Ethylidene derivatives of tricyclic carbapenems

Details Ethylidene derivatives of tricyclic carbapenems Ethylidene derivatives of tricyclic carbapenems

1999-06-10

2002-12-03

Berch, Mark L. (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S302000

Reexamination Certificate

active

06489318

ABSTRACT:

TECHNICAL FIELD
(C07D 477/00, A61K 31/40)
The invention belongs to the field of pharmaceutical industry and relates to novel ethylidene derivatives of tricyclic carbapenems in the form of pure diastereoisomers and in the form of pure geometric isomers, to processes for the preparation thereof, to pharmaceutical compositions containing them and to the use thereof in human and veterinary medicine. Novel ethylidene derivatives of tricyclic carbapenems are used as inhibitors of action of &bgr;-lactamases and/or as antibiotics.
Technical Problem
Due to the phenomenon of resistance to various antibiotics and synthetic chemotherapeutics, there exists a constant need to prepare novel effective antiinfection agents. There also exists a constant need to prepare novel inhibitors of enzymes &bgr;-lactamases which are responsible for the resistence against &bgr;-lactam antibiotics. Novel ethylidene derivatives of tricyclic carbapenems are chemical compounds which are inhibitors of enzymes &bgr;-lactamases and/or antibiotics.
Prior Art
In prior art carbapenem compounds are known as effective antibacterial agents. A novel sub-group of carbapenem compounds are tricyclic carbapenems (first disclosed in EP-A-416953 and EP-A-422596) which are novel antibacterial agents in a broad spectrum of pathogenic gram-negative and gram-positive bacteria as inhibitors of the enzyme D,D-peptidase (A. Perboni et al. in Recent Advances in the Chemistry of Antiinfective Agents, Bentley, H. H., Ponsford, R. Eds., The Royal Society of Chemistry, T. Graham House, Cambridge, 1992, p. 21 and S. Hannesian et al., Bioorg. Med. Chem. Lett. 5, (1995) 2535).
Tricyclic carbapenem compounds with an antibacterial action are also disclosed in U.S. Pat. No. 5,459,260, EP-A-502464, EP-A-502465, EP-A-502468, EP-A-517065, PCT-WO-94/05666, U.S. Pat. Nos. 5,372,993, 5,374,630, PCT-WO-94/21637, PCT-WO-94/21638, PCT-WO-95/03700, PCT-WO-95/13278, PCT-WO-95/23149, JP 06,166688 and JP 08,53459.
The compound 4S,8S-4methoxy-(9R)10S,12R)-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo-[7.2.0.0
3.8
]undec-2-ene (GV104326 or sanfetrinem) is a biologically active molecule with an action on the enzyme D,D-peptidase which is essential for the formation of the cell wall in the process of bacterial multiplication (E. di Mvodugno et al., Antimicrob. Agents Chemother. 38 (1994) 2362).
Bycyclic carbapenem compounds with an antibacterial action are described in EP-A-0005349 and U.S. Pat. No. 4,235,922. There are no data about said compounds being inhibitors of enzyme &bgr;-lactamase.
In all hitherto disclosed tricyclic carbapenem compounds there are no data on any inhibition action to enzymes of the &bgr;-lactamase species. Thus, the object of the present invention are novel ethylidene derivatives of tricyclic carbapenem compounds with a completely novel structure and with the property of inhibiting the enzyme &bgr;-lactamase. This property does not reduce the possibility of potential antibacterial activity thereof.
The Technical Solution
The invention relates to novel ethylidene derivatives of tricyclic carbapenems of the formula I
wherein the ring marked C fused to the basic carbapenem nucleus in 3and 4 positions is a five-, six- or seven-membered ring whereat
1. one or more carbon atoms in the ring marked C may be mono or disubstituted with substituents which may be the same or different and may mean:
a) a hydrogen atom.
b) a saturated alkyl chain with 1 to 20 carbon atoms and the saturated alkyl chain may be straight (such as methyl, ethyl, n-propyl, n-butyl) or branched in any position (such as isopropyl, s-butyl, isobutyl, isoamyl, tert-butyl) and each chain member may be mono or disubstituted with substituents such as halo (such as fluoromethyl, trifluoromethyl, 2-chloroethyl), hydroxy (such as hydroxymethyl, 2-hydroxyethyl), (C
1
-C
4
)-alkyloxy (such as methoxymethyl, 2-methoxyethyl), mercapto and (C
1
-C
4
)-alkylmercapto (such as mercaptomethyl, 2-methylmercaptoethyl), (C
1
-C
4
)-alkanesulfonyl (such as methanesulfonylmethyl), amino, (C
1
-C
4
)-alkylamino and di-(C
1
-C
4
)-alkylamino (such as 2-aminoethyl, 2-methylaminoethyl, 2-dimethylaminoethyl), alkyleneamino (such as 2-(1-piperidinyl)ethyl, 1-pyrrolidinylmethyl), guanidino (such as guanidinomethyl), unsubstituted N
1
-mono, N
3
-mono, N
1
,N
3
-di and N
3
,N
3
-di-(C
1
-C
4
)-formamidino (such as iminomethylaminomethyl, 2-(dimethylaminomethyleneamino)ethyl), aromatic or heteroaromatic five- or six-membered ring (such as phenyl, furyl, 2-pyridyl), (C
1
-C
4
)-alkyloxycarbonyl (such as carbethoxymethyl), cyano (such as 2-cyanoethyl), oxo (such as acetyl, propionyl, 2-oxopropyl),
c) an unsaturated alkyl chain with 1 to 20 carbon atoms and the unsaturated alkyl chain may be straight with double bonds or triple bonds (such as vinyl, propenyl, allyl, ethinyl, propargyl) or branched in any position with double bonds or triple bonds (such as 2-propenyl) and each chain member may be mono or disubstituted with substituents such as halo, hydroxy, (C
1
-C
4
)-alkyloxy, thio and (C
1
-C
4
)-alkylthio, (C
1
-C
4
)-alkanesulfonyl, amino, (C
1
-C
4
)-alkylamino and di-(C
1
-C
4
)-alkylamino, aromatic or heteroaromatic five- or six-membered ring (such as phenyl, furyl, 2-pyridyl), (C
1
-C
4
)-alkyloxycarbonyl, cyano, oxo,
d) a saturated or partly unsaturated cycloalkyl radical with 3 to 7 members (such as radicals from cyclopropyl to cycloheptyl, cyclohex-1-enyl) and the ring may comprise one or more oxygen, sulfur or nitrogen atoms (such as 2-tetrahydrofuranyl, 1-piperidinyl, 1-pyrrolidinyl) and each ring member may be mono or disubstituted with substituents such as halo, hydroxy, (C
1
-C
4
)-alkyloxy, thio and (C
1
-C
4
)-alkylthio), (C
1
-C
4
)-alkanesulfonyl, amino, (C
1
-C
4
)-alkylamino and di-(C
1
-C
4
)-alkylamino, (C
1
-C
4
)-alkyloxycarbonyl, cyano, oxo,
e) an aromatic or heteroaromatic five- or six-membered ring (such as phenyl, furyl, 2-pyridyl),
f) a hydroxy, C
1
-C
10
)-alkyloxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, cyclohexyloxy), mono or disubstituted (C
1
-C
10
)-alkyloxy (such as 2-hydroxyethyloxy), 2,3-dihydroxyprop-1-yloxy, 2-methoxyethyloxy, fluoromethyloxy, aminoethyloxy, 2-dimethylaminoethyloxy), acyloxy (such as formyloxy, acetyloxy, benzoyloxy, ethoxycarbonyloxy, allyloxycarbonyloxy), mono, di or tri-(C
1
-C
4
)-alkylsilyloxy (such as trimethylsilyloxy, tert-butyldimethylsilyloxy) group,
g) a mercapto, (C
1
-C
10
)-alkylmercapto (such as methylmercapto, ethylmercapto), mono or disubstituted (C
1
-C
10
)-alkylmercapto (such as 2-hydroxyethylmercapto, 2,3-dihydroxyprop-1-ylmercapto, 2-methoxyethylmercapto, 2-mercaptoethylmercapto, 2-methylmercaptoethylmercapto, 2-aminoethylmercapto, 2-dimethylaminoethylmercapto), acylmercapto (such as acetylmercapto) group,
h) an amino, (C
1
-C
4
)-alkylamino and di-(C
1
-C
4
)-alkylamino (such as methylamino, dimethylamino, 2-hydroxyethylamino, bis(2-hydroxyethyl)amino, aminoethyloxy, 2-dimethylaminoethyloxy, 2-aminoethylamino, 2-piperidinoethylamino), acetylamino, allyloxycarbonylamino, iminomethylamino, N-methylaminomethyleneamino, N,N-dimethylaminomethyleneamino, guanidino, cyanoguanidino, methylguanidino group,
i) a halo atom (such as fluoro, chloro, bromo, iodo),
j) an azido, nitro, cyano, (C
1
-C
4
)-alkyloxycarbonyl (such as carbomethoxy, carbethoxy) group,
k) a (C
1
-C
4
)-alkanesulfonyl group (such as methanesulfonyl, ethanesulfonyl);
2. one or more carbon atoms in the ring marked C may be substituted with a substituted or unsubstituted alkyl chain which is linked to the ring marked C via double bond in the form of >C*=CR
1
R
2
, and C* means a carbon atom in the ring marked C,=means an exocyclic double bond and the substituents R
1
and R
2
, which may be the same or different, may mean:
a) a hydrogen atom so that the substituent is methylene,
b) an unsubstituted saturated alkyl chain with 1 to 20 carbon atoms and the unsubstituted saturated alkyl chain may be straight (such as ethylidene, n-propylidene, n-butylidene, isopropylidene) or branched in any position (such as 2,2-dimethylprop

Affiliated with

Also associated with

Rating

Ethylidene derivatives of tricyclic carbapenems does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Ethylidene derivatives of tricyclic carbapenems, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Ethylidene derivatives of tricyclic carbapenems will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2957103