JPS6126551B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel 7α-methoxycephalosporin and a method for producing the same, and aims to have a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, as well as β-methoxycephalosporin.
The object of the present invention is to provide 7α-methoxycephalosporins that are stable against lactamases and are effective against human and animal diseases. Conventional 7α-methoxycephalosporins are
Although it is known to exhibit antibacterial properties against Gram-positive bacteria, it does not show particularly effective antibacterial properties against Pseudomonas aeruginosa, which is known to be a clinically serious infection, and it does not exhibit antibacterial properties against β-lactamase. However, it has drawbacks such as instability. The present inventors have discovered that β-
As a result of intensive research to obtain a compound that is stable against lactamases, we discovered a novel 7α compound that we had previously invented.
-Methoxycephalosporin (Japanese Patent Application Laid-open No. 1983-
No. 89695) was found to fully satisfy the above objectives. Further, the present inventors conducted extensive research on analogous compounds of these novel 7α-methoxycephalosporins, and as a result, discovered a novel 7α-methoxycephalosporin represented by the general formula () below. The present invention has been completed based on the discovery that the above-mentioned object can be fully satisfied by the above-mentioned object. The 7α-methoxycephalosporin of the present invention has the following general formula () [In the formula, R ¹ is a hydrogen atom, a carboxyl protection-forming group, or a salt-forming cation; R ² is a carboxyl group or a lower alkyl group which may be substituted with an esterified carboxyl group; A is a lower alkyl group shows. ] The 3rd position of the cefem ring is an alkylthiomethyl group with or without a substituent, the 7th position is substituted with an α-methoxy group, and the 7th position β-amino group is an alkylthiomethyl group with or without a substituent. [In the formula, A has the meaning described above. ] It is a novel compound disclosed for the first time by the present invention. Among the compounds represented by the above general formula (),
Among the following compounds (a), the compound (b) is excellent. [In the formula, R ¹ and R ² have the meanings described above, and A ¹ represents a methyl group or an ethyl group. ] Further, the present invention can be applied to, for example, the conventionally known method (Japanese Unexamined Patent Publication No. 51
-70788 and JP-A-51-113890). General formula () [In the formula, R ¹ , R ² and A have the meanings described above. ] A cephalosporin represented by the general formula M ^+- OCH ₃ () [wherein M represents an alkali metal] is added in the presence of methanol. ] A novel 7α- expressed by the general formula (), which is characterized by reacting with an alkali metal salt of methanol expressed by
A method for producing methoxycephalosporins is provided. The present invention will be explained in more detail below. As used herein, "carboxyl protection-forming group" and "salt-forming cation" refer to those conventionally used in the penicillin and cephalosporin fields. Specifically, examples of the "carboxyl protection forming group" include the following. (a) Ester-forming groups that have the property of being eliminated by catalytic reduction, chemical reduction, or treatment under mild conditions, such as substituted arenesulfonylalkyl groups such as p-toluenesulfonylethyl; benzyl, 4-nitrobenzyl, Diphenylmethyl, trityl, 3,5-di(tert.-butyl)-
Substituted or unsubstituted aralkyl groups such as 4-hydroxybenzyl; benzoyloxyethyl groups; substituted or unsubstituted alkyl groups such as tert.-butyl and trichloroethyl; phenacyl groups,
Alkyloxyalkyl groups such as methoxymethyl. (b) Ester-forming groups that have the property of being easily eliminated by enzymes in vivo, such as acyloxyalkyl groups such as pivaloyloxymethyl; alkyloxycarbonyloxymethyl groups such as ethoxycarbonyloxymethyl; phthalidyl groups; Indanyl group etc. (c) An organic silyl group, organic phosphorus group, or organic tin group that has the property of being easily eliminated by treatment with water or alcohol, such as (CH ₃ ) ₃ Si−;
(CH ₃ ) ₂ Si〓;

【formula】

[Formula] (C ₂ H ₅ O) ₂ P−; (C ₂ H ₅ ) ₂ P−; (C ₄ H ₉ ) ₃ Sn−, etc. Examples of "salt-forming cations" include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; ammonium salts; procaine, dibenzylamine, N-benzyl-β-phenethylamine, -Efenamine, N・N′-dibenzylethylenediamine, trimethylamine,
Triethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine,
Examples include salts with nitrogen-containing organic bases such as dicyclohexyl. In the present invention, "lower alkyl group" means a straight chain alkyl group having 1 to 4 carbon atoms. The invention extends to all optical isomers and racemates as well as all crystal forms and hydrates of the compounds of the invention. Further, the alkali metal salt of methanol represented by the general formula () includes lithium methoxide, sodium methoxide, potassium methoxide, and the like. Next, embodiments of the method of the present invention will be explained. First, a cephalosporin represented by the general formula () is reacted with an inert solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, methylene chloride, chloroform, N/N-
It is dissolved or suspended in one or more mixed solvents such as dimethylformamide, N·N-dimethylacetamide, acetonitrile, methanol, etc., and an alkali metal salt of methanol () is added together with methanol to react. At this time, it is preferable to use an excess amount of methanol and to use the alkali metal salt of methanol () in an amount of 2 to 6 equivalents relative to the cephalosporin of the general formula (). Moreover, an excess amount means 1 equivalent or more with respect to the cephalosporin of formula (). Then, a halogenating agent is added and reacted. All of the above reactions are generally carried out at reaction temperatures of -120 to -10
C, preferably -100 to -50 C, and the reaction time is 5 to 30 minutes. Thereafter, the reaction is stopped by making the inside of the reaction system acidic. The halogenating agents that can be used in this method are generally those commonly known as positive halogen sources. That is, it refers to any halogen compound capable of supplying a positive halogen atom, such as Cl ⁺ , Br ⁺ or I ⁺ . Specifically, for example, halogens such as chlorine and bromine; N-chlorosuccinimide, N-
N-haloimides such as promosuccinimide;
N-haloamides such as N-chloroacetamide and N-bromoacetamide; N-halosulfonamides such as N-chlorobenzenesulfonamide and N-chloro-p-toluenesulfonamide; 1
-Halobenzotriazoles; 1-halotriazines; organic hypohalogenides such as tert.-butylhypochloride and tert.-butyliodide; N.
Examples include N′-dibromohydantoin.
A preferred halogenating agent is tert.-butylhypochloride. The halogenating agent is used in an amount sufficient to supply an equivalent amount of positive halogen to the cephalosporins represented by the general formula (). Suitable acids for terminating the reaction are also those which, when added to the cold reaction mixture, do not cause the reaction mixture to solidify or freeze into a heavy viscous mixture. For example, 98% formic acid, glacial acetic acid, trichloroacetic acid, methanesulfonic acid, etc. can be used. After stopping the reaction, excess halogenating agent is removed by treatment with a reducing agent such as trialkyl ester of phosphorous acid or sodium thiosulfate. The 7α-methoxycephalosporins () thus obtained are isolated and collected from the reaction mixture according to a conventional method. Moreover, the object compound () of the present invention is JP-A-52-
It can be obtained by the method disclosed in the specification of No. 89695. Furthermore, in the compound of the present invention of general formula (),
When R ¹ is a hydrogen atom, R ₁ becomes a salt-forming cation or a carboxyl-protecting group, and when R ¹ is a salt-forming cation, R ¹ becomes a hydrogen atom or a carboxyl-protecting group, or R ¹ becomes a hydrogen atom or a carboxyl-protecting group. When it is a carboxyl protection-forming group, R ¹ can be changed to a hydrogen atom or a salt-forming cation, respectively, by a conventional method. In addition, in the present invention, if there is a group active in the reaction, it can be protected with any protecting group that is normally used to protect carboxyl groups etc. during this reaction, and after the reaction, it can be protected by a conventional method. The protective group may be removed by The novel compound of the present invention thus obtained not only has a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, but also has extremely excellent antibacterial activity against Pseudomonas aeruginosa and is highly effective against β-lactamase. It is stable and extremely valuable as a therapeutic agent for human and animal diseases. The compounds of formula () of the present invention are administered to humans and animals in the form of free acids, or in the form of non-toxic salts or physiologically acceptable esters. Dosage forms applied to, for example,
It is prepared in the form of tablets, capsules, syrups, and injections and administered orally or parenterally. Next, the present invention will be explained by examples. Example 1 (1) Diphenylmethyl=7β-[D(-)-α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetamide]
-3-n-propylthiomethyl-Δ ³ -cephem-4-carboxylate [IR (KBr) cm ^-1 ;
vc=o 1770, 1705, 1690, 1670] 0.76 g is dissolved in 20 ml of chloroform and 5 ml of dry tetrahydrofuran and cooled to -75°C in a methanol-dry ice bath. 3.5ml of methanol solution of 1.425mmole/ml of lithium methoxide at the same temperature
was added and stirred for 30 minutes, then 0.18 ml of tert.-butylhypochloride was added, and after stirring at -70°C for 15 minutes, 0.29 ml of glacial acetic acid and triethyl phosphite were added.
Add 0.1 ml one by one and warm to room temperature. Add the above reaction mixture to citrate buffer (PH7.0)
30 ml of water, separate the organic layer and add 20 ml of water.
Wash twice. Add 20ml of fresh water to the organic layer,
The pH was adjusted to 2.0 with 2N hydrochloric acid, the organic layer was washed twice with 20 ml of water, and then dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with benzene-ethyl acetate) to obtain diphenylmethyl=7β[D(-)-α-(4-ethyl-2.3
-dioxo-1-piperazinecarboxamide)
Phenylacetamide]-7α-methoxy-3
-n-propylthiomethyl-Δ ³ -cephem-
0.43 g (54.4%) of 4-carboxylate is obtained. IR (KBr) cm ^-1 ; νc=o 1770, 1705,
1690, 1675 NMR δ ( _CDCl3 ) 0.78~1.20 (6H; m; _-CH3 ×2), 1.30~
1.65 (2H; m; 〓CH ₂ ), 2.40 (2H; t; 〓
CH ₂ ), 3.25-3.75 (6H; m; 〓CH ₂ × 3),
3.50 (3H; s; _-CH3 ), 3.75-4.20 (4H;
m; 〓CH ₂ × 2), 5.00 (1H; s; C ₆ −
H), 5.70 (1H; d; Cα-H), 6.87
(1H;s;

【formula】 ), 7.30 (16H; m;

[Formula] 〓NH), 7.70 (1H; d; 〓NH) (2) Diphenylmethyl = 7β-[D(-)-α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetamide]
-7α-methoxy-3-n-propylthiomethyl-Δ ³ -cephem-4-carboxylate
Dissolve 0.30 g in 3 ml of anisole, add 2.0 ml of trifluoroacetic acid under ice cooling, and stir at the same temperature for 30 minutes. Trifluoroacetic acid and anisole are distilled off under reduced pressure and the mixture is dried. Add 5 ml of ethyl acetate to the resulting residue, adjust the pH to 2.0 with 6N hydrochloric acid, separate the organic layer, and wash twice with 5 ml of water.
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was treated with ether to obtain a white powder 7β-[D(-)-α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetamide]
-7α-methoxy-3-n-propylthiomethyl-Δ ³ -cephem-4-carboxylic acid 0.21 g
(88.6g) is obtained. IR (KBr) cm ^-1 ; νc=o 1770, 1720,
1705, 1685, 1670 NMR δ (DMSO-d ₆ ) 0.77-1.20 (6H; m; -CH ₃ ×2), 1.30-
1.65 (2H; m; 〓CH ₂ ), 2.40 (2H; t; 〓
CH ₂ ), 3.25-3.75 (6H; m; 〓CH ₂ × 3),
3.40 (3H; s; _-CH3 ), 3.80-4.15 (4H;
m; 〓CH ₂ × 2), 5.10 (1H; s; 〓CH),
5.65 (1H; d; 〓CH), 7.38 (5H, s,

[Formula] ), 9.73 (2H; m; 〓NH×2) Example 2 (1) Diphenylmethyl=7β-[D(-)-α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetamide]
-3-Ethoxycarbonylmethylthiomethyl-
^Δ3 -Cefem-4-carboxylate 0.8g
[IR (KBr) cm ^-1 ; νc=o 1770, 1700,
1680, 1670] in the same manner as in Example 1-(1), diphenylmethyl=7β-[D
(-)-α-(4-ethyl-2,3-dioxo-
1-piperazinecarboxamide)phenylacetamide]-7α-methoxy-3-ethoxycarbonylmethylthiomethyl-Δ ³ -cephem-
0.55 g (66.4%) of 4-carboxylate is obtained. IR (KBr) cm ^-1 ; νc=o 1775, 1715,
1700, 1685, 1670 NMR δ ( _CDCl3 ) 0.95-1.24 (6H; m; _-CH3 x 2), 3.10
(2H; s; 〓CH ₂ ), 3.28-3.75 (8H; m;
〓CH ₂ × 4), 3.40 (3H; s; −CH ₃ ), 3.75
~4.15 (4H; m; 〓CH ₂ × 2), 4.95 (1H;
s; 〓CH), 5.50 (1H; d; 〓CH), 6.90
(1H; s; 〓CH), 7.35 (16H; m;

[Formula] 〓NH), 7.70 (1H; d; 〓NH) (2) Diphenylmethyl = 7β-[D(-)-α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetamide]
If 0.05 g of -7α-methoxy-3-ethoxycarbonylmethylthiomethyl-Δ ³ -cephem-4-carboxylate is reacted and treated in the same manner as in Example 1-(2), 7β[D(-)-α-( 4-Ethyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetamide]-7α-
Methoxy-3-ethoxycarbonylmethylthiomethyl-Δ ³ -cephem-4-carboxylic acid 0.35
g (87.5%). IR (KBr) cm ^-1 ; νc=o 1770, 1715,
1700, 1680, 1670 NMR δ (DMSO-d ₆ ) 0.98-1.27 (6H; m; -CH ₃ ×2), 3.29-
3.78 (10H; m; 〓CH ₂ ×5), 3.41 (3H;
s; −CH ₃ ), 3.78 to 4.20 (4H; m; 〓CH ₂
×2), 5.08 (1H; s; 〓CH), 5.62 (1H;
d;〓CH), 7.40(5H;s;

[Formula] ), 9.72-9.80 (2H; m; 〓NH×2) Example 3 (1) Diphenylmethyl = 7β-[D(-)-α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetamide]
-3-diphenylmethoxycarbonylmethylthiomethyl- ^{Δ 3} -cephem-4-carboxylate [IR (KBr) cm ^-1 ; νc=o 1775,
If 1.42 g of 1710, 1680, 1670 is reacted and treated in the same manner as in Example 1-(1), diphenylmethyl=
7β-[D(-)-α-(4-ethyl-2,3-
dioxo-1-piperazinecarboxide)phenylacetamide]-7α-methoxy-3-
Diphenylmethoxycarbonylmethylthiomethyl-Δ ³ -cephem-4-carboxylate
Obtain 1.0g (68.5%). IR (KBr) cm ^-1 ; νc=o 1780, 1715,
1705, 1695, 1680 NMR δ( _CDCl3 ) 1.08(3H;t; _-CH3 ), 3.00(2H;s;〓
CH ₂ ), 3.16 (2H; s; 〓CH ₂ ), 3.43 (3H;
s; −CH ₃ ), 3.25 to 3.70 (4H; m; 〓CH ₂
×2), 3.70×4.10 (4H; m; 〓CH ₂ ×2),
4.90 (1H; s; 〓CH), 5.60 (1H; d; 〓
CH), 6.73 (2H; m; 〓CH×2), 7.20
(25H; m;

[Formula] ), 7.75 (1H; br; 〓NH), 9.85 (1H; d;
〓NH) (2) Diphenylmethyl=7β-[D(-)-α-
(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetamide]
-7α-methoxy-3-diphenylmethoxycarbonylmethylthiomethyl-Δ ³ -cephem-
If 1.0 g of 4-carboxylate is reacted and treated in the same manner as in Example 1-(2), 7β-[D(-)-
α-(4-Ethyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetamide]-7α-methoxy-3-carboxymethylthiomethyl-Δ ³ -cephem-4-carboxylic acid
Obtain 0.58g (87.9%). IR (KBr) cm ^-1 ; νc=o 1770, 1715,
1700, 1690, 1670 NMR δ(DMSO- _d6 ) 1.13 (3H; t; _-CH3 ), 3.05-3.80 (8H;
m; 〓CH ₂ ×4), 3.40 (3H; s; -CH ₃ ),
3.80~4.10 (4H; m; 〓CH ₂ × 2), 5.00
(1H; s; 〓CH), 5.55 (1H; d; 〓CH),
7.34 (5H;s;

【formula】 ), 9.70 (2H; m; 〓NH×2)

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom, a carboxyl protection-forming group, or a salt-forming cation; R ² is a carboxyl group or a lower alkyl group which may be substituted with an esterified carboxyl group; A is a lower alkyl group shows. ] 7α-methoxycephalosporins represented by: 2 General formula [In the formula, R ¹ is a hydrogen atom, a carboxyl protection-forming group, or a salt-forming cation; R ² is a carboxyl group or a lower alkyl group optionally substituted with an esterified carboxyl group; A ¹ is a methyl group Or represents an ethyl group. ] 7α- according to claim 1 expressed as
Methoxycephalosporins. 3 General formula [In the formula, R ¹ represents a hydrogen atom, a carboxyl protection-forming group, or a salt-forming cation; R ² represents a carboxyl group or a lower alkyl group optionally substituted with an esterified carboxyl group. ] 7α- according to claim 2, which is expressed by
Methoxycephalosporins. 4 General formula [In the formula, R ¹ is a hydrogen atom, a carboxyl protection-forming group, or a salt-forming cation; R ² is a carboxyl group or a lower alkyl group which may be substituted with an esterified carboxyl group; A is a lower alkyl group shows. ] A compound represented by is reacted with an alkali metal salt of methanol represented by the general formula M ^+- OCH ₃ [wherein M represents an alkali metal] in the presence of methanol, and then reacted with a halogenating agent. A general formula characterized by [In the formula, R ¹ , R ² and A have the meanings described above. ] A method for producing 7α-methoxycephalosporins represented by: