Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-24
2001-07-03
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S228000, C548S170000
Reexamination Certificate
active
06255480
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application is the national stage of application no. PCT/EP97/06654, filed on Nov. 28, 1997, which application claims priority from IT MI97A002439 filed Oct. 30, 1997.
The present invention regards aminothiazole derivatives, and more in particular aminothiazole derivatives with the carboxyl activated by means of thicesters, which may be used for the preparation of &bgr;-lactam antibiotics.
&bgr;-lactam antibiotics are well known in the literature, and many of them, the cephalosporins, are widely used in medical treatment, whilst many others are still being developed, as described in the literature, for instance in patents WO 97/13772 and No 97/12890.
Also a large number of methods are known for the preparation of aminothiazole cephalosporins (third generation), one of which is described in the aforementioned patent WO 97/13772, where the &bgr;-lactam nucleus is condensed with a derivative of the compound having the following formula:
where R is a trityl group and X is a chlorine atom, the definition “derivative” meaning that the compound (II) has the carboxyl activated by means of chloride. The drawback of this condensation system is that it requires a subsequent chromatographic purification phase of the cephalosporin obtained, with a consequent decrease in the yield and increase in production costs.
In addition, in the literature activation processes are described which employ dicyclohexylcarbodiimide (DCC) or DCC/hydroxvbenzotriazole, but these activation processes, besides being very costly, are not suitable for the production of &bgr;-lactam antibiotics on an industrial scale.
Patents EP-A-037380 and EP-A-210815 describe other methods of activation on aminothiazole derivatives that are similar to those described by formula (II), but the conversion yields that may be obtained in the condensation with the &bgr;-lactam nucleus are low.
Patent U.S. Pat. No. 4,767,852 describes aminothiazole derivatives of compounds of formula (II) in which the activation of the carboxyl group is obtained by means of thioesters; in this formula, however, the meaning of X is in every case exclusively H (hydrogen): when these derivatives are condensed, according to a method described in the patent itself, with a &bgr;-lactam nucleus, in all cases cephalosporins or &bgr;-lactam antibiotics are obtained in which X is always and exclusively H. Following the teachings of patent U.S. Pat. No. 4,767,852, it is therefore not possible to obtain all &bgr;-lactam antibiotics, such as those described in patent WO 97/13772, which are useful against the strains producing &bgr;-lactamase (resistant strains) in a similar way as with all other third-generation &bgr;-lactam antibiotics having an aminothiazole structure.
The main purpose of the present invention is hence that of producing aminothiazole derivatives that may be condensed with &bgr;-lactam nuclei to yield a wide range of &bgr;-lactam antibiotics (among which those described in patent WO 97/13772) with high levels of purity and yield.
More in particular, the invention regards aminothiazole derivatives having the formula
where
X is a halogen, C
1
-C
4
alkyl;
Het is a 5- or 6-term heterocyclic ring having in the ring at least one hetero-atom chosen from the group made up of N, S, 0, either just as it is or condensed with a benzene ring;
R is H, C
1
-C
4
aikyl, —CH
2
—COOH or C(CH
3
)
2
—COOH, the acid functions of which are free, salified or esterified, CH
o
—CN, CH
2
CF
3
, CH
2
F,
or a protective group of the easily removable type.
Preferably, X is Cl; Het is chosen from among the group consisting of
R is chosen from among the group consisting of trityl (Tr), tetrahydropyranyl (THP), tert-butyldimethylsilyl (TBDMS), trimethylsilyl (TMS), and methoxymethyl (MOM).
The derivatives of formula (I) may in turn be easily obtained starting from the corresponding acids (described in patent WO 97/13772) according to the procedure described in patent U.S. Pat. No. 4767852.
The aminothiazole derivatives (I) may be easily condensed with &bgr;-lactam nuclei (is necessary, protected) to give &bgr;-lactam antibiotics with complete retention of the stereochemistry of the oxime formula C═N—OR (and hence with high levels of purity and high yields).
In particular, it may be noted that the condensation reaction of the derivatives (I) with the &bgr;-lactam nuclei may be conducted at temperatures of between −30° C. and +80° C., preferably of between −5° C. and +40° C., using highly polar organic solvents (pure, or mixed together, or mixed with water up to 50% of water, also in two-phase systems) capable of solubilizing (even only partially) the reagents (in particular the derivatives I), such as methylene chloride, ethyl acetate, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, acetone, dimethyl sulphoxide, methanol, ethanol, isopropanol, and sulpholane, having a high dielectric constant. The examples that follow are illustrative of the present invention.
REFERENCES:
patent: 4293550 (1981-10-01), Blumbach et al.
patent: 4703046 (1987-10-01), Ueda et al.
patent: 5003073 (1991-03-01), Ascher
patent: 5411874 (1995-05-01), Ellwood et al.
patent: 5654425 (1997-08-01), Zenoni et al.
patent: 5869649 (1999-02-01), Khanna et al.
patent: 0 037 380 (1981-10-01), None
patent: 0 055 465 (1982-07-01), None
patent: 210 815 (1987-04-01), None
patent: WO 97/12890 (1997-04-01), None
patent: 96/20198 (1996-07-01), None
patent: WO 97/13772 (1997-04-01), None
Filippi Mauro
Leone Mario
Serra Maurizio
Zenoni Maurizio
Ortho-McNeil Pharmaceutical , Inc.
Stockton Laura L.
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