Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-02
2001-07-24
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S350000
Reexamination Certificate
active
06265396
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel &bgr;-lactam compound represented by the formula [1] as described below.
BACKGROUND ART
By the wide clinical application of the third-generation cephalosporins, Gram-positive bacteria have become to be frequently isolated. Particularly, methicillin-resistant
Staphylococcus aureus
(hereinafter, referred to as MRSA) has been more frequently isolated, and becomes a serious problem in clinical field, because infectious diseases caused by MRSA are difficult to be treated. For example, vancomycin, which has been broadly used for infectious diseases caused by MRSA in these days, is difficult to be administered because of its side effects, and glycopeptide-resistant bacteria are supposed to increase in future by administration thereof. Moreover, it has recently been reported the increase in isolation of methicillin-resistant and coagulase-negative Staphylococci (MRCNS). Under these circumstances, it has been desired to develop a safe drug having potent anti-MRSA and anti-MRCNS activities.
DISCLOSURE OF INVENTION
An object of the present invention is to provide a &bgr;-lactam antibiotic having an excellent antibacterial activity against Gram-positive bacteria, especially against MRSA and MRCNS.
The present inventors have intensively studied, and have found that a compound of the following formula [1] shows a potent effect on Gram-positive bacteria, and shows an excellent antibacterial activity especially against MRSA and MRCNS, and have accomplished the present invention.
That is, the present invention relates to a compound of the formula [1]:
wherein R
1
is a lower alkyl group or a lower alkyl group being substituted by a hydroxy group, R
2
is a hydrogen atom or a lower alkyl group, X is O, S or NH, n is 1 to 3, and R
3
is —C(R
a
)═NH, in which R
a
is a hydrogen atom, a lower alkyl group, or a substituted lower alkyl group, or a pharmaceutically acceptable salt thereof, or a non-toxic ester thereof.
Moreover, the present invention also relates to a process for preparing a compound of the formula [1]:
wherein R
1
, R
2
, R
3
1
, X and n are the same as defined above, or a pharmaceutically acceptable salt thereof, or a non-toxic ester thereof, which comprises
reacting a compound of the formula [2]:
wherein R
2
is the same as defined above, R
1a
is a lower alkyl group, a lower alkyl group being substituted by a hydroxy group, or a lower alkyl group being substituted by a hydroxy group protected by a protecting group, R
4
is a protecting group for carboxyl group, and L is an active ester of hydroxy group, with a compound of the formula [3]:
wherein X and n are the same as defined above, R
3a
is —C(R
a
)═NRb, in which R
a
is the same as defined above, and Rb is a hydrogen atom or a protecting group for imidoyl group, or R
3a
is a protecting group for amino group, in the presence of a base, or reacting the compound of the formula [2] with a thiolate salt of the compound of the formula [3] to give a compound of the formula [4]:
wherein R
1a
, R
2
, R
3a
, R
4
, X and n are the same as defined above,
followed by reactions which are properly selected
from the removal of the protecting group for hydroxy group for R
1a
, the removal of the protecting group for amino group for R
3a
and the subsequent imidoylization reaction of the de-protected amino group, or the removal of the protecting group for imidoyl group for R
3a
, and the removal of the protecting group for carboxyl group for R
4
.
The lower alkyl group for R
1
, R
1a
, R
2
, R
3
or R
3a
in the above formulae [1], [2], [3] and [4] includes alkyl groups having 1 to 5 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and n-pentyl.
The lower alkyl group being substituted by a hydroxy group for R
1
or R
1a
includes alkyl groups having 1 to 5 carbon atoms and being substituted by a hydroxy group, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-l-methylethyl, 1-hydroxypropyl, and 2-hydroxypropyl.
The substituent for the substituted lower alkyl group in the present invention includes, for example, a hydroxy group; a lower alkoxy group; a lower alkoxy group being substituted by a hydroxy group or an amino group; a lower alkylcarbonyloxy group; a lower alkoxycarbonyl group; an amino group; an amino group being substituted by one or two group selected from a lower alkyl group and a lower alkyl group being substituted by a hydroxy group or an amino group; a guanidino group; a quaternary ammonium group being substituted by three groups selected from a lower alkyl group and a lower alkyl group being substituted by a hydroxy group or an amino group; a carboxyl group; an aminocarbonyl group; an aminocarbonyl group being substituted by one or two groups selected from a lower alkyl group and a lower alkyl group being substituted by a hydroxy group or an amino group; a halogen atom; a cyano group; an alkylamidino group having 1 to 3 carbon atoms; and a guanidinocarbonyl group. These substituents may optionally be protected by an appropriate protecting group. The positions of these substituents may be any position which is chemically possible, and the substitution either at one position or at more positions such as 1 to 3 positions is also available. The substituted lower alkyl group also includes ones forming a 3- to 7-membered ring via a heteroatom that is a substituent. The 3- to 7-membered ring thus formed includes rings such as aziridine, azetidine, pyrrolidine, piperidine, morpholine, homopiperazine, and tetrahydrofuran.
The protecting group for carboxyl group for R
4
in the above formulae [2] and [4] may be any conventional protecting groups, but preferably a straight chain or branched chain lower alkyl group having 1 to 5 carbon atoms (e.g., methyl, ethyl, isopropyl, tert-butyl, etc.), a halogeno-lower alkyl group having 1 to 5 carbon atoms (e.g., 2-iodoethyl, 2,2,2-trichloroethyl), a lower alkoxymethyl group having 1 to 5 carbon atoms (e.g., methoxymethyl, ethoxymethyl, isobutoxymethyl), a lower aliphatic acyloxymethyl group having 2 to 5 carbon atoms (e.g., acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl), a 1-(C
1
-C
5
)alkoxycarbonyloxyethyl group (e.g., 1-ethoxycarbonyloxyethyl), an aralkyl group (e.g., benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl), a lower alkenyl group having 3 to 7 carbon atoms (e.g., allyl, 3-methylallyl), a benzhydryl group, or a phthalidyl group.
The protecting group for hydroxy group for R
1a
in the formulae [2] and [4], and the protecting group for imidoyl group and the protecting group for amino group for R
3a
in the formulae [3] and [4] may be any conventional ones, but preferably an alkoxycarbonyl group having 1 to 5 carbon atoms (e.g., tert-butyloxycarbonyl), a halogenoalkoxycarbonyl group having 1 to 5 carbon atoms (e.g., 2-iodoethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl), a substituted or unsubstituted alkenyloxycarbonyl group having 3 to 7 carbon atoms (e.g., allyloxycarbonyl), an aralkyloxycarbonyl group (e.g., benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl), or a trialkylsilyl group (e.g., trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl).
The pharmaceutically acceptable salt of the compound of the above formula [1] is a conventional non-toxic salt thereof. Such salts include, as a salt with an intramolecular carboxylic acid, a salt with an inorganic base such as sodium, potassium, calcium, magnesium, ammonium, a salt with an organic base such as triethylammonium, pyridinium, diisopropylammonium, or an intramolecular salt being formed with a cation at the 3-side chain such as a quaternary ammonium ion. As a salt with an intramolecular base, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or a salt with an organic acid such a
Nouda Hiroshi
Shinagawa Hisatoshi
Sunagawa Makoto
Yamaga Hiroshi
Berch Mark L.
Birch, Stewart, Kolasch and Birch LLP
McKenzie Thomas C.
Sumitomo Pharmaceuticals Co. Ltd.
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