Pentapeptide antibiotics

• US 5,602,229 A
• Filed: 05/15/1995
• Issued: 02/11/1997
• Est. Priority Date: 07/18/1989
• Status: Expired due to Fees

• Current Assignee: Vicuron Pharmaceuticals Inc. (Abbvie Incorporated)
• Original Assignee: Gruppo Lepetit S.p.A..
• Inventors: Kettenring, J urgen K., Malabarba, Adriano, Ciabatti, Romeo
• Primary Examiner(s): SCHAIN, HOWARD
• Application Number:
  US08/440,868
• Time in Patent Office: 638 Days
• Field of Search: 530/317, 530/322
• US Class Current: 530/317
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07K 9/008 directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin

Abstract

Pentapeptide antibiotics of the formula ##STR1## wherein W, Z, X₁, X₂ and T represent the relative portions of an antibiotic of the dalbaheptide group (glycopeptide antibiotics), Y represents a carboxyacid group, a functional derivative of a carboxyacid group or a hydroxymethyl group. The invention includes the salts of the above represented pentapeptide antibiotics with acids or bases as well as their inner salts.

Claims

1. A pentapeptide antibiotic of formula (I) ##STR16## wherein W, Z, X₁, X₂, and T represent the relative portions of an antibiotic derived from the ristocetin type dalbaheptides or the vancomycin type dalbaheptides wherein y represents a carboxy acid group, a lower alkyl carboxy ester, or a hydroxymethyl group;

the salts of the pentapeptide with acids or bases;

or the innersalts of the pentapeptide.

2. A pentapeptide antibiotic of claim 1 wherein W is represented by the formula ##STR17## wherein R₁ is represented by hydrogen, or a sugar of from one to four saccharide units linked to the oxygen where D-glucose is the saccharide conjugated with the oxygen and the other saccharide units are selected from the group consisting of D-mannose, L-rhamnsoe, D-arabinose, Vancosamine, epi-Vancosamine, and ristosamine, or

N--(C₉ -C₁₂)-acyl-beta-D-glucosamine;

R₂, R₃ and R₄ are each independently hydrogen or halogen;

R₅ and R₆ are each independently hydrogen,

hydroxy, or

a hydroxy conjugated with a sugar where the sugar is selected from the group consisting of L-ristosamine, D-mannose, vancosamine, n-acetyl-beta-D-glucosamine, and epivancosamine;

Z is represented by the formula ##STR18## wherein the groups --OR₈ and --OR₉ are respectively in the para and the ortho position with respect to the bond connecting the two phenyl rings and R₈ and R₉ are each independently hydrogen, or

alpha-d-mannosyl;

the group --OR₁₀ is ortho to the bond connecting the two phenyl rings,

R₁₀ is hydrogen;

the group --R₁₁ -- is meta to the bond connecting the two phenyl rings and R₁₁ represents hydrogen;

X₁ is represented by an asparagine residue --CH₂ --CO--NH₂ and X₂ is represented by a leucine residue --CH₂ --CH--(CH₃)₂ or

X₁ and X₂ taken together represent an oxybis (phenylene) where one or both phenyl rings may bear a hydroxy or methyl substituent;

T represents an amino group or a methylamino or a trimethylamino group;

Y represents a carboxy acid group, a carboxy methyl, or a hydroxy methyl;

the salts of the pentapeptide with acid base;

or

the inner salts of the pentapeptide.

3. A pentapeptide antibiotic of claim 2 wherein R₂, R₃, and R₄ are in the ortho position with respect to the ether bond.

8. A pentapeptide antibiotic of claim 2, which is represented by the formula (Ic):

##STR20## or the corresponding aglycone wherein the disaccharide sugar moiety is replaced by a hydrogen atom;

or salts with acid or bases or the inner salts.

4. A pentapeptide antibiotic from dalbaheptide antibiotic of the ristocetin-type selected from the teicoplanin A₂ complex represented by the formula:

##STR19## wherein R₁ is represented by N--(C₉ -C₁₂) aliphatic acyl-beta-D-glucosaminyl, or hydrogen;

R₃ and R₄ are chloro;

R₆ is represented by a hydroxy group conjugated with n-acetyl-beta-D-glucosaminyl;

R₉ is represented by alpha-D-mannosyl, or hydrogen;

R₂, and R₅, are hydrogen;

T is represented by an amino group;

Y is represented by a carboxy acid group;

the salts of the pentapeptide with acid or base;

the inner salts of the pentapeptide.

5. A pentapeptide antibiotic of claim 4, wherein R₁ and R₉ are each independently hydrogen.

6. A pentapeptide antibiotic of claim 4 wherein R₁ and R₉ may each independently represent hydrogen.

7. A pentapeptide antibiotic of claim 4 wherein R₁ is N(8-methylnonanoyl)-beta-D-glucosaminyl or salts with acid or bases or the inner salts.

9. A pentapeptide antibiotic which is represented by the formula (Ia):

##STR21## wherein Y is hydroxymethyl;

or the corresponding compound wherein Y is carboxy and all the sugar moieties are replaced by hydrogen atoms;

or salts with acid or bases or the inner salts.