JPS58128387A - Novel beta-lactam compound, manufacture and use - 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 β-lactam compounds and their salts with pharmacologically acceptable non-toxic acids or bases, methods for producing the novel compounds, unit dosages of compositions thereof, and methods for producing the novel compounds. and a method of treating a patient suffering from an infectious disease using the composition.

Shows particularly strong activity against bacteria.

Compounds of the invention that are valuable antibiotics in human and veterinary therapy have the general formula: 0 where k is hydrogen, cl-c4 alkyl or C2-C
5-acyl, kl is hydrogen, methyl, ethyl, benzyl or phenyl, and An represents a cephalosporin-type residue or an amidinopenicillanic acid residue bonded via a carboxy group). For more details, see A.
n is a general formula ■ or ■: In the formula C, the formula R2C0NH- is the 7-position side chain of a known cephalosporin, R3 is a substituent at the 3-position of a known cephalosporin, R4 is hydrogen or methoxy, and the 6-chain ).

Useful cephalosporins forming the residue (IIa) are, for example, Furi7 (E, HoFlynn),
cephalosp-orins and Pen1
cill ins, 7 Kademik Press (Acad
emic press), New York, London, Sams (P, G, Sa+nmes), Chem, R
ev,, 1976゜vol.76, K1.113-155, Jasberenyi (J, Cs, Jasberenyi)
and Gunda (T, E, Gunda).

Prog, Med, Chem, Volume 12, 1
975. pp. 395-477, Elks (J, Elks)
, Recent Advances 1nthe C
hemisLry ofβ-1actam antib
iotics, The Chemiriki JLt-7 Saiatei (T
he Chemical 5oci-ety), London, 1977, Merck Index (Merck
Index), 9th edition, Merck and Co., Ltd.
dCo, Inc.), o-way (Rahway)
, N.J., ,USA.

1976, Encyclopedia of Antibiotics
biotics).

2nd edition, John Wiley & Sons (Jolln)
Wiley and 5ons) (1978), and Chemistry and Biology of β
-1actam Antibiocics, 3 volumes, Academic Press, New York and London, 1
982, pages 387-392.

Useful amidinopenicillanic acids forming the residue (IIT) are described, for example, in British Patent No. 1,293,590;
゜315.566 and West German Patent No. 2,055,53
It is stated in No. 1.

Particularly useful cephalosporins forming the residue (I[a) include cefoxitin, cefperacin, cephalexin, cephalexin, cefamandole, cefsulodin, cefothiam, cefmetuxime, cefperacin,
cefmetazole, cephaloglycin, cephalexin,
Included are cefrazine, cefadroxil, cefaclor, cefatridine, cephaloridine, cephapirin, cefazolin, cefazolin, cefazetri/L/, ceftazidime and cefuroxadrine.

A particularly useful 1-oxacephalosporin of general formula mb is moxalactam.

Particularly useful amidinopenicillanic acids forming the residue rIII) include mecillinum.

The above examples of particularly useful cephalosporins and amidinopenicillanic acids are merely illustrative of the invention and are not intended to limit it.

- Compounds (I) in which R are both hydrogen, especially A
Of particular interest are compounds in which n is a residue formed by cephradine, cefaclor, cephalexin or mecillinam.

The present invention encompasses all possible diastereomeric combinations as well as mixtures of compound (I).

As mentioned above, the invention also relates to salts of esters (I) with pharmacologically acceptable non-toxic acids or bases, depending on whether An has a basic or acidic function.

Suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid,
Phosphoric acid, sulfuric acid, nitric acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, formic acid, acetic acid,
Examples include propionic acid, citric acid, tartaric acid, maleic acid, pamonic acid, and P-(dipropylsulfamyl)benzoic acid (probenecid).Suitable bases include sodium hydroxide, potassium hydroxide, magnesium hydroxide. ,
Alkali metal hydroxides such as calcium hydroxide, alkali metal hydroxides, other ammonia, lower alkyl amines (e.g. triethylamine), hydroxy-lower alkyl amines (e.g. 2-hydroxyethylamine, bis(2-hydroxyethyl)) Examples include suitable non-toxic amines such as tris(2-hydroxyethyl)amine), cycloalkylamines (e.g. dicyclohexylamine), or tahapendylamines (e.g. N,N-dibenzylethylenediamine or dibenzylamine). However, these examples are not intended to limit the invention. Salts with acidic or basic antibiotics are also within the scope of the invention. In some cases,
Although it is preferred to use readily soluble salts, it is appropriate to use only slightly soluble salts such as napsylate or tosylate salts for other purposes, for example to achieve a sustained effect. In particular, a sustained effect can be achieved by using salts with probenecid, which inhibit the ductal excretion of β-lactam compounds.

The increasing frequency of β-lactamase producing bacteria is a serious problem in the clinical treatment of bacterial infections. This enzyme can inactivate β-lactam antibiotics, and it is well known that both β-lactamases from Durham-positive bacteria and β-lactamases from Durham-negative bacteria are highly sensitive to β-lactam antibiotics. Contributes significantly to resistance.

Several natural β-lactamase inhibitors have been reported, including clapulanic acid and olipanic acids, as well as some semisynthetic β-lactam compounds (e.g. penicillanic acid 1,1-dioxide, 6α-chloropenicillanic acid 1, 1-dioxide), a series of clapulanic acid derivatives, 6β-halopenicillanic acids (e.g., 6β-iodopenicillanic acid, 6β-bromopenicillanic acid), methicillin sulfone, and quinacylin sulfone were found to have similar biological properties. With a few exceptions, these compounds exhibit only low antibacterial activity against most Durum-positive and Durum-negative bacteria, but are strong inhibitors of various β-lactamases.

A particularly useful β-lactamase inhibitor is 6β-hydroxymethylpenicillanate sulfone, the preparation of which is described in Belgian Patent No. 885,812 and Swiss Patent Application No. 4017/80.

According to the findings of the present inventors, this compound has been found to be a potent inhibitor of various types of β-lactamases, including cephalosporinases, for which other known inhibitors show only weak activity. It was done.

To successfully treat bacterial infections, one or more β-lactam antibiotics and one or two β-lactams on α-
It is known to perform combination therapy with lactamase inhibitors.

According to the invention, such combined therapy can advantageously be carried out using compound (I) which is converted in the body after absorption and degradation into two active drugs, namely a β-lactam antibiotic and a β-lactamase inhibitor. .

Thus, compound (I) is considered a mutual prodrug for the antibiotic and inhibitor in question.

However, two preconditions are necessary to take advantage of this feature of the new compound (I). That is, these compounds can be absorbed from the gastrointestinal tract, and during or after absorption these compounds must be hydrolyzed to liberate the antibiotics and inhibitors in question.

Since it has been shown that both of these prerequisites are met, the compounds of the invention are valuable active compounds for the intended purpose.

That is, animal studies have revealed that these new compounds are easily absorbed from the gastrointestinal tract.

During or after absorption, these compounds are hydrolyzed to liberate equimolar amounts of both components of interest and at the same time exhibit high blood and tissue concentrations of both components. Therefore, antibiotics
Inactivation is most effectively protected by inhibitors that counteract it.

By using the compounds of the present invention, even β-lactamase-producing bacteria can be easily treated, so that the antibacterial spectrum of the β-lactam antibiotics in question is widened. Such β-lactamase producing bacteria occur with increasing frequency and, as mentioned above, are a serious problem in clinical therapy. The compounds of this invention are extremely valuable for such purposes.

2. These new compounds have distinct advantages over the simple combination of β-lactam antibiotics and β-lactamase inhibitors they are hydrolyzed to produce or the combination of their orally active esters. .

For example, 6β-hydroxymethylpenicillanic acid 1.1-
Many β-lactamase inhibitors, including dioxide, are absorbed incompletely or irregularly from the gastrointestinal tract. Furthermore, many of the antibiotics that form part of the compounds of the invention are only incompletely absorbed when administered orally. Additionally, individual variations in absorption rates for various antibiotics and β-lactamase inhibitors often result in situations in which their active components are not present at the site of infection at the same time or in optimal proportions, even when both drugs are administered simultaneously. bring about.

Certain easily hydrolyzed esters of both antibiotics and β-lactamase inhibitors, whose residues are combined in compound (I), are better removed from the gastrointestinal tract than the corresponding free acids. Absorbed. However, hydrolysis of such esters in organisms results in the formation of inert by-products, and although these by-products are relatively non-toxic, it is undesirable to expose the organism to unnecessary metabolites. do not have. Another disadvantage of using a combination of easily hydrolyzable esters of antibiotics and β-lactamase inhibitors is that the ester moiety increases the molecular weight of the compound and, as a result, the unit dosage size. . By using the compounds of the invention, the unit dosage size can be significantly reduced.

Furthermore, absorption of such esters does not usually occur simultaneously, even if these compounds are administered to a patient at the same time.

All these disadvantages are overcome by using the compounds of the invention.

The in vitro synergy of 6β-hydroxymethylpenicillanic acid 1,1-dioxide with various cephalosporins and substituted aminopenicillanic acids has been demonstrated when the proportions of the same components are 3.
:1 to 1:3, it was found to be particularly remarkable. Since different antibiotics have different biological half-lives and distribution characteristics, the proportions between the free components of these new compounds in organs and tissues may vary to some extent, but usually within the preferred limits mentioned above. It is something that stops.

The synergistic effect is illustrated in the table below: Prior to testing the susceptibility of β-lactamase producing strains to compounds of the invention containing groups, the compounds were subjected to enzymatic degradation.

Note 1) Antimicrobial Age End Chemotherapy
ntsand C11emothcC11e),
Expressed as IC5o values (p!/ml) determined on agar plates according to 3, 266 and 271 (1975).

2) Not I) etermined The present invention also includes:
It includes methods for producing these new compounds and their salts. According to one method, general formula=11 R1 6 In the formula, R□ has the same meaning as above. R7 may be R in some cases.
(same meaning as above) or easily cleavable esterified or etherified groups, such as benzyloxycarbonyl, 2,2.2-trichloroethoxycarbonyl, benzyl, 2,2.2-) IJ chloroethyl or trialkylsilyl (for example, 1erL-butyldimethylsilyl) and X represents a free radical [for example, a halogen atom, preferably iodine], respectively).
e may be An (same meaning as above) or,
For example, a carboxylate ion corresponding to a protected or masked derivative of An containing an azide group or a benzyloxycarbonyl group in place of the amine 7 group present in An, Al or An'' can be converted into a cephalosporin type at an appropriate stage. A suitable penicillin-type residue which can be transferred to the residue An, and - represents a cation, e.g. Na+, K+, ammonium ion, tri- or tetraalkylammonium ion (e.g. tetrabutylammonium ion), respectively. to R7\ and/or in the case of An''\An, further suitable chemical modifications, e.g. R
Cleavage replacing 7 with hydrogen and optionally subsequent alkylation or acylation and/or converting An'' to A
The desired compound (I) can be obtained by carrying out the reaction necessary for conversion to n, such as hydrogenation of an azide group or a benzyloxycarbonyl group to an amino group.

The reaction of the compound OV) with An width is carried out in a suitable solvent such as dimethylformamide, ethyl acetate, methylene chloride, acetone or hexamethylphosphoric triamide for a sufficient time and at a temperature sufficient to achieve the desired conversion. , usually at a temperature of 0°C to 60°C.

Compound (TV) is a compound represented by the general formula: -CH-X 1 (■) 10 where k□ and X have the same meanings as above. Y is a radical (e.g. bromine or chlorine), halosulfonyloxy (e.g. chlorosulfonyloxy), alkylsulfonyloxy, α-haloalkoxysulfonyloxy or unsubstituted or substituted arylsulfonyl, t-oxy (e.g. benzenesulfonyloxy, tosyloxy or bromobenzenesulfonyloxy). ] If Y is a free radical that is better than X, it can be obtained by reacting the compound represented by the following and optionally further substituting X in the general formula IV with a free radical that is better.

Alternatively, compound (■) can be obtained by reacting compound (Vb) with compound (■) and further oxidizing. If desired, it is also possible to replace X in the general formula (1) with a more favorable free radical.

The oxidation step is performed in an inert solvent such as CH2C12,
It is carried out using a peracid such as m-chloroperbenzoic acid or by using potassium permanganate in a mixed solvent containing acetic acid.

Compound (I) can also be prepared with the general formula An*eM as the first step.
It can also be obtained by a method in which compound (VI) is reacted with the compound (2) to produce an intermediate represented by the general formula %0 (where A'', R□ and X have the same meanings as above).

Compound (■) and compound (V) or A n ”OM
The reaction with (1) is carried out in a suitable solvent such as dimethylformamide, ethyl acetate, methylene chloride, acetone or hexamethylphosphoric triamide, usually at a temperature of 0°C to 60°C.

A preferred compound (■) is chloromethyl chlorosulfate, and preferred reaction conditions include a base, such as Na
It involves the use of a two-phase solvent system of organic solvent and water and a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate in the presence of HCO3.

In the second step, when the intermediate (■) is reacted with the compound (Va), if necessary, 7 to k and An'' to A
After appropriate conversion to n, the desired compound (I) is obtained.

If desired, X in the compound (■ ) can be carried out at the stage of compound (4).

The reaction between compound (■) and compound (Va) is carried out in an inert organic solvent such as dimethylformamide, ethyl acetate, methylene chloride, acetone or hexamethylphosphoric triamide under the above conditions, usually at a temperature between 0°C and 60°C. It will be carried out in

After this reaction, if necessary, from An''' to An and/or
Alternatively, necessary functional group conversion may be performed to convert 7 to 1(.

Some of the intermediates of formulas (1), (1), vb and (2) are hitherto unknown compounds and constitute a part of the present invention.

The starting materials of general formula (1) are either known or prepared by methods analogous to those used for the synthesis of other known compounds.

Compound (1) is purified and isolated by conventional methods, and can be obtained as it is or in the form of a salt.

These compounds are in some cases obtained as diastereomeric mixtures which can be separated by known methods such as chromatography if desired.

Another object of the invention is to provide pharmaceutical compositions that are useful in the treatment of infectious diseases in human and veterinary medicine and can be used for oral, parenteral or topical administration.

For this purpose, the composition of the present invention contains at least one member selected from the group consisting of the above-mentioned compound (I) and salts thereof as an active ingredient, and further includes a solid or liquid pharmaceutical carrier and/or diluent. including.

In the above compositions, the ratio of therapeutically active substance to carrier substance is between 1 and 95% by weight. This composition Δ consists of compound C mixed with a carrier and/or diluent.
I) or a non-toxic salt thereof can be formulated into various formulations, such as tablets, pills, sugar-coated tablets, active ingredients, capsules, sustained release tablets, and suspensions.

Pharmaceutically acceptable, non-toxic, organic or inorganic, solid or liquid carriers and/or diluents can be used to prepare compositions containing the compounds of the invention. Gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats, gums, polyalkylene glycols, buffers or other known pharmaceutical carriers, auxiliaries and/or diluents are all suitable.

Furthermore, the compositions of the invention may include other therapeutically active substances that may be suitably administered together with the compounds of the invention in the treatment of infectious diseases, such as other antibacterial agents, analgesics, antitussives,
Probenecid etc. may be added. In particular, antibacterial agents such as penicillins or cephalosporins that act synergistically with one or both of the active ingredients produced by in vivo hydrolysis of the compounds of the invention are suitable. The ratio of therapeutically active ingredients, such as compounds of the invention, to known penicillins is 1:20 to 20:1, preferably 1:5 to 5:1.
It is.

A particularly advantageous complex composition is 6β-hydroxymethyl-1,1-dioxopenicilanoylmethyl 6β-[(hexahydr -1■-I-Azepine-1-
yl]-methyleneamino]penicylanate and 5-[:D
-α-amino-α-phenylacetamide] penicillanic acid as an active ingredient.

Compound (I) can be used as such or in the form of a salt.

The neat compound is only slightly soluble in water, but when A n contains an amine group, many of the salts, such as the hydrochloride, are readily soluble in water.

As noted above, the compounds of the present invention can be prepared in pharmaceutical forms including suspensions and non-aqueous ointments. Preparations for oral administration are in the form of suspensions containing one of the compounds of the invention, containing 10 to 100 m!/ml of excipient. ? of the compound.

Another object of the present invention is to determine the dosage of the compound of the present invention and the unit of composition of the present invention so that the dosage, amount and unit dose may be administered such that the desired activity is achieved without causing side effects at the same time. The point is to select the dosage. In the treatment of humans, the compound of the present invention is calculated as compound (I).
~2500rng, preferably 100-11000rn
It is conveniently administered (to adults) as part of the posthumous administration of a composition comprising:

``One unit dose'' means the active substance as such or together with diluents, carriers, solvents and/or in solid or liquid preparations.
or for a physically stable unit, including a mixture with adjuvants, which is administered to a patient and which can be easily handled and packaged, i.e., a single dose.

In unit dosage form, the compound may be administered once per day at appropriate intervals.
It may be administered in one or more doses, always depending on the patient's situation and following the prescription written by the doctor.

Thus, the daily dose is preferably an amount of 0.25 to 15 g of compound (I) or an equivalent amount of the above-mentioned salt, but these are conveniently divided into several single doses.

For continuous treatment of patients with infectious diseases, tablets or capsules, and optionally sustained release formulations, are suitable pharmaceutical forms.

For veterinary treatment, the above formulations preferably contain compound (I)
50ml? It may be used as a unit dose containing ~25 g or the corresponding amount of its salt.

For the treatment of udder diseases, particularly cow's milk pneumonia, the antibacterial agent of the invention may be administered intramammary in liquid or semi-liquid form such as an ointment, or together with a substantially water-insoluble and oil-insoluble binder in granular form.

Yet another object of the invention is the treatment of patients with infectious diseases, which comprises administering to adult patients the active compound (Il) either as such or as a salt as mentioned above, preferably in the form of a unit dose as mentioned above. An object of the present invention is to provide a method for preparing a compound (
I) corresponds to an amount of 0.25 to 15 g/day or an equivalent amount of said salt of compound (I) to human adult patients, typically 3 to 200719/Kq (administered at a dose of 97 days of patient weight). be done.

In treating patients, the compounds of the invention may be administered alone or in conjunction with other therapeutically active compounds, such as probenecid, to help attack bacterial infections.

Such combined therapy may also be carried out using formulations containing multiple or all therapeutically active compounds, or these formulations may be administered simultaneously or at appropriate intervals in separate preparations.

In treating patients, the daily dose may be administered at once or in divided doses, eg, two, three or four times per day.

The invention is further illustrated by the following examples, which should not be construed as limiting the invention.

Regarding the properties of the compounds described below, it should be noted that
The melting point (mP, ) is Biichi
-Tottol i) The measurements were made using the instrument, but are uncorrected, and the NMR spectra are measured using CDCJ as the solvent unless otherwise specified, and J EOLFX.
It was recorded at 100 MHz on a 100 spectrometer. Chemical shift (δ) is determined by CDC No. 3 solution tetramethylsilane (δ-0) or D20 solution by HD.
It is stated as ppm relative to O(δ-4,66). The organic solvent was dried with anhydrous sodium sulfate.

Example 1 Chloromethyl 6β-hydroxymethylpenicillate 1
．． Production of 1-dioxide: 6β-hydroxymethylpenicillanic acid 1,1-dioxide (0,20!i'), sodium hydrogen carbonate (0°40
g), tetrabutylammonium hydrogen sulfate (0,055
Redistilled chloromethyl chlorosulfate (0.10 ml) was added to a mixture of 1. dichloromethane (5-) and water (2 ml) with stirring, and stirring was continued for 0.5 hour at room temperature. The organic layer was then separated and the aqueous layer was extracted with dichloromethane (10 rnl).

The organic layers were combined, washed with brine, and dried. Concentration under reduced pressure gave a gum. This was flash chromatographed on silica gel (15 g) eluting with 85% ethyl acetate in cyclohexane to give the title compound.

NMR: δ-1,47(31(,5), 1.62(31
(,S), 2.49 (IH, bs), 4.2 (31-1
, m), 4.51 (11-1, S ), 4.73 (I
H, d, J=4Hz), 5.65 (IH
, d, J=6.2112), and 5.95
(IH, d, J=6.2l-IZ).

Example 2 Iodomethyl 6β-hydroxymethylpenicillate 1
, 1-dioxide production Nichloromethyl 6β-hydroxymethylpenicylanate 1
,1-dioxide (0,21) in acetone (5 m/) without stirring was added sodium iodide (0°39) and stirring was continued for 2 days at room temperature. The reaction mixture was partitioned between ethyl acetate (40 rnl) and water (40 ml), the ethyl acetate layer was separated, washed with 5% sodium bicarbonate solution containing a few drops of 10% sodium thiosulfate solution and brine, and dried. .

The solvent was distilled off under reduced pressure to obtain the title compound.

NMR: δ-1,49(31(,S), 1.61(3
1 (,S), 2.4 (IH, bs), 4.2 (
31-1, m), 4.45 (IH, s),
4,72 (IH, d, J=4.511z), 5.
89 (IH, d, J = 5.IH2) and 6.11 (I
H, d, J = 5.1) IZ).

Example 3 Preparation of chloromethyl 7β-(D-α-azido-α-phenylacetamide)-3-methyl-3-cephem-4-carboxylate m-chloroperbenzoic acid (90%, 10.0ii') A solution of dichloromethane (100ml) was added to a water-cooled solution of chloromethyl 6β-CD-α-azido-α-phenylacetamido]penicylanate (22.0g) in dichloromethane (200rnl) over 2.5 hours with stirring, and the reaction was carried out. This was continued until TLC analysis of the mixture showed complete consumption of the penicillate starting material. At this point,
The mixture was filtered and Part F was washed with 5% sodium bicarbonate solution (3X, OOmA) and brine and dried. The solvent was distilled off under reduced pressure to give chloromethyl 6β-CD-α.
-azido-α-phenylacetamido)penicylanate 1-oxide was obtained.

NMR: δ-1,27(31-1,S), 1.74(
311, S), 4.70(l)1. s), 5.07(1
1(, d, J=4..7l-IZ), 5.11 Cli
t.

S], 5.64 (IH, d, J=61-17.), 5.
94 (11], d, J=51-1z), 5.9
9 (11-1, dd, J=4.7Hz and
lQ1-1z), 7.39 (sl]ps), and 8.03 (1N, d, J=lQtlz).

A solution of the above 1-oxide (10,21 and monopyridinium dichloromethanephosphonate (0,25P) in dry dioxane C70ml) was heated under reflux for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled and a portion was concentrated in vacuo F. The residue was added to ethyl acetate (150rn1.), washed with 5% sodium bicarbonate solution (50ml) and brine and dried. Evaporation of the /8 solvent gave a foam which was flash chromatographed on silica gel (300 g) and eluted with a 50% solution of betrol in ethyl acetate to give a solid. This was recrystallized from ethyl acetate-cyclohexane to obtain the title compound. Melting point 134-135°C.

NM: δ-2,19 (3■], S ), 3.38 (
21-1, ABq, J-Igl-1z), 4.98 (
111, d, J=4.7Hz), 5.10 (IH.

S), 5.73 (11-1, dd, J=4.7
and 9l-1z), 5.79 (2H, ABq,
J = 51-1z), 7.25 (IH, d, J = g
Hz), and 7.39 (5H,S).

Example 4 Preparation of methyl iodide 7β-CD-α-azido-α-phenylacetamide]-3-methyl-3-cephem-4-carboxylate! : -Chloromethyl 7β-(D-α-
Azido-α-phenylacetamide)-3-methyl-3
Thorium iodide (
The reaction mixture was partially concentrated under reduced pressure and the residue was dissolved in ethyl acetate (
200ml) and water (200ml).

Separate the organic layer and add 1% sodium thiosulfate solution (50 m
1), washed with water and brine, and dried. The solvent was distilled off under reduced pressure to obtain a solid, which was recrystallized from ethyl acetate-cyclohexane to obtain the needle-shaped title compound. Melting point 153
~154°C (decomposed).

NMR: δ-2,19(31-1,8), 3.37(2
H, ABq, J=18Hz), 4.97 (IH, d,
J=4.7H7), 5.10 (11-1,8), 5.
73 (IH, dd, J=4.7 and 9Hz), 5.
98 (2H.

ABq, J = 51 (z), 7.25 (11-kame, d, J = 91-1z) and 7.39 (5H
,S).

Example 5 Preparation of 6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl 7β-(D-α-azido-α-phenylacetamide)-3-methyl-3-cephem-4-carboxylate Methyl 7β-CD-α
-Azide-α-phenylacetamide]-3-methyl-
3-cephem-4-carboxylate (150m!7)
Dry N,N-dimethylformamide (DMF) (3
mg) solution of potassium 6β-hydroxymethylpenicillate 1,1-dioxide (757 nl/) in dry DM.
F (1 ml) was added to the suspension with stirring. 10 minutes later,
The clear reaction solution was diluted with ethyl acetate (40, nl) and
Washed with water (4×20.n) and brine and dried. The solvent was evaporated under reduced pressure to give a gum which was subjected to flash chromatography on silica gel (15 g).
Elution with 75% ethyl acetate in cyclohexane gave the title compound.

NMR: δ-1,44(3H,S), 1.59(31(
, S), 2.18 (3H, s), 2.59 (IT(,
, b s ), 3.40(2I-(, ABq ,, r-
19Hz), 4.15 (ar■, m), 4.52 (
II(,S), 4.72(1r1.d, J=4
．． 4Hz), 5.00(1) f, d, J=4.7H2
), 5.13 (IH, S), 5.72 (11-1, dd
, J=9Hz and4.7Hz), 5.94 (2
H,S), 7.18 (IH,d, J=9H2), and 7.40(5)T,S).

Example 6 6β-Hydroxymethyl-1,1-dioxopenicilanoyloxymethyl 7β-(D-α-benzyloxycarbonylamino-α-phenylacetamido)-3-methyl-3-cephem-4-carboxylate Manufacture N-pendyloxysulfonylcephalexin (0,
48F) in water (2
0 ml) solution, and the mixture was dissolved in dichloromethane (20 ml).
rnl). When all the benzyloxycarbonyl-cephalexin went into solution, the pH of the aqueous phase was adjusted to 8.0 by addition of a small amount of saturated sodium bicarbonate solution, and after shaking again, the dichloromethane phase was separated,
Dry and concentrate under reduced pressure to approximately 2rnl. This solution of the tetrabutylammonium salt of N-benzyloxycarbonyl-cephalexin was added to methyl iodide 6β-hydroxymethyl-1,1-dioxopenicillane-1 (0,4
02) in ethyl acetate (5rnl). 15
After minutes, the reaction mixture was partially concentrated to remove dichloromethane, diluted to 20 i with ethyl acetate, and diluted with water [20 □l].
Extracted with. The ethyl acetate layer was dried and concentrated to give the product, which was purified by chromatography on silica gel (30f7) eluting with a 75% solution of ethyl acetate in cyclohexane to give the title compound.

Example 7 6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl 7β-(D-α-amino-α-phenylacetamido)-3-methyl-3-cephem-4-carboxylate hydrochloride Production 6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl 7β-[D-α-azido-α-phenylacetamide)-3-methyl-3-cephem-4-carboxylate Cl00m? ) of ethyl acetate (20,n
solution, water (20rnIV) and 10% palladium/
Hydrogen gas was passed through the mixture of activated carbon (100"Li) with good stirring. During this time, the pH of the mixture was maintained between 2.4 and 2.6 by dropwise addition of πN hydrochloric acid over 40 minutes. The aqueous phase was separated and lyophilized to give the title compound as a solid.

NMR: δ = 1.35 (3H, S), 1.49 (3H,
S), 2.04 (3H, s), 3.3 (21-1, Al
3q, J = 18F-Iz), 4.1 (31r.

m), 5.17 (11(, S ), 5.56(], H
, cl, J-4,41(z), 5.93(2H,
s), and 7.45 (5H, s).

The title compound is 6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl 7β-(D-α-benzyloxino)l lehonylamino-α-phenylacetamide)-3-methyl-3 as the starting material in “1. It could also be produced by repeating the same procedure except using -cephem-4-carboxylate (100''IF).

Furthermore, the title compound could be prepared by the following procedure: Cephalexin (0.35 g) was mixed with dichloromethane (10 g).
mj), and a 1.5M tetrabutylammonium hydroxide solution (0.67 m/m) was added dropwise. The resulting clear two-phase mixture was concentrated under reduced pressure to constant weight to obtain cephalexin tetrabutylammonium salt. This was redissolved in dichloromethane (2ml) and methyl iodide 6β~
Hydroxymethyl-1,1-dioxopenicillanate (
0.4(1) of ethyl acetate (5-)g solution. 1
After 5 minutes, the reaction mixture was partially concentrated under reduced pressure to remove dichloromethane and diluted to 201 nl with ethyl acetate.
Washed with water (2 x 10ml). The ethyl acetate phase was then diluted with pl-12,5 (maintained by addition of the required amount of IN hydrochloric acid)
Extracted with water (20 ml). The aqueous extract was separated and lyophilized to yield the solid title compound.

Example 8 Preparation of 6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl 7β-(D-α-amino-α-phenylacetamido)-3-methyl-3-cephem-4-carboxylate: Hydrochloride obtained in Example 7 (2
Dissolve 0 ml in water (5 ml) and add ethyl acetate (10'm
A) was added and the mixture was treated with saturated sodium bicarbonate solution (1 ml) while stirring. After separation, the ethyl acetate layer was dried and concentrated under reduced pressure to obtain the title compound.

NMR: δ=1.45(31(,S), 1.59(31
(,S), 2.16(3F(,s'), 3.39(2H
, ABq, ■-131-17,), 4.2 (3H, m
), 4.52(ljl,S), 4.59(IT(
, S), 4.72 (1H, d, J = 4,1L(
z), 4.99 (IH, d, J-4, 7Hz), 5.7
5 (l)I, dd, J=I QI4z an
d 4.7Hz), 5.94 (2 to -1,S), 7
．． 36 (5H, s'), and 7.91 (IH, d,
J-10H2).

Example 9 The following compounds were prepared according to the last method of Example 7, except that cephalexin was replaced by 1 mmol of the appropriate cephalosporin: (a) Cefacrono V, (b) Cefadroxil,
(Cl cefatridine, (d) cefrazine and (el
The hydrochloride of 6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl ester of cefuroxazine was prepared.

Example 10 Preparation of 6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl 6β-[(hexahydro-IH-azepin-1-yl)methyleneaminocopenicylate] t-Sahit o -lH-azepin-1-yl)methyleneaminocopenicylanate (
Sodium iodide (2 g) was added to a stirring solution of Mecillinam chloromethyl ester (0°5 g) in acetone (5 mz) and stirring was continued at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (30ml) and water (30+n/)
Separate the ethyl acetate layer and add a few drops of sodium thiosulfate 10% solution to 5% sodium bicarbonate.
Washed with solution and brine and dried. The solvent was distilled off under reduced pressure to obtain a gum-like product. Dry this with DMF (2rd)
and add a certain amount (2,0rnl) of the solution to potassium 6β
-Hydroxymethylpenicillate 1,1-dioxide (75'Ing) was added to a suspension in dry DMF (1 rnl) with stirring. After stirring for 10 minutes, the reaction mixture was partitioned between water (25i) and ethyl acetate (35ml). The ethyl acetate layer was washed with water (3x20mA) and brine and dried. The solvent was evaporated under reduced pressure. A gum-like product was obtained, which was mixed with Sephadex L.
Purification by column chromatography on H20®, eluting with 65% chloroform in hexanes afforded the title compound.

NMR: δ-1,58 (6H,s), 1.67 (6
1 (, S ), 1.5 (B H, m ), 3.09 (
11i, b s ), 3.35 (4H, m), 4.2
(3H,m), 4.39(1)(,S)4.49(
If(,S), 4.71 CIH,d, J=4H
z), 5.10 (11-I, d,, J=4f-(
z), 5.45 (IH, d, J=4Hz), 5.8
9 (2H, ABq, J = 5Hz), and 7.61 (IH,S).

Example 11 Preparation of 6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl 6β-[(hexahydro-Ill-azepin-1-yl)methyleneaminocopenicylate] Disodium 6β-[(hexahydro-IH -Azepine-
Dry DMF (5fn
l) Methyl iodide 6β-hydroxymethylpenicylanate 1°1-dioxide (403”) was added to the suspension with stirring.
A solution of 9) in dry DMF (5 ml) was added and stirring continued for 30 minutes at room temperature. The reaction mixture was diluted with ethyl acetate (70rnl
), washed with water (4x 25 ml) and brine, and dried. The solvent was distilled off under reduced pressure to obtain the title compound. Its NMR spectrum was the same as that of Example 10.

Example 12 The procedure of Example 11 is repeated except that 1 mmol of the sodium or potassium salt of the appropriate antimicrobial agent is used in place of mecillinum sodium salt to prepare the following antimicrobial agents: (a) Cefuroxime, (b) Cephalexin, (C) Cefmetazole, (a) 3-desacetoxycefotaxime, (e13-methoxy-3-desacetoxycefotaxime to produce 6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl ester) did.

Patent applicant LEO Pharmaceutical Products Limited A/Vars (Levens Cheminuke)
Fabric Production Acti Cell Scape) Agent Patent Attorney Aoyama Aoyama (2 others)

Claims (1)

[Claims] 1. General formula: In the formula C, k is hydrogen, C□-C4 alkyl or C2-C
s-acyl, R1 is hydrogen, methyl, ethyl, benzyl or phenyl, and An represents a cephalosporin-type residue or an amidinopenicillanic acid residue bonded via a carboxy group) and their pharmacology Non-toxic salts allowed above. 2. The compound according to item 1, which is a pure diastereomer, a salt of a diastereomer, and a mixture thereof when R and/or the ester residue has a chiral center. 3. An is General formula: General formula: C In the formula, R2C0N11- is the 7-position side chain of a known cephalosporin, R3 is a substituent at the 3-position of a known cephalosporin, R4 is hydrogen or methoxy, and a chain The first residue is a residue selected from the group consisting of residues represented by
Compounds described in Section. 4. An is a residue represented by the general formula [a and R2 is D
-α-aminobenzyl, D-α-amino-P-hydroxybenzyl or ■)-α-amino-α-(1,4-cyclohexadien-1-yl)methyl, and R3 is chlorine, methyl, methoxy or 3. The compound according to claim 3, wherein R4 is hydrogen. 5. The compound according to item 3, wherein An is a residue represented by the general formula [ and Rs and 6 are bonded to nitrogen and combined to form a heterocyclic ring. 6.6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl 7β-(D-α-amino-α-phenylacetamide)-3-methyl-3-cephem-4
- The compound according to item 1, which is a carboxylate and a pharmacologically acceptable non-toxic salt thereof. 7.6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl 6β-[(hexahydro-1f-
1-Azepin-1-yl)methyleneamino]penicillanate and its pharmacologically acceptable non-toxic salts
Compounds described in Section. 8. (a) General formula: C where ■ (1 is hydrogen, methinopeethyl, benzyl or phenyl, R7 is optionally k (hydrogen, C-C alkyl or C2-C5 acyl) 4 or easily cleaved an esterified or etherified group that can be esterified or etherified, and X represents a free radical, and a compound of the general formula: group or amidinopenicillanic acid residue) or a protected or masked derivative of An, and - represents a cation), followed by reaction of R7\ and/or An''\ In the case of An, cleavage to replace R7 with hydrogen and optionally subsequent alkylation or acylation and/or the necessary reactions to convert An'' to An to give the desired compound (I). or (as the first step of bl), a compound/substance represented by the general formula: %Formula% C, where An" and M■ have the same meanings as above), □ and X have the same meanings as above.■ represents a free radical, and Y is a better free radical than An intermediate represented by k□ and ) is reacted with a compound represented by the general formula: C (in which R7 and M have the same meanings as above), and if necessary, 7 is replaced with k, and/
Or, a method for producing compound (I) by modifying An" to An to obtain compound (I). 9. In method (b), compound (VI) is chloromethyl chlorosulfate, and the reaction is carried out in water. 10. Pharmacology of unit doses for oral, parenteral or topical treatment of patients suffering from infectious diseases. formulation, compound CI
) 0.050 to 2.5 g together with a pharmacologically acceptable carrier. 11. Active ingredient 0.1-1! 11. The pharmaceutical formulation according to clause 10, which is a unit dosage formulation for oral treatment comprising i2. 12. 6β-hydroxymethyl-1゜1 as an active ingredient
-Dioxopenicilanoyloxymethyl 6β-[(hexahydro-1it-azepin-1-yl]methyleneamino]penicillate or its salt with a pharmacologically acceptable wild acid). 13. 6β-hydroxymethyl-1゜agedioxopenicilanoyloxymethyl 7β-CD-α as an active ingredient
-amino-α-phenylacetamide)-3-methyl-
11. The pharmaceutical preparation according to item 10, comprising 3-cephem-4-carboxylate or a salt thereof with a pharmacologically acceptable non-toxic acid. 14. The pharmaceutical preparation according to item 12 or 13, which is a tablet, pill or capsule. 15. 1-95% active ingredient together with carrier substances and diluents
A compound (I)-containing pharmacological composition comprising: 16. The active ingredient together with known penicillin from 1=20 to
16. The composition according to claim 15, which is a composite composition comprising a ratio of 20:1, preferably 1:5 to 5:1. 17. The active ingredient is 6β-hydroxymethyl-1,1-dioxopenicilanoyloxymethyl 6β-[(hexahydro-1,1-I-azepin-1-yl)methyleneaminocopenicillate or its pharmacological a salt with an acceptable non-toxic acid, wherein the penicillin is 6-CD-α-amino-α-phenylacetamido]penicillanic acid;
Composition according to item 6.