US2006004185A1PendingUtilityA1
Peptide antibiotics and peptide intermediates for their prepartion
Est. expiryJul 1, 2024(expired)· nominal 20-yr term from priority
C07K 5/06086C07K 5/0815Y02P20/55A61P 43/00C07K 7/64A61P 31/04C07K 7/62A61K 38/00A61P 31/00Y02A50/30
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Claims
Abstract
Novel protected cyclopeptide intermediates are prepared from polymyxin B are used to synthesize new peptide antibiotics. Intermediates are readily derivatized and deprotected to provide new families of antibiotics, which have potent anti-bacterial activity against gram-negative bacteria; but also are useful and potent against gram-positive bacteria.
Claims
exact text as granted — not AI-modified1 . A method for preparing an intermediate for use in the synthesis of a new peptide antibiotic, including the steps of:
(a) Protecting the amino groups of the polymyxins or other related antibiotics chosen from the group consisting of colistin, a circulin, and an octapeptin, with (2-sulfo)-9-fluorenylmethoxycarbonyl or another acidic derivative of 9-fluorenylmethoxycarbonyl; (b) Treating the product from the reaction of step (a) with a deacylase to provide a protected peptide intermediate; and (c) Using a modified Edman degradation method or peptidase enzymatic reaction to obtain another protected intermediate peptide by reducing in size by one to three amino acids in the exocyclic peptide side chain of the protected peptide.
2 . A method for producing an antibiotic active against gram-negative and gram-positive bacteria, including strains resistant to clinically used antibiotics, comprising the steps of:
(a) Protecting the amino groups of the polymyxins or other related antibiotics chosen from the group consisting of colistin, a circulin, and an octapeptin, with (2-sulfo)-9-fluorenylmethoxycarbonyl or another acidic derivative of 9-fluorenylmethoxycarbonyl; (b) Treating the product from the reaction of step (a) with a deacylase to provide a protected peptide intermediate; (c) Using a modified Edman degradation method or peptidase enzymatic reaction to obtain another protected intermediate peptide by reducing in size by one to three amino acids in the exocyclic peptide side chain of the protected peptide. (d) Chemically modifying the intermediate to produce a protected antibacterial derivative; and (e) Removing the acidic protecting groups to produce the antibiotic.
3 . An intermediate, which is a chemically protected form of a peptide derived from the polymyxins, octapeptins, colistin, or circulins, and selected from a group consisting of the following, or their corresponding salts:
Case 1) H-(X1)(X2)(X3)-peptide-[(2-sulfo)-9-Fmoc] n Case 2) H-(X2) (X3)-peptide-[(2-sulfo)-9-Fmoc] n Case 3) H-(X2)-peptide-[(2-sulfo)-9-Fmoc] n Case 4) H-peptide-[(2-sulfo)-9-Fmoc] 3 wherein for Case 1) H-(X1)(X2)(X3)-peptide-[(2-sulfo)-9-Fmoc] n
H is hydrogen, X1 is L-Dab or another amino acid, 2 is L-Thr or another amino acid, X3 is L-Dab or D-Dab or another amino acid, and n=3-6;
for Case 2) H-(X2)(X3)-peptide-[(2-sulfo)-9-Fmoc] n
H is hydrogen, X2 is L-Thr or another amino acid, X3 is L-Dab or D-Dab or another amino acid, and n=3-5;
for Case 3) H-(X3)-peptide-[(2-sulfo)-9-Fmoc] n
H is hydrogen X3 is L-Dab or D-Dab or another amino acid and n=3-4; and
for Case 4) H-peptide-[(2-sulfo)-9-Fmoc] 3
H is hydrogen.
4 . Acidic protected peptide intermediates, derived from the corresponding protected polymyxin B, which can be used to synthesize new peptide antibiotics or their prodrugs where the protecting group is preferably HSO 3 -Fmoc and the protected peptide intermediates have the structure:
protected PBpeptide: R = H
5 . Acidic protected peptide intermediates, derived from the corresponding protected colistin, which can be used to synthesize new peptide antibiotics or their prodrugs where the protecting group is preferably. HSO 3 -Fmoc- and the protected peptide intermediates have the structure:
protected Cpeptide: R = H
6 . Acidic protected peptide intermediates, derived from the corresponding protected circulin A, which can be used to synthesize new peptide antibiotics or their prodrugs where the protecting group is preferably HSO 3 -Fmoc- and the protected intermediates have the structure:
protected CApeptide: R = H
7 . Acidic protected peptide intermediates, derived from the corresponding protected octapeptin, which can be used to synthesize new peptide antibiotics or their prodrugs where the protecting group is preferably HSO 3 -Fmoc- and the protected peptide intermediates have the structure:
P = Protective group
protected octapeptin peptide: R = H
8 . The protected peptide intermediate of claim 7 , wherein another component of the octapeptin antibiotic includes L-phenylalanine instead of L-leucine at the 5-position and wherein the component forms a similar, but alternative, protected peptide intermediate.
9 . An antibacterial compound or protected compound prepared from a chemically protected form of PBpeptide having the following structure where p equals the protective group HSO 3 -Fmoc- or hydrogen:
Compound
R
X1*
X2
X3*
P
(P) 5 Polymyxin B
C 8 H 17 CO—
Dab-P
Thr
Dab-P
HSO 3 -Fmoc-
1
n-C 9 H 19 CO—
Dab
Thr
Dab
H
1P
n-C 9 H 19 CO—
Dab-P
Thr
Dab-P
HSO 3 -Fmoc-
2
n-C 10 H 21 CO-PAPA-**
Dab
Thr
Dab
H
2P
n-C 10 H 21 CO-PAPA-**
Dab-P
Thr
Dab-P
HSO 3 -Fmoc-
3
n-C 8 H 17 NHCO—
Dab
Thr
Dab
H
3P
n-C 8 H 17 NHCO—
Dab-P
Thr
Dab-P
HSO 3 -Fmoc-
4
phenyl-NHCS—
Dab
Thr
Dab
H
4P
phenyl-NHCS—
Dab-P
Thr
Dab-P
HSO 3 -Fmoc-
5
phenyl-NHCO—
Dab
Thr
Dab
H
5P
phenyl-NHCO—
Dab-P
Thr
Dab-P
HSO 3 -Fmoc-
6
phenyl-CO—
Dab
Thr
Dab
H
6P
phenyl-CO—
Dab-P
Thr
Dab-P
HSO 3 -Fmoc-
7
2-naphthyl-OCH 2 —CO—
Dab
Thr
Dab
H
7P
2-naphthyl-OCH 2 —CO—
Dab-P
Thr
Dab-P
HSO 3 -Fmoc-
8
4-CH 3 —C 6 H 4 —SO 2 —
Dab
Thr
Dab
H
8P
4-CH 3 —C 6 H 4 —SO 2 —
Dab-P
Thr
Dab-P
HSO 3 -Fmoc-
9
n-C 8 H 17 NHCO—
—
Thr
Dab
H
9P
n-C 8 H 17 NHCO—
—
Thr
Dab-P
HSO 3 -Fmoc-
10
n-C 10 H 21 SO 2 —
Gly
Thr
Dab
H
10P
n-C 10 H 21 SO 2 —
Gly
Thr
Dab-P
HSO 3 -Fmoc-
11
n-C 9 H 19 CO
Lys
Thr
Dab
H
11P
n-C 9 H 19 CO
Lys-P
Thr
Dab-P
HSO 3 -Fmoc-
12
n-C 9 H 19 CO
Phe
Thr
Dab
H
12P
n-C 9 H 19 CO
Phe
Thr
Dab-P
HSO 3 -Fmoc-
*Dab-P is 4-N—(HSO 3 -Fmoc)-diaminobutyryl, Lys-P is 6-N—(HSO 3 -Fmoc)-lysyl
**PAPA is p-aminophenylacetyl
All amino acids are the L-isomers unless indicated otherwise.
10 . Peptide antibiotics having the following structure and concentration for use against gram-positive and gram-negative bacteria:
Com-
E. coli
Staph
pound
R
X1
X2
X3
MIC*
MIC*
Poly-
C 8 H 17 CO—
Dab
Thr
Dab
0.6
>10
myxin
B
1
n-C 9 H 19 CO—
Dab
Thr
Dab
0.6
2
n-C 10 H 21 CO-PAPA-**
Dab
Thr
Dab
1.25
2.5
3
n-C 8 H 17 NHCO—
Dab
Thr
Dab
1.25
10
4
phenyl-NHCS—
Dab
Thr
Dab
0.6
>10
5
phenyl-NHCO—
Dab
Thr
Dab
0.6
>10
6
phenyl-CO—
Dab
Thr
Dab
1.25
>10
7
2-naph-
Dab
Thr
Dab
1.25
>10
thyl-OCH 2 —CO—
8
4-CH 3 —C 6 H 4 —SO 2 —
Dab
Thr
Dab
9
n-C 8 H 17 NHCO—
—
Thr
Dab
2.5
>10
10
n-C 10 H 21 SO 2 —
Gly
Thr
Dab
2.5
5
11
n-C 9 H 19 CO—
Lys
Thr
Dab
2.5
10
12
n-C 9 H 19 CO—
Phe
Thr
Dab
*MIC values were determined by serial twofold broth dilution method using Escherichia coli, ATCC #26, and Staphylococcus aureus Smith as assay organisms which were grown in Mueller Hinton broth.
**p-aminophenylacetyl
11 . An antibiotic prepared from an intermediate, which is a chemically protected form of a peptide derived from the polymyxins, octapeptins, colistin, or circulins, said antibiotic selected from a group consisting of the following, or their corresponding salts:
Case 1) A-(X1)(X2)(X3)-peptide Case 2) A-(X2)(X3)-peptide Case 3) A-(X3)-peptide Case 4) A-peptide wherein for Case 1) A-(X1)(X2)(X3)-peptide
A=R′—(C═O)—, R′—SO 2 —, R′—(C═NH)—, R′—NH—(C═S)—, R′—NH—(C═O)—, R′—O—(C═O)—, R′CH 2 —
where R′ is alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, or heterocyclic and X1 is L-Dab or another amino acid, X2 is L-Thr or another amino acid, and X3 is L-Dab, D-Dab or another amino acid, excluding colistin peptides where X1 is an aliphatic amino acid and where R′(C—O)— is alkyl, for Case 2) A-(X2)(X3)-peptide “A” is the same as described for Case 1, X2 is L-Thr or another amino acid and X3 is L-Dab, D-Dab or another amino acid, excluding N-acyl colistin nonapeptide derivatives where R′ is alkyl, aryl, or cycloalkyl, for Case 3) A-(X3)-peptide
“A” is the same as described in Case 1, and X3 is L-Dab, D-Dab or another amino acid, excluding R′—(CO)— where R′ is alkyl for octapeptin peptides,
for Case 4) A-peptide
“A” is the same as described for Case 1.Join the waitlist — get patent alerts
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