Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-05
2002-09-24
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S267000
Reexamination Certificate
active
06455576
ABSTRACT:
The present invention relates to macrolides with anti-inflammatory activity and, more particularly, it relates to des-dimethylamino macrolide derivatives with anti-inflammatory activity, their pharmaceutically acceptable salts and pharmaceutical compositions containing them as active ingredients.
It is known that many antibiotics, in particular the class of macrolides with 14 atoms derived from erythromycin, are endowed with anti-inflammatory properties in addition to the antibacterial activity [Clin. Immunother., (1996), 6, 454-464].
Erythromycin is a natural macrolide (The Merck Index, XII edition, n° 3720, page 625) that has had a very broad clinical use in the treatment of infections caused by Gram-positive bacteria, by some Gram-negative ones or by Mycoplasma.
Recently the interest of the scientific community has been focused on the anti-inflammatory and immunomodulatory component of erythromycin and derivatives [Journal of Antimicrobial Chemotherapy, (1998), 41, Suppl.B, 37-46].
Such activity is well documented by both clinical studies and in vivo and in vitro experiments.
For example, macrolides have proved to be effective in the therapy of inflammatory diseases such as panbronchiolitis [Thorax, (1997), 52, 915-918], bronchial asthma [Chest, (1991), 99, 670-673] and cystic fibrosis [The Lancet, (1998), 351, 420], or in animal models of inflammation such as, for example, the zymosan-induced peritonitis in mice [Journal of Antimicrobial Chemotherapy, (1992), 30, 339-348] and the neutrophil recruitment induced by endotoxin in rat trachea [Antimicrobial Agents and Chemotherapy, (1994), 38, 1641-1643] or in in vitro studies on immune system cells, such as neutrophils [The journal of Immunology, (1997), 159, 3395-4005] and T-lymphocytes [Life Sciences, (1992), 51, PL 231-236] or in the modulation of cytokines, such as interleukin 8 (IL-8) [Am. J. Respir. Crit. Care Med., (1997), 156, 266-271] or interleukin 5 (IL-5) (EP 0 775 489 and EP 0 771 564, Taisho Pharmaceutical Co., Ltd).
The peculiar therapeutic efficacy of macrolides on diseases in which the conventional anti-inflammatory drugs, such as for example corticosteroids, have demonstrated to be ineffective [Thorax, (1997), 52, 915-918, already cited] justifies the high interest towards this new potential class of anti-inflammatories.
Nevertheless the strong antibacterial activity of the conventional macrolides does not allow an enlarged use in the chronic treatment of inflammatory processes not due to pathogens because of the rapid onset of resistant strains.
Therefore, it would be desirable to have new substances with a macrolide structure that show anti-inflammatory activities and, in the mean time, that are devoid of antibiotic properties.
For a greater clarity we show the formula of erythromycin in which the numbering adopted in the present patent application is indicated.
Some classes of erythromycin derivatives endowed with a high anti-inflammatory activity are described in the literature.
For example, in the already cited European patent applications in the name of Taisho derivatives of erythromycin modified at 3, 9, 11 and 12 position, as strong inhibitors of the synthesis of IL-5 are claimed.
N-alkyl derivatives of azithromycin, without cladinose and desosamine, of formula
wherein
R
1
is hydrogen, a lower alkyl or a lower alkanoyl; R
2
, R
3
and R
4
, the same or different, are hydrogen or a lower alkanoyl; are described as anti-inflammatories in EP 0 283 055 (Sour Pliva).
The use of erythromycin as anti-inflammatory that acts by reducing the release of interleukin 1 through the inhibition of the mammalian mdr-P glycoprotein is claimed WO 92/16226 in the name of Smith-Kline Beecham Corporation.
Among the macrolide derivatives described in the literature a few are 3′-desdimethylamino-9-oxyimino derivatives. The limited interest towards this class of compounds is justified by the fact that the relevance of the dimethylamino group for the activity of ribosomal binding typical of macrolides is known [Tetrahedron Letters, (1994), 35, 3837-3840].
In U.S. Pat. No. 3,928,387 (Hoffmann-La Roche Inc.) 3′-desdimethylamino-3′,4′-dehydroerythromycin A oxime is described, as intermediate useful for the preparation of the antibiotic 1745A/X.
In EP 0 254 534 (Robinson, William S.) a very broad class of macrolides with antiviral activity is claimed. Among them the compound of formula
whose correct chemical name is 3′-desdimethylamino-3′,4′-dehydroerythromycin A 9-O-methyloxime notwithstanding in the text of EP 0 254 534 is erroneously reported as des-dimethylaminoerythromycin 9-O-methyloxime (page 10, line 46) is described.
Now we have found that by removing the dimethylamino group from the 3′ position of desosamine of 9-oxyimino macrolides, compounds endowed with anti-inflammatory activity and essentially devoid of antibiotic properties are obtained.
Therefore, object of the present invention are compounds of formula
wherein
R is hydrogen or methyl;
R
1
and R
2
are both hydrogen or they together form a bond;
R
3
is hydrogen, a linear or branched C
1
-C
5
alkyl group, a benzyl group, optionally substituted by one or more substituents selected among nitro groups, hydroxy groups, carboxylic groups, amino groups, linear or branched C
1
-C
5
alkyl groups, C
1
-C
4
alkoxycarbonyl groups, aminocarbonyl groups or ciano groups, or a chain of formula
wherein
A is hydrogen or a phenyl group optionally substituted by one or two substituents selected among nitro groups, hydroxy groups, carboxylic groups, amino groups, linear or branched C
1
-C
5
alkyl groups, C
1
-C
4
alkoxycarbonyl groups, aminocarbonyl groups or ciano groups, or a 5 or 6 membered heterocycle, saturated or unsaturated, containing from 1 to 3 heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted by one or two substituents selected among C
1
-C
5
alkyl groups, phenyl groups, hydroxy groups, oxo (═O) groups, nitro groups, C
1
-C
4
alkoxycarbonyl groups, aminocarbonyl groups, mono or di-C
1
-C
4
-alkylaminocarbonyl groups, C
1
-C
4
-alkylcarbonyl groups;
X and Y, the same or different, are O, S, SO, SO
2
or NR
4
, in which R
4
is hydrogen, a linear or branched C
1
-C
5
alkyl group, a C
1
-C
5
alkoxycarbonyl group, a benzyloxycarbonyl group;
r is an integer from 1 to 6;
m is an integer from 1 to 8;
n is an integer from 0 to 2;
and their pharmaceutically acceptable salts; the compounds 3′-desdimethylamino-3′,4′-dehydroerythromycin A oxime (R
1
and R
2
=bond; R═H; R
3
═H) and 3′-desdimethylamino-3′,4′-dehydroerythromycin A 9-O-methyloxime (R
1
and R
2
=bond; R═H; R
3
═CH
3
) being excluded.
A further object of the present invention is the use of the compounds 3′-desdimethylamino-3′,4′-dehydroerythromycin A oxime and 3′-desdimethylamino-3′,4′-dehydroerythromycin A 9-O-methyloxime as anti-inflammatories.
The compounds of formula I are anti-inflammatory macrolides devoid of antibiotic activity and therefore they are useful in the treatment of inflammatory diseases.
With the term linear or branched C
1
-C
5
alkyl groups a group selected among methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and isopentyl is meant. With the term 5 or 6 membered heterocycle, saturated or unsaturated, containing from 1 to 3 heteroatoms selected among nitrogen, oxygen and sulphur, heterocycles such as pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, isothiazole, isoxazole, oxazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, thiadiazole and their partially o totally saturated forms are meant.
Preferred compounds of formula I are the compounds in which R, R
1
and R
2
are hydrogen.
Within this class the compounds in which R
3
is a chain of formula
wherein
X, Y, A, r, m and n have the already reported meanings are part
Botta Daniela
Moriggi Ermanno
Pellacini Franco
Pradella Lorenzo
Romagnano Stefano
Owens Amelia
Zambon Group S.p.A.
LandOfFree
Macrolides with anti-inflammatory activity does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Macrolides with anti-inflammatory activity, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Macrolides with anti-inflammatory activity will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2898610