JPS5857384A - Antibacterial penicillanic acid 6'-(2-amino- 2-(4-acyloxyphenyl)acetamide)penicillanoyloxymethyl- 1,1-dioxide compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention relates to novel compounds of value as antibacterial agents.

More specifically, it relates to certain novel bis-esters of methanediol, in which one hydroxy group of methanediol is 6-(2-amino-2
-[4-7 syloxyphenyl]acetamide) is esterified with the carboxy group of the nidilanic acid compound, and the other hydroxy group is esterified with the carboxy group of the -talactamase inhibitor. The latter beta-lactamase inhibitors mentioned above are of the type containing a beta-lactam ring as well as a carboxy group.

U.S. Patent No. 4,244,951, Ilgy Patent No. 88
No. 7.173 and published UK Patent Application No. 2,04
No. 4.255 describes bis-esters of methanediol of various formulas and their Pharmaceutical Q.
K acceptable salts [wherein R1 represents a certain acyl group, and the group w-c(=o)-o- represents an eta-lactamase inhibitor containing one tarlactam ring at the same time as a carboxy group, W- C(=O)-OH, and the compounds of formula I above are useful as antimicrobial agents. In particular, R1 can represent a 2-amino-2-(4-hydroxyphenyl)acetyl group. However, now the group R1 is a certain 2-amino-2-(4-
It has been found that compounds of formula 1, representing an acyloxyphenyl)acetyl group, constitute a new genus of methanediol bis-esters of significant value in the treatment of bacterial infections in mammals. Moreover, compounds of formula I in which R1 represents a 2-(protected amino)-2-(4-acyloxyphenyl)acetyl group are useful as intermediates to the antimicrobial agents of the present invention. .

The antimicrobial agents of the present invention are effectively absorbed from the gastrointestinal tract of mammals, and after absorption they are 6-(2-amino-2-(4
-Hibyloxyphenyl]acetamide is transformed into 2-nialanic acid (amoxicillin) and an eta-lactamase inhibitor.

6-(2-amino-2-[4-hyP-roxyphenyl]acetamide)-! Nidylanic acid and 6-(2-amino-[
4-acyloxyphenyl]acetami r)-? Nidylanic acid is known; furthermore, U.S. Pat. No. 2,985.64
8, 3.520.876 and 4,053.360
Please refer to the issue. a Nidylanic acid 1,1-dioxide is disclosed in US Pat. No. 4.2! 14.579.

In its broadest sense, the present invention provides novel antimicrobial agents of the formula, pharmaceutically acceptable acid addition salts thereof and pharmaceutically acceptable base salts thereof.

In the formula, R2 is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms,
HOOC-(CH2)n-, HOOG-C(OH3)2
−.

selected from the group consisting of 3-carboxycyclohynchyl group, 4-carboxycyclohexyl group R8R9pJ-, and groups of formula, where n is an integer from 0 to 6;
R8 and R9 are each hydrogen, an alkyl group having 1 to 6 carbon atoms, a 7enyl group, fluorine, chlorine, bromine, iodine, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms; a phenyl group substituted with a group,
with the proviso that RB and R9 are not both hydrogen; and R3 is hydrogen, carbon 1 to 4
alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, fluorine, chlorine, bromine, iodine and cyano groups); and a group w" -c (
=o)-o- is an eta-lactase inhibitor w'- which contains an eta-lactam ring as well as a carboxy group.
Represents a group of a<=o>-OH.

Eta-lactamase inhibitor group, w”-c (=O>
R5 is selected from the group consisting of chlorine, bromine and iodine; R6 is -CH2-Gt, -CH, -0-Go-
selected from the group consisting of OH3 and -C(=O)-OR, where R is an alkyl group having 1 to 4 carbons; and R is a hydroxy group and the equivalent of C1avulanic acid. The group is selected from the group consisting of groups known to confer eta-lactamase inhibitory activity to clapulanic acid when bound to the position where

However, the preferred antimicrobial agent of the present invention is yl-C (=
O) - O- is 2 and R4 is hydrogen. Among this preferred group, particularly preferred compounds are those in which R2 is an alkyl group as described above. Particularly suitable individual compounds of the invention are w' −c (=o
)-o- is the formula ■, R4 is hydrogen, and R
This is the compound 2) in which 2 is a propyl group. - The invention also provides compounds of formula. where wt-c(=o)-o- is as defined above and (R7)' is the group R2 provided that all free carboxy groups therein are protected and where X represents a certain amino group-protecting group. The compound of formula (1) above is useful as an intermediate to the compound of formula (2) above.

In the compound of formula (1), when w'' -c(=o) -o-(R' is hydrogen), the group used as X is a 1-methyl-2-alkoxycarbonylvinyl group, They are an indyloxycarbonyl group and a 4-nitroindyloxycarbonyl group.

Particularly preferred is the 1-methyl-2-methoxycarbonylvinyl group.

The present invention relates to a derivative of inisilanic acid, which is represented by the following structural formula. In formula 1, a dashed bond of a substituent to the bicyclic nucleus indicates that the substituent is below the plane of the bicyclic nucleus, and such substituent is said to be in the alpha configuration. Conversely, a solid bond of a monosubstituent to a bicyclic nucleus indicates that the substituent is attached above the plane of the nucleus, and this latter configuration is referred to as a monoter configuration. Furthermore, the wavy bond of a substituent to the bicyclic nucleus indicates that the substituent is in the alpha or mono-configuration or that a mixture is present.

Thus, for example, using this system, Wl-C(=
Compounds of formulas ■ and ■ in which O)-0- is formula ■ and R4 is hydrogen are inisidunoyμoxymethyl inisillanate (
■), where the primed and unprimed positions are used to distinguish between the two ring systems, i.e.: 1 Additionally, throughout this specification, the 6
2-amino-2-(substituted)acetamide 9 or 2 at -position
Whenever we refer to a compound having 9 -(substituted amino)-2-(substituted)acetamide groups, this refers to the 2-amino-2-(substituted)acetamide group or the 2-(substituted amino)-2-( It is to be understood that the (substituted) acetamide group refers to compounds with the D-configuration.

R2 is as defined earlier, and w'−c(=0
) -0- is either formula fil (R' is hydrogen), 2) or formula V, the compound of formula 2 can be prepared as follows. A suitable phenolic human 9 in a compound of the formula (wherein X can also be an amino-protecting group)
0xy group, (1) R7-C(=O)-Of ((in the formula, R7, R2 other than R8R9N-, all free carboxyl groups therein are protected) Activated derivative of carboxylic acid: (ii) 2R8R'N-0 (=O
)-cznomization force#/:Moyle:'l takt(ii
i) inocyanate of 2R8-N=C=O; acylated with any of the corresponding formula (wherein (R')' is R7 or R8R9N-,
The compound wl-c(=0)-0- is as defined above) is obtained. Following this acylation, the protecting group X is removed and, if necessary, all protecting groups in (R')' are removed.

Various protecting groups can be used as group X.

In Shikashinagara, the group x is the group vr'−c<=o> −o
- They must be able to interact with each other. The group X is the group vrt
It must be possible to remove it using conditions that do not adversely affect -c(=O)-0-. Thus W'
-G(=O)-0-(Formula 111, where R' is hydrogen), convenient groups as X are 1- They are a methyl-2-flukoxycarbonyl vinyl group, a benzyloxycarbonyl group, and a 4-indyloxycarbonyl group. Particularly preferred is 1-methyl-2=methoxycarbonylvinyl (-C(OH3)=CH-C00CH8).

Acylation of the compound of formula =O)-Gt, or by reacting with a carbamoyl chloride of formula R8-N=C=00 above.

The acylation reaction is usually carried out in a solvent system that is inert to the reaction. In a typical process, 0.5 to 2.0 molar equivalents,
and preferably about 1 molar equivalent of 2R'-Go-Ot,
(R'-GO)20. R"R'N-G<=O)-
at or R8-N=Q==Q in the presence of a tertiary amine in a solvent inert to the reaction, from -10 to 3
The compound of formula X above is contacted at a temperature in the range of 0°C. Solvents inert to the reaction that can be used in this acylation are: chlorinated hydrocarbons such as chloroform and dichloromethane, diethyl ether and dichloromethane.
ethers such as hydrofuran; low molecular weight esters such as ethyl acetate and butyl acetate; low molecular weight aliphatic ketones such as acetone and methyl ethyl ketone;
tertiary amides such as N,N-dimethylformamide and N-methyl-pyrrolidone; acetonitrile; and mixtures thereof. Tertiary amines usually have the formula R2
-Go-C/, (R12-Co)20. R"R'
N-C(=O)-Gt Mat, :HaR8-N=G=O(
7) Typical tertiary amines which are and can be used in equivalent amounts in the compound are triethylamine, triditylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine.

Compounds of formula (II) can be isolated by conventional means such as removal of the solvent by evaporation.

They can be purified, if desired, by common methods such as recrystallization or chromatography; alternatively, the protecting group X can be removed from the crude acylated product.

The protecting group
Careful attention must be paid to the instability of the lactam ring and methylenedioxy bond.

The 1-mef-2-alkoxycarbonyl vinyl group can be removed by simply exposing the compound of formula 1 to an aqueous or partially aqueous solvent system at acidic pH, i.e. pH 0.5 to 3. .

This is conveniently achieved by treating the acylated product with water and one molar equivalent of a strong acid, optionally in the presence of a co-solvent, at room temperature. Typical examples of strong acids that may be used are hydrochloric acid, hydrobromic acid, perchloric acid, sulfuric acid, nitric acid and sulfonic acids such as methanesulfonic acid, ininsulfonic acid, toluenesulfonic acid and +7talenesulfonic acid.

Although various co-solvents may be used, the primary requirements for such a solvent are that it be at least partially miscible with water and that neither the starting materials nor the product be adversely affected. It should not affect Typical cosolvents are low molecular weight ketones such as acetone and low molecular weight ethers such as tetrahedral and 1.2-:)methoxyethane. The reaction is usually complete within 1 hour and the product is isolated in conventional manner. In many cases, it is sufficient simply to remove the co-solvent by vacuum evaporation, remove the alkyl acetoacetate by extraction with an immiscible solvent such as diethyl ether, and then freeze-dry the remaining aqueous solution. This gives the required compound of formula (1) as a salt corresponding to the initially added acid.

Indyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups can be converted to the formula ■ by catalytic hydrogenolysis.
can be removed from compounds of In this case,
is a benzyloxycarbonyl ts'*taha4-nitroinzyloxycarbonyl group, which is mixed with hydrogen or an inert diluent such as nitrogen or argon in the presence of a catalytic amount of a hydrogenolysis catalyst. hydrogen,
Stir or shake under an atmosphere of Convenient solvents for this hydrogenolysis include lower alkanols such as methanol and impropanol; ethers such as tetrahydrofuran and dioxane; low molecular weight esters such as ethyl acetate and butyl acetate; dichloromethane and chloroform. Chlorinated hydrocarbons such as: water:
and mixtures of these solvents. However, it is common to choose conditions under which the starting material is soluble. Hydrogenolysis is typically carried out at temperatures of 0 to 60°C and pressures of 20 to 100 psig, preferably about 50 psig.
Performed at psig. The catalysts used in this hydrogenolysis reaction are of the type known in the art for this type of modification, typical examples being noble metals such as nickel, noradium, platinum and rhodium. It is often convenient to disperse the catalyst on an inert support; a particularly convenient catalyst is noceradium dispersed on an inert support such as carbon, such as 10% palladium on carbon. When 10% R radium on carbon is used, it is usually used at a weight of 0.5 to 5.0 times, and preferably about 10 times, the weight of the compound of formula (1).

As indicated hereinabove, when it is desired to prepare a compound of formula (I) in which the group R2 has a carboxy group, for example R2 is HOOC-(CH2)n-, the acylation of a compound of formula It is advantageous to protect the carboxy group during this period. Convenient groups for effecting this carboxy group protection are benzyl and 4-nitrobenzyl groups. Therefore, when it is desired to produce a compound of 2H in which R2 has a carboxyl group, it is necessary to remove the carboxyl group protecting group from the compound of formula (2) in the same way as the protecting group X.

As those skilled in the art will appreciate, when X is an indyloxycarbonyl group or a 4-nitroindyloxycarbonyl group, which is removed by catalytic hydrogenolysis as described above In this case, the mercury or 4-nitrobenzyl carboxyl protecting group is concomitantly removed.

However, if a method other than hydrogenolysis is used to remove the protecting group X, the benzyl or 4-nitrobenzyl protecting group must be removed in a separate step. In this case they are conveniently removed by hydrogenolysis using the methods described for the removal of the benzyloxycarbonyl or 4-nitrobenzyloxycarboel groups.

R2 is as defined earlier, and w'−c(=0
) -0- is formula 111 (R' is a hydroxymethyl group) or formula (2), a compound of formula (2) can be produced as follows. First, a compound of formula R7-
Activated derivatives of carboxylic acids of C(=O)-0H, formula R'
A carbamoyl chloride of R'N-C(=O)-OA or an isocyanate of the formula R8N=C=O, where M is a carboxylate-forming cation and X is an amine group-protecting group of the type previously described. and R''1. R8 and R9 are as defined above) to form a compound of the formula (wherein (R7') is R7 or R8R2H-)
The compound is obtained.

This acylation is performed on activated derivatives of carboxylic acids of the formula R7-C(=O)-0H, 2R8R9N-C(=O)-Gt
is carried out in the same manner as previously described for the acylation of compounds of formula Examples for M are sodium, potassium and tetra-n-butylammonium.

Second, the Nikari compound is converted into an ester of the formula: where 2 is a good leaving group, such as chlorine, bromine, or iodine. This is done in the usual manner for this type of deformation. For example, US Patent No. No. 1.850.908 and No. 4, 244.9
No. 51, Published UK Patent Application No. 2, 044.255
No., published Dutch patent application no. 61100209 and Ilgy patent no. 887.17! Please refer to the issue.

Third, a compound of formula XIIT can be prepared with a suitable formula wt-c(-
o)-〇M compound (wherein W''-C(=O)-0-OyohiM is as indicated above). This gives a compound of formula The thing is
The amino group-protecting group X and, if necessary, all the carboxy group-protecting groups in (R7') are removed by the method described above to convert the compound of formula (2).

Compounds 2 and 3 will form acid addition salts.

and these acid addition salts are considered to be within the scope of this invention. The above acid addition salts may be prepared using standard methods for penicillin compounds, for example by preparing a solution of the compound of formula (1) in a suitable solvent (e.g. water, diethyl acetate, acetone, methanol, ethanol or butanol) in stoichiometric equivalents. It is prepared by combining with a solution containing the appropriate acid. If the salt precipitates, it is recovered by filtration. Alternatively, it can be recovered by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization. Of particular value are sulfates, hydrochlorides, hydrobromides, nitrates, phosphates, citrates, tartrates1. R moinate, perchlorate, sulfosalicylate, inine sulfonate, 4-) luenesulfone e salt, and 2-f phthalene sulfonate.

Compounds of formula (1) having a carboxy group in the radical R2 will form base salts. and these base salts are considered to be within the scope of this invention. These salts can be prepared by standard techniques such as contacting the acidic and basic components in normally stoichiometric proportions in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They are then optionally recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent or, in the case of aqueous solutions, by freeze-drying. Basic reagents suitable for use in the formation of salts belong to both organic and inorganic types and include ammonia, organic amines, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. , alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides. Representative examples of such bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, yne:)/L/amine and octylamine; diethylamine, morpholine, pytetralysine and biyridine. Secondary amines such as nitriethylamine, N-ethylpiperidine, N-methylmorpholine and tertiary amines such as t5-diazabicyclo(4,1]non-5-ene:
Hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides 9 such as sodium ethoxide and potassium ethoxide; hydrides such as calcium hydride and sodium hydride carbonates such as potassium carbonate and sodium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate; and alkali metal salts of long chain fatty acids such as 2-ethylhexanoic acid sodium salt.

When the salts of the antibacterial compounds of the invention are to be used therapeutically, it is necessary to use pharmaceutically acceptable salts;
However, salts other than these can be used for various purposes. Such purposes include the isolation and purification of specific compounds, and the interchange of pharmaceutically acceptable salts and non-salt forms thereof.

Compounds of formula II and their salts can be purified by conventional methods for nidiline compounds, such as recrystallization or chromatography, but with careful attention to the instability of the -tarlactam ring system and methylenedioir bond. I have to do it.

The known compounds of formula X are prepared by known methods,
Compounds of formula X, which are homologs of known compounds, are then prepared by methods analogous to known methods. In general, compounds of formula
<=o> -o-aH2-z C wherein z is a good leaving group, for example chlorine, bromine or iodine). Examples of M are sodium, potassium and tetra-n-butyla/monium.

See also US Pat. No. 4,244.951, published British Patent Application No. 2,044.255, published Dutch Patent Application No. 81100209 and Lugie Patent No. 887.173.

A method for preparing compounds of formula X is described in U.S. Patent No. 4.244,9.
No. 51 and No. 5.525.479.

2WI -C(=O) -0-OH, -Z Compound No. 5 Some of the compounds are known compounds, and the rest are homologs of the known compounds. Compounds that are known are prepared by published processes, and compounds that are homologues of known compounds; are prepared by methods analogous to published processes. Generally, the corresponding free acid, Wl-C(=O)
-0H, is reacted with a compound of the formula Z-OH2-21 (where 21 is a leaving group, which is the same as Z or a better leaving group). Further, for example, U.S. Patent No. 4,244.951, published British Patent Application No. 2,044.255, published Dutch Patent Application No. 81100209 and Rugie Patent No. 8
See No. 87,175.

For the preparation of compounds 2W'-C(=O)-OH and their salts, see, for example, US Pat. No. 4.2! 14.57
No. 9, No. 4,287,181, No. 4.256.733
No. and No. 4,110,165, published Dutch Patent Application No. 81100209; Ilgy Patent No. 887
．． No. 173 and Published European Patent Application No. 13
, No. 517.

Compound 2 has in vivo antibacterial activity in mammals, and this activity can be demonstrated by standard techniques for honeycillin compounds. For example, a compound of formula (II) is administered to acutely infected mice by intraperitoneal inoculation with a standardized culture of the pathogen. The severity of infection is determined by mouse force LD. . (LDl..:1
Standardized to receive 1 to 10 times the minimum inoculum required to consistently kill control mice of 0.00 nocent. At the end of the test, the activity of the compound is
It is evaluated by counting the number of survivors challenged by the bacteria and also administered the compound of formula (II). Compound 2) was administered orally (p, 0°) and subcutaneously (s, c,
) can be administered by both routes.

Due to the in vivo activity of the antimicrobial compounds of the present invention, they
Both Oral and Parenteral Dosage Forms Compounds of formula 1 form 6-(2-amino-2-(4-hydroxyphenyl)acetamide) after being administered to mammalian patients by both oral and parenteral routes. is decomposed into a compound of the formula W1-C(-〇)-OH, such as inisilanic acid 1.1-t-ocito9 (sulbactam). The compound then acts as a beta-lactamase inhibitor, increasing the antibacterial effect of amoxicillin. Thus, the compound of formula
: 1 will find use in the control of bacteria susceptible to the mixture, such as susceptible strains of Escherichia coli and Methophylococcus aureus.

The previously described in vivo test can be used to determine the Alternatively, amoxicillin formula wlc(=O)-0
Minimum inhibitory concentration (MIC) of a 1=1 mixture with a compound of H
can be measured. This MIC is an international collaborative research project on antibiotic susceptibility testing.
Co11aborative 5tucly on
Antibiotic S@n-5itiWity T
The method recommended by E'sting (Ericcgon and 5hers)
ria), Acta, Pathologica e
t Microbiologia 5candinav
.

Supplement 217, Section 8: 64-68 (1971)), which uses brain heart infusion (BHI) agar and a repeat inoculation device. For use as a standard inoculum, dilute the growth tube 100 times (about 0.002 - 20.000 - 10,0
00 cells are placed on the agar surface; 20 dBHI agar/
dish). Twelve 2-fold dilutions of test compound are used, the initial concentration of test drug being 200 mcr/-. Disregard single colonies when reading the plates after 18 hours at 37°C. Susceptibility of test bacteria (MIG) is expressed as the lowest concentration of compound that can completely inhibit growth when judged visually.

When the antimicrobial compounds of the present invention or salts thereof are used in mammals, particularly humans, the compounds can be administered alone or they can be administered with other antibiotics and/or pharmaceutically acceptable carriers or diluents. Can be mixed. The carrier or diluent is selected based on the intended dosage format.

For example, when considering oral dosage forms, the antimicrobial compounds of the present invention can be formulated into tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like according to standard formulation methods. , can be used in the form of The ratio of active ingredient to carrier will, of course, depend on the chemical nature, solubility and stability of the active ingredient as well as the intended dosage. In the case of tablets for oral use, commonly used carriers include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used in tablets. For oral dosing in capsule form, useful diluents include lactose and high molecular weight polyethylene glycols, such as molecular weight 200
Polyethylene glycol having a molecular weight of 0 to 4000.

When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.

If desired, certain sweetening and/or flavoring agents can be added. For parenteral administration, including intramuscular, intraperitoneal, subcutaneous, and intravenous use, sterile solutions of the active ingredient are usually prepared and the pH of the solutions suitably adjusted and buffered. For intravenous use, the total concentration of solutes must be adjusted to make the formulation isotonic.

As previously indicated, the antimicrobial compounds of the present invention are useful in human patients, and the daily dosage to be used is not significantly different from other clinically used inicillin antibiotics. Dew. The attending physician will ultimately determine the appropriate dosage for the individual human patient, which will vary depending on the age, weight, and response of the individual patient, as well as the nature and severity of the patient's symptoms. I can think.

The compounds of this invention will normally be administered orally at doses ranging from 20 to about 100 q/kg body weight per day, and parenterally at doses ranging from about 10 to about 100 q/kg body weight per day. Doses of up to 100 capsules may be used, usually in divided doses. In some cases, it may be necessary to use dosages outside these ranges.

The following examples and methods are given merely for further illustration. Nuclear magnetic resonance spectrum (NMR)
is measured for solutions in deuterated chloroform (CDCl2) or deuterated dimethyl sulfoxide (DMSO-a6), and the peak position is in ppm downfield from tetramethylsulfoxide (partspsr
m1llion). The following abbreviations are used for peak shapes: b82 broad single line;
S, single line; d, double line; t, triple line; q.

Quadruple: m, multiplet.

Example t Banidiranic acid 6'-C2-amino-2-(4-isobutyryloxyphenyl]acetamide)honisilanoyloxymethyl 1,1-dioxide hydrochloride 15 in 7305 g of acetate If)-! Nidylanic acid 6'-(2-[1-,)
'Chiru-2-methoxycarbonylvinylaξノ)-2-
, (4-Inbutyryloxyphenyl]acetamido)inisilanoyloxymethyl 1.1-dioxide was stirred, and 20 g of α1N hydrochloric acid was added thereto. After continued stirring for 5 minutes, the acetone was removed by vacuum evaporation. The remaining aqueous solution was extracted twice with 30 portions of diethyl ether. The two extracts were discarded and the aqueous layer was filtered through Celite (a diatom silica product).

The filtrate was lyophilized to give the title product t092 as a solid.

The NMRX of this product (in DMSO-a6) is 1l20-160(,18H), 2.64-3.00
(rn.

IH), 5.05-5.92 (m, 2H), 4.40 (
g, IH).

4.50(s, IH>, 5.05-5.50(o, 2H
), 5. ! 12-5.60 (m, 2H), 5.85 (s
, 2H), 7.10ra.

2H) and 7.50 (d, 2H) ppm.

Example 2゜Substantially following the steps of Example 1, Examples 5 and 7
−9 product to 0. Hydrolysis with IN hydrochloric acid gave the following compound.

Example 5 is Nidyranic acid 6'-(2-amino-2-(4-acetoxyphenyl)acetamide) inisilanoyloxymethyl 1,1-dioxide 9 Inicrane[6'-(2-benzyloxycarbonylamino-2- [4-acetoxyphenyl]acetamido)inisilanoyloxymethyl 1,1-dioxide 019F
, dichloromethane 50-, Impropatol 50/and 10% palladium on carbon 2. The Of mixture was shaken for 20 minutes at approximately 45 psig under an atmosphere of hydrogen. At this point, add 2.0 additional palladium on carbon. Of was added and the mixture was shaken under hydrogen at approximately 45 psig for 20 minutes. After that, additional 2. The steps of addition of palladium on carbon and shaking at about 45 pang under hydrogen were repeated four more times. The reaction mixture was then filtered through Celite (a diatom silica product) and the residue (filter cake) was washed thoroughly with 1=1 dichloromethane-isopro2ol. The combined filtrate and washings were evaporated in vacuo to give a white solid, which was triturated under diethyl ether. This yields a first crop of the title compound of 0.32
I got it.

The upper filter cake was washed successively with 100 liters each of acetone, dichloromethane and isopro-2-nol.

The combined washings were concentrated in vacuo to give a gray solid. This solid was triturated under diethyl ether. by this,
0.22 of a second crop of the title compound was obtained.

The NMR spectrum of the first crop of the title compound is cutol (DMSO).
-a, middle) is 1.35 (s, 6H), 148 (
a, 6H).

2.28(s, 3H), ! LOO-3,90 (1!
l, 2H), 4.42 (8, IH).

4.50 (tz, IH), 5.00 (1)8. I
H), 5.05-5.20 (1El, IH).

5.34-5.58 (!11.2H), 5.90 (s
, 2H), 7.10(d, 2H) and 7.54
(d, 2H) 1) p! ! It showed absorption at 1.

Example 4° is penicillanic acid 6'-(2-amino-
2-(4-acetoxyphenyl]acetamide 9) Honeysilanoyloxymethyl 1. The two crops of 1-dioxide are combined to form water 20- and the Q,IN salt! 6.7+, /
was added to the cold (0° C.) stirred mixture prepared from After continued stirring for 15 minutes, the mixture was filtered. The filtrate was lyophilized to yield 0.54f of the title salt.

Example 5 Penicillanic acid 6'-(2-(1-methyl-2-methoxycarbonylvinylamino)-2-[:'4-acetoxyphenyl]acetamide) is nisilanoyloxime 30y
In dichloromethane, 3.5F is nidilanic acid 6'-
(2-[1-methyl-2-methoxycarbonylvinylamino]-2-(4-hydroxyphenyl]acetamide)
To a stirred solution of inisilanoyloxymethyl 1.1-:) oxide and 0.611 of 4-:) methyl amine/pyridine was added 0.47 m of acetic anhydride. After continued stirring for 30 minutes, the reaction mixture was concentrated to half the volume. The latter solution was then diluted with an equal volume of ethyl acetate and chromatographed on silica gel 100f using 1:1 ethyl acetate-dichloromethane as eluent.

The appropriate portions were combined and evaporated in vacuo to give the title compound 2.7F as a pale orange foam.

Examples & Penicillanic acid<S'-(2-[1-methyl-2-methoxycarbonylvinylamino]-2-(4-isobutyryloxyphenyl]acetamide)honisilanoyloxymethyl 1,1-dioxide 0 Dichloromethane Penicillanic acid 6'=(2-
(1-methyl-2-methoxycarbonylvinyl)-2-
C4-hibiroxyphenyl]acetamide e) inisilanoyloxymethyl 1,1-:)oxy to 2.12r and 4
-A solution of dimethylaminopyridine Q, 566f was stirred, and 314 wt of isobutyryl chloride Q was added thereto.

Stirring was continued for 30 minutes before additional 75-dichloromethane was added. The mixture was washed successively with water and saturated chloride solution and then dried using sulfuric acid solution. The solvent was removed by vacuum evaporation and the residue was chromatographed on silica gel 15Of using 60:40:) chloromethane-ethyl acetate as eluent. This gave the title compound 15f as a colorless foam.

Example 1 Penicillanic acid <5' substantially according to the steps of Example 6
-(2-(1-methyl-2-methoxycarbonylvinylamino)-2-(4-hydroxyphenyl)acetamide #)-, nisilanoyloxymethyl 1,1-dioxide, propionyl chloride, piparoyl chloride, t chloride Acylation was carried out separately with -butylacetyl, indiyl chloride, 4-methoxyindiyl chloride and 4-cyanoindiyl chloride. This gave the following compounds.

Qin This product was not chromatographed.

Example 8.4 Penicillanic acid 6'-(2-(1-methyl-2-methoxycarbonylvinylamino 1-2-[4-ethoxycarbonyloxyphenyl]acetamide)inisilanoyl odichloromethane 3owIt) -(2-
[1-Methyl-2-methoxycarbonylvinylamino]
2.12V
and 4-dimethylaminopyridine Q, 366f was stirred, and 0.28 m of ethyl chloroformate was added thereto. After continued stirring for 45 minutes, the reaction mixture was diluted to 100 d with dichloromethane.

The mixture thus obtained was washed with water and then with saturated sodium chloride solution, dried (Na2So4) and evaporated in vacuo. This resulted in a foam of 2.12. This foam was redissolved in 50-dichloromethane, and α
52 Mt of diisopropylethylamine followed by 028
+d of ethyl chloroformate was added. After about 10 minutes, the solvent was removed by vacuum evaporation and the residue was dissolved in ethyl acetate. This ethyl acetate solution was mixed with water, 0.05N hydrochloric acid,
Washed successively with water and saturated sodium chloride. The dried (Na2So4) solution was then evaporated in vacuo to yield the title compound 2. Of was obtained as a foam.

Example 9 Penicillanic acid 6'-(2-(1-methyl-2-methoxycarbonylvinylamino)-2-(4-isonodoxycarbonyloxyphenyl)acetamyr)-2 in dichloromethane 50-, is nidilanic acid 6'-(2-(1
-Methyl-2-methoxycarbonylvinyl7mi/)-
2-(4-hydroxyphenyl]acetami) #) is nisilanoyloxymethyl 1,1-dioxyl'2.12F
and 0.52 m of diisopro2-ethylamine were stirred, and 0.388 m of isobutyl chloroformate was added thereto. Stirring was continued for 10 minutes, then about 20 μ of 4-dimethylaminopyridine was added. After continued stirring for 30 minutes, the solvent was removed by vacuum evaporation. The residue was dissolved in ethyl acetate and the solution was washed with water and then with saturated sodium chloride solution. Dry this solution and add rNa
2So4) was evaporated in vacuo to give a 2.2f foam. This foam was purified by chromatography on silica gel 75 using 60:40 dichloromethane-ethyl acetate as eluent. As a result, 1.
The title compound 4f was obtained as a foam.

Example 10 Penicillanic acid 6'-(2-(-''ndyloxycarbonylamino)-2-(4-acetoxyphenyl)acetamide) in nisilanoyloxymethyl 1.1-:)oxide dichloromethane 50- 2.23y 4-nidylanic acid 6
'-(2-indyloxycarbonylamino-2-(4
-Hydroxyphenyl]acetamide #) Hanisilanoyloxymethyl 1. A solution of 1-y oxide was stirred, and to this was added acetic anhydride α28-1 and then 0.566f of 4-dimethylamino♂lysine.

After continued stirring for 10 minutes, the solvent was removed by vacuum evaporation. The residue was dissolved in ethyl acetate and the resulting solution was washed with water. This was then dried using sodium sulfate and concentrated in vacuo to yield the title compound 2. O2 was obtained as a foam.

NhtR vector (in CDCh) is t35-1.6
0 (m, 12H), 2.25 (e, 3H), 3
．． 40 (eL, 2H), 4.38 (s, 2H), 4
．． 56 (t, IH), 5.04 (@, 2H), 5.20
-5, (50(1!I, 3H), 5.80(s, 2H)
, 6.12 (11, IH).

+S, 48 (d, 2H), 7.24 (g, 5H),
Absorption was observed at 7.30 ((L, 2H) ppm).

Example 11° is nidylanic acid 6'-<2-amino-2-[4-butyryloxyphenyl]acetamide 9) 71ff)-' in 755 g of ethyl hanisilanoyloxymeacetate? Stirring a solution of Nidylanic acid 6'-(2-(1-methyl-2-methoxycarbonylvinylamino)-2-(4-hydroxyphenyl)acetamyr)-<Nicinnoyloxymethyl 1,1-dioxide, To this was added 4-dimethylaminopyridine 122F, then butyric anhydride 1.63-.2
After continued stirring for 0 min, the reaction medium is diluted with ethyl acetate to 125- and water and saturated chloride) I
Washed with Jum solution. The obtained solution was diluted with sulfuric acid) I
Dry with Jum and then ethyl acetate 35-
and 4-toluenesulfonic acid/hydrate 19 in water 1-
The solution of f was added over 2 minutes with stirring. After 30 minutes, the precipitate was removed by filtration, after which it was washed with ethyl acetate and air-dried. The product was then triturated under diethyl ether and further dried. Since this is K,
6.21 of the title compound was obtained.

The NMR spectral (DMSO-46) of this product is:
t03 (t, 2H), t3-1.9 (m, 14
H), 2.55 (s, 3H).

2.4-2.8 (m, 2H), 3.1-5.9 (m
, 2H), 4.46(a, IH).

4.56 (s, IH), 5.06-5.3 (m,
2H), 5.4-5.66 (m.

2H), a93(be, 2H), 7.0-7.36(m
, 4H) and 7.4-7.66 (m, 4H>, ppm
showed absorption.

The IR spectrum (Nujol Mal) of the product is 17
It showed absorption at 903.

Example 12゜Hanishira:/rl! 6'-C2-amino-2-1:4-
(N-n-butylcarbamoyloxy)phenyl]acetamide@)penicillanoyloxymethyl 1.1-:)oxide hydrochloride t2t penicillanic acid 6'-(2-(1-methyl-2- Stir the solution of methoxycarbonylvinyl ξ)-2-(4-(N-n-methylcarbamoyloxy)phenyl]acetamiy)-<nisilanoyloxymethyl 1,1-:) oxide 9, and 0.1N hydrochloric acid 15- was added to the solution. Stirring was continued for 20 minutes and then the acetone was removed by vacuum evaporation. The remaining aqueous phase was washed with diethyl ether and then lyophilized. This gave the title compound 0.97F.

NMR slurry (DMSO-d6) was 0.7-1.
1 (m.

3H), 11-1.6'(m, 16H), 2.8
-3+, 9 (m, 4H), 4.15 (a, IH), 4
．． 5 (s, IH), 5.0-5.3 (m, 2H), 5.
36-5.6 (m, 2H), 5.9 (bs, 2H)
, 7.1 ((1,2H), 7.53(d,
2H), 7.8 (m, IH), 8.6-9.3
(m, 3H) and 9.4 (d, IH) pp
m te absorption 'it shows L ta.

Example 13゜penicillanic acid 6'-(2-(1-methyl-2-methoxycarbonylvinylamino)-2-[4-(N-n-,butylcarbamoyloxy)phenyl]acetamido)penicilanoyloxymethyl 1 .1-Dioxytoinidylanic acid 6'-(2-(1-methyl-2-methoxycarbonylvinylamino)-2-[4-hydroxyphenyl]acetamide 0)-!Nicilanoyloxymethyl 1.1-: )
Oxide 7.1F, 4-dimethylaminopyridine 1.4
A mixture of 6F and 50-dichloromethane was stirred until a clear solution was obtained.

To the solution was added 2.2 m/l of n-butyl iso-l cyanate and stirring was continued for 20 minutes. The solvent was removed by vacuum evaporation and the residue was eluted with 60:40 dichloromethane-ethyl acetate. Chromatographed on silica gel 5002. The product containing fractions were combined and evaporated in vacuo to give the title compound t22 as a white foam.

NMR spectrum (CD C4) is 0.7-1.1
(m, 3H) 12-165 (m, 16H), 5.6(
a, 5H), 4.4 (s, 2H).

4.5-4.7 (m, 2H), 5.1 (6, IH
), 5.3-5.65 (!El, 2H).

5.9 (be, 2H), 6.85 (d, 2H
), 7.06 (6,2H), 7.53 (4,2H)
and 9.4(d, 2H) I) showed absorption at Pm.

Production method 1゜Inisilanic acid 6'-(2-[1-methyl-2-methoxycarbonylvinylamino')-2-[4-hyroxyphenyl]acetamide)-! Nisilanoyloxymethyl 1
．． 1300- of dichloromethane IC6-(2-amino-2-[4-hydroxyphenyl]acetamihi)hanisilanic acid trihydrate 419F and water 50- are added,
The pH was adjusted to 8.5 using 40% aqueous tetra-n-butylammonium hydroxide solution. Three layers were obtained. The upper layer was removed and saturated with IJ sulfate and then extracted with dichloromethane. The extracts were combined with the middle and bottom layers and the resulting mixture was evaporated in vacuo to give an oil which crystallized upon trituration with acetone. As a result, 6-(2-
Amino-2-[4-human90xyphenyl]acetamide 9)-! Tetra-n-butylammonium dilanate was obtained.

The above salt was added to 150-methyl acetoacetate and the suspension was heated to about 65° C. until a clear solution was obtained (8 minutes). Once the mixture had cooled, the solids were collected by filtration. The solid was washed with methyl acetoacetate and then diethyl ether to give 49.25 t of 6-(2-[1
-Methyl-2-methoxycarbonylvinylamino')-
2-[4-Hyviroxyphenyl]acetamide 0) Tetra-n-butylammonium hanisilanate was obtained.

47.5 f of the latter product in 250 - of dimethylformamide) was added with 50 of the same solvent while stirring at 0°C.
18.2<S- iodomethyl inisillanate 1.1
- Dioxide was added over 20 minutes. 10 minutes after this addition was complete, the reaction mixture was poured into 6 t of ethyl acetate and
The resulting precipitate was filtered off. This precipitate was mixed with ethyl acetate (
10 (ld) and then the combined ethyl acetate solution was mixed with syline solution (4 x 500 m), water (4 x 500 m)
m) and brine solution (2×500 m′) and dried over sodium sulfate. The residue remaining after removing the solvent was chromatographed on silica gel 750 using ethyl acetate as eluent. Fractions 2-5 (250/each) were combined and concentrated to 312V.
The title compound was obtained.

NMR suction unit (DMSO-(16” H10)
0-IM Hvs) is t37(s, 3H), t
38 (a, 3H), 14B (s, 3H).

1.57 (s, 3H), t76cm, 5H), 3.
14-3.82 (m, 2H).

3.51 (a, 3H), 4.42 (s, IH),
4.44 (s, IH).

4.54 (s, IH), 5.1-5.22 (m, IH)
, 53-5.64 (m.

3H), 5.9 (s, 2H), 6.7 (d, 2H),
7.14(d, 2H).

9.02((1,IH), 9.24((1,IH),
and 9.34-9.54 (be, lH') pp-.

Production method 2゜Inisilane H6'-C2-inzyloxycarbonylamino-2-[4-human 90xyphenyl]acetamide #
)-! Tetra-n-butylammonium 6-(2--'?ndyloxycarbonylamino-2-C4-hibiloxyphenyl]acetamido)inisilane in 1.1-dioxide 50% dry acetone 9.5% f, iodomethyl inisillanate 1.1-:)
4.78F of oxide was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was
Chromatographed on silica gel 200f using ethyl acetate/dichloromethane (1:IV:V), 25-
I took two cuts. Fractions 29-49 were combined and concentrated to yield the desired product 6.5f as a yellow foam.

NMRx vector) (DMSO-a6) is t42(
8゜3H), 152 (s, 3H), +6 (s, 3H)
, 5.1-&9(m, 2H).

4.45 (s, IH), 4.58 (s, IH), 5.0
8 (s, 2H), 4.98-5.7 (m, 4H),
5.95 (a, 2H), 6.68 (6,2H
), 7.2 (+1, 2H) and 7.35 (a, 5H
) showed absorption at ppm@Production method 3゜6-<2-<ndyloxycarbonylamino-2-C4
-hyroxyphenyl]acetamide) is rapidly stirring n-butylammonium nidilanic acid, 6-(2--?ndyloxycarbonylamino-2-C4-human90xyphenyl]acetamide)inidic acid tOf, :) Chloromethane 30-
and water to a mixture of 20-40% pHaO.
m aqueous solution of tetra-n-butylammonium hydroxide was added. Stirring was continued for 30 minutes at pH 8.0 and then the layers were separated. After extracting the aqueous layer with dichloromethane, the combined dichloromethane solution was dried (Na2S04),
Evaporated in vacuo. This gave the title compound t1f.

NMR spectral (DMSO-d, medium) is α770-
180 (, 34H), 2.9O-3-50 (1!l, 8
H), 3.95 (a, IH).

5.10 (s, 2H), 5.23-5.50 (m, 3f
(), 6.76 (d, 2H).

7.20 (d, 2H), 7.40 (s, 5H), 7.7
6(d,IH) and 8.6((1,IH) ppm
Shows absorption at the bottom.

Preparation method 4゜Inisilanic acid 1.1-: A mixture of 4.66f of inisilanic acid, 50wl of dichloromethane and 55d of water was added to sufficient amount of tetra-n-butylammonium hydroxide (40g in water).
The pH was adjusted to 6.0. The dichloromethane layer was separated and the aqueous phase was extracted with fresh dichloromethane (2x50-). The organic layers were combined, dried over sulfuric acid, and concentrated to give nidilanic acid 1,1-dioxide 9.
10.1F of the tetra-n-butylammonium salt was obtained.

Tetra-n-butylammonium 4-nidylanate 1 as described above
．． The 1-dioxide was added to 50-chloroiodomethane and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to half volume and chromatographed on 20 Of silica gel using ethyl acetate/hexane as eluent, taking 12-cuts every 30 seconds. Fractions 41-73 were combined and concentrated to dryness to yield 5.22 of the title compound.

NMRx-<cutol (C; DCl, ) is 15 (g, 3
H).

166 (s, 3H), 3.42 (d, 2H), 4.38
(s, IH).

4.6(t, IH), and 5.7(M, 2H)e
Absorption was shown at Ppm.

Preparation 5゜R Iodomethyl Nidylanate 1,1-dioxide To a solution of μrotathylic inisilanate 1,1-dioxidoph, 9 F in 100 wt of dry acetone kept under a nitrogen atmosphere, 21 Of sodium iodide is added and the reaction is carried out. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in 150° of ethyl acetate and 150° of water. The organic layer was separated and the aqueous layer was extracted with fresh ethyl acetate. The organic extracts were combined, washed with water (IX500y) and brine (IX50m) and dried over sodium sulfate. Removal of the solvent yields the title product, mp 10
IQ of 0-102°C and 5F were obtained.

NMRx-< ctor(CDCl2) is +55(s, 3
H').

168 (s, 3H),! 1.5 (+1,2H), 4.4
(8, IH).

4.65 (t, IH), and 6.0 (aa, 2
H) Absorption was shown in ppm.

Preparation & Heptadyl ester of dimethylmalonic acid A mixture of monobenzyl ester of dimethylmalonic acid, 1.0 m of thionyl chloride, and 15 m of dichloromethane was stirred at room temperature for 1 hour, then heated for 4 hours. and refluxed. The volatile components were then removed by vacuum evaporation to give the title compound, which was used directly for the acylation of the compound of formula X.

Process Z 75, 3.12f (4,
A solution of 85-dipotassium hydroxide (8 mmol) was dissolved in diindyl dimethylmalonate 1-1 in R-endyl alcohol.
5. Added to Or. The solution thus obtained was stirred for 60 hours, 15 liters of ethyl ether were added, and the resulting mixture was extracted twice with 100 liters of water. The combined aqueous layers were washed with ether 100-. In this aqueous layer,
100-ethyl ether was added and the mixed eyelid was acidified with 6N hydrochloric acid to pH 2.5. The ether layer was separated and the aqueous phase was extracted again with ether. The ether extract was dried (Na2SOa) and the solvent was evaporated, leaving the product as a colorless oil.8. T! 5P (81%) was obtained.

Production method 8゜Diindyl dimethylmalonate 4, Of water containing sodium hydroxide 75. ．． /K
At 0°C, 17. Of (α05 mol) of tetrazotylammonium hydrogen sulfate was added and the mixture was stirred for 15 minutes.
Warm, and dibenzyl malonate 14.2r (0,
05 mol) and 100 d of chloroform containing 6.6-(α10 mol) of methyl iodide were added. This mixture (
Initial pH>12) was stirred for 60 minutes, at which point the mixture was at pH approximately 8. Stirring was continued for 10 minutes and the organic phase was separated.

To this organic layer was added another 4 ml of sodium hydroxide in 75 ml of water.
A charge of 170F of tetrazotylammonium hydrogen sulfate and 6.6f of methyl iodide was added. The resulting mixture was stirred at room temperature for 60 min, the chloroform layer was separated, dried (Na Z SO4) and concentrated in vacuo. The resulting residual oil was triturated with 500 m of ethyl ether, the resulting solid was filtered, washed thoroughly with ether, and the filtrate and washings were evaporated to 15.0 r.
(96%) of product was obtained.

Patent applicant: Pfizer Inc. No. 1
Continued pagePriority claim 06/28/1982ΦUnited States (US)■
392139

Claims (1)

Claims: 1) A pharmaceutically active compound of the formula, its pharmaceutically acceptable acid addition salts and its pharmaceutically acceptable base salts. [wherein R2 is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms,
HooG-(CH2)n-9)1000-C(OH,)
selected from the group consisting of 2-, 3-carboxycyclopentyl, 4-carboxycyclohexyl, R8R'N-, and groups of formula (where n is an integer from 0 to 6; R8 and R9 are each hydrogen, Alkyl groups having 1 to 6 carbon atoms, phenyl groups, fluorine, chlorine, bromine, iodine, and 1 to 4 carbon atoms). Ayayaya group again. The number of carbon atoms is 1 and 4. phenyl substituted with an alkoxy group, provided that R8 and R9 are not both hydrogen; and R3 is hydrogen, a C1-C4 alkyl group, a carbon atom number 1 to 4
alkoxy groups, fluorine, chlorine, bromine, iodine and cyano groups); and a group W1-C
(=0)-0- is a beta-lactamase inhibitor having not only a carboxy group but also a beta-lactam ring, W'
-C(=O)-OH residue]. 2) Wl −C(,=o>−0−force([in the formula,
R4 is selected from the group consisting of hydrogen and hydroxymethyl; R5 is selected from the group consisting of chlorine, bromine and iodine: R' ha, -0H2-C4-0H2-0-cO-CH,
Oyo? J-C(=O)-OR" (wherein R11 is an alkyl group having 1 to 4 carbon atoms): and RIO represents a hydroxy group and the corresponding position of clapulaic acid. 2. A compound according to claim 1, wherein the compound is selected from the group consisting of groups known to confer beta-lactamase inhibitory activity to clapulanic acid when bound to clapulanic acid. 3) The compound according to claim 2, characterized in that W'-C(==O)-0- is 4) R2 is the above alkyl group, the above alkoxy group or the above formula 5) The compound according to claim 4, wherein R2 is the alkyl group. 6) R2 6. The compound according to claim 5, wherein is a propyl group.