Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1996-12-30
2002-10-22
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S227000
Reexamination Certificate
active
06468995
ABSTRACT:
TECHNICAL FIELD
This invention relates to new cephem compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
BACKGROUND ART
Some cephem compounds have been known as described, for example, in Japanese Kokai H2-134385.
DISCLOSURE OF INVENTION
The present invention relates to new cephem compounds and pharmaceutically acceptable salts thereof.
More particularly, it relates to new cephem compounds and pharmaceutically acceptable salts thereof, which have antimicrobial activities, to processes for preparation thereof, to pharmaceutical composition comprising the same and to a method for treating infectious diseases in human being and animals.
Accordingly, one object of the present invention is to provide the cephem compounds and pharmaceutically acceptable salts thereof, which show highly active against a number of pathogenic microorganisms.
Another object of the present invention is to provide processes for the preparation of the cephem compounds and salts thereof.
A further object of the present invention is to provide pharmaceutical compositions comprising, as an active ingredient, said cephem compounds or their pharmaceutically acceptable salts.
Still further object of the present invention is to provide a method for treating infectious diseases caused by pathogenic microorganisms, which comprises administering said cephem compounds to infected human being or animals.
The object cephem compounds of the present invention are novel and can be represented by the following general formula (I):
wherein R
1
is amino or protected amino,
R
2
is hydrogen, lower alkyl or hydroxy protective group,
R
3
is carboxy or protected carboxy,
R
4
is 3-pyridyl, 4-pyridyl or optionally substituted heteromonocyclic group containing two nitrogen atoms as hetero atoms, and which may also contain one oxygen or sulfur atom, and
n is 0, 1 or 2, provided that when R
2
is lower alkyl, then n is 1 or 2, and
R
4
is optionally substituted heteromonocyclic group containing two nitrogen atoms as hetero atoms,
and which may also contain one oxygen or sulfur atom, or pharmaceutically acceptable salt thereof.
The object compound (I) of the present invention can be prepared by the following processes.
wherein R
1
, R
2
, R
3
, R
4
and n are each as defined above,
R
a
2
is hydroxy protective group,
R
a
3
is protected carboxy,
R
8
is ester moiety of esterified carboxy represented by group of formula: —COOR
8
,
one of X and Y is acid residue and
the other is mercapto or activated mercapto group, or salt thereof.
Some of the starting compound (II) and (V) are new and the new compounds can be prepared by the following processes, preparations or equivalent processes of those.
wherein R
3
, R
a
3
, R
4
, n, X and Y are each as defined above,
R
6
is amino or protected amino,
R
a
6
is protected amino and
R
7
is acyl.
Regarding the compounds (I), (Ia), (Ib), (Ic), (Id), (Ie), (III) and (IV), it is to be understood that said compounds include syn isomer(Z), anti isomer(E) and a mixture thereof.
For example, with regard to the object compound (I), syn isomer(Z) means one geometrical isomer having the partial structure represented by the following formula:
(wherein R
1
and R
2
are each as defined above), and anti isomer(E) means the other geometrical isomer having the partial structure represented by the following formula:
(wherein R
1
, R
2
and Z are each as defined above), and all of such geometrical isomers and mixture thereof are included within the scope of this invention.
In the present specification and claim, the partial structure of these geometrical isomers and mixture thereof are represented for convenient sake by the following formula:
(wherein R
1
, R
2
and Z are each as defined above).
It is to be noted that the compound (I) and the other compounds may include one or more stereoisomers due to asymmetric carbon atom(s), and all of such isomers and mixture thereof are included within the scope of this invention.
It is also to be noted that the solvate of the compound (I) [e.g. hydrate, lower alcohol solvate (e.g. methanol solvate, ethanol solvate, isopropanol solvate, etc), etc.] and any form of the crystal of the compound (I) are included within the present invention.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions, which the present invention include within the scope thereof, are explained in detail as follows.
The term “lower” is intended to mean 1 to 6 carbon atom(s) unless otherwise indicated.
Suitable “lower alkyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like, in which more preferred one may be C
1
-C
4
alkyl and the most preferred one may be methyl, ethyl or propyl.
Suitable “protected amino” group may include an amino group substituted by a conventional amino protective group which is easily removable such as acyl as defined below, such as organic silyl group which may have suitable substituent(s) (e.g., mono-, di- or tri(lower)alkylsilyl, etc.), such as ar(lower)alkyl which may have suitable substituent(s) (e.g. benzyl, trityl, p-nitrobenzyl, etc.) or the like.
Suitable “acyl” may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. The aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, such as alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiarybutoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.) and the like. The acyl group containing aromatic or heterocyclic ring may include arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like. The acyl moiety as stated above may have suitable substituent(s) such as halogen (e.g. chlorine, bromine, iodine or fluorine), lower alkyl as defined above, or the like.
Suitable “protected carboxy” may include an esterified carboxy and the like. Suitable example of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); lower alkoxyalkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); lower alkylthioalkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.); mono(or di or tri)halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-acetoxyethyl ester, 1-propionyloxyethyl ester, etc.); cyclo(lower)alkylcarbonyloxy(lower)alkyl ester (e.g., 1-(cyclohexylcarbonyloxy)ethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, 1-(or 2-)[methoxycarbonyloxy]ethyl ester, 1-(or 2-)[ethoxycarbonyloxy]ethyl ester, 1-(or 2-)[propoxycarbonyloxy]ethyl ester, 1-(or 2-)[isopropoxycarbonyloxy]ethyl ester, etc.); cyclo(lower)alkyloxycarbonyloxy(lower)alkyl ester (e.g., 1-(cyclohexyloxycarbonyloxy)ethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g. mesylmethyl ester, 2-me
Kawabata Kohji
Ohki Ayako
Shirai Fumiyuki
Terasawa Takeshi
Yamamoto Hirofumi
Ford John M.
Fujisawa Pharmaceutical Co. Ltd.
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