Imidazo[4,5-b]pyridiniummethyl-containing cephem...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C540S224000

Reexamination Certificate

active

06518263

ABSTRACT:

TECHNICAL FIELD
The present invention relates to cephem compounds having a broad antibacterial spectrum over various pathogenic bacteria and to pharmaceutical compositions containing the same. The compounds of the present invention are particularly efficacious against MRSA (methicillin resistant S. aureus).
BACKGROUND ART
Study of so-called broad spectrum cephem compounds having potent antibacterial activities against various Gram-positive and Gram-negative bacteria has recently been focused on cephem compounds at which 7-side chain is substituted with aminothiazole or aminothiadiazole and 3-position with a cyclic-type quarternary ammoniummethyl group. For example, the known 7-aminothiazole types include cefepime hydrochloride (U.S. Pat. No. 4,406,899), cefpirome sulfate (U.S. Pat. No. 4,609,653, JP(A) S57-192394), and cefoselis sulfate (JP(A) H07-196665, WO97/41128), and the 7-aminothiadiazole types include cefclidin (U.S. Pat. No. 4,748,171), and cefozopran hydrochloride (U.S. Pat. No. 4,864,022, JP(A) S62-149682, JP(A) H03-47189). These cephem compounds show almost none or extremely weak activities against MRSA which has been a clinical concern.
The other documents, disclosing the same types of cephem compounds, include, for example, JP(A) 4789/1983, JP(A) 155183/1985, JP(A) 97982/1985, JP(A) 97983/1985, JP(A) 24389/1982, JP(A) 57390/1983, JP(B) 65350/1991, JP(B) 14117/1992, JP(A) 231684/1985, JP(A) 30786/1987, WO92/22556, JP(A) 222058/1993, JP(A) 157542/1994, JP(A) 101958/1995, and JP(A) 101960/1995.
Among them, JP(A) 4789/1983 discloses cephem compounds which have an optionally substituted and 2 or more N atoms-containing heterocycle cation at the 3-position. JP(A) 155183/1985 discloses cephem compounds which have a 2 or more N atoms-containing and unsaturated condensed heterocycle cation at the 3-position. These documents, however, describe or suggest no concrete embodiment of a cephem compound having an imidazopyridiniummethyl group at the 3-position.
Though JP(A) 105685/1985, equivalent to J. Med. Chem. 1990, 33, P2114-2121, discloses cephem compounds having an imidazopyridiniummethyl group at the 3-position, any of the 3-substituents of the working example compounds is limited to imidazo[4,5-c]pyridiniummethyl. On the other hand, a compound having an imidazo[4,5-b]pyridiniummethyl group at the 3-position is shown by the chemical name without any physical data or the like. Further, the [4,5-b]-type compounds have only aminothiazole group as part of the 7-side chain. Namely, the document does not concretely describe a cephem compound at which 3-position is substituted with an imidazo[4,5-b]pyridiniummethyl group and 7-side chain with aminothiadiazole.
Therefore, it has been desired to develop cephem compounds of broad antibacterial spectrum which have anti-MRSA activity applicable enough to clinical use.
DISCLOSURE OF INVENTION
The present inventors have intensively studied to find out that introduction of an imidazo[4,5-b]pyridiniummethyl group into the 3-position of cephem compounds leads to broad antibacterial spectrum and excellent anti-MRSA activity, and have accomplished the present invention shown below.
(1) a compound of the formula (I):
wherein,
X is N or CY and Y is H or halogen;
R
1
is amino or protected amino;
R
2
is hydrogen, optionally substituted lower alkyl or optionally substituted cycloalkyl;
R
3
is hydrogen, hydroxy, halogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio or optionally substituted amino;
R
4
is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkyl(lower)alkyl or an optionally substituted N-containing heterocyclic group;
R
5
is hydrogen, amino, optionally substituted lower alkyl, optionally substituted lower alkoxy or optionally substituted lower alkylthio, or R
4
and R
5
taken together may form lower alkylene in which an optional hetero atom(s) intervene; and
a wavy line means syn- or anti-isomerism or a mixture thereof, an ester, a pharmaceutically acceptable salt, a prodrug, or a solvate thereof (herein after may be referred to as compound (I)).
(2) the compound described in above (1) wherein X is N.
(3) the compound described in above (1) wherein R
1
is amino.
(4) the compound described in above (1) wherein R
2
is hydrogen or optionally substituted lower alkyl.
(5) the compound described in above (4) wherein R
2
is lower alkyl optionally substituted with halogen.
(6) the compound described in above (1) wherein R
3
is hydrogen.
(7) the compound described in above (1) wherein R
4
is hydrogen, optionally substituted lower alkyl or an optionally substituted N-containing heterocyclic group.
(8) the compound described in above (7) wherein R
4
is hydrogen, lower alkyl optionally substituted with amino, lower alkylamino or hydroxy(lower) alkylamino, or an optionally substituted 4- to 6-membered N-containing saturated heterocyclic group.
(9) the compound described in above (1) wherein R
5
is hydrogen.
(10) the compound described in above (1) wherein the wavy line means syn-isomerism.
(11) the compound described in above (1) wherein X is N; R
1
is amino; R
2
is hydrogen or optionally substituted lower alkyl; R
3
is hydrogen; R
4
is hydrogen, optionally substituted lower alkyl or an optionally substituted N-containing heterocyclic group; R
5
is hydrogen; and the wavy line means syn-isomerism.
(12) the compound described in above (11) wherein X is N; R
1
is amino; R
2
is hydrogen or lower alkyl optionally substituted with halogen; R
3
is hydrogen; R
4
is hydrogen, lower alkyl optionally substituted with amino, lower alkylamino or hydroxy(lower)alkylamino, or an optionally substituted 4- to 6-membered N-containing saturated heterocyclic group; R
5
is hydrogen; and the wavy line means syn-isomerism.
(13) the compound described in above (12) wherein X is N; R
1
is amino; R
2
is hydrogen, —CH
3
, —CH
2
F, —CH
2
CH
3
or —CH
2
CH
2
F; R
3
is hydrogen; R
4
is hydrogen, —CH
3
, —CH
2
CH
3
, —(CH
2
)
2
CH
3
, —(CH
2
)
3
NH
2
, —(CH
2
)
3
NHCH
3
, —(CH
2
)
3
NH(CH
2
)
2
OH, azetidinyl, pyrrolidinyl or piperidyl; R
5
is hydrogen; and the wavy line means syn-isomerism.
(14) the compound described in above (13) wherein X is N; R
1
is amino; R
2
is hydrogen, —CH
2
F or —CH
2
CH
3
; R
3
is hydrogen; R
4
is hydrogen, —(CH
2
)
3
NH
2
, —(CH
2
)
3
NHCH
3
or —(CH
2
)
3
NH(CH
2
)
2
OH; R
5
is hydrogen; and the wavy line means syn-isomerism.
(15) the compound described in above (14), a pharmaceutically acceptable salt or hydrate thereof wherein X is N; R
5
is amino; R
2
is —CH
2
F; R
3
is hydrogen; R
4
is —(CH
2
)
3
NHCH
3
; R
5
is hydrogen; and the wavy line means syn-isomerism.
(16) the compound described in above (15) which is a sulfate or a hydrate thereof.
(17) the compound described in any of above (1) to (16), which shows an antibacterial activity against Gram-positive bacteria including MRSA and Gram-negative bacteria.
(18) the compound described in (17) of which MIC
50
value against MRSA is 50 &mgr;g/ml or less.
(19) A method for preparing the compound described in any of above (1) to (18), which comprises reacting a compound of the formula(V):
wherein R
6
is a leaving group and the other symbols are the same as defined above, an ester, or a salt thereof with a compound of the formula(IV):
wherein each symbol is the same as defined above, followed by optional deprotection.
(20) a compound of the formula(IV):
wherein each symbol is the same as defined above.
(21) the compound described in above (20) wherein R
3
is hydrogen; R
4
is —(CH
2
)
3
NR
a
CH
3
wherein R
a
is H or an amino-protecting group; and R
5
is hydrogen,
(22) a pharmaceutical composition which contains a compound described in any of above (1) to (18).
(23) a composition for use as an antibacterial agent which contains a compound described in any of above (1) to (18).
(24) a method for

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