JPH043398B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to 6-(1'-fluoromethyl)- and 6-(1'-fluoro-1'-methylethyl)carbapenem, their preparation and their use as chemotherapeutic agents. European Patent Application No. 1628 discloses a wide range of carbapenem derivatives with antibacterial activity, but says nothing about the fluoroalkyl compounds of this invention and their superior antibacterial action. More specifically, the present invention utilizes the formula () [In the formula, R ₁ is hydrogen or methyl, R ₂ is amino,
Lower alkyl, which may be mono- or di-substituted with substituents selected from lower alkylamino, di-lower alkylamino, lower acylamino and carboxy, or of the formula (c) -( _CH2 )p- _R7 (c) ( In the formula, R ₇ is a 5- or 6-membered saturated or unsaturated heterocycle, p represents 0, 1, 2 or 3),
or the formula below (In the formula, R ₄ , R ₅ and R ₆ are each hydrogen or lower alkyl, and m is 2
or 3, n represents 1, 2 or 3). However, if R ₁ is hydrogen and the group containing it has an R-coordination, R ₂ shall be a group other than acetylaminoethyl], or its -OH, -NH ₂ or - a protective form for COOH or an acceptable physiologically hydrolyzable ester form thereof;
Concerning free acids, salts or zwitterions. Among the above target compounds (), examples of preferred compounds include R ₁ being hydrogen or methyl, R ₂ being amino, lower alkylamino, di-lower alkylamino, lower acylamino, carboxy, imino, lower alkylimino, methyltetrazolyl. and morpholinyl, which may be mono- or di-substituted, especially (5RS,6RS)-1-aza-6-(1
(RS)-fluoroethyl)-3-(N-dimethyl-
N'-methylamidinomethylthio)-7-oxobicyclo[3.2.0]hept-2-ene-2-carboxylic acid and (5RS,6RS)-1-aza-6-(1
(RS)-fluoroethyl)-3-(N-dimethylamidinomethylthio)-7-oxobicyclo[3.2.0]hept-2-ene-2-carboxylic acid may be mentioned. The above target compound () has the formula A () [In the formula, R ₁ has the same meaning as above. R ₈ is a leaving group. ] or its -OH, -NH ₂
or a protected form for -COOH, or a physiologically hydrolyzable acceptable ester thereof, a free acid, a salt or a zwitterion with a group -S-
R ₂ [In the formula, R ₂ has the same meaning as above. ] or react with the introduction reagent of B formula () [In the formula, R ₁ and R ₂ have the same meanings as above. ] A compound represented by the above, or a protected form of -OH, _-NH2 or -COOH, or an acceptable physiologically hydrolyzable ester thereof,
It can be produced by reacting a free acid, salt, or zwitterion with a reagent capable of converting a hydroxyl group into a fluorine atom. Process A) is carried out in a conventional manner, for example in an inert solvent such as an aromatic hydrocarbon, for example benzene, or acetonitrile, preferably for example at about 0.
It can be carried out at temperatures as low as ℃. Process B) can be carried out in conventional manner using, for example, dialkylaminosulfatrifluoride, such as diethylaminosulfatrifluoride. Removal of the protecting group is carried out in the same manner as in the isolation and purification method of the obtained product according to a conventional method. Preparation and exchange of esters, protectors and salts are carried out by conventional methods. Methods for producing various forms of carbapenems are described, for example, in European Patent Application Publication No. 1628, 10316, 17992;
37080, 37081, 388869, 50334, 33209, 44142,
60612, 61231, 44170, 59478, 58317 and can be applied analogously, if appropriate, to the preparation of the compounds of the invention. The starting material of formula () is new and the formula () (In the formula, R ₁ and R ₃ have the above meanings.) It can be produced by introducing a group R ₈ (wherein R ₈ has the above meanings). Examples of leaving groups R ₈ are those formed by the reaction of a hydroxy group with a phosphoric ester chloride, such as phosphoric acid diphenyl ester chloride, or a sulfonic acid, such as p-toluenesulfonic acid. A compound of formula () is a compound of formula (a) It can be produced from the compound in the same manner as in method A) above. This method is a conventional method, and after introducing the group R ₈ the group -S
−R ₂ is introduced. Compounds of formula () are also new and can be prepared, for example, according to the reaction scheme below or by methods analogous to the above reaction scheme. The reaction shown in the above reaction scheme can be carried out using methods commonly used for that type of reaction. For example, the ring closure reaction can be carried out in an inert solvent such as an aromatic hydrocarbon, eg benzene, in the presence of a transition metal catalyst. Examples of transition metal catalysts include rhodium acetate () or copper acetylacetonate. Compounds of formulas () and (a) can exist in the following tautomorphic forms. Other intermediates are known or can be produced using known methods and/or methods described in the Examples below. The carbapenems of this invention contain two chiral centers (5, 6 positions) within the ring. These are 6R, 5R−, 6S, 5S, 6S, 5R−,
It can exist in various configurations such as 6R, 5S-isomers or mixtures thereof. If the starting materials used have a particular configuration, the final product obtained will have the same configuration, and the starting materials of the mixture will yield the final product of the mixture. Thus, the configuration of these compounds does not change during reactions such as A) or B) above. Isomer mixtures can be resolved by conventional methods such as fractional crystallization. Biological activity is known to belong to compounds in which the 5-position is in the R-configuration. Another chiral center is present when R ₁ is hydrogen,
This is also not affected by reactions like A) above. However, the reversal occurs when fluorine is introduced in a reaction such as B). That is,
8-R-Hydroxy due to the fluorine starting material
The -S-fluoro final product is obtained and vice versa. The free form or easily eliminable ester form of the compound of formula () can be used in various bacteria such as Pseudomonas aeruginosa, Enterobacter cloacae, Enterobacter agglomerans, Staphylococcus epidermides, Streptococcus spp. Aronson, Streptococcus
Pneumoniae, Aeroccoccus viridans,
Staphylococcus aureus, Streptococcus pyogenes, Streptococcus fuecalis, Escherichia coli, Broteus vulgaris, Broteus mirabilis, Broteus
morgananii, Klebscilla pneumoniae, Serratia marquescens, Salmonella lilifemurium, in vitro serial dilution tests at concentrations of e.g. 0.001 to 50 μg/ml, and in mice at doses of e.g. It shows inhibitory effects in in vivo tests and has chemotherapeutic activity, especially antibacterial activity. Further, the above compound exhibits an inhibitory effect on β-lactamase at a concentration of 0.1 to 10 μg/ml. The antibacterial activity of Gram-positive and Gram-negative β-lactamases preparations can be tested using the chromogenic substrate nitrocefin (Reference: Ocalagan et al., New method for the detection of β-lactamases using a chromogenic cephalosporin substrate. , Antimicrobial Engineers and Chemotherapy, Vol. 1, No. 4, pp. 283-288, 1972). Inhibition of β-lactamase is tested in 0.1M phosphate buffer using the same substrate. Either the enzyme is pre-incubated at 25° C. with the appropriate concentration of inhibitor, or the inhibitor and substrate (nitrocefin) are added simultaneously and the inhibition of substrate hydrolysis by the inhibitor is determined compared to uninhibited hydrolysis. Activity is expressed as % inhibition or IC ₅₀ (concentration of inhibitor that inhibits the enzyme by 50%). This inhibitory effect can also be seen from the remarkable synergistic effect when used in combination with other β-lactam antibiotics against β-lactamase producing bacteria. The compounds of this invention are stable to β-lactamases. The compounds of this invention are therefore useful as chemotherapeutic agents, especially antibiotics with antibacterial activity. In use, a suitable total daily dose is about 1 to 6 g, administered in doses of about 250 to 3000 mg two to four times a day, or as a specific release formulation. Compounds of formula () can be administered analogously to known standards for this indication, such as cefotaxime. The appropriate daily dose for a particular compound will vary depending on a number of factors, such as its relative potency. For example, (5RS,6RS)-1-aza-6-[1-
(RS)-fluoroethyl]-3-[N,N,N'-trimethylcarbamidomethyl]thio-7-oxobicyclo[3.2.0]hept-2-ene-2-carboxylic acid, and (5RS, 6RS) -1-Aza-6-[1
(RS)-Fluoroethyl]-3-[N,N-dimethylcarbamidomethyl]thio-7-oxobicyclo[3.2.0]hept-2-ene-2-carboxylic acid is
whereas in a murine Streptococcus sepsis model, a therapeutic dose of approximately 4 mg/Kg was demonstrated.
Cefotaxime was 5 mg/Kg. It has therefore been found that these compounds can be administered at the same or lower doses than conventionally used cefotaxime. Compounds containing free salt-forming groups can be used in that form or in the form of chemotherapeutically acceptable salts, which have the same order of activity as the free form. Suitable salts are alkali or alkaline earth metal salts and ammonium salts or amino acid salts. The above compounds can be mixed with conventional chemotherapeutically acceptable diluents and carriers and administered as tablets, capsules or parenteral formulations. These compositions also form part of this invention. Accordingly, this invention comprises administering to a subject in need of treatment an effective amount of a compound of formula () or a chemotherapeutically acceptable salt thereof and a chemotherapeutic agent, particularly a compound having antibacterial activity. It provides a way to combat this. Lower alkyl moieties include those having 1 to 6 (eg 1-4), especially 1 or 2 carbon atoms. Corresponding alkenyl and alkynyl moieties include those having 2 to 4, especially 2 or 3 carbon atoms. Preferably, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of lower acylaminoalkyl include -
CH ₂ CH ₂ NHCOC ₂ H ₅ , −CH ₃ , −CH ₂ CH ₂・
NHCOCH ₂ C ₆ H ₅ , −
CH ₂ CH ₂ NHCOCH ₂ CH ₂ NH ₂ , −
_{Contains CH2CH2NHCOCH2NH2 . _} As the heterocycle of R ₇ , for example,

【formula】

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【formula】

【formula】

【formula】

【formula】 【formula】

【formula】

【formula】

[Formula] and morpholino are included. As a protecting group, in antibiotic chemistry
Protecting groups for OH, NH ₂ and COOH are used, such as p-nitrobenzyl, p-
Includes nitrobenzyloxycarbonyl, tertiary butyldimethylsilyl, and trimethylsilyl. Physiologically hydrolyzable acceptable ester groups (also easily removable ester groups) are those that are hydrolyzed under physiological conditions to form a base and are themselves physiologically acceptable. meaning, acetoxymethyl, 1-acetoxyethyl, 1-ethoxycarbonyloxyethyl, 5-indanyl,
or preferably bivaloyloxymethyl, hexanoyloxymethyl, phthalidyl, ethoxycarbonylmethoxymethyl, or 3-ethoxycarbonyl-1-acetonyl. Certain protecting groups are acceptable groups that are physiologically hydrolyzed and vice versa. Preferred substituents are R ₁ =a) H, b) CH ₃ R ₂ =a) lower alkyl optionally mono- or di-substituted with amino, mono- or di(lower) alkylamino, acylamino, carboxy;
b) -( _CH2 )P- _R7 , c), a or b,
Preferably a R ₄ , R ₅ , R ₆ =a) H, alkyl, especially methyl,
b) Ring closure R ₇ = a) Each of the above heterocycles b) Methyltetrazolyl, morpholinyl P = 0, 1, 2, 3, preferably 0 or 2 m = 2 or 3, preferably 2 n = 1, 2, or 3, preferably 1. The combination of these definitions and their preferred examples is particularly useful. Examples are R ₁ = hydrogen or methyl, R ₂ = lower alkyl optionally mono- or di-substituted with amino, alkylamino, dialkylamino, acylamino, carboxy, imino, alkylimino and/or methyltetrazolyl or morpholinyl. It is. Examples of a group of compounds belonging to formula () are: R ₁ is hydrogen, R ₂ is hydrogen, lower alkyl, lower alkenyl, cycloalkyl (these include amino, mono- or di(lower) alkylamino, lower acylamino, carboxy, lower may be substituted with alkoxycarbonyl or carbamoyl, and when the cycloalkyl group is substituted with amino or mono- or di(lower) alkylamino,
the nitrogen atom may form part of a ring),
or a group of formula () or (a) (wherein,
R ₄ , R ₅ and R ₆ are the same or different and represent hydrogen or lower alkyl, m and n are as defined above), and the carboxyl group at the 2-position is in free form, protected form, or easily removable ester form , or in the form of a salt with an organic or inorganic cation. [Compound group P1(2))] Another group of compounds is such that R ₁ is hydrogen or methyl,
R ₂ is hydrogen, lower alkyl, lower alkenyl, cycloalkyl (which may be substituted with amino, mono- or di(lower) alkylamino, lower acylamino, carboxy, lower alkoxycarbonyl or carbamoyl, and the cycloalkyl group is or mono- or di(lower) alkylamino, the nitrogen atom may form part of a ring), or the formula -( _CH2 )P- _R7 (wherein, P is 0, 1, 2 or 3, and R ₇ is phenyl, or a 5- or 6-membered saturated or unsaturated heterocycle containing one or more heteroatoms selected from O, S and/or N. ), or formula () or (a)
group (wherein R ₄ , R ₅ and R ₆ are the same or different and represent hydrogen or lower alkyl, m and n
is the above-mentioned meaning), and the carboxy group at the 2-position is in a free form, a protected form, an easily removable ester form, or a salt form with an organic or inorganic cation. [Compound group P3] Examples of particularly suitable individual compounds are (5RS, 6RS)
-1-aza-6-(1(RS)-fluoroethyl)-
3-(N-dimethyl-N'-methylamidinomethylthio)-7-oxobicyclo[3.2.0]hepta-2
-ene-2-carboxylic acid, and (5RS, 6RS)
-1-aza-6-(1-(RS)fluoroethyl)-
3-(N-dimethylamidinomethylthio)-7-oxobicyclo[3.2.0]hept-2-ene-2-
It is a carboxylic acid. The examples given below illustrate the invention, temperatures given in degrees Celsius. Example 1 (5RS, 6RS)-1-aza-6-[1-(RS)-
Fluoroethyl]-3-(2-(4-nitrobenzyloxycarbonyl)aminoethylthio)-
7-oxobicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester (method a) (5RS,6RS)-1-aza-3,7-dioxo-6-[1- (RS)-Fluoroethyl]bicyclo[3.2.0]hebutane-2-carboxylic acid 4-nitrobenzyl ester 90mg and anhydrous acetonitrile 20ml
Cool the solution on ice, add 0.06 ml of diisopropylamine, and then add phosphoric acid diphenyl ester chloride.
Add 0.06ml. After 15 minutes at 0°C, another 0.06 ml of diisopropylamine was added, followed by 73 mg of 4-nitrobenzyloxycarbonylcysteamine.
and 5 ml of anhydrous acetonitrile. 0℃
Stir for 1 hour and saturated the reaction mixture with ethyl acetate.
Partition between aqueous NaCl solutions. The organic layer is dried over MgSO ₄ and concentrated to dryness, and the residue is chromatographed on silica gel (eluent: ethyl acetate/diisopropyl ether = 9/1). NMR
( _CDCl3 ): 1.52 (dd, 3, J=25.6Hz); 2.7−3.6
(m, 7); 4.26 (tm, 1, J=7Hz); 4.98 (dq,
1, J = 48, 7Hz); 5.22 (s, 2); 5.26 (d,
1, J = 13.5Hz); 5.52 (d, 1, J = 13.5Hz);
7.53 (d, 2, J = 9Hz); 7.68 (d, 2, J =
9Hz); 8.25 (d, 4, J = 9Hz). (5RS, 6RS)-3-(2-
aminoethylthio)-1-aza-6-[1(RS)-
Fluoroethyl]-7-oxobicyclo[3.2.0]
Hept-2-ene-2-carboxylic acid can be produced as follows. (5RS, 6RS)-1-aza-6-[1-(RS)-
Fluoroethyl]-3-[2-(4-nitrobenzyloxycarbonyl)aminoethylthio]-7-
Oxobicyclo[3.2.0]hept-2-ene-2
-Carboxylic acid 4-nitrobenzyl ester 50mg
and a suspension of 50 mg of 10% palladium on carbon, 20 ml of tetrahydrofuran, and 10 ml of water at room temperature.
Hydrogenation is carried out in the presence of 5 ml of 0.5M morpholinopropanesulfonic acid buffer (PH7) at a hydrogen pressure of 3 bars. The catalyst was removed, the residue was washed with water, the liquids were combined and extracted with ethyl acetate, and the aqueous layer was freeze-dried. The lyophilizate is purified by chromatography on XAD2 (eluent: water). The fractions that absorb UV at 300 nm are combined and lyophilized to give the title compound. UV (PH7 buffer): λ _nax = 295 nm (ε = 8000) Example 2 (5RS, 6RS)-3-(2-acetylaminoethylthio)-1-aza-6-[1-fluoro-1-
Methyl ethyl]7-oxobicyclo[3.2.0]
Hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester (method a) (5RS,6RS)-1-aza-3,7-dioxaso-6-[1-fluoro-1-methylethyl]bicyclo[ 3.2.0] Heptane-2-carboxylic acid 4
- A solution of 150 mg of nitrobenzyl ester and 10 ml of anhydrous acetonitrile is cooled on ice, 0.11 ml of N-ethyldiisopropylamine is added, and then 0.13 ml of phosphoric acid diphenyl ester chloride is added. 15 at 0℃
After a further 0.22 ml of N-ethyldiisopropylamine is added, followed by a solution of 70 mg of N-acetylcysteamine and 5 ml of anhydrous acetonitrile. Stir for 1 hour at 0° C. and partition the reaction mixture between ethyl acetate and saturated aqueous NaCl. organic layer
Dry over MgSO ₄ , concentrate to dryness and chromatograph the residue on silica gel (eluent: ethyl acetate/acetone = 7/3). Example 3 (5RS,6RS)-3-(2-acetylaminoethylthio)-1-aza-6-(1-fluoro-1-
methylethyl)-7-oxobicyclo[3.2.0]
Hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester (method b) Diethylaminosulfa trifluoride 0.12
A solution of 75 mg of potassium fluoride and 5 ml of anhydrous dichloromethane was cooled to -78°C, and (5RS, 6RS) -
3-(2-acetylaminoethylthio)-1-aza-6-(1-hydroxy-1-methylethyl)-7
-oxobicyclo[3.2.0]hept-2-ene-
2-carboxylic acid/4-nitrobenzyl ester
Add a solution of 150 mg and 5 ml of anhydrous dichloromethane.
The mixture is stirred at −78° C. for 15 minutes and mixed with water.
After further addition of dichloromethane, the layers are separated, and the organic layer is washed with saturated NaCl solution, dried over MgSO ₄ and concentrated to dryness. The residue is chromatographed on silica gel (ethyl acetate/acetone=7/3) to give the title compound. mp206−210℃. The following compounds belonging to formula () can be produced by methods similar to these examples or by the methods described above. (Arrangement: 6RS, 5RS, 8RS if R ₃ = H)

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N( _CH3 ) ₂

Claims (1)

[Claims] 1 Formula () [In the formula, R ₁ is hydrogen or methyl, R ₂ is amino,
Lower alkyl, which may be mono- or di-substituted with substituents selected from lower alkylamino, di-lower alkylamino, lower acylamino and carboxy, or of the formula (c) -( _CH2 )p- _R7 (c) ( In the formula, R ₇ is a 5- or 6-membered saturated or unsaturated heterocycle, p represents 0, 1, 2 or 3),
or the formula below (In the formula, R ₄ , R ₅ and R ₆ are each hydrogen or lower alkyl, and m is 2
or 3, n represents 1, 2 or 3). However, if R ₁ is hydrogen and the group containing it has an R-coordination, R ₂ shall be a group other than acetylaminoethyl], or -OH, -NH ₂ or - Protective forms for COOH or physiologically hydrolyzable acceptable esters, free acids, salts or zwitterions thereof. 2 R ₁ is hydrogen or methyl, R ₂ is mono or mono depending on the substituent selected from amino, lower alkylamino, di-lower alkylamino, lower acylamino, carboxy, imino, lower alkylimino, methyltetrazolyl and morpholinyl. 2. A compound according to claim 1, which is lower alkyl which may be di-substituted. 3 (5RS, 6RS)-1-aza-6-(1(RS)-
(5RS,6RS)-1-aza-6 -(1(RS)-fluoroethyl)-3-(N-dimethylamidinomethylthio)-7-oxobicyclo[3.2.0]hepta-
The compound according to claim 2, which is 2-ene-2-carboxylic acid. 4 formula () [In the formula, R ₁ is hydrogen or methyl, R ₂ is amino,
Lower alkyl, which may be mono- or di-substituted with substituents selected from lower alkylamino, di-lower alkylamino, lower acylamino and carboxy, or of the formula (c) -( _CH2 )p- _R7 (c) ( In the formula, R ₇ is a 5- or 6-membered saturated or unsaturated heterocycle, p represents 0, 1, 2 or 3),
or the formula below (In the formula, R ₄ , R ₅ and R ₆ are each hydrogen or lower alkyl, and m is 2
or 3, n represents 1, 2 or 3). However, if R ₁ is hydrogen and the group containing it has an R-coordination, R ₂ shall be a group other than acetylaminoethyl], or its -OH, -NH ₂ or - a protective form for COOH or an acceptable physiologically hydrolyzable ester form thereof;
In preparing free acids, salts or zwitterions, the formula () [In the formula, R ₁ has the same meaning as above. R ₈ is a leaving group. ] A compound represented by the above, or a protected form of -OH, _-NH2 or -COOH, or an acceptable physiologically hydrolyzable ester thereof,
A free acid, salt or zwitterion has a group -S- _R2 [wherein _R2 has the same meaning as above]. ] A method characterized by reacting an introduction reagent. 5 formula () [In the formula, R ₁ is hydrogen or methyl, R ₂ is amino,
Lower alkyl, which may be mono- or di-substituted with substituents selected from lower alkylamino, di-lower alkylamino, lower acylamino and carboxy, or of the formula (c) -( _CH2 )p- _R7 (c) ( In the formula, R ₇ is a 5- or 6-membered saturated or unsaturated heterocycle, p represents 0, 1, 2 or 3),
or the formula below (In the formula, R ₄ , R ₅ and R ₆ are each hydrogen or lower alkyl, and m is 2
or 3, n represents 1, 2 or 3). However, if R ₁ is hydrogen and the group containing it has an R-coordination, R ₂ shall be a group other than acetylaminoethyl], or its -OH, -NH ₂ or - a protective form for COOH or an acceptable physiologically hydrolyzable ester form thereof;
In preparing free acids, salts or zwitterions, the formula () [In the formula, R ₁ and R ₂ have the same meanings as above. ] A compound represented by the above, or a protected form of -OH, _-NH2 or -COOH, or an acceptable physiologically hydrolyzable ester thereof,
A method characterized by reacting a free acid, salt or zwitterion with a reagent capable of converting a hydroxyl group into a fluorine atom.