Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-06-06
2002-07-09
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C540S225000, C540S227000
Reexamination Certificate
active
06417175
ABSTRACT:
This application is the National Stage of International Application No. PCT/JP98/05709, filed on Dec. 17, 1998.
TECHNICAL FIELD
This invention relates to a novel cephem compound having excellent antibacterial activities on a broad range of Gram-positive and Gram-negative bacteria, especially
Staphylococus aureus
, methicillin-resistant
Staphylococcus aureus
(MRSA) and a bacteria belonging to Pseudomonas and being sufficiently water-soluble, to a method of producing the compound and to a medicine, especially an antibacterial composition containing the compound.
BACKGROUND ART
Various cephem compounds having, at the 7-position, 2-(5-amino-1,2,4-thiadiazole -3-yl)-2(Z)-alkoxy-iminoacetamido group, and having, at the 3-position, 3- or 4-(pyridinium) thiazole-4-ylthio group or condensed heterocyclic ring-thio group containing N
+
as a ring constituting atom, have been reported in JPA H9(1997)-100283. However these compounds are not sufficiently soluble in water, and it is preferable to use solubilizing, agents when these compounds are dissolved in water. Thus these compounds are sufficiently satisfactory when they are used in a pharmaceutical preparation, especially for injection.
And various cephem compounds having, at the 7-position, 2-(5-phosphonoamino-1,2,4thiadiazole-3-yl)-2(Z)-methoxyiminoacetamido group, and having at the 3-position, a substituted methyl, i.e., pyridiniummethyl group or 1-methylpyridiniumthiomethyl group which are different from substituted —(CH═CH)
n
—S-group in chemical structure, have also been reported in JPA S59(1984)-31791.
Though some recently developed cephalosporin compounds have sufficient activity against methicillin-resistant staphylococcus aureus (MRSA), they are poorly soluble in water or physiologically acceptable saline, which is necessary for administration, and have not been put into practical use. Thus creation of novel compounds, overcoming these problems has been desired.
DISCLOSURE OF INVENTION
Taking the foregoing circumstances into consideration, the present inventors diligently conducted extensive studies and synthesized, for the first time, a cephem compound characterized by having, at the 3-position of its cephem, oxacephem or carbacephem nucleus, a group of the formula:
wherein one of R
3
and R
4
is a pyridinium group which may be substituted and the other is a hydrogen atom or hydrocarbon group which may be substituted, or R
3
and R
4
taken together may form a quaternalized nitrogen-containing heterocyclic ring which may be substituted; X is a nitrogen atom or CH; and n is 0 or 1, and, at the 7-position, a group of the formula:
wherein R
1
is a phosphono group or a group convertible to a phosphono group; R
2
is a hydrogen atom or a group having a linkage through a carbon atom; Q is a nitrogen atom or CH, or an ester or salt thereof, and further found that the compound thus synthesized showed good solubility to water and has excellent medicinal properties such as antibacterial activity.
Based on these findings, the present invention was accomplished.
More specifically, the present invention relates to.
(1) A compound of the formula:
wherein R
1
is a phosphono group or a group convertible to a phosphono group; R
2
is a hydrogen atom or a group having a linkage through a carbon atom; each of Q and X is a nitrogen atom or CH; Y is S, O or CH
2
; n is 0 or 1; one of R
3
and R
4
is a pyridinium group which may be substituted and the other is a hydrogen atom or hydrocarbon group which may be substituted, or R
3
and R
4
taken together may form a quaternalized nitrogen-containing heterocyclic ring which may be substituted, salt or ester thereof;
(2) A compound according to the above (1), wherein R
1
is a phosphono group which may be protected;
(3) A compound according to the above (1), wherein R
1
is phosphono, dialkoxy-phosphoryl, O-alkyl-phosphono, diaminophosphoryl, (amino)(hydroxy)phosphoryl, (alkoxy)(morpholino)phosphoryl or dihalophosphoryl;
(4) A compound according to the above (1), wherein R
1
is a phosphono group;
(5) A compound according to the above (1), wherein y is S;
(6) A compound according to the above (1), wherein R
2
is a C
1-6
alkyl group which may be substituted or a C
3-5
cycloalkyl group;
(7) A compound according to the above (1), wherein R
3
is a pyridinium group which may be substituted and R
4
is a hydrogen atom;
(8) A compound according to the above (1), wherein
wherein R
5
is a hydrocarbon group which may be substituted;
(9) A compound according to the above (1) wherein Q is a nitrogen atom;
(10) A compound according to the above (1), wherein X is a nitrogen atom;
(11) A compound according to the above (1), wherein n is 0;
(12) A compound according to the above (1), which is 7&bgr;-[2(Z)-ethoxyimino-2-(5-phosphonoamino-1,2,4-thiadiazole-3-yl)acetamido]-3-[4-(1-methyl-4-pyridinio)-2-thiazolylthio]-3-cephem-4-carboxylate, its ester or its salt;
(13) A compound according to the above (1), which is 7&bgr;-[2(Z)-fluoromethoxyimino-2-(5-phosphonoamino-1,2,4-thiadiazole-3-yl)acetamido]-3-[4-(1-methyl-4-pyridinio)-2-thiazolylthio)-3-cephem-4carboxylate, its ester or its salt;
(14) A method for producing a compound shown in the above (1) which comprises reacting a compound of the formula:
wherein each symbol has the meaning given above, its ester or its salt, with a compound of th e formula:
wherein each symbol has the meaning given above, its salt or its reactive derivative, if necessary, followed by converting R
1
to a phosphono group;
(15) A method for producing a compound shown in the above (1) which comprises subjecting a compound of the formula:
wherein one of R
3′
and R
4′
is a pyridyl group which may be substituted, and the other is a hydrogen atom or a hydrocarbon group which may be substituted, or R
3′
and R
4′
, taken together, represent a nitrogen-containing heterocyclic ring which may be substituted, and the other symbols have the meanings given above, its ester or its salt to the nitrogen quaternalization reaction in which quaternalized-ammonium is formed, if necessary, followed by converting R
1
to a phosphono group;
(16) A pharmaceutical composition containing the compound as shown in the above (1);
(17) A pharmaceutical composition containing the compound shown in the above (1) and at least one of pharmaceutically acceptable carriers, diluents and bulking agents;
(18) A pharmaceutical composition as shown in the above (16) which is an anti-bacterial composition;
(19) A pharmaceutical composition as shown in the above (16) which is an anti-MRSA agent;
(20) A pharmaceutical composition as shown in the above (16) which is an injectable composition;
(21) Use of the compound as shown in the above (1) for producing a pharmaceutical composition;
(22) Use as shown in the above (21), wherein the pharmaceutical composition is an antibacterial agent;
(23) Use as shown in the above (21), wherein the pharmaceutical composition is an anti-MRSA agent;
(24) Use as shown in the above (21), wherein the pharmaceutical composition is an injectable composition;
(25) A method for treating a bacterial infection which comprises administering an effective amount of a compound as shown in the above (1) to a patient suffering from the bacterial infection;
(26) A method for treating a bacterial infection which comprises administering an effective amount of a compound as shown in the above (1) together with at least one of pharmaceutically acceptable carriers, diluents and excipients to a patient suffering from the bacterial infection;
(27) A method as shown in the above (25), wherein the bacterial infection is a MRSA infection; and
(28) A method as shown in the above (25), wherein the compound is administered by injection.
BEST MODE FOR CARRYING OUT THE INVENTION
The cephem compound in the present specification includes a group of compounds named on the basis of “cepham” disclosed in “The Journal of The American Chemical Society” Vol. 84, p.3400 (1962), which means a compound, among the cepham compounds,
Hashiguchi Shohei
Iizawa Yuji
Ishikawa Tomoyasu
Berch Mark L.
Chao Mark
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
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