Claims
- 1. A compound of the formula: ##STR252## wherein R.sub.1 is a hydrogen atom or a lower alkyl group, R.sub.2 is a hydrogen atom or a conventional protecting group for a carboxyl group, R.sub.0 is a hydrogen atom or a conventional protecting group for a hydroxyl group, X is a protected or unprotected amino group, a carboxyl group, a lower alkoxycarbonyl group, an ar(lower)alkyloxycarbonyl group, a cyano group, a hydroxyl group, a lower alkyloxy group, a lower alkylthio group, a lower alkylsulfonyl group or a group of either one of the following formulas: ##STR253## wherein R.sub.3 and R.sub.4, which may be the same or different, each represent a hydrogen atom or a lower alkyl group, or they are taken together to represent an alkylene chain to form, in combination with the adjacent nitrogen atom, a 3- to 7-membered cyclic amino group,
- --ZCOR.sub.5 ( 2)
- wherein Z represents --NH-- or --O-- and R.sub.5 represents an amino group, a mono(lower)alkylamino group, a di(lower)alkylamino group, a lower alkyloxy group or a lower alkyl group, ##STR254## wherein R.sub.6 represents a hydrogen atom or a lower alkyl group,
- --CH.dbd.N--R.sub.7 ( 4)
- wherein R.sub.7 represents a mono(lower)alkylamino group, a di(lower)alkylamino group or a lower alkyloxy group, or ##STR255## wherein R.sub.8, R.sub.9 and R.sub.10, which may be the same or different, each represent a hydrogen atom or a lower alkyl group, Y represents a hydrogen atom, a conventional protecting group for an amino group or a group of either one of the following formulas: ##STR256## wherein R.sub.11 and R.sub.12, which may be the same or different, each represents a hydrogen atom or a lower alkyl group or ##STR257## wherein R.sub.6 is as defined above and n is an integer of 1 to 6, and a pharmacologically acceptable salt thereof.
- 2. A compound as claimed in claim 1, wherein R.sub.0 and R.sub.2 each are a hydrogen atom and X is an amino group, a carboxyl group, a lower alkoxycarbonyl group, an ar(lower)alkyloxycarbonyl group, a cyano group, a hydroxyl group, a lower alkyloxy group, a lower alkylthio group, a lower alkylsulfonyl group or a group of either one of the following formulas: ##STR258## wherein R.sub.3 and R.sub.4 are as defined in claim 1,
- --ZCOR.sub.5 ( 2)
- wherein Z and R.sub.5 are as defined in claim 1, ##STR259## wherein R.sub.6 is as defined in claim 1,
- --CH.dbd.N--R.sub.7 ( 4)
- wherein R.sub.7 is as defined in claim 1, or ##STR260## wherein R.sub.8, R.sub.9 and R.sub.10 are as defined in claim 1, and Y is a hydrogen atom or a group of either one of the following formulas: ##STR261## wherein R.sub.11 and R.sub.12 are as defined in claim 1, or ##STR262## wherein R.sub.6 is as defined in claim 1.
- 3. A compound as claimed in claim 1, wherein R.sub.0 and R.sub.2 each are a hydrogen atom, X is a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a hydroxyl group, a lower alkyloxy group or a group of either one of the following formulas: ##STR263## wherein R.sub.3 and R.sub.4 are as defined in claim 1,
- --CH.dbd.N--R.sub.7 ( 4)
- wherein R.sub.7 is as defined in claim 1, or ##STR264## wherein R.sub.8, R.sub.9 and R.sub.10 are as defomed om claim 1, and Y is a hydrogen atom.
- 4. A compound as claimed in claim 3, wherein X is a group of the formula: ##STR265## wherein R.sub.3a and R.sub.4a each represent a hydrogen atom or a methyl group.
- 5. A compound as claimed in claim 3, wherein X is a hydroxyl group or a lower alkyloxy group.
- 6. A compound as claimed in any one of claims 1 to 5, wherein R.sub.1 is a methyl group.
- 7. A compound as claimed in claim 6, which has a (5S)-configuration.
- 8. A compound as claimed in claim 7, which has a (4R,5S,6S,8R)-configuration.
- 9. A compound as claimed in claim 3, wherein R.sub.1 is a hydrogen atom.
- 10. A compound as claimed in claim 9, which has a (5R)-configuration.
- 11. A compound as claimed in claim 10, which has a (5R,6S,8R)-configuration.
- 12. A compound as claimed in claim 1, which is (4R,5S,6S,8R,2'R,4'S)-3-[(2-dimethylaminocarbonylmethyl-pyrrolidin)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid, or a salt thereof.
- 13. A compound as claimed in claim 1, which is (4R,5S,6S,8R,2'R,4'S)-3-[(2-methylaminocarbonylmethylpyrrolidin)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid, or a salt thereof.
- 14. A compound as claimed in claim 1, which is (4R,5S,6S,8R,2'R,4'S)-3-[(2-carbamoylmethylpyrrolidin)-4-ylthio]-b 4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid, or a salt thereof.
- 15. A compound as claimed in claim 1, which is (4R,5S,6S,8R,2'R,4'S)-3-[(2-(2-dimethylaminocarbonylethyl)-pyrrolidin)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid, or a salt thereof.
- 16. A compound as claimed in claim 1, which is (4R,5S,6S,8R,2'R,4'S)-3-[(2-(2-methylaminocarbonylethyl)-pyrrolidin)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid, or a salt thereof.
- 17. A compound as claimed in claim 1, which is (4R,5S,6S,8R,2'R,4'S)-3-[(2-(2-carbamoylethyl)pyrrolidin)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid, or a salt thereof.
- 18. A compound as claimed in claim 1, which is (4R,5S,6S,8R,2'S,4'S)-3-[(2-hydroxymethylpyrrolidin)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid, or a salt thereof.
- 19. A compound as claimed in claim 1, which is (4R,5S,6S,8R,2'S,4'S)-3-[2-methoxymethylpyrrolidin)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid, or a salt thereof.
- 20. A compound as claimed in claim 1, which is (4R,5S,6S,8R,2'R,4'S)-3-[(2-(2-carboxyethyl)pyrrolidin)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo-[3.2.0]-hept-2-en-7-one-2-carboxylic acid, or a salt thereof.
- 21. A compound as claimed in claim 1, which is (4R,5S,6S,8R,2'R,4'S)-3-[(2-methoxycarbonylmethylpyrrolidin)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid, or a salt thereof.
- 22. A compound as claimed in claim 1, which is (4R,5S,6S,8R,2'R,4'S)-3-[(2-(2-N,N-dimethylhydrazonoethyl)pyrrolidin)-4-ylthio]-4-methyl-6-(1-hydroxyethyl)1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid, or a salt thereof.
- 23. A pharmaceutical composition for antimicrobial use which comprises as an active ingredient a pharmaceutically effective amount of a compound according to claim 1, and at least one pharmaceutically acceptable inert carrier or diluent.
- 24. A pharmaceutical composition for antimicrobial which comprises as an active ingredient a pharmaceutically effective amount of a compounding according to claim 2, and at least one pharmaceutically acceptable carrier or diluent.
- 25. A method for treating an infectious disease caused by bacteria, which comprises administering an effective amount of a compound according to claim I as an antimicrobial agent to a patient suffering from said disease caused by bacteria.
- 26. A compounding according to claim 1, which is represented by the formula: ##STR266##
- 27. A compound according to claim 1, which is represented by the formula: ##STR267##
- 28. A compound according to claim 1, which is represented by the formula: ##STR268##
- 29. A compound according to claim 1, which is represented by the formula: ##STR269##
Priority Claims (3)
| Number |
Date |
Country |
Kind |
| 59-234064 |
Nov 1984 |
JPX |
|
| 60-577 |
Jan 1985 |
JPX |
|
| 60-1925 |
Jan 1985 |
JPX |
|
Parent Case Info
This application is a continuation of application Ser. No. 796,329, filed on Nov. 8, 1985, now abandoned.
The present invention relates to novel carbapenem compounds useful as antimicrobial agents or intermediates therefor, and their production.
Since the discovery of thienamycin having a potential antimicrobial activity against Gram-negative and Gram-positive bacteria, studies on the syntheses of carbapenem derivatives which are analogous to thienamycin have been widely developed. As a result, it has now been found that carbapenem derivatives having, as their 2-side chain, a substituent easily derived from 4-hydroxy-proline, i.e. a pyrrolidinyl group substituted on its 2-position, exhibit a potential antimicrobial activity and are useful as medicines or as intermediates for antibiotic substances.
This invention provides novel carbapenem compounds of the formula (I): ##STR7## wherein
R.sub.1 is a hydrogen atom or a lower alkyl group;
R.sub.2 is a hydrogen atom or a conventional protecting group for a carboxyl group;
R.sub.0 is a hydrogen atom or a conventional protecting group for a hydroxyl group;
X is a protected or unprotected amino group, a carboxyl group, a lower alkoxycarbonyl group, an ar(lower)alkyloxycarbonyl group such as phenyl(lower)alkyloxycarbonyl, a cyano group, a hydroxyl group, a lower alkyloxy group, a lower alkylthio group, a lower alkylsulfonyl group or a group of either one of the following formulas: ##STR8## wherein R.sub.3 and R.sub.4, which may be the same or different, each represent a hydrogen atom or a lower alkyl group, or they are taken together to represent an alkylene chain to form, in combination with the adjacent nitrogen atom, a 3- to 7-membered cyclic amino group,
Y is a hydrogen atom, a conventional protecting group for an amino group or a group of either one of the following formulas: ##STR11## wherein R.sub.11 and R.sub.12, which may be the same or different, each represent a hydrogen atom or a lower alkyl group, or ##STR12## wherein R.sub.6 is as defined above; and
n is an integer of 1 to 6.
The present invention also provides the pharmacologically acceptable salts of the carbapenem compounds (I).
In the above formula (I), the term "lower" as used in connection with any group is intended to mean generally a group having not more than 8 carbon atoms, particularly not more than 5 carbon atoms, unless otherwise defined. For instance, specific examples of lower alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, etc. Further, for instance, specific examples of lower alkyloxy are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, etc.
The protecting group for a hydroxyl group as represented by R.sub.0 may be any of those commonly employed, and its preferred examples are C.sub.1 -C.sub.4 alkoxycarbonyl (e.g. t-butyloxycarbonyl), halo(C.sub.1 -C.sub.3)alkoxycarbonyl (e.g. 2-iodoethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl), substituted or unsubstituted ar(lower)alkyloxycarbonyl such as substituted or unsubstituted phenyl(C.sub.1 -C.sub.3)alkyloxycarbonyl (e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl), tri(C.sub.1 -C.sub.4)alkylsilyl (e.g. trimethylsilyl, t-butyldimethylsilyl), etc.
The protecting group for a carboxyl group as represented by R.sub.2 may be any of those commonly employed, and its preferred examples include C.sub.1 -C.sub.4 alkyl (e.g. methyl, ethyl, isopropyl, t-butyl), halo(C.sub.1 -C.sub.3)alkyl (e.g. 2-iodoethyl, 2,2,2-trichloroethyl), C.sub.1 -C.sub.4 alkoxymethyl (e.g. methoxymethyl, ethoxymethyl, isobutoxymethyl), C.sub.1 -C.sub.8 aliphatic acyloxymethyl (e.g. acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl), 1-(C.sub.1 -C.sub.4)alkoxycarbonyloxyethyl (e.g. 1-methoxycarbonyloxyethyl, 1-ethoxycorbonyloxyethyl), substituted or unsubstituted ar(lower)alkyl such as substituted or unsubstituted phenyl(C.sub.1 -C.sub.3)alkyl (e.g. benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl), benzhydryl, phthalidyl, etc.
In the definitions for R.sub.1, X and Y, the term "lower" is preferred to mean any group having not more than 3 carbon atoms. For instance, examples of lower alkyl are methyl, ethyl, n-propyl and isopropyl.
When X is the group (1), R.sub.3 and R.sub.4 may be the same or different from each other. In the definitions for R.sub.3 and R.sub.4, the lower alkyl group represents preferably the one having not more than 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl).
In the case where R.sub.3 and R.sub.4 jointly represent an alkylene chain to form, in combination with the adjacent nitrogen atom, a 3- to 7-membered cyclic amino group, specific examples include a saturated cyclic amino group (e.g. aziridino, azetidino, pyrrolidino, piperidino).
The lower alkoxycarbonyl group for X includes, for example, C.sub.1 -C.sub.4 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and isopropoxycarbonyl. The ar(lower)alkyloxycarbonyl group for X includes, for example, substituted or unsubstituted ar(lower)alkyloxycarbonyl such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and o-nitrobenzyloxycarbonyl.
When Y is the group (6), the lower alkyl group represented by R.sub.11 or R.sub.12 is preferred to have 1 to 4 carbon atoms and may be, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.
The protecting group for an amino group as represented by Y or used in the protected amino group of X may be any of those commonly employed. Preferred examples are C.sub.1 -C.sub.4 alkoxycarbonyl (e.g. t-butyloxycarbonyl), halo(C.sub.1 -C.sub.3)alkoxycarbonyl (e.g. 2-iodoethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl), substituted or unsubstituted ar(lower)alkyloxycarbonyl such as substituted or unsubstituted phenyl(C.sub.1 -C.sub.3)alkyloxycarbonyl (e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl), tri(C.sub.1 -C.sub.4)alkylsilyl (e.g. trimethylsilyl, t-butyldimethylsilyl), etc.
The carbapenem compounds (I) wherein --COOR.sub.2 or X represents a carboxyl group may be converted into their pharmacologically acceptable salts, if desired. Specific examples of such salts are inorganic metal salts (e.g. lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt), ammonium salts (e.g. ammonium salt, cyclohexylammonium salt, diisopropylammonium salt, triethylammonium salt), etc., among which sodium salt and potassium salt are the most preferred. The carbapenem compounds (I) wherein X represents an amino group or a group of the formula (3) or Y represents a hydrogen atom or a group of the formula (7) may be also converted into their pharmacologically acceptable salts, if desired. Examples of such salts are those with mineral acids such as hydrochloric acid and sulfuric acid.
Among the carbapenem compounds (I) of the invention, preferred are those of the formula (I-a): ##STR13## wherein R.sub.1a is a hydrogen atom or a lower alkyl group, Xc is either one of the groups (1) to (5), an amino group, a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a hydroxyl group, a lower alkoxy group, a lower alkylthio group or a lower alkylsulfonyl group, Yc is a hydrogen atom or either one of the groups (6) and (7) and n is an integer of 1 to 6.
Particularly preferred are the carbapenem compounds of the formula (I-b): ##STR14## wherein Xc and Yc are each as defined above.
Preferred examples of the substituent: --(CH.sub.2).sub.n --Xc at the 2-position of the pyrrolidinyl group include those of the following formulas (a) to (e): ##STR15## wherein R.sub.3, R.sub.4, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are each as defined above and R.sub.13 represents a hydrogen atom or a lower alkyl group, the groups (a) and (d) being particularly favorable.
The carbapenem compounds (I) can be produced by various procedures, among which some typical ones are set forth below.
(A) The carbapenem compound of the formula (II): ##STR16## wherein R.sub.0, R.sub.1 and n are each as defined above, R.sub.2a is a protecting group for a carboxyl group, Xa is either one of the groups (1), (2), (4) and (5), a protected amino group, a lower alkoxycarbonyl group, an ar(lower)alkyoxycabonyl group, a cyano group, a hydroxyl group, a lower alkyloxy group, a lower alkylthio group or a lower alkylsulfonyl group and Ya is a protecting group for an amino group or the group (6), is prepared by reacting the carbapenem compound of the formula (III): ##STR17## wherein R.sub.0, R.sub.1 and R.sub.2a are each as defined above and Za is a reactive ester group with a mercaptan of the formula (IV): ##STR18## wherein Xa, Ya and n are each as defined above, in an inert solvent in the presence of a base.
The term "reactive ester group" herein used is intended to mean a leaving group such as a halide or a sulfonate. It may be the residue of a substituted or unsubstituted arylsulfonate, a lower alkanesulfonate, a halo(lower)alkanesulfonate, a diarylphosphoric acid ester, a halide or the like. Examples of the substituted or unsubstituted arylsulfonate are benzenesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, p-bromobenzenesulfonate, etc. Examples of the lower alkanesulfonate are methanesulfonate, ethanesulfonate, etc. Examples of the halo(lower)alkanesulfonate are trifluoromethanesulfonate, etc. As the diarylphosphoric acid ester, there may be exemplified diphenylphosphoric acid ester, etc. The halide includes, for example, chloride, bromide, iodide, etc. Of these reactive esters, preferred are p-toluenesulfonate, methanesulfonate, diphenylphosphoric acid ester, etc.
The protecting group for a carboxyl group as represented by R.sub.2a corresponds to the one as represented by R.sub.2, and the same preferred groups as enumerated for R.sub.2 can also be applied to R.sub.2a.
In the process, the carbapenem compound (III) and the mercaptan (IV) are reacted normally by the use of a large excessive amount, particularly from 1 to 1.5 equivalents, of the latter to the former.
As the inert solvent, there may be used dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, etc. Their mixtures are also usable. Among them, acetonitrile, dimethylformamide, etc. are preferred. Examples of the base include inorganic bases (e.g. sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, potassium t-butoxide) and organic bases (e.g. pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine), among which organic bases are preferred. The base may be used in such an amount as sufficient to promote the reaction and usually from 1 to 1.5 equivalents per mol of the mercaptan (IV).
The reaction can be carried out at a temperature of from about -78.degree. to 60.degree. C., preferably from -40.degree. to 40.degree. C.
Recovery of the reaction product from the reaction mixture may be accomplished by a per se conventional procedure, for instance, by washing the reaction mixture with water, drying and evaporating the solvent. The reaction product may, if necessary, be further purified by a per se conventional means, for example, by recrystallization, preparative thin layer chromatography, column chromatography or the like.
The thus obtained carbapenam compound (II) may be subjected, if necessary, to reaction for removal of the hydroxyl-protecting group on R.sub.0, removal of the amino-protecting group on Ya, removal of the carboxyl-protecting group on R.sub.2a and/or removal of the protecting group on Xa to obtain the carbapenem compound (I). Removal of the protecting group may be achieved by adoption of an appropriate per se conventional procedure depending upon the type of the protecting group. For instance, the carbapenem compound (II) bearing a halo(lower)alkoxycarbonyl group or an ar(lower)alkyloxycarbonyl group as the hydroxyl-protecting group or the amino-protecting group or a halo(lower)alkyl group, an ar(lower)alkyl group or a benzhydryl group as the carboxyl-protecting group may be subjected to reduction for removal of any of those protecting groups. The reduction is preferably carried out, for instance, by treatment with zinc in an organic solvent (e.g. acetic acid, tetrahydrofuran, methanol) when the protecting group is a halo(lower)alkoxycarbonyl group or a halo(lower)alkyl group, or by catalytic reduction using a catalyst (e.g. platinum, palladium-on-carbon) when the protecting group is an ar(lower)alkyloxycarbonyl group, an ar(lower)alkyl group or a benzhydryl group. The catalytic reduction is usually effected in any liquid medium chosen from organic solvents such as lower alcohols (e.g. methanol, ethanol), ethers (e.g. tetrahydrofuran, dioxane) and acetic acid or from their mixtures with water or buffer solutions (e.g. phosphoric acid, morpholinopropanesulfonic acid). The reduction is normally conducted at a temperature of from about 0.degree. to 100.degree. C., preferably from about 0.degree. to 40.degree. C., in a hydrogen atmosphere under the atmospheric or an elevated pressure.
When the protecting group is an o-nitrobenzyl group or an o-nitrobenzyloxycarbonyl group, it can also be removed by photo-reaction.
(B) The carbapenem compound of the formula (V): ##STR19## wherein R.sub.1 and n are each as defined above, R.sub.6 is a hydrogen atom or a lower alkyl group and Yb is the group (6) can be prepared by reacting the carbapenem compound of the formula (VI): ##STR20## wherein R.sub.1, Yb and n are each as defined above with an imidate of the formula (8): ##STR21## wherein R.sub.6 is as defined above and R.sub.14 represents a lower alkyl group or a benzyl group, or a salt thereof under a basic condition.
In the formula (8), the lower alkyl group for R.sub.14 may be preferably alkyl of 1 to 5 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl). As the salt of the imidate (8), there are exemplified hydrohalides such as hydrochloride, hydrobromide and hydroiodide.
The reaction is normally effected under a basic condition at a pH ranging from about 8 to 14, preferably from about 9 to 10. Such basic condition may be prepared by the use of an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide), an alkaline earth metal hydroxide (e.g. calcium hydroxide, barium hydroxide), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate), etc. The reaction is preferably carried out in water, but can be done in a mixed solvent of water with an organic solvent chosen from lower alcohols (e.g. methanol, ethanol, n-propanol), ethers (e.g. tetrahydrofuran, dioxane), dimethylformamide, acetonitrile, etc. The reaction temperature is preferred to be from 0.degree. C. to room temperature, but the reaction rate may be suppressed or promoted by cooling or heating if necessary.
Separation of the reaction product from the reaction mixture may be accomplished by a per se conventional procedure. For example, the reaction mixture is neutralized with a conventional acid (e.g. hydrochloric acid, sulfuric acid) and purified by column chromatography on an adsorbent to give a fraction containing the desired product. Concentration or lyophilization of the fraction affords the reaction product.
(C) The carbapenem compound of the formula (VII): ##STR22## wherein R.sub.1, R.sub.6 and n are each as defined above, Xb is either one of the groups (1), (2), (4) and (5), a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a hydroxyl group, a lower alkyloxy group, a lower alkylthio group or a lower alkylsulfonyl group, can be prepared by reacting a carbapenem compound of the formula (VIII): ##STR23## wherein R.sub.1, Xb and n are each as defined above with the imidate (8) or its salt under a basic condition by the same procedure as (B).
In the carbapenem compounds (I), asymmetric carbon atoms are present at the 5-, 6- and 8-positions. The carbon atoms at the 2'- and 4'-positions in the 2-side chain are also asymmetric. Further, when R.sub.1 is an alkyl group, the carbon atom at the 4-position is asymmetric. Therefore, the carbapenem compounds (I) have optical isomers and steric isomers due to these asymmetric carbon atoms. Although all of these isomers are represented by a respective single formula for the sake of convenience, the scope of the invention extends to and covers all of them.
Among those isomers, preferred are the ones having the same relative-configuration as thienamycin on the carbon atom at the 5-position. The compounds wherein R.sub.1 is an alkyl group and which have a 5S-configuration, i.e. the (5S,6S)- or (5S,6R)-compounds, are preferred. The compounds wherein R.sub.1 is a hydrogen atom and which have a 5R-configuration, i.e. the (5R,6S)- or (5R,6R)-compounds, are favorable. With respect to the carbon atom at the 8-position, those having an R-configuration are preferred. With respect to the 4-position, the compounds wherein R.sub.1 is an alkyl group and which have an R-configuration, i.e. the (4R)-compounds, are favorable.
More preferred are the compounds (I) wherein R.sub.1 is an alkyl group and which have a (4R,5S,6S,8R)-configuration, the compounds (I) wherein R.sub.1 is a hydrogen atom and which have a (4R,5R,6S,8R)-configuration, etc.
The most preferred compounds include those of the formulas: ##STR24## wherein R.sub.0, R.sub.1, R.sub.2, X, Y, and n are each as defined above.
The isomers having the steric configurations as stated above can be prepared from the starting compounds (III) or (IV) having the corresponding configurations.
The starting compounds (III) can be prepared by various conventional methods. The compounds (III) wherein R.sub.1 is a hydrogen atom are known per se in (1) Japanese Patent Publication (unexamined) No. 27169/80, (2) J. Am. Chem. Soc., Vol. 103, 6765-6767 (1981), (3) J. Chem. Soc., Perkin I, 964-968 (1981), etc. and can be produced by the methods as described in said literatures (1) to (3). The compounds (III) wherein R.sub.1 is a lower alkyl group are known per se in (4) Heterocycles, Vol. 21, 29-40 (1984), (5) EP-A-No. 0071908, (6) EP-A-No. 0126587, etc. and can be produced according to the methods as described in the literature articles (4) to (6).
The starting mercaptan derivatives (IV) can be prepared from trans-4-hydroxy-L-proline or cis-4-hydroxy-D-proline by application of a series of per se conventional reactions thereto.
Of the carbapenem compounds (I), those wherein R.sub.0 and R.sub.2 are all hydrogen atoms exhibit an excellent antimicrobial activity against a wide variety of disease-causing bacteria including Gram-positive bacteria such as Staphylococcus aureaus, Staphylococcus epidermidis, Streptococcus pyrogenes and Streptococcus faecalis and Gram-negative bacteria such as Escherichia coli, Proteus mirabilis, Serratia marcescens and Psudomonas aeruginosa and are useful as antimicrobial agents. Further, these compounds are characteristic in exhibiting an excellent antimicrobial activity against beta-lactamase-producing strains.
Other compounds according to the invention are important intermediates for the synthesis of the carbapenem compounds having an antimicrobial activity.
The compounds according to the invention are also characterized in general by their high physiochemical stability and excellent water solubility, although some variation is observed depending on the respective compounds.
Carbapenem compounds including thienamycin are known to have very poor stability in the human body, especially to dehydropeptidase (DHP-I) existing in a part of renal. The compounds of invention, particularly those represented by the formula (I) wherein R.sub.1 is a (R)-methyl group, are also characterized in general by their high stability to said enzyme DHP-I, although varying depending on the respective compounds. Some of the compounds of the invention have extremely high stability.
The compounds of the present invention can be used as antimicrobial agents for treating bacteria-caused infectious diseases in the form of oral preparations such as tablets, capsules, powders, syrups, etc. or non-oral preparations such as intravenous injections, intramuscular injections, rectal preparations, etc.
The dosage of the antimicrobial agent varies depending upon the symptoms, ages, bodyweight, dosage forms, times of doses and the like, but usually ranges from about 100 mg to 3,000 mg per day in a single dose or several divided doses for adults. The above dose level can be increased or decreased according to necessity.
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| Number |
Date |
Country |
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Apr 1980 |
EPX |
| 0071908 |
Feb 1983 |
EPX |
| 0072710 |
Feb 1983 |
EPX |
| 0089139 |
Sep 1983 |
EPX |
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| Entry |
| "Synthesis and in vitro Activity of a New Carbapenem, RS-533", The Journal of Antibiotics, pp. 1034-1039. |
| "Synthetic Carbapenem Antibiotics I.1-.beta.-methylcarbapenem", Heterocycles, pp. 29-40. |
Continuations (1)
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Number |
Date |
Country |
| Parent |
796329 |
Nov 1985 |
|
Patent Grant
4962103
