Cyclic decapeptide antibiotics

Details Cyclic decapeptide antibiotics Cyclic decapeptide antibiotics

1998-09-29

2004-09-14

Brumback, Brenda (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S015800, C530S317000, C530S328000

Reexamination Certificate

active

06790829

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel cyclic peptide compounds with potent activity against antibiotic-resistant pathogens.
BACKGROUND OF THE INVENTION
Methicillin-resistant strains of
Staphylococcus aureus
(USA) cause infections that are refractory to standard anti-staphylococci antibiotics, and in many cases vancomycin is the antibiotic of last resort. Consequently, it is of great concern that vancomycin-resistant strains of MRSA may develop.
Infections due to enterococci have been difficult to treat for many years because these organisms are intrinsically resistant to many antibiotics. Ampicillin has been the mainstay for treatment of uncomplicated enterococcal infections, but many strains have now become resistant to ampicillin. Vancomycin is again the only effective treatment for these ampicillin-resistant enterococcal infections. In the past few years, vancomycin-resistant enterococcal strains (VRE) have begun to appear and they are rapidly spreading across North America. There are no effective antibiotics currently available for such organisms and the recent report of an outbreak of VRE with a 73% mortality rate has highlighted the seriousness of the situation. See Edmond, M. B. et al.,
Clinical Infectious Diseases
20:1126-33, 1995.
One area where new drugs are desperately needed is in the treatment of antibiotic-resistant strains of gram positive human pathogens. The present invention is directed to fulfilling this need, and provides related advantages as described herein.
SUMMARY OF THE INVENTION
In a first aspect, the invention is directed to isolated cyclic decapeptides of the formulas (1), (2) and (3):
(1): cyclo [L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-Asp-L-Tyr] (SEQ ID NO:1);
(2): cyclo [L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:2); and
(3) cyclo [L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Trp-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:3).
The decapeptide of Formula (1) is referred to herein as Loloatin A. The decapeptide of Formula (2) is referred to herein as Loloatin B. The decapeptide of Formula (3) is referred to herein as Loloatin C.
The invention is directed to the above-identified cyclic decapeptides in an isolated, i.e., substantially purified form, preferably in a quantity of more than about 1 gram, more preferably in a quantity of more than about 10 grams, still more preferably in a quantity of more than about 100 grams, and yet still more preferably in a quantity of more than about 1 kilogram. A substantially purified form is a composition wherein the above-listed cyclic decapeptides constitute at least about 1 weight percent of the composition, preferably at least about 10 weight percent, more preferably at least about 30 weight percent, still more preferably at least about 50 weight percent, yet still more preferably at least about 70 weight percent, and yet still more preferably at least about 95 weight percent, and most preferably at least about 99 weight percent.
The invention is also directed to the above-identified cyclic decapeptides in a pharmaceutical composition. A pharmaceutical composition of the invention may not necessarily contain the cyclic decapeptide in a substantially purified form because the composition may contain diluent and/or other materials commonly found in pharmaceutical compositions.
The invention is also directed to a method of treating bacterial infection, comprising administering to a patient having a bacterial infection, an amount of the above-identified cyclic decapeptides effective to relieve symptoms associated with or due to the bacterial infection.
In another aspect, the invention is directed to various derivatives and analogs of Loloatin A, B and C.
Loloatin derivatives of the invention include the solvates, salts (either acid- or base- addition salts, depending on whether the amino acid sidechain being converted to a salt is basic or acidic, respectively), esters (derivatives of amino acid sidechains containing a carboxylic acid group), amines (derivatives of amino acid sidechains containing an amino group), ethers (derivatives of amino acid sidechains containing an hydroxyl group) and amides (derivatives of amino acid sidechains containing either an amine or carboxylic acid group) of Loloatin A, B or C.
For example, the invention provides for a salt of a compound selected from the group:
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-L-Asp-L-Tyr] (SEQ ID NO:1);
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:2); and
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Trp-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:3).
The salt may contain at least one negatively charged ion selected from chloride, bromide, sulfate, phosphate, C
1-15
carboxylate, methanesulfonate and p-toluenesulfonate, which are exemplary only. Exemplary C
1-15
carboxylates include acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, tartarate, citrate, ascorbate, maleate, hydroxymaleate, benzoate, hydroxybenzoate, phenylacetate, cinnamate, salicylate and 2-phenoxybenzoate.
The salt may contain at least one positively charged ion selected from lithium, sodium, potassium, beryllium, magnesium, calcium and quaternary ammonium ions, which are exemplary positively charged ions. Exemplary quaternary ammonium ions cinlude tetraallylammonium, and trialkylaralkylammonium ions.
The invention also provides for derivatives of a compound selected from
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-L-Asp-L-Tyr] (SEQ ID NO:1);
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:2); and
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Trp-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:3).
For example, the derivative may have the amine group of the ornithine sidechain being a secondary, tertiary or quaternary amine group, and other amino acid sidechains are optionally in a derivative form as well. Exemplary ornithine sidechains have the formula —CH
2
—CH
2
—CH
2
—NHR
3
, —CH
2
—CH
2
—CH
2
—N(R
3
)
2
or —CH
2
—CH
2
—CH
2
—N(R
3
)
3
wherein R
3
is an alkyl group that may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or an acyl group that may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities.
In other derivatives, the hydroxyl group of one or more tyrosine sidechains has been converted to an ether or ester group, and other amino acid sidechains are optionally in a derivative form as well. For example, at least one tyrosine sidechain may have the formula —CH
2
—C
6
H
4
—O—R
2
, wherein C
6
H
4
is an aromatic ring and —O—R
2
is in the para position, and R
2
is a C
1-15
alkyl group so as to form an ether, where the alkyl group may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or a C
1-15
acyl group so as to form an ester, where the acyl group may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities.
In other derivatives, the carboxyl group of the aspartic acid sidechain has been converted to an amide or ester group, and other amino acid sidechains are optionally in a derivative form as well. For example, the aspartic acid sidechain may have the formula —CH
2
—C(═O)O—R
1
, and R
1
is a C
1-15
alkyl group that may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or an aryl group. In another example, the aspartic acid sidechain has the formula —CH
2
—C(═O)N—R
1
, and R
1
is a C
1-15
alkyl group that may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or an aryl group.
The invention al

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