Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-11-16
1997-12-16
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514204, 540224, 540225, C07D50157, A61K 31545
Patent
active
056985444
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP 95/00471 F.D. Mar. 17, 1995.
TECHNICAL FIELD
This invention relates to a novel cephem compound, a process for producing the compound and an antimicrobial composition comprising the same.
PRIOR ART
With the spreading use of third-generation cephalosporins in recent years, infectious diseases associated with methicillin-resistant Staphylococcus aureus (MRSA) are presenting serious problems. These cephalosporins of the third generation have potent activity against gram-negative bacilli but because of their relatively low activity against gram-positive cocci, the strains of S. aureus which are resistant to .beta.-lactam antibiotics have increased in number and the resultant refractory infections constitute a serious threat today. The only therapeutic drug available for MRSA infections today is vancomycin which is a polypeptide antibiotic but since it has side effects such as eczema and renal toxicity, vancomycin calls for caution in administration.
Numerous cephalosporin antibiotics having a quaternary ammonium salt have been known. These compounds have a high antimicrobial activity but a low solubility in water. Because of this defect, an attempt to develop a medicament from the compound has been abandoned. For example, Japanese Unexamined Patent Publication No.130292/1984 (EP-A-111281) describes compounds having a thiovinyl quaternary ammonium salt in the 3-position of the cephalosporin skeleton but does not refer to the introduction of a new quaternary ammonium substituent in the skeleton. Furthermore, there is no disclosure in the publication that the disclosed compound is active against MRSA.
Generally the antimicrobial activity of conventional cephalosporin compounds against gram-positive cocci inclusive of MRSA decreases with an increase of its water-solubility. Namely the antimicrobial activity of cephalosporin compounds is in inverse relation to its water-solubility. Thus it has been very difficult to develop a cephalosporin compound having both a high water-solubility and an excellent antimicrobial activity. Now there is a need for development of a cephem compound which is superior in the activity against MRSA and also in the water-solubility.
DISCLOSURE OF INVENTION
It is an object of this invention to provide a novel cephem compound having a high water-solubility and an excellent antimicrobial activity and, in particular, a novel cephem compound which is active and highly safe against gram-positive cocci inclusive of MRSA.
For the purpose of accomplishing the above-mentioned object, the inventors of this invention synthesized and investigated a variety of cephem compounds and discovered that when a new quaternary ammonium group is introduced as a substituent into a compound having a thiovinyl quaternary ammonium salt in the 3-position of the cephalosporin skeleton, the resulting cephem compound is imparted a high water-solubility and a high antimicrobial activity, particularly against gram-positive cocci inclusive of MRSA. This invention has been developed on the basis of the above discovery.
The cephem compound of this invention is a novel compound represented by the formula (1) ##STR3## wherein Q represents CH or N, R.sup.1 represents a carboxylate or a carboxyl group, R.sup.2 represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted lower cycloalkyl group, an optionally substituted carboxy(lower)alkyl group, an optionally substituted hydroxy(lower)alkyl group, or an optionally substituted lower alkoxy(lower)alkyl group, and R represents ##STR4## wherein R.sup.3 represents a group --(CH.sub.2).sub.m --Y or a group --(CH.sub.2).sub.m --CO--Y (wherein m is an integer of 1 to 5, and Y represents a quaternary ammonium group), n is an integer of 0 to 4, B.sup.- represents an anion, f is 0 or 1 when R.sup.1 represents a carboxylate, and 2 when R.sup.1 represents a carboxyl group, and the ring C represents a 5-membered heteroc
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Akagi Hiroshi
Hanaki Hideaki
Hyodo Akio
Ito Masahiro
Yamada Takae
Otsuka Kagaku Kabushiki Kaisha
Shah Mukund J.
Sripada Pavanaram K.
Taiho Pharmaceutical Co. Ltd.
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