，t，J＝5.6Hz)，4.52(2H，d，J＝5.6Hz).
Compound 35
Ice-cooled down on one side agitate compounds 34 (39.9g, acetonitrile solution 128.6mmol) (280mL), on one side to wherein add 37% formalin (46.2mL, 643mmol), and add subsequently sodium cyanoborohydride (40.3g, 643mmol).At the ice-cooled acetate (40mL) that in the mixed solution that obtains, drips down, down mixing solutions was stirred 30 minutes ice-cooled.(28mL 386mmol), stirred 60 minutes the solution that concentrating under reduced pressure obtains down ice-cooled to add 37% formalin.In residue, add the 2N aqueous sodium hydroxide solution, with pH regulator to 8～9, to cause precipitation.Leaching should precipitate, and water and Di Iso Propyl Ether wash, and obtained the compound 35 of pale yellow powder form.Receipts amount 42.7g (98%)
1H-NMR(DMSO-d6)δ：10.32(1H，s)，7.73(1H，s)，7.68(1H，d，J＝8.1Hz)，7.50(2H，d，J＝12.6Hz)，7.31(1H，t，J＝7.7Hz)，7.08-7.06(2H，m)，5.24(1H，br s)，4.53(2H，d，J＝11.4Hz)，3.05(6H，s).
Compound 36
(drip oxalyl chloride (16.5mL, dichloromethane solution 189mmol) (100mL) among the 26mL, dichloromethane solution 267mmol) (100mL) at-78 ℃ to dimethyl sulfoxide (DMSO).-78 ℃ mixed solution stirred 15 minutes after, (37.6g, methylene dichloride 111.2mmol) (300mL) and dimethyl sulfoxide (DMSO) (30mL) mixing solutions were-30 ℃ of stirrings 1 hour to drip compounds 35 at-78 ℃.(47mL, dichloromethane solution 334mmol) (50mL) stirred 30 minutes at-20 ℃ to drip triethylamine in reaction solution.The solution that concentrating under reduced pressure obtains adds entry in residue, the crystallization that leaching is separated out with the Di Iso Propyl Ether washing, obtains the compound 36 of pale yellow powder form.Receipts amount: 36g (96%).
1H-NMR(DMSO-d6)δ：10.60(1H，s)，10.03(1H，s)，8.36(1H，s)，8.10(1H，d，J＝10.6Hz)，7.70(1H，t，J＝6.2Hz)，7.62(1H，t，J＝9.1Hz)，7.53(2H，d，J＝13.6Hz)，7.10(1H，s)，3.06(6H，s).
Compound 37
(44.6g, 30mmol) (10.6g, (10.5mL 60mmol), stirred 2 hours at 70 ℃ to add diisopropylethylamine in the mixing solutions of methyl alcohol 31.5mmol) (300mL) and dimethyl formamide (300mL) with compound 36 to vancomycin hydrochloride.(7.5g 120mmol), stirred 12 hours at 70 ℃ to add sodium cyanoborohydride in reaction solution.Reaction solution is added in the ether (1500mL), the precipitation that leaching is separated out, by the reversed-phase column chromatography purifying, lyophilize obtains the compound 37 of white powder form.
Receipts amount: 17.1g (28%).
Ultimate analysis: C83H90Cl2F3N11O252.5HCl10H2O
Calculated value C:56.34%, H:5.13%.N:8.71%, Cl:4.01%, F:3.22%
Measured value: C:48.75%, H:5.36%.N:7.77%, Cl:7.68%, F:2.73%
MS(ESI)：1770[M+3]+，1768[M+1]-
Embodiment 11
Prepare following compound to be similar to aforesaid mode.
[table 3]
[table 4]
[table 5]
[table 6]
[table 7]
[table 8]
[table 9]
[table 10]
[table 11]
[table 12]
[table 13]
[table 14]
[table 15]
[table 16]
[table 17]
[table 18]
[table 19]
[table 20]
[table 21]
[table 22]
[table 23]
[table 24]
[table 25]
[table 26]
[table 27]
[table 28]
[table 29]
[table 30]
[table 31]
[table 32]
[table 33]
[table 34]
[table 35]
[table 36]
[table 37]
[table 38]
[table 39]
[table 40]
[table 41]
[table 42]
[table 43]
[table 44]
[table 45]
[table 46]
[table 47]
[table 48]
[table 49]
[table 50]
[table 51]
[table 52]
[table 53]
[table 54]
Embodiment 12
Prepare following compound to be similar to aforesaid mode.
[table 55]
[table 56]
[table 57]
[table 58]
[table 59]
[table 60]
[table 61]
[table 62]
[table 63]
[table 64]
[table 65]
[table 66]
[table 67]
[table 68]
[table 69]
[table 70]
[table 71]
[table 72]
[table 73]
[table 74]
[table 75]
[table 76]
[table 77]
[table 78]
[table 79]
[table 80]
[table 81]
[table 82]
[table 83]
[table 84]
[table 85]
[table 86]
[table 87]
[table 88]
[table 89]
[table 90]
[table 91]
[table 92]
[table 93]
[table 94]
[table 95]
[table 96]
[table 97]
[table 98]
[table 99]
[table 100]
[table 101]
[table 102]
[table 103]
[table 104]
[table 105]
[table 106]
[table 107]
[table 108]
[table 109]
[table 110]
[table 111]
Embodiment 13
Prepare following compound to be similar to aforesaid mode.
[table 112]
[table 113]
Embodiment 14
Prepare following compound to be similar to aforesaid mode.
[table 114]
[table 115]
[table 116]
[table 117]
[table 118]
[table 119]
[table 120]
[table 121]
[table 122]
[table 123]
[table 124]
[table 125]
[table 126]
[table 127]
Reference example
Prepare following compound to be similar to aforesaid mode.
[table 128]
Test example 1
The external test of anti-microbial activity
(test method)
By well known to a person skilled in the art the microdilution that utilizes positively charged ion to regulate the Mueller-Hinton liquid nutrient medium, measure the minimal inhibitory concentration (MIC) of several compounds of the present invention.
(result)
Compound of the present invention has strong anti-microbial activity to the various bacteriums that comprise vancomycin patience bacterium.Particularly, as shown in the table, The compounds of this invention has than the remarkable stronger activity of existing medicine resistance of vancomycin enteritis coccus (VRE VanA).
[table 129]
| Strain number | Compound 6 (embodiment 1) | Compound 10 (embodiment 2) | Compound 16 (embodiment 4) | VCM | TEIC |
| Enterococcus faecalis SR7914 (VRE:Van A) | 4 | 2 | 4 | ＞64 | ＞64 |
| Faecium SR7917 (VRE:Van A) | 4 | 2 | 4 | ＞64 | ＞64 |
In the table, VCM represents vancomycin, and TEIC represents Teicoplanin Targocin.
Formulation example
Following formulation example 1～8 only is an example, invention scope is not constituted any restriction.Term " activeconstituents " expression The compounds of this invention, their tautomer, their prodrug, their pharmaceutically useful salt or their solvate.
Formulation example 1
Hard gelatine capsule prepares with following compositions.
Dosage
(mg/ capsule)
Activeconstituents 250
Starch (drying) 200
Magnesium Stearate 10
Add up to 460mg
Formulation example 2
Tablet uses the following compositions preparation.
Dosage
(mg/ tablet)
Activeconstituents 250
Mierocrystalline cellulose (crystallite) 400
Silicon-dioxide (pyrogenic) 10
Stearic acid 5
Add up to 665mg
Mix each composition, compression is to make the tablet that weight is 665mg.
Formulation example 3
Preparation contains the aerosol solution of following composition:
Weight
Activeconstituents 0.25
Ethanol 25.75
Propellent 22 (chloro methylene fluoride) 74.00
Add up to 100.00
Activeconstituents is mixed with ethanol, this mixture is added in the part of propellent 22, be cooled to-30 ℃, be transferred to device for filling.Then required amount is supplied with stainless steel vessel, with remaining propellent dilution.Valve unit is installed on the container.
Formulation example 4
Be prepared as follows the tablet that contains activeconstituents 60mg separately.
Activeconstituents 60mg
Starch 45mg
Microcrystalline Cellulose 35mg
Polyvinylpyrrolidone (as 10% aqueous solution) 4mg
Sodium starch glycolate 4.5mg
Magnesium Stearate 0.5mg
Talcum 1mg
Add up to 150mg
Activeconstituents, starch and Mierocrystalline cellulose are sieved thorough mixing by No.45 order U.S..To contain the aqueous solution of polyvinylpyrrolidone and the powder mixes that obtains, then mixture be sieved by No.14 order U.S..The particle that so obtains 50 ℃ of dryings, is sieved by No.18 order U.S..The sodium starch glycolate, Magnesium Stearate and the talcum that have passed through No.60 order U.S. sieve are in advance added in this particle, after the mixing,, obtain the tablet of each heavy 150mg with the tabletting machine compression.
Formulation example 5
Be prepared as follows the capsule that contains activeconstituents 80mg separately:
Activeconstituents 80mg
Starch 59mg
Microcrystalline Cellulose 59mg
Magnesium Stearate 2mg
Add up to 200mg
Activeconstituents, Mierocrystalline cellulose, starch and Magnesium Stearate are mixed,, be fills up in the hard gelatine capsule with the amount of 200mg by No.45 order U.S. sieve.
Formulation example 6
Be prepared as follows the suppository that contains activeconstituents 225mg separately.
Activeconstituents 225mg
Saturated fatty acid glyceride 2000mg
Add up to 2225mg
Activeconstituents is sieved by No.60.U.S., and be suspended in and be heated to necessary inferior limit in advance so that in the saturated fatty acid glyceride of its fusion.Then this mixture is added in the suppository mould of nominal 2g capacity, and make its cooling.
Formulation example 7
Be prepared as follows the suspension agent that every 5ml dosage contains activeconstituents 50mg:
Activeconstituents 50mg
Xylo-Mucine 50mg
Syrup 1.25ml
Benzoic acid solution 0.10ml
Spices is an amount of
Pigment is an amount of
Add pure water to total amount 5ml
Activeconstituents is sieved by No.45.U.S., and mix, to make sliding thickener with Xylo-Mucine and syrup.Benzoic acid solution, spices and pigment are diluted with a part of water, and under agitation add.The water that then adds q.s makes it reach necessary volume.
Formulation example 8
Can be prepared as follows intravenous formulation:
Activeconstituents 100mg
Isotonic saline solution 1000ml
The speed of the common per minute 1ml of the solution of mentioned component is carried out intravenously administrable to the patient.
Industrial applicability
Glycopeptide derivatives of the present invention, its pharmaceutically useful salt and their solvate are useful at medical treatment, and have shown the biologically active that comprises antibacterial activity. Therefore, the invention provides the method for the disease that is caused by Pueraria lobota Lan Shi positive microorganism of disposal infectious diseases, particularly animal, compound of the present invention especially dispose aspect the infection that methoxypenicillin patience staphylococcus aureus causes useful. In addition, compound of the present invention comprises aspect the enterococcal infection of vancomycin patience enterococcus (VRE) useful in disposal. The example of this disease is by the severe staphy lococcus infection, for example staphylococcus endocarditis and staphylococcal septicemia.
Claims (33)
1. compound, its pharmaceutically useful salt or their solvate represented of following formula:
(glycopeptide antibiotic derivatives aglycon part)-(Sac-NH)-R
A
In the formula,
(glycopeptide antibiotic derivatives aglycon part) is for to remove the part that sugar moieties obtains from known glycopeptide antibiotic derivatives;
(Sac-NH) be aminosugar or the sugar chain that contains aminosugar;
R
ABe formula:
-X
1-Ar
1-X
2-Y-X
3-Ar
2，
In the formula, X
1, X
2And X
3Be independently respectively
1) singly-bound
2) be selected from-N=,=N-,-NR
1-and R wherein
1For hydrogen or low alkyl group ,-O-,-S-,-SO-and-SO
2-in contain heteroatom group or their linking group, perhaps
3) optional heteroatoms identical or different more than 1 or 1 and optional substituted alkylidene group or the alkenylene of being mingled with;
Y is-NR
2CO-,-CONR
2-and R wherein
2Be hydrogen or low alkyl group, or the group represented of following formula;
[formula 1]
In the formula, R
3Be alkylidene group; And
Ar
1And Ar
2Be optional carbocyclic ring or the heterocycle that is substituted and can has unsaturated link(age) respectively independently,
Its condition is that (glycopeptide antibiotic derivatives aglycon part)-(Sac-NH) part is not the group of following formula:
[formula 2]
In the formula, R is a saccharide residue.
2. the described compound of claim 1, its pharmaceutically useful salt or their solvate; wherein, (Sac-NH) part is L-vancosaminyl, 3-demethyl-vancosaminyl, 3-table-vancosaminyl, 4-ketone-vancosaminyl, acosaminyl, actinosaminyl, daunosaminyl, 3-table-daunosaminyl, ristosaminyl, N-methyl D-glucaminyl, N-ethanoyl-D-glucosamyl or N-acyl group-D-glucosamyl.
3. the described compound of claim 1, its pharmaceutically useful salt or their solvate wherein, are L-vancosaminyl partly (Sac-NH).
4. each described compound, its pharmaceutically useful salt or their solvate in the claim 1～3 wherein, do not comprise R
ASituation for 4-(single fluorobenzoyl amino) benzyl.
5. each described compound, its pharmaceutically useful salt or their solvate in the claim 1～3 wherein, do not comprise Ar
1Be phenylene; Y is-NR
2CO-; And Ar
2Situation for single fluorophenyl.
6. each described compound, its pharmaceutically useful salt or their solvate in the claim 1～3 wherein, do not comprise Ar
2Situation for single fluorophenyl.
7. the described compound of claim 1, its pharmaceutically useful salt or their solvate, described compound is expressed from the next:
[formula 3]
In the formula,
R
ABe formula:
-X
1-Ar
1-X
2-Y-X
3-Ar
2，
In the formula, X
1, X
2And X
3 minutesBe not independently
1) singly-bound
2) be selected from-N=,=N-,-NR
1-and R wherein
1For hydrogen or low alkyl group ,-O-,-S-,-SO-and-SO
2-in heteroatom group or their linking group, perhaps
3) optional heteroatom group identical or different more than 1 or 1 and optional substituted alkylidene group or the alkenylene of being mingled with;
Y is-NR
2CO-,-CONR
2-and R wherein
2Be hydrogen or low alkyl group, or the group represented of following formula:
[formula 4]
In the formula, R
3Be alkylidene group; And
Ar
1And Ar
2Be optional carbocyclic ring or the heterocycle that is substituted and can has unsaturated link(age) respectively independently;
R
BFor-OH ,-NR
5R
5' and R wherein
5And R
5' respectively be independently hydrogen, optional substituted alkyl ,-NH-R ,-NH-COR ,-NH-CONHR ,-OR or aminosugar residue, wherein each R is respectively hydrogen or optional substituted alkyl independently, perhaps-OR
6, R wherein
6Be optional substituted alkyl, this moieties can comprise heteroatom group;
R
CBe hydrogen or optional substituted alkyl, this moieties can comprise heteroatom group; With
R is optional substituted alkyl.
8. the described compound of claim 1, its pharmaceutically useful salt or their solvate, wherein said compound is expressed from the next:
[formula 5]
In the formula,
R
ABe formula:
-X
1-Ar
1-X
2-Y-X
3-Ar
2，
In the formula, X
1, X
2And X
3Be independently respectively
1) singly-bound
2) be selected from-N=,=N-,-NR
1-and R wherein
1For hydrogen or low alkyl group ,-O-,-S-,-SO-and-SO
2-in contain heteroatom group or their linking group, perhaps
3) optional heteroatom group identical or different more than 1 or 1 and optional substituted alkylidene group or the alkenylene of being mingled with;
Y is-NR
2CO-,-CONR
2-and R wherein
2Be hydrogen or low alkyl group, or the group represented of following formula:
[formula 6]
Or
In the formula, R
3Be alkylidene group; And
Ar
1And Ar
2Be optional carbocyclic ring or the heterocycle that is substituted and can has unsaturated link(age) respectively independently;
R
BFor-OH ,-NR
5R
5' and R wherein
5And R
5' respectively be independently hydrogen, optional substituted alkyl ,-NH-R ,-NH-COR ,-NH-CONHR ,-OR or aminosugar residue, wherein each R is respectively hydrogen or optional substituted alkyl independently, perhaps-OR
6, R wherein
6Be optional substituted alkyl, this moieties can comprise heteroatom group;
R
CBe hydrogen or optional substituted alkyl, this moieties can comprise heteroatom group, and is preferred-NH-; With
R
DBe hydrogen or low alkyl group.
9. the described compound of claim 8, its pharmaceutically useful salt or their solvate, wherein said compound is the compound that following formula is represented:
[formula 7]
In the formula, R
A, R
B, R
CAnd R
DIdentical with the definition in the claim 8.
10. each described compound, its pharmaceutically useful salt or their solvate in the claim 7～9 wherein, do not comprise R
ASituation for 4-(single fluorobenzoyl amino) benzyl.
11. each described compound, its pharmaceutically useful salt or their solvate wherein, do not comprise Ar in the claim 7～9
1Be phenylene; Y is-NR
2CO-; And Ar
2Situation for single fluorophenyl.
12. each described compound, its pharmaceutically useful salt or their solvate wherein, do not comprise Ar in the claim 7～9
2Situation for single fluorophenyl.
13. each described compound, its pharmaceutically useful salt or their solvate in the claim 1～12, wherein, Y is-NR
2CO-or-CO NR
2-, and R
2Be hydrogen or low alkyl group.
14. each described compound, its pharmaceutically useful salt or their solvate in the claim 1～12, wherein, Ar
1And Ar
2Be optional substituted aryl, optional substituted heteroaryl or optional substituted cycloalkyl.
15. each described compound, its pharmaceutically useful salt or their solvate in the claim 1～12, wherein, Ar
1And Ar
2Be optional substituted aryl, and Y be-NHCO-or-CONH-.
16. each described compound, its pharmaceutically useful salt or their solvate in the claim 1～12, wherein, X
1Be low-grade alkylidene.
17. each described compound, its pharmaceutically useful salt or their solvate in the claim 1～12, wherein, X
2Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group.
18. each described compound, its pharmaceutically useful salt or their solvate in the claim 1～12, wherein, X
3Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group.
19. each described compound, its pharmaceutically useful salt or their solvate in the claim 1～12, wherein, X
1It is low-grade alkylidene; X
2Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group; X
3Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group; Y is-NHCO-or-CONH-; Ar
1It is optional substituted phenyl; And Ar
2Be optional substituted phenyl, optional substituted heterocyclic radical or optional substituted cycloalkyl.
20. each described compound, its pharmaceutically useful salt or their solvate in the claim 1～12, wherein, X
1It is low-grade alkylidene; X
2And X
3Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group independently of one another; Y is the group that following formula is represented:
[formula 8]
R wherein
3It is alkylidene group;
Ar
1It is optional substituted phenyl; And Ar
2Be optional substituted aryl, optional substituted heterocyclic radical or optional substituted cycloalkyl.
21. each described compound, its pharmaceutically useful salt or their solvate in claim 1～14 and 16～18, wherein, Ar
2Be any one in aryl, heterocyclic radical or the following fused rings:
[formula 9]
Substituting group replaces on optional 1 or 11 of being selected from the following substituting group of described aryl, heterocycle or above-mentioned fused rings: low alkyl group, lower alkoxy, cycloalkyl, aryloxy, aralkoxy, optional substituted aryloxy low alkyl group, optional substituted aryloxycarbonyl, elementary alkoxy carbonyl, nitro, hydroxyl, carboxyl, cyano group, oxo base, SO
2NH
2, SO
2Me, SO
2-cyclic amino; optional substituted amino; optional substituted formamyl; optional substituted carbamoyloxy; halogen; junior alkyl halides; halogenated lower alkoxy; halogenated lower alkylthio; the junior alkyl halides carbonyl; the heterocycle low alkyl group; the heterocycle lower alkoxy; the cycloalkyl lower alkoxy; aralkoxy; optional substituted heteroaryl; optional substituted heteroaryl-low alkyl group; optional substituted heteroaryl-lower alkoxy; heterocyclic radical; the heterocycle lower alkoxy; optional substituted aryl and optional substituted heteroaryl.
22. any one compound, its pharmaceutically useful salt or their solvate in claim 1～18 and 20, wherein, Ar
2It is optional 1 or 1 aryl that above substituting group replaces that is selected from the following radicals: halogen; Single, two or three junior alkyl halides; Single, two or three halogenated lower alkoxies; Single, two or three halogenated lower alkylthios; List or two elementary alkyl amido; The cycloalkyl methoxyl group; Benzyloxy; Elementary alkoxy carbonyl amino; Nitro.
23. any one compound, its pharmaceutically useful salt or their solvate in the claim 1～20, wherein, Ar
1Be optional by the amino phenyl that replaces, described amino is optional to be substituted.
24. any one compound, its pharmaceutically useful salt or their solvate in the claim 1～13, wherein, Ar
1It is optional substituted heteroaryl.
25. any one compound, its pharmaceutically useful salt or their solvate in the claim 1～12, wherein, X
1It is low-grade alkylidene; X
2Be singly-bound, low-grade alkylidene or above-mentioned heteroatom group; X
3Be singly-bound, low-grade alkylidene or heteroatom group; Y is-NHCO-or-CONH-; Ar
1Be optional substituted heteroaryl or optional substituted heterocyclic radical; And Ar
2Be optional substituted phenyl, optional substituted heterocyclic radical or optional substituted cycloalkyl.
26. each compound, its pharmaceutically useful salt or their solvate in the claim 8～25, wherein, R
BBe-OH; R
CBe hydrogen; And R
DBe hydrogen.
27. any one compound, its pharmaceutically useful salt or their solvate in the claim 8～25, wherein, R
BBe-NR
5R
5'; R
5And R
5' be independently of one another hydrogen, optional substituted alkyl ,-NH-R ,-NH-COR ,-NH-CONHR ,-O-R or aminosugar residue; And R is hydrogen or optional substituted alkyl independently of one another; R
CBe hydrogen; R
DBe hydrogen;
28. any one compound, its pharmaceutically useful salt or their solvate in the claim 8～25, wherein, R
BBe-NR
5R
5'; R
5Be hydrogen; R
5' replaced by the wetting ability substituting group alkyl ,-NH-R ,-NH-COR ,-NH-CONHR ,-O-R or aminosugar residue; R is hydrogen or optional substituted alkyl independently of one another; R
CBe hydrogen; R
DBe hydrogen.
29. any one compound, its pharmaceutically useful salt or their solvate in the claim 8～25, wherein, R
BBe-OH; R
CBe optional substituted alkyl, this moieties can contain heteroatom group; R
DBe hydrogen.
30. any one compound, its pharmaceutically useful salt or their solvate in the claim 8～25, wherein, R
BBe-OH; R
CBe the optional alkyl that is replaced by the wetting ability substituting group, this moieties can contain heteroatom group; R
DBe hydrogen.
31. any one compound, its pharmaceutically useful salt or their solvate in the claim 7～12, wherein, X
1It is low-grade alkylidene; X
2Be singly-bound, low-grade alkylidene or heteroatom group; X
3Be singly-bound, low-grade alkylidene or heteroatom group; Y is-NHCO-or-CONH-; Ar
1Be optional substituted phenyl, optional substituted heteroaryl or optional substituted heterocyclic radical; Ar
2Be optional substituted phenyl, optional substituted heterocyclic radical or optional substituted cycloalkyl; And R for described compound
B, R
C, R
DPart satisfies following condition 1)～3) at least one:
1) R
BBe-NR
5R
5' and R wherein
5And R
5' be independently of one another hydrogen, optional substituted alkyl ,-NH-R ,-NH-COR ,-NH-CONHR ,-O-R or aminosugar residue; And R is hydrogen or optional substituted alkyl independently of one another;
2) R
CBe optional substituted alkyl, wherein this moieties can be mingled with heteroatom group;
3) R
DIt is low alkyl group.
32. the described compound of claim 1, its pharmaceutically useful salt or their solvate, wherein said compound is represented with following formula:
[formula 10]
Wherein,
R
AIt is formula
-X
1-Ar
1-X
2-Y-X
3-Ar
2，
Wherein, X
1, X
2And X
3Be independently of one another
1) singly-bound;
2) be selected from-N=,=N-, NR
1-,-O-,-S-,-SO-and-SO
2-in heteroatoms or heteroatom group, R wherein
1Be hydrogen or low alkyl group; Perhaps
3) optional described heteroatoms identical or different more than 1 or 1 and optional substituted alkylidene group or the alkenylene of being mingled with;
Y is-NR
2CO-,-CONR
2-and R wherein
2Be hydrogen or low alkyl group, the perhaps group represented of following formula:
[formula 11]
R wherein
3It is alkylidene group; With
Ar
1And Ar
2Be optional carbocyclic ring or the heterocycle that is substituted and can has unsaturated link(age) independently of one another;
R
BBe-OH or-NR
5R
5' and R wherein
5And R
5' respectively do for oneself hydrogen or optional substituted alkyl;
R
CBe hydrogen or optional substituted alkyl, this moieties can contain heteroatom group;
R
DBe hydrogen or low alkyl group.
33. the compound of claim 32, its pharmaceutically useful salt or their solvate, wherein, X
1It is low-grade alkylidene; X
2It is the low-grade alkylidene that singly-bound maybe can contain heteroatom group; X
3It is singly-bound; Y is-NHCO-or-CONH-; Ar
1It is optional substituted phenyl; Ar
2It is optional substituted phenyl; R
BBe OH; R
CAnd R
DBe hydrogen.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004344231 | 2004-11-29 | ||
| JP344231/2004 | 2004-11-29 | ||
| JP212471/2005 | 2005-07-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101111513A true CN101111513A (en) | 2008-01-23 |
Family
ID=39043040
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800474219A Pending CN101111513A (en) | 2004-11-29 | 2005-11-24 | Glycopeptide antibiotic monomer derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101111513A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109071607A (en) * | 2016-04-29 | 2018-12-21 | 中国科学院上海药物研究所 | A kind of vancomycin derivatives, preparation method, pharmaceutical composition and purposes |
| CN116515102A (en) * | 2022-01-21 | 2023-08-01 | 苏州万维生命科学技术有限公司 | Star-shaped beta-antibacterial glycopeptide, and preparation method and application thereof |
-
2005
- 2005-11-24 CN CNA2005800474219A patent/CN101111513A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109071607A (en) * | 2016-04-29 | 2018-12-21 | 中国科学院上海药物研究所 | A kind of vancomycin derivatives, preparation method, pharmaceutical composition and purposes |
| CN109071607B (en) * | 2016-04-29 | 2022-09-27 | 中国科学院上海药物研究所 | Vancomycin derivatives, preparation method, pharmaceutical composition and application thereof |
| CN116515102A (en) * | 2022-01-21 | 2023-08-01 | 苏州万维生命科学技术有限公司 | Star-shaped beta-antibacterial glycopeptide, and preparation method and application thereof |
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