Bicyclic leucomycins

Details Bicyclic leucomycins Bicyclic leucomycins

2001-02-16

2002-10-08

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S028000, C536S007100

Reexamination Certificate

active

06462026

ABSTRACT:

TECHNICAL FIELDS
The present invention relates to novel leucomycins having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to bicyclic leucomycins, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
BACKGROUND OF THE INVENTION
Macrolide antibiotics play a therapeutically important role, particularly with the emergence of new pathogens. Structural differences are related to the size of the lactone ring and to the number and nature (neutral or basic) of the sugars. Natural macrolides are classified according to the size of the lactone ring (12, 14, 15 or 16 atoms). The macrolide antibiotic family (14-, 15- and 16-membered ring derivatives) shows a wide range of characteristics (antibacterial spectrum, side-effects and bioavailability). Among the commonly used macrolides are erythromycin and josamycin.
The 16-membered ring macrolide antibiotics constitute an important clinically useful series of naturally occurring compounds within the macrolide class of antibiotics, as they show some advantages over 14-membered ring compounds (gastrointestinal tolerance and activity against strains expressing resistance of the inducible type. Sixteen membered macrolides usually contain an amino disaccharide -4-O-(L-mycarosyl)-D-mycaminose and/or D-desosamine. One class has only neutral sugars. The sixteen membered macrolides can be classified into two major groups—the leucomycins and the tylosin series.
The leucomycins, represented by Formulas Ia and Ib, are further divided, as follows, into five groups according to the chromophores:
1. Leucomycin group containing platenomycin A1, A0 and C2, josamycin (leucomycin A3) and midecamycin A1 and A2.
2. Maridomycin group containing platenomycin C1.
3. Carbomycin B group containing platenomycin W1, midecamycin A4 and A3 and niddamycin
4. Carbomycin A group containing the deltamycin complex
5. Spiramycin complex.
The leucomycins, carbomycins, maridomycins, platenomycins, midecamycins and spiramycins are members of the magnamycin group of 16-membered macrolides, having D-mycaminose and L-mycarose as sugar moieties and an aglycone with an identical carbon skeleton. The antibiotics differ from each other in terms of the acyl group on positions O-3 and O-4″ and the C12, 13 epoxy group. Within a given chromophoric group, it is possible to differentiate the various compounds by the substituent at C-3 and C-4″.

Leucomycin
R2
R4
A1
H
C(O)CH2CHMe2
(Kitasamycin) A5
H
C(O)CH2CH2CH3
A7
H
C(O)CH2CH3
A9
H
C(O)CH3
V(A11)
H
H
(Josamycin) A3
C(O)CH3
C(O)CH2CHMe2
A4
C(O)CH3
C(O)CH2CH2CH3
A6
C(O)CH3
C(O)CH2CH3
A8
C(O)CH3
C(O)CH3
U
C(O)CH3
H
Miokamycin
1
C(O)CH2CH3
C(O)CH2CH2CH3
Rokitamycin
2
H
C(O)CH2CH2CH3
1
9-OAc; 3″-OAc
2
3″-OC(O)CH2CH3; 4″-OC(O)CH2CH2CH3
Josamycin is produced by
Streptomyces narbonensis
var.
josamyceticus
. Josamycin was found to be identical to leucomycin A3. Josamycin belongs to the leucomycin Ac group and differs from the other members by the 4″-O-substituent. Josamycin has a 4″-O-isovaleryl side-chain. In acidic aqueous solution, josamycin is transformed into isojosamycin (isoleucomycin A3) in which the hydroxyl group at C-13 is transferred from C-9. Four metabolites have been isolated from the urine and plasma of adults given oral josamycin. Two show poor antimicrobial activity [(5-hydroxyjosamycin (O
1
) and &bgr;-hydroxyisovaleryl josamycin (O
2
)] and two are inactive (desisovaleryl josamycin and demycarosyl josamycin or josambose). The pediatric formulation is josamycin propionate.
Leucomycin A5 is one of the components of the leucomycin complex named kitasamycin, and is produced from the fermentation broth of a strain of
Streptomyces kitasatoensis
. It was obtained as a single component by controlling the culture conditions.
Rokitamycin is a semisynthetic 16-membered-ring macrolide obtained by attaching a propionate to the 3″-position of leucomycin A5. 3″-O-propionyl leucomycin A5 is the most active derivative of 3″-O-butyryl derivatives and shows the highest serum levels in dogs and monkeys. The 3″-O-acetyl and 3″-O-butyryl derivatives were less active than 3″-O-propionyl leucomycin A5.
The in vitro activity of rokitamycin against Gram-negative bacteria is twice as high as that of leucomycin A5, josamycin, and midecamycin. Rokitamycin is highly metabolized into four metabolites—10″-hydroxyrokitamycin, leucomycin A7, leucomycin V and 14-hydroxyleucomycin V. Leucomycin A7 and Lecomycin V (4″-debutyryl leucomycin A5) are the main metabolites. Their in vitro potency is respectively one-half and one-tenth that of the parent compound.
Midecamycins are fermentation products of
Streptomyces mycarofaciens
and include four components—A1, A2, A3, and A4. Midecamycin A1 and A2 belong to chromophoric group I, and midecamycin A3 and A4 to chromophoric group III.
Midecamycin A2, A3 and A4 are minor components of the mixture produced by
Streptomyces mycarofaciens
; the major component, A1, has been marketed.
Miokamycin is a semisynthetic 16-membered-ring macrolide derived from midecamycin A1 by introducing two acetyl groups at C-3″ and C-9. A large number of acyl derivatives has been prepared by modifying the hydroxyl groups at C-9, C-2′ and C-3″ of midecamycin A1, in order to improve the biological activities and pharmaceutical properties.
Platenomycins were isolated from the fermentation broth of
Streptomyces platensis
MCRL 0388. Platenomycin complex is composed of nine components—A
o
, (YL-7
04
), A1 (turimycin P5), B1, C1, C2 (espinomycin A3), C4 (maridomycin II), W1, W2 and W3. The chemical structure of the different compounds has been elucidated. Platenomycin C1 was found to be identical to maridomycin III, and platenomycin B1 to midecamycin III, and platenomycin B1 to midecamycin and espinomycin A1.
Platenomycin has a 16-membered-ring lactone, one aminosugar (D-mycaminose) and one neutral sugar (L-mycarose).
The members of platenomycin complex can be differentiated by the aglycone moiety: platenolide I has a 9-hydroxyl (platenomycins W1, W2).
Carbomycin was isolated from the fermentation broth of
Streptomyces halstedii
. The carbomycin complex has two components—carbomycin A and carbomycin B.
Carbomycin A is identical to deltamycin A4. Carbomycin B (magnamycin B) is used in veterinary medicine.
Niddamycin was isolated from the fermentation broth of a strain of
Streptomyces djaktensis
. It is a substituted 16-membered lactone with an amino sugar (D-mycaminose) and a neutral sugar (L-mycarose). The D-mycaminose is bound to C-5 of the aglycone nucleus, while the L-mycarose (substituted at C-4″ with an isovaleryl) binds to the C-4′ hydroxyl of D-mycaminose. The lactone ring has a C-6 formylmethyl group. It has no acetyl group at C-3.
Niddamycin shows good antibacterial activity in vitro against Gram-positive bacteria and Mycoplasma spp.
Spiramycin complex consists of three major (I, II, III) and three minor components (IV, V, VI). They were derived from the fermentation broth of
Streptomyces ambofaciens
, a soil organism isolated in the north of France.
Spiramycins consist of four structural components—a 16-membered lactone (platenolide), two amino sugars (D-mycaminose and D-forosamine) and one neutral sugar (L-mycarose). Of the 16-membered-ring macrolide antibiotics, only the spiramycins bear D-forosamine. This amino-sugar is attached to position 9 of the platenolide ring. The three major components differ by the substituent at position 3, as follows: spiramycin I (3-OH), spiramycin II (3-O-acetyl) and spiramycin III (3-O-propionyl). Spiramycin IV and spiramycin VI have a secondary alcohol at C-6 instead of a formylmethyl group. Spiramycin V differs from spiramycin I by the presence of an L-mycarose instead of a D-forosamine. Spiramycin IV bears a D-forosamine and spiramycin VI an L-mycarose.
The antibacterial spectrum of the spiramycins is similar to that of

Affiliated with

Also associated with

Rating

Bicyclic leucomycins does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Bicyclic leucomycins, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bicyclic leucomycins will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2920520