JPS6366187A - 2alpha-substituted penicillin derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I. USE:A beta-lactamase inhibitor, normally used in combination with a beta-lactam based anibiotic. PREPARATION:For example, first a 2beta-chloromethyl derivative expressed by formula II (R represents protecting group for penicillin carboxyl group) is isomerized, treated with nitrogen tetroxide in dichloromethane, etc., and further heated in the presence of pyridine while refluxing. Then the obtained diazo derivative expressed by formula III is reacted with hydrogen bromide in ethyl acetate, etc., while cooling with ice, converted into a bromo derivative, followed by reduction thereof to form a dihydro body expressed by formula IV. Then the resultant compound is reacted with both pyridine and phosphorus pentasulfide in dichloromethane, etc., to form a penam derivative and further reacted with sodium azide in DMF, etc., to afford a compound expressed by formula V. Subsequently oxidation thereof with an oxidizing agent is carried out in an aqueous solution of acetic acid, etc., to form a sulfon derivative expressed by formula VI, further absorption of an excess acetylene is carried out in acetone, etc., and agitation thereof is carried out in a sealed tube at 80-100 deg.C for 20-30hr to afford a triazole derivative expressed by formula VII, followed by hydrogenation thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 2α-substituted penidiline derivatives, salts thereof and esters thereof.

The 2α-substituted penidillin derivatives, their pharmaceutically acceptable salts, and their esters of the present invention are all new compounds, which have β-lactamase inhibitory activity and β-lactamase inhibitory activity.
Useful as a lactamase inhibitor.

Problems to be Solved by Ming Among commercially available antibiotics, β-lactam antibiotics having a β-lactam ring, ie, penicillins and cephalosporins, are the most well-known and frequently used. These β-
Although lactam antibiotics are widely used as useful chemotherapeutic agents, they are not sufficiently effective against certain microorganisms due to their resistance. The resistance of certain microorganisms to β-lactam antibiotics is usually due to the β-lactamases produced by the microorganisms,
That is, it uses an enzyme that cleaves the β-lactam ring of a β-lactam antibiotic to produce a product that does not have antibacterial activity. Therefore, in order for the β-lactam antibiotics to exhibit sufficient efficacy, it is necessary to eliminate or minimize the action of β-lactamase. This β
- Eliminating or inhibiting the action of lactamases is achieved by β-lactamase inhibitors, and such β-lactamase inhibitors can be used together with β-lactam antibiotics to enhance the antibacterial activity of the antibiotics. can be raised.

As a result of synthesizing and researching various compounds, the present inventors found that a specific 2β-substituted penidiline derivative represented by the following formula (1), its salt, and its ester have an excellent inhibitory effect on β-lactamase. The present invention has been completed based on the discovery that the present invention has the following properties.

Means for Solving the Problems The present invention relates to a 2α-substituted penicillin derivative represented by the following formula (1), a salt thereof, and an ester thereof.

Examples of the ester of the above-mentioned derivative (I) of the present invention include esters protected by well-known penicillin carboxyl protecting groups and esters that are hydrolyzed in vivo. Examples of secondary esters and protective groups for forming the esters include those described in JP-A-49-81380.
Publications and H.E. Flying editions of cephalosporins
Any of the commonly used β-lactam antibiotics described in Andpenicillins, Chemistry and Biology (published by Academic Press, 1972) may be used. Typical examples include substituted or unsubstituted alkyl groups such as methyl, ethyl, propyl, butyl, tert-butyl, trichloroethyl, etc.
Substituted or unsubstituted aralkyl groups such as benzyl, diphenylmethyl, p-nitrobenzyl; acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxymethyl, pivaloyloxypropyl, benzoyloxymethyl, benzoyloxyethyl, benzylcarbonyl Acyloxyalkyl groups such as oxymethyl, cyclohexylcarbonyloxymethyl; methoxymethyl,
Alkoxyalkyl groups and aralkyloxyalkyl groups such as ethoxymethyl and benzyloxymethyl; lactones and substituted or unsubstituted phenyl groups such as 3-phthalidyl groups, 4-crotonolactonyl groups, and γ-butyrolactone-4-yl groups; others (2-oxo-1,3-dioxothene-
4-yl)methyl group, (5-methyl-2-oxo-1,
3-dioxoten-4-yl)methyl group, (5-phenyl-2-oxo-1,3-dioxoten-4-yl)methyl group, tetrahydropyranyl group, dimethylaminoethyl group, dimethylchlorosilyl group, trichlorosilyl group Examples include groups.

Examples of the salts of the compound of the present invention represented by formula (I) include alkali metal salts such as sodium, potassium, and lithium, alkaline earth metal salts such as calcium and magnesium, cyclohexylamine, trimethylamine, triethylamine, and jetanolamine. Examples include organic amine salts such as , ethyldiisopropylamine and N-methylmorpholine, basic amino acid salts such as arginine and lysine, and ammonium salts.

Antibiotics that can be used in combination with the compound of the present invention to increase antibacterial activity include common penicillins such as ampicillin, amoxicillin, hetacillin, cyclacillin, mecillinum, carbenicillin, sulpenicillin, ticarcillin, piperagiline, ampicillin, methicillin, mezlocillin, etc. and esters such as bacampicillin, calindacillin, talampicillin, carbenicillin, pibmecillinam, and cephalosporins such as cephaloridine, cephalothin, cefapirin, cefacedryl, cefazolin, cephalexin, cefrazine, cefoxin, cefamandole, cefoxin, cefoxin, cefmetazole , cephalothin, cefuoxin,
Examples include cephalexin, cephalexin, cefmetuxime, latamoxef, cefaclor, cefoxin, cefatridine, cefadroxil, cephaloglycin, and their salts, as well as β-lactam antibiotics that exhibit antibacterial activity against various Gram-negative bacteria and Gram-negative bacteria. The compounding ratio of the compound of the present invention and the β-lactam antibiotic used in combination with the compound is usually 1:about 0.1 to 10 by weight.
．． Preferably, the ratio is 1:about 0.2 to 5.

The 2β-substituted penidiline derivative (1) of the present invention can be produced, for example, according to the method shown in the following reaction scheme.

<Reaction process formula> (II) OC00R (III) (1v) C process OC0ORD process (V) ↑ 0'C0ORF process (W) OC0ORC process (■) (IX> 0 'C0ORI process (X) O (I> above) In each formula, Ph represents a phenyl group, and the same shall apply hereinafter.Also, in the above, the penicillin carboxyl protecting group represented by R may be a commonly known one, and specifically,
For example, the above-mentioned Japanese Patent Application Laid-Open No. 49-81380@publication and Etch.
E. Frain, ed. Cephalosporins and Penicillins, Chemistry and Biology (1972)
You can use any of the ones listed in the 2008 Academic Press (published by Academic Press). Preferred R groups include, for example, methyl,
Substituted or unsubstituted alkyl groups such as ethyl, propyl, butyl, tert-butyl, trichloroethyl; benzyl,
Substituted or unsubstituted aralkyl groups such as diphenylmethyl, p-nitrobenzyl, etc.: acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxyethyl, pivaloyloxyprobyl, benzoyloxymethyl, benzoyloxyethylsimethylthyl, etc. Acyloxyalkyl groups: alkoxyalkyl groups and aralkyloxyalkyl groups such as methoxymethyl, ethoxymethyl, and benzyloxymethyl; other examples include tetrahydropyranyl, dimethylaminoethyl, dimethylchlorosilyl, and trichlorosilyl groups.

Each step in the above reaction scheme is carried out in more detail as follows.

That is, in the step, the 2β-chloromethyl derivative represented by the general formula (II>) is mixed with about (1 5
The mixture is heated under reflux for ~2 hours to effect isomerization to obtain the 2α-chloromethyl derivative (III).

In step B, the derivative (I[I) obtained above is treated with dinitrogen tetroxide in dichloromethane, for example, to obtain a nitroso compound, and then, without purification, the derivative (I[I) is treated with dinitrogen tetroxide in dichloromethane, and then purified in dichloromethane in the presence of pyridine to approx. The mixture is heated under reflux for 3 to 5 hours to obtain a diazo compound (IV>).

In step C, the bromine compound (V) is obtained by reacting the diazo compound <IV) with hydrogen bromide in, for example, ethyl acetate while cooling with water.

In step D, the bromine compound (V) is reduced to the dihydro compound (Vl) by using zinc powder in, for example, acetic acid under water cooling.

In Step E, the 2α-chloromethylpenam compound (VI) is obtained by reacting the above dihydro compound (l) with pyridine and phosphorus pentasulfide in, for example, dichloromethane at room temperature.

In the FI stage, the above 2α-chloromethylpenam body (VI)
By reacting sodium azide with, for example, dimethylformamide under water cooling, 2α-azidomethylpenam compound (■) is obtained.

The above-mentioned 2α-azidomethylpenam compound (■) is prepared without purification in the subsequent step C, for example, in an aqueous acetic acid solution.
The sulfone compound (IX) is produced by reacting with an oxidizing agent such as potassium permanganate or hydrogen peroxide at room temperature.

The obtained sulfone compound (IX) is then made into, for example, an acetone solution in step 1, absorbs excess acetylene, and is heated in a sealed tube at about 80 to 100°C for about 20 to 30 minutes.
By heating and stirring for 0 hours, the triazole compound (X)
be guided by.

The triazole compound (X) thus obtained is deesterified by hydrogenation in step (2), for example, in an aqueous ethyl acetate-sodium hydrogen carbonate solution using palladium-carbon as a catalyst under about 3 to 5 atmospheres. The compound of the present invention can be represented by (I>).

In the above reaction scheme, the 2β-chloromethyl derivative (II) used as the starting material is a known compound, for example,
It is described in No. 68591.

In addition, each reaction in steps B to E can be carried out according to methods known and commonly used in the field, and steps F and C, and steps H and (2) are carried out in accordance with Japanese Patent Laid-Open No. 58-185589 and JP-A-58-185589, respectively. Kaisho 61-1 2
It can be carried out according to the method described in Japanese Patent No. 6087.

The derivatives of the present invention thus obtained can be converted into pharmaceutically acceptable salts and esters according to salt formation reactions and/or esterification reactions commonly used in the art.

The above-obtained derivatives of the present invention, pharmaceutically acceptable salts and esters thereof are separated and collected in accordance with conventional methods after the completion of the reaction in each step, and, if necessary, are subjected to recrystallization, thin layer chromatography, column chromatography. It can be purified by eg.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be briefly described in detail with reference to Examples.

Example 1 (2) Step Diphenylmethyl 2β-chloromethyl-2α-methyl-6β-phenylacetamidopenam-3α-carboxylate 1β-oxide 6q was heated under reflux in toluene 12Q for 30 minutes.

After the reaction, the solvent was distilled off and the residue was subjected to silica gel column chromatography (developing solvent: hexane: ethyl acetate).
7:3) to obtain diphenylmethyl 2α-
Chlormethyl-2β-methyl-6β-phenylacetamidopenam-3α-rupoxylate 1β-oxide 3Ω was obtained.

Yield: 50% Melting point: 125-128°C (decomposed) Properties: White crystal Infrared absorption spectrum (IR) (cm-') = 3394.1802. '1753
゜max× 1688.1507 Nuclear magnetic resonance spectrum ('H-NMR>(CDC(23
>: δ(Dpm)=1.73 (S, 3H, CH3)3.
13,3.5 (ABCl, J=13H2,2H.

CH2CQ) 3.58 (S, 2H, PhCH2) 4.73 (s, 1H, 3-H) 5.03 (d, J=4.5Hz, IH, 5-1-()
6.0 (dd, J=4.5Hz, 9.0Hz, 1H.

6-H) 6.92 (S, 1H, CHPh2) 6.97 (d
, J=9.0Hz, IH, NH) L 29 (s,
15H, aromatic> Elemental analysis value: (%) Calculated value C63,2184,90N5.08 Actual value C
63,54H4,94N5.08■ Step B 3.0 CI of the compound obtained above and 1.55 l of anhydrous sodium acetate were suspended in 20 mQ of dry dichloromethane, and dinitrogen tetroxide was added to this under ice cooling. Add 1 mQ,
Then, after 30 minutes, 0.6 ml of dinitrogen tetroxide was added to the colander, and after stirring at the same temperature for 1 hour, 1 ml of dichloromethane was added.
00mQ was added, washed with an aqueous sodium bicarbonate solution, then washed with water, and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off and the resulting residue was dissolved in dichloromethane 10
After the reaction, the dichloromethane layer was washed with water,
It was washed with an aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off, the resulting residue is thoroughly washed with hexane, dried, and diphenylmethyl
2.1 g of 2α-chlormetal-2β-methyl-6-diacypenam 3α-carboxylate 1β-oxide was obtained.

Yield: 87.1% Properties: Two oily substances IR (CHCQ3) max (cm-') = 2101.1787.174
1'l-l-1-N (CDCQ3): δ (ppm
) = 1, 68 (S, 3H
, CH3) 3.29, 3.68 (ABQ, 2H, CH
2CQ) 4.5 (s, IH, 3-H> 5.85 (s, 1H, 5-H> 6.94 (S, 1H, CHpH2) 7, 35 (S, 10H, aromatic) ■
Step C: Compound 2.10 obtained above was added to 40 mQ of ethyl acetate.
To this was added dropwise 10 mQ of ethyl acetate containing 0.76 q of hydrogen bromide at 0°C. After dropping, keep at the same temperature for 30 minutes.
The mixture was stirred for a minute and washed with an aqueous sodium thiosulfate solution. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off.

The resulting residue was subjected to silica gel column chromatography (
Purification was performed using a developing solvent: hexane:ethyl acetate-75:25>. The elution solvent was distilled off and diphenylmethyl 2
α-chloromethyl-2β-methyl-6α-bromopenam-3α-carboxylate 1β-oxide 1.50
I got it. □ Yield: 63.8% Properties: Two oily substance'HNMR (CDCQ3): δ(1)I)m)=1.72 (S, 3H, CH3)
3.32, 3.66 (ABQ, 2H, CH2G (1!
) 4.73 (s, 1H, 3-H) 5.14 (d, IH) 5.20 (d, 1H) 7.0 (S, 1H, CHPh2) 7, 4 (S, 10H, aromatic) ■
Step D Compound 1 obtained above. OC] was dissolved in 6 mQ of acetonitrile, and 2 mf2 of acetic acid was added thereto at 0°C. Subsequently, 0.26C of zinc powder was added at once, and the mixture was stirred at around 10°C for 2 hours. After the reaction is complete, excess zinc powder is separated from the furnace.
100 mQ of dichloromethane was added to the furnace liquid. The organic layer was washed with water, washed with an aqueous solution of hydrogen carbonate, and dried over anhydrous sodium sulfate.

After drying, the solvent was distilled off, the resulting residue was purified by silica gel column chromatography (developing solvent: hexane: ethyl acetate - 70:30), the eluate was concentrated, and the resulting residue was purified from dichloromethane-ether. Recrystallize to obtain diphenylmethyl 2α-chloromethyl-2β-methyl-6
,6-cyhydropenamu 3α-carboxylate 1β
- oxide 0.41;I was obtained.

Yield: 47.6% Melting point: 132-134°C IR (CHCQ3) <cm”) = 1793.1750ax 'HNMR (CDCG!3): δ (pDm) = 1.75 (S, 3H, CH3)3 ．．
28,3.64 (ABQ, 2H, CH2CQ) 3.3
0 (d, 2H, 6β-H and 6α-H) 4.7 (s,
IH, 3-H) 5.02 (S, IH, 5α-H) 7.0 (S, IH, CHPh2 > 7, 38 (s, 10H, aromatic > Elemental analysis value: (%) Calculated value C60,3584 , 79N3.35 actual value C
60,63H4,96N3.25■ Step E: 0.104CI of the compound obtained above, 0.10% of the compound obtained above, 0.63H of phosphorus pentasulfide.
055CI and pyridine 0.0790 were dissolved in dichloromethane 51TIQ and stirred at room temperature for 5 hours under a nitrogen stream. Next, 0.06 C of phosphorus pentasulfide] was added again and stirred for 16 hours. After the reaction was completed, 50 mQ of water was added and the mixture was extracted three times with 30 mQ of dichloromethane.

The organic layer was washed successively with an aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and then the solvent was distilled off to give diphenylmethyl 2α-chloromethyl-2β-methyl-6,6-cyhydropenamum 3α-carboxylate 0 .07CI increased by 1.

Yield near 0% Properties: Two oily substance'H-NMR (CD093): δ(1)l)m)=1.78 (S, 3H, CH3
) 3.23, 3.65 (ABQ, 2H, CH2CQ)
3.60 (s, 2H, 6-H) 4.73 (s, 1H, 3-H) 5.30 (t, IH, 5-H) 6.98 (S, 1H, CHPh2) 7, 40
(s, 10H, aromatic) ■ Step F: Dissolve 0.32 g of the compound obtained above in a mixture of 6 mQ of dimethylformamide and 2 mQ of water, add 0.31 CI of sodium azide under water cooling, and stir at room temperature for 4 hours. Stirred. After the reaction, it was poured into ice water and diluted with 20 mQ of chloroform.
Extracted twice. After washing the organic layer with water, it was concentrated to obtain diphenylmethyl 2α-azidomethyl-2β-methyl-6,6-dihydropenamum 3α-carboxylate in the form of an oil.
．． Obtained 29G. This product was used in the subsequent reaction without being purified.

(G process) The oil obtained above was dissolved in a mixture of 12111Q acetic acid and 2mQ water, and 0.2% potassium permanganate was added under water cooling.
50 was added little by little over 30 minutes, and the mixture was stirred at room temperature for 3 hours. After the reaction, the mixture was poured into 50ml of ice water and extracted three times with 30mG of chloroform. The organic layer was washed successively with an aqueous sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off to obtain diphenylmethyl 2α-azidomethyl-2β-methyl-6,6-cyhydropenamyl 3α-carboxylate. ]-didiokioid 0.255C was obtained.

Yield near 2.8% Properties: White oil 'H-NMR (CDC (!3): δ (ppm) = 1.60 (s, 3H, CH3) 3.
48 (d, 2H, CH2N3)3.68 (d, 2
H,6-H) 4,. 52 (s, 1H, 3-H> 4.73 (t, IH, 5-H) 7.06 (s, 'IH, CHPh2) 7, 40 (
S, 'I 0f-(, aromatic)■H step 0.05CI of the above compound was dissolved in 5rlIQ of acetone, 4.2g of acetylene was inhaled under water cooling, and then heated at 80-85℃ for 24 hours in a sealed tube. Stirred.

After the reaction, the solvent was distilled off, and the resulting residue was recrystallized from hexane-ethyl acetate to give diphenylmethyl 2
0.03 CI of α-(1,,2,3-triazol-1-yl)methyl-2β-methyl-6,6-cyhydropenam 3α-carboxylate 1,1-dioxide was obtained.

Yield: 56.7% Melting point: 156-159°C Properties: White powder IR (CHC93): νmax (Ctn-') = 3016.1802
．． 1745'H-NMR (CDC(!3): δ(ppm) = 1.70 (S, 3H, CH3)3,
30-3. 60 (m, 2H,6-to1
)3, 60-3. 80 (m, IH,
5-t1) 4, 80 (s, 1H, 3-H
) 4.66.5.00 (ABq, 2H.

2α-CH2> 7.05 (s, IH, CHPh2) 7, 45 (S, 10H, aromatic) 7
．． 60 (2H,s, -CH=CH-) ■ Step 0.012 CI of the above compound was dissolved in 10 ml of ethyl acetate, and 0.0023 C of sodium bicarbonate was dissolved in 5 mg of water.
and 10% palladium-carbon 0.05C1
was added to perform hydrogenation at 2 to 3 atm. After the reaction, the palladium-carbon was separated in a furnace, the aqueous layer was concentrated, and then MCI gel (
The product was purified using water (developing solvent: water). Lyophilize the eluate and
Sodium 2α-(1,2,3-triazole-1-
yl) Methyl-2β-methyl-6,6-cyhydropenamyl 3α-carboxylate 1,1-dioxide 0.
006g was obtained.

Yield near 2.3% Decomposition point: 235℃'H-NMR (D20): δ(pI)m)=1.56 (S, 3H, CH3)3
．． 41,3.67 (dd, 2H, 6-H) 4.52
(s, IH, 3-H) 4.56 (dd, 1H, 5-H) 4.92, 5.18 (ABQ, 2H.

2α-CH2) 7.83 (s, IH) 8.10 (s, IH) Takeshi (that's all)

Claims (1)

[Claims] (1) 2α-substituted penicillin derivatives, salts thereof, and esters thereof, represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. are available.