Erythromycin A derivatives

Details Erythromycin A derivatives Erythromycin A derivatives

1999-04-23

2001-02-20

Kight, John (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06191118

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel derivatives of antibiotic erythromycin A.
BACKGROUND ART
Erythromycin A is an antibiotic clinically widely used as an agent for treating infectious diseases caused by Gram-positive bacteria, mycoplasmas, etc. However, erythromycin A is decomposed by the gastric acid due to instability to acids, and thus have a drawback of no constancy of movement in the body. Hitherto many erythromycin A derivatives have been prepared for the purpose of the improvement of the biological or pharmacological properties. For example, it is reported that 6-O-methylerythromycin A derivatives have an improved stability to acids and have a superior in vivo antibacterial activity in comparison with erythromycin A when administered orally (U.S. Pat. No. 4,331,803). There are also recent reports relating to 11,12-cyclic carbamate derivatives prepared from 6-O-methylerythromycin A as a starting material with the aim of expansion of antibacterial spectrum as well as a stability to acids (EP. patent No. 487411 and U.S. Pat. No. 4,742,049). In addition, the present inventors refer to the antibacterial activity of the ester derivatives at the 3-position (EP. Patent No. 619320).
An object of the present invention is to provide a novel antibiotic erythromycin A derivative or a salt thereof having a strong antibacterial activity against not only known erythromycin-sensitive bacteria but also erythromycin-resistant bacteria which recently are showing a tendency to increase, and a composition comprising the same as an effective component.
Other objects of the present invention are to provide a method for the treatment of a bacterially infectious disease which comprises administering a pharmaceutically effective amount of the above-mentioned erythromycin A derivative or a salt thereof to patients, and use of the above-mentioned erythromycin A derivative or a salt thereof for the treatment of a bacterially infectious disease.
DISCLOSURE OF THE INVENTION
As a result of various researches on the antibacterial activity of erythromycin A derivatives, the present inventors have found that, among 6-O-methylerythromycin A 11,12-cyclic carbamate derivatives, in particular, the derivatives which are substituted by a substituted aminoalkyl group on the nitrogen atom forming the cyclic carbamate ring and converted into an ester at the 3-position have a strong antibacterial activity against erythromycin-resistant bacteria, and have further studied about analog compounds thereof, whereby the present invention has been accomplished.
The present invention relates to an eythromycin A derivative represented by Formula (I):
[wherein n is an integer of from 1 to 4,
R
1
is a group represented by the formula:
(wherein p is 0 or 1, Z is a nitrogen atom or CH; R
7
, R
8
and R
9
are each a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, a nitro group, an amino group, an acetylamino group, an amino group substituted by 1 or 2 alkyl groups having 1 to 3 carbon atoms, a hydroxyl group, a cyano group, an alkyl group having 1 to 3 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 5 carbon atoms or a phenyl group, or R
7
and R
8
are attached to the carbon atoms which are attached side by side, and together form a methylenedioxy group, or R
7
and R
8
are attached to the carbon atoms which are attached side by side, and together with the carbon atoms to which they are attached form a benzene ring, R
10
and R
11
are each a hydrogen atom, or R
10
and R
11
together form an oxo group), a group represented by the formula:
(wherein R
10
and R
11
are as defined above, M is an oxygen atom, a sulfur atom, —NCH
3
or —NH, or R
12
and R
13
are each a hydrogen atom, or R
12
and R
13
together with the carbon atoms to which they are attached form a benzene ring), a pyridylacetyl group, a cycloalkylmethyl group having 4 to 8 carbon atoms or a 1,2-bis(ethoxycarbonyl)vinyl group,
R
2
is the same group as defined for R
1
, a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkanoyl group having 2 to 6 carbon atoms or an alkoxycarbonyl group having 2 to 6 carbon atoms, R
1
and R
2
together form a group of the formula: ═CH—R
14
(wherein R
14
is a phenyl group, a phenyl group substituted by nitro group(s), cyano group(s) or alkyl group(s) having 1 to 3 carbon atoms substituted by 1 to 3 halogen atoms, or an imidazolyl group), or R
1
and R
2
together with the nitrogen atom to which they are attached form a group represented by the formula:
(wherein W is CH, a carbon atom or a nitrogen atom, Y is a group of —C(═O)— or —(CH
2
)
m
— (wherein m is 1 or 2), R
15
and R
16
are each a hydrogen atom or when W is a carbon atom, R
15
and R
16
together with the carbon atoms to which they are attached form a benzene ring or a naphthalene ring,
R
3
is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or a cinnamyl group,
R
4
is a hydrogen atom, an acetyl group, an ethylsuccinyl group or a nicotinoyl group,
A is a group represented by the formula:
—OC(═O)—R
17
,
—OC(═O)—CH
2
—R
17
,
—OC(═O)—NH—R
17
,
—O—R
17
or
—OC(═O)—O—R
17
(wherein R
17
is a phenyl group, a pyridyl group, a quinolyl group, or those groups which are each substituted by 1 to 3 members selected by the group consisting of an alkyl group having 1 to 5 carbon atoms, a nitro group, an alkoxy group having 1 to 5 carbon atoms and a halogen atom), and
R
5
and R
6
are each a hydrogen atom or an alkyl group having 1 to 5 carbon atoms] or a pharmaceutically acceptable salt thereof.
In the present invention, the alkyl group having 1 to 5 carbon atoms refers to a straight or branched chain alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group or a pentyl group. The alkoxy group having 1 to 5 carbon atoms refers to a straight or branched chain alkoxy group, preferably a methoxy group or an ethoxy group. The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Examples of the 6-membered ring and the condensed ring in the group represented by Formula (a) are a benzene ring, a naphthalene ring, a pyridine ring, a quinoline ring and an isoquinoline ring. Examples of the 5-membered ring and the condensed ring in the group represented by Formula (b) are a furan ring, a thiophene ring, a pyrrole ring, a benzofuran ring, a benzothiophene ring and an indole ring. Examples of the 5-membered ring, the 6-membered ring and the condensed ring in the group represented by Formula (c) are a pyrrolidine ring, a piperidine ring, an imidazolidine ring, an isoindoline ring, a 1,2,3,4-tetrahydroisoquinoline ring and a 2-oxoisoindoline ring.
The amino group substituted by 1 or 2 alkyl groups having 1 to 3 carbon atoms as defined for R
7
, R
8
and R
9
is preferably an amino group substituted by methyl group(s), more preferably a dimethylamino group.
The alkyl group having 1 to 3 carbon atoms substituted by 1 to 3 halogen atoms as defined for R
7
, R
8
, R
9
and R
14
is preferably an alkyl group substituted by fluorine atom(s), more preferably a methyl group substituted by fluorine atom(s), and most preferably a trifluoromethyl group.
The pharmaceutically acceptable salt refers to a salt used in chemotherapy or prophylaxis of bacterially infectious diseases, for example, a salt with acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, laurylsulfuric acid, malic acid, aspartic acid, glutaminic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanic acid, polyacrylate or carboxyvinyl polymer.
The co

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