&bgr;-lactam compounds and process for producing the same

Details &bgr;-lactam compounds and process for producing the same &bgr;-lactam compounds and process for producing the same

2001-01-12

2003-07-29

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

06599895

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. Although vancomycin has been broadly used for infectious diseases caused by MRSA in these days, it has a defect in difficulty of administration because of its side effects, and further 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 medicament 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 &bgr;-lactam compound of the following formula [1], a pharmaceutical composition containing the same as an active ingredient, and a process for producing the same.
(1) A &bgr;-lactam 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 an oxygen atom or a sulfur atom; R
3
is a hydrogen atom, an anion, a pharmaceutically acceptable metal, or a protecting group for a carboxyl group; Ring W is a 6- or 7-membered heterocyclic group containing 1 to 2 nitrogen atoms and 1 to 3 double bonds, which may optionally contain 1 to 2 carbonyl carbon atoms at any position which is chemically possible, and the carbon atoms of Ring W are not substituted or have the following substituents: a) R
a
(R
a
is a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted cycloalkyl group), b) A (A is a substituted or unsubstituted aryl group), c) —OH or —OP
a
(P
a
is a protecting group for a hydroxy group), d) —OR
a
(R
a
is as defined above), e) —OA (A is as defined above), f) —NH
2
or —NHP
b
(P
b
is a protecting group for an amino group), g) —NHR
a
, —N(R
b
)R
c
or —N(R
a
)P
b
(R
a
and P
b
are as defined above, R
b
and R
c
are a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted cycloalkyl group, or R
b
and R
c
may combine each other together with the nitrogen atom to which they bond, and form a 3- to 7-membered heterocyclic group having optionally 1 to 2 other heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and having optionally a substituent, h) —NHA or —N(A)P
b
(A and P
b
are as defined above), i) —N(R
a
)A (A and R
a
are as defined above), j) —CONH
2
, k) —CONHR
a
, —CON(R
b
)R
c
(R
a
, R
b
and R
c
are as defined above), l) —CONHA (A is as defined above), m) —CON(R
a
)A (A and R
a
are as defined above), n) —CONHC(═NH)NH
2
or —CONHC(═NP
b
)NHP
b
(P
b
is as defined above), o) —COOH or —COOP
c
(P
c
is a protecting group for a carboxyl group), p) —COOR
a
(R
a
is as defined above), q) —COOA (A is as defined above), r) —COR
a
(R
a
is as defined above), s) —COA (A is as defined above), t) a halogen atom. The nitrogen atoms of Ring W are not substituted or have the following substituents: a) R
a
(R
a
is as defined above), b) —CH═NH or —CH═NP
b
(P
b
is as defined above), c) —C(R
a
)═NH or —C(R
a
)═NP
b
(R
a
and P
b
are as defined above), provided that when the nitrogen atoms of Ring W are not substituted, then the carbon atoms of Ring W are not substituted either, and one nitrogen atom of Ring W may be quaternary one, and when said nitrogen atom has no double bond, then said nitrogen atom may be a quaternary one having 2 substituents mentioned above, or a pharmaceutically acceptable salt thereof, or a non-toxic ester thereof.
(2) The &bgr;-lactam compound according to the above (1), wherein X is a sulfur atom, or a pharmaceutically acceptable salt thereof, or a non-toxic ester thereof.
(3) The &bgr;-lactam compound according to any one of the above (1) and (2), wherein R
1
is a 1-(R)-hydroxyethyl group, or a pharmaceutically acceptable salt thereof, or a non-toxic ester thereof.
(4) The &bgr;-lactam compound according to any one of the above (1), (2) and (3), wherein Ring W is a 6-membered ring, or a pharmaceutically acceptable salt thereof, or a non-toxic ester thereof.
(5) The &bgr;-lactam compound according to any one of the above (1), (2), (3) and (4), wherein Ring W contains one nitrogen atom, or a pharmaceutically acceptable salt thereof, or a non-toxic ester thereof.
(6) The &bgr;-lactam compound according to any one of the above (1), (2), (3), (4) and (5), wherein the carbon atoms of Ring W are not substituted, or a pharmaceutically acceptable salt thereof, or a non-toxic ester thereof.
(7) The &bgr;-lactam compound according to any one of the above (1), (2), (3), (4), (5) and (6), wherein the nitrogen atom of Ring W has a substituent as mentioned above, or a pharmaceutically acceptable salt thereof, or a non-toxic ester thereof.
(8) The &bgr;-lactam compound according to any one of the above (1), (2), (3), (4), (5), (6) and (7), wherein Ring W is a pyridine ring, and the nitrogen atom thereof is substituted by a R
a
, or a pharmaceutically acceptable salt thereof, or a non-toxic ester thereof.
(9) A process for producing a &bgr;-lactam compound of the formula [1]:
wherein R
1
, R
2
, R
3
, X and Ring W are 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 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
3′
is a protecting group for a carboxyl group, and L is an active ester of hydroxy group, with a compound of the formula [3]:
wherein X is as defined above, Ring W′ is a 6- or 7-membered heterocyclic group containing 1 to 2 nitrogen atoms and 1 to 3 double bonds, which may optionally contain 1 to 2 carbonyl carbon atoms at any position which is chemically possible, and the carbon atoms of Ring W′ are not substituted or substituted by the above-mentioned substituents, and the nitrogen atoms of Ring W′ are not substituted or substituted by the following substituents: a) R
a
(R
a
is as defined above), b) —CH═NH or —CH═NP
b
(P
b
is as defined above), c) —C(R
a
)═NH or —C(R
a
)═NP
b
(R
a
and R
b
are as defined above), d) P
b
(P
b
is as defined above), provided that when the nitrogen atoms of Ring W′ are not substituted, then the carbon atoms of Ring W′ are not substituted either,
 in the presence of a base, or reacting the compound of the formula [2] with a salt of the compound [3] with a base (hereinafter, simply referred to as a thiolate) to give a compound of the formula [4]:
wherein R
1a
, R
2
, R
3′
, X and Ring W′ are as defined above,
 followed by an appropriate combination of reactions which are properly selected from the removal of the protecting group for hydroxy group for R
1a
, the removal of each protecting group for Ring W′, the subsequent alkylation reaction or the imid

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