FR2509311A1 - BETA-LACTAM DERIVATIVES, THE PHARMACEUTICAL COMPOSITIONS CONTAINING SAME, AND PROCESS FOR THEIR PREPARATION - Google Patents

Abstract

THE COMPOUNDS OF THE INVENTION MEET THE GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH IN PARTICULAR: R IS HYDROGEN, A IS A GROUP OF THE GENERAL FORMULA A, R IS A PHENYL GROUP, R AND R ARE OF HYDROGEN ATOMS, N AND T REPRESENT EACH ZERO, X IS A GROUP OF THE FORMULA -CH-C (CH) -, Q IS AN OXYGEN ATOM.

Description

The present invention relates to novel penicillin derivatives and

  cephalosporin with antibacterial and beta-lactamase inhibitory effects, as well as

  as a process for their preparation.

  Published literature indicates several beta-lactamase inhibitors (JMT HamiltonMiller, Jo T Smith, ed) Academic Press, London, 1979/7 The members of the isoxazolylpenicillin group (oxacillin, cloxacilli De, dicloxacillin, flucoxaciline) have, in addition to their inhibitory effects on the beast, -actaa se, important antibacterial properties, also, which makes it possible to produce effective combinations (such as ampiclox). However, these compounds act mainly on Gram-positive beta-lactamases Gree Dwood, D, and O'Grady, F: Chemotherapy, 21, 330 (1975). Similar effects can be observed on nafcillin and quinacillin; these two compounds possess, in addition to their beta-lactamase inhibitory effects, also interesting antibacterial activities. Certain other beta-lactams, such as monocyclic bela-lactams, exert only the inhibitory effects of ta-l actamase without any antibacterial activity { Belgian patent N

766,534).

  Several publications deal with the preparation of ureides, acylureides and similar compounds from 6-aminopenicillanic acid or ampicillin (see, for example, Naito, X, and others). Antibiotics (A). 18, 145 (1965); Nayler, J C: Adv Drug Res, 7, 1 (1973); German Offen N 1 904 851; German Offen N 1,770,620; German Offen N 1 929 997; Patent of

  U.S. Patent No. 3,479,339; Bodey, G, et al .: Antimicrob.

  Ag Chemother 13, 14 (i 978) 7 These derivatives were examined only for their antimicrobial effects Although a broadening of the antibacterial spectrum towards Gram-negative microorganisms was observed with certain compounds, none of them they did not reveal themselves

  to be more effective than ampicillin.

  German Offenlegungsschrift No. 2,634,431 describes the preparation of compounds corresponding to general formula (I). However, this publication does not disclose compounds having a penam skeleton.

  b) does not describe compounds in which R 6 and R 7 represent

  substituted alkyl groups, aryl groups, hetero groups,

  aryl, phenyl, substituted phenyl or heterocyclyl, c) relates only to thiourea derivatives, d) relates only to compounds in which X is a CH-group Het, e) does not describe compounds having inhibitory effects of beta-lactamase and synergistic, f) relates only to derivatives in which t is

always equal to zero.

  A common disadvantage of the above compounds is that although they have antibacterial effects of appropriate potency and antibacterial spectra of appropriate width, they most often retain the beta-lactamase sensitivity of the starting molecules. , so they can not be used against resistant strains or

  should be used in combination with an

  beta-lactamase bitumen, such as clavulanic acid.

  It has now been found that new acid derivatives

  ceph-3-em-4-carboxylic acid and 2,2-dimethyl-penam-3-

  carboxylic acid corresponding to the general formula (I), wherein: A is a group of the general formula (a) or (b-, Y is a group of the formula -C (CH 3) 2-, -CH 2-C (CH 3) -, -CH 2 -C (CH 2 O Ac) = or -CH 2 -C (CH 2 S Het) = and in the last formula, Het is a 5- to 7-membered heterocyclic group

  saturated or not containing from 1 to 4 nitrogen atoms and possibly

  one or more other hetero atoms, possibly

  is condensed with one or more phenyl groups and / or substituted by one or more alkyl, aralkyl, aryl, substituted aryl or substituted aralkyl groups, R 1 is a hydrogen atom, a C 14 alkyl group or a group phenyl optionally bearing a halo, hydroxy, alkoxy or alkyl substituent, R 2 is a hydrogen atom, a C 1-4 alkyl group or a phenyl group optionally carrying a halo, hydroxy, alkoxy or alkyl substituent, R 3 and R 8 each represent a hydrogen atom, a

  C 1 -C 4 alkyl group or a phenyl group carrying

  halogen, hydroxy, alkoxy or alkyl, Q is oxygen, sulfur or selenium, R 4 is hydrogen, straight or branched chain C 1-4 alkyl or a group of general formula -COOR 5, and in the latter formula, R 5 is a C 18 alkyl group, a benzyl group, a benzhydryl group or a phenyl group optionally carrying a halo, hydroxy, alkoxy or alkyl substituent, R 6 is a group phenyl optionally bearing one or more halo, C 16 alkyl, nitro, alkoxycarbonyl, trifluoromethyl, dialkylamino, hydroxy, carboxylic acid or sulfonic acid substituents, a C 1-8 alkyl group bearing an alkoxycarbonyl, hydroxy, dialkylamino or alkoxy substituent, a C 3 -C 8 cycloalkyl group, a C 2 -C 6 alkenyl group, a naphthyl group, a heteroaryl group, a 3 to 8 membered heterocyclyl group optionally condensed with one or more groups phenyl and / or bearing one or more substituents, or an adamantyl group, and R 7 is hydrogen, or R and R form, with the adjacent nitrogen atom, a 4- to 8-membered heterocyclic group, not substituted or preferably substituted, optionally containing one or more additional nitrogen atoms, oxygen or sulfur and optionally fused with one or more phenyl rings, Z is hydroxy, N is zero or one and t is zero, one or two, and their non-toxic organic or inorganic salts,

  pharmacologically acceptable or their biological esters

  actively possess powerful anti-

  microbials and enzyme inhibitors, in particular

  antibacterials and beta-lactamase inhibitors.

  In the substituent X, the group Het preferably represents a pyrazolyl, imidazolyl or thiazolyl group,

  1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thia-

  diazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridine

zinyl or triazinyl.

  Among the biologically active esters, those containing a group of the formula (e), (f), (g), (h), (i), (j), (k), (1), (m), ( n) or (o) as esterifying group are

preferred.

  The novel compounds of the general formula (I) can be prepared according to the invention a) by reacting a compound of the general formula (II) with a compound of the general formula (III), b) by reacting a compound of the general formula (V) with a compound of the general formula (IV), or c) by reacting a compound of the general formula

  (II) with a compound of the general formula (VI).

  When using cephalexin and 4-flavanyl-

  isothiocyanate as starting substances, the reaction can be carried out according to method a), which produces compounds of the general formula (I) in which

R 4 is hydrogen.

  According to method a) of the invention, a compound of the general formula (II), or R 1, R 2 RR 8, X, Z, t and n -5- are as defined above, or a salt or a biologically active ester of such a compound is reacted with a compound of the general formula (III), where B is a group of the general formula (a) or (d), R 6 is a trimethylsilyl group or a group as defined for

6 7 '

  R above and R is a trimethylsilyl group or a group as defined for R 7 above The reaction is carried out in an aprotic solvent or a mixture of such solvents, at a temperature of 0 r i'00 C, preferably at room temperature The reaction can be conducted

with or without agitation of the mixture.

  Depending on the nature of the starting materials, chlorinated aliphatic hydrocarbons, in particular dichloromethane, dichlcrethane or chloroform,

  aliphatic ethers, such as n-bu-tyloxide, titra-

  furan or dioxane, or other aprotic solvents, preferably acetonitrile or ethyl acetate, or mixtures thereof may be used as the reaction medium. The amount of the solvent (s) is selected in such a way that the solution contains 3 to 30% of the

  starting material of the general formula (II).

  Depending on the reactivity of the compound of the general formula (III), the reaction occurs in a period of 5 minutes

at 48 hours.

  The method a) can preferably be carried out using, for example, from 2 to 10 cram 3 of anhydrous acetonitrile, dimethylformamide, dimethylacrylate, ethyl acetate and dioxane blothe acetate. of tetrahydrofuran, diglyme or an appropriate mixture of these compounds, for one gram of the starting beta-lactam, as a solvent medium, and if a free acid is used as starting material, the reaction mixture of 1 at 5 molar equivalents of a pharmacologically acceptable tertiary organic base, such as triethyl

  amine, ethyl diisopropyl amine, an N, N-dialkyl ester,

  amino acid, etc. The resulting solution is filtered, if

  necessary, and then add 1 to 3 equivalents

  from a compound of the general formula (III) to the solution (or filtrate), either as such or in the form of a 30-50% solution formed with any of the solvents or solvent mixtures herein. The reaction is carried out at 0.degree.-1000.degree. C., preferably at ambient temperature. According to the characteristics of the starting substances and of the solvent or of the solvent mixture, the final product of the general formula (I) separates generally.

  reaction mixture in the form of a crystalline substance

  In some cases, the reaction mixture is evaporated to separate the product. The separated crystalline product is isolated by filtration, washed with a mixture of the above solvents and an aliphatic ether if necessary, and dried at room temperature, possibly under vacuum When the product separates in the form of an oil, it is

  crystallized from a suitable solvent.

  The product obtained according to method a) of the invention can be further purified, if necessary, in the following manner: the compound of the general formula (I) is dissolved in the minimum amount of water, the aqueous solution is treated with an immiscible solvent with

  water, such as dichloromethane, chloroform, tetra-

  carbon chloride, ethyl acetate, butyl acetate, etc., then the aqueous phase is acidified with a calculated amount of a mineral acid, such as acid

  hydrochloric acid, sulfuric acid or phospho-

  The organic phase is treated by a calculated amount of a pharmaceutically acceptable salt-forming agent and then evaporated.

  The resulting purified general formula (I) is dried.

  This purification method, which is not usually necessary, gives very pure products with

high yields.

  According to method b) of the invention, a compound of the general formula (V), where the general symbols have the meanings defined above, or a salt or a biologically active ester of such a compound, is reacted with a compound of the general formula (IV), wherein A, R, R, R, R, Q and N are as defined above, Y is oxygen or sulfur and R 13 represents a phenyl group bearing one or more halo substituents, an unsubstituted or substituted quinolyl group or a substituted amidino group. The reaction may be

  conducted under the conditions discussed above.

  1 S above about method a).

  According to method c) of the invention, a compound of the general formula (II) is reacted with a compound of the general formula (VI). In these formulas, the general symbols are as defined above. be carried out in a solvent medium, such as in an aliphatic ether, a ketone or a

chlorinated hydrocarbon.

  The novel compounds of the invention are useful antibacterial agents having broad activity spectra and can also be used as beta-lactamase inhibitory agents in combination with semi-synthetic penicillins or cephalosporins with broad beta-sensitive activity spectra. For example, when the novel compounds according to the invention are combined with ampicillin, carbenicillin, amoxycillin, ticarcillin, azlocillin, cephalexin, cephaloglycine, Cephradine, cephalchlor, cephadroxyl, etc., in a ratio of 3: 1 to 1: 8, we obtain combinations that are applicable even

2509311-

  -8 - in the treatment of severe infections caused by

resistant strains.

  The new compounds can also be combined

  with aminoglycoside antibiotics, such as

  mycine, gentamycin or kanamycin. In some cases, the novel compounds may also be used as antifungal agents or as

  intermediate products in the synthesis of other

biologically active substances.

  In some cases, the new compounds can also be used as weight gain additives in pet foods, and also as preservatives in paper, wool, leather and

textile industry.

  When used as feed additives, the novel compounds can be introduced into animal organisms in the usual manner, mixed with a food or food additive or added to the drinking water, and thus the bacterial infection of the animals. animals can be avoided and better use of

the food can be obtained.

  The invention is illustrated in detail with the help of

following non-limiting examples.

  Examples 1 to 53 Method a) Preparation of derivatives of urea, thiourea and seleno-urea 10 mmol of amino-beta-lactam are dissolved in a mixture of 25 cm 3 of absolute acetonitrile and 3 cm 3 of triethylamine and added to the solution, in one or

  several portions, 10 mmol of the isocyanate, the iso-

  Depending on the reactivity of the isocyanate used, the product separates from the mixture over a period of from 5 minutes to 24-48 hours in the form of a solid material, depending on the reactivity of the isocyanate used. crystalline or sometimes in the form of an oil When a crystalline substance is obtained, the crystals are separated by filtration and washed with anhydrous acetonitrile or with an anhydrous aliphatic ether. When an oily substance is obtained, it is treated with an aliphatic ether. anhydrous, toluene, petroleum ether, hexane, heptane, light spirit or a suitable mixture of these materials to effect solidification, after which the product is

separated by filtration and dried.

  When the resulting compound is not sufficiently pure, as indicated by thin layer chromatography, it can be purified as follows: the impure substance is dissolved in the minimum amount of water, the aqueous solution is washed in such a manner as to eliminate traces of the isocyanate, isothiocyanate or isoselnocyanate which may be present, then acidified with dilute sulfuric or hydrochloric acid and reprocessed by extraction with a water-immiscible or water-soluble lipemic ester. The organic phase is separated, dried, and then the acid is precipitated in the form of its salt, using sodium or potassium salt of 2-ethylcapronic acid or treating the solution with an organic base. salt does not precipitate from the

solution, the solvent is evaporated.

  A similar procedure is used when an alpha or beta-sulfoxide, sulfone or amino-beta-lactam ester is used as the starting material.

  Oxidized derivatives are morin soluble in food esters.

  phages and chlorinated hydrocarbons, some

  sometimes a dipolar aprotic solvent or cosolvent like

reaction medium.

  The products prepared by the above method are

shown in Tables 1 and 2.

  -10- Notes on Tables 1 and 2: The elemental analysis results (C, H, N, S, and Hal) of the products are in good agreement with those calculated; the differences do not exceed 1% and are usually less than 0.4%. According to IR spectroscopic examinations, the derivatives

  thio-urea do not even contain traces of iso-

  cyanate and, as shown by the very high maximum (lactam carbonyl at 1765-1772 cm -), the

beta-lactam nucleus is intact.

  Some of the compounds have also been subjected to mass spectrometry; however, the observed results did not provide any information because of the low

  volatility of samples and thermal decomposition

  Measurements made on samples made more volatile by silylation confirmed, however,

the planned structures.

  1 H nuclear magnetic resonance spectroscopic examinations confirmed the expected structures

  shown by these spectra, there is no epimerism

  C-7 or Ceph-3-em / ceph-2-em isomerization with

the compounds examined.

Table 1

1 3 7

  Cephalexin-urea derivatives of the general formula (I); R = R = R = hydrogen, R 2 = phenyl, N = t = zero, X = -CH 2 -C (CH 3) =, Q = oxygen, Z = OH N (C 2 H 5) 3, A = a group of formula (a) Empirical formula Molecular weight% yield Melting point o C Analysis,% calculated IR spectrum, Aasr found C = O from CHNS lactam, cm 1 methyl C 24 H 35 N 5055

2 3-methyl

phenyl

C 30 H 39 N 5055

  3-naphthyl C 33 H 39 N 5055 4 t-butyl methoxymethyl

6 ethoxy-

carbonyl

methyl

C 27 H 41 N 505

C 25 H 37 N 5065

C 27 H 39 N 5075

505.66

581.75

92.5 203-204

94.3 202-204

617.76 89.1

547.74

535.69

577.72

207-209

57.0 6.98 13.86 6.34

56.15 6.82 13.72 6.39

56.77 6.88 13.69 6.30

61.93 6.75 12.04 5.51

61.82 6.47 12.01 5.41

61.85 6.63 12.11 5.47

64.16 6.36 11.34 5.19

63.87 63.94 6.22 6.28

96.2 amorph.

92.4

94.2 231-232

  11.21 11.37 12.77 12.72 13.1 13.0 11.6 11.75, 07, 12

N R 6

H i i_ r% 3 t A C> 1

% O -

w

Table 2

  Cephalexin-thiourea derivatives of the general formula (I); R = R = RR = phenyl, N = t = zero, X = -CH 2 -C (CH 3) =, Q = sulfur, Z = OH N (C 2 H 5) 3, of formula (a) = hydrogen , A = a group Formula Molecular empirical weight Yield% melting point, C 7 methyl 8 ethyl 9 isopropyl n-butyl 11 tert-butyl

12 -CH 2 CH 2 OH

13 allyl 14 cyclohexyl

-CH (CH 3) - (CH 2) 3 N (CH 3) 2

  16 Phenyl 17 Benzyl 18 Benzoyl 19 Phenoxyacetyl 1-Naphthyl 21 3 Fluorophenyl 22 4-Fluorophenyl 23 2-Chlorophenyl

C 24 H 35 N 50452 521.69

C 25 H 37 N 50452 535.72

C 26 H 39 N 50452 549.75

C 27 H 41 N 50452 563.78

C 27 H 41 N 50452 563.48

37 N 5 552 551.72

C 26 H 37 N 50452 547.74

C 29 H 43 N 50452 589.83

C 30 H 48 N 60452 620.86

C 29 H 37 N 50452 583.78

C 30 H 39 N 50452 597.81

C 30 H 37 N 40552 611.79

C 31 H 39 N 50652 641.82

C 33 H 39 N 50452 633.84

C 29 H 36 N 5 452 601.77

C HN

29 36 50452 F 601.77

  C 29 H 3 (1 N 618.23 c 29 36, 34.61 93.82, 00 81.59 92.85 88.22 84.15, 63 92.17, 74, 22 91.20, 60, 70 94.85 87.74

128-130

-111

127-128

-131

123-124

174-175

154-155

126-127

amorph. -186

171-172

142-143

116-117

182-183

-182

138-140

64.10 137-138

  NR 6 Rf 0.22 0.26 0.26 0.29 0.31 0.40 0.39 0.44 0.43 0.40 o To LM o '0, 38 ll R 6 No Formula Weight Yield Point of ## STR1 ## wherein: ## STR1 ## wherein: ## STR1 ## 3-chlorophenyl c 29 H 36 N 50 452 ci-chlorophenyl c 29 H 36 N 50 452 ci 26 2,5-dichlorophenyl c 29 H 35 N 50 452 ci 2 27 2,6-dichlorophenyl c 29 H 35 N 50 452 ci 2 28 3,4-dichlorophenyl c HII CN OS ci

29 5 4 2 2

  29 3,5-dichlorophenyl c 29 A 35 N -; O 452 CL) 2,4,6-trichlorophenyl C M m S 1

29 34 4 3

31 3-bromophenyl r

2 31 5 4

32 4-bromophenyl N O E r

U'36 5 4 '2

  33 3-iodophenyl c E N O O -L 29 3 65 S t 2 34 4-iodophenyl c

29 5 4 2

  2 m 6 t h v 1 p h e w h e n o

1 3 CI 3 9 5 4 2

  36 3-Methylphenyl M, -1 O O

-15 5 4-2

  38 2, 4, 6 t r im t hy 1 -p ii to N -v i c C H N O S

32 43 5 É 2

39 O S

  4 2 yl c 33 H 45 N 50 I 52 41 4-diethylamino-phenyl C H M O S

33 "46 6 4, 2

  42 2-methyl-4-diethylamino-C 34 H, il 452 phenyl 4-carboxyphenyl c _q N O S

37 5 6 2

6 1 8 23

61 8, 2 3

652, 68

652, 68

652, 68

652, 68

6 -87I 4

E, 'a 2, E, 9

6 6 2, (, 9

709, 68

-; O 9, 6 a

7, 'SO

59 7,

59 '7, 20

625, 36

625, 86

639.87

654, 89

668, 9-1

78, 62

1 O 0, O O

84 1 6

67, 48

9 2, 5 5

87, 1 5

88, 23

92, 1 7

8 4, I 4

76, 28

914-11 1 6

8 4, 2 5

76, c; 5 to 5, A 2 38 33

81 46

, 93

* 7 7 2, 5

, 1 3

1 68-1 70

1 4 2-1 43

189 -1 9 O

1 8 2-1 8 3

amorph.

1 7 7-1 78

182-1 63

99-200 al, orpi-i.

61 -163

amorph. amorph I 79

167-168

163-164.

1 03-1 04

113-114

  -167 auiorph. 0.38 0, 40 0, 43 0, 41 w 0 4 7 0, 38 0.38 r 1%) Ln

C> 1

% O Uà b

627.80 91.96 161

  Empirical formula Molecular weight Yield% melting point, OC 44 3-hydroxy-4-carboxyphenyl 2-methyl-4-sulfonylphenyl 46 2trifluoromethylphenyl 47 3-trifluoromethylphenyl 48 3-nitrophenyl 49 4nitrophenyl 4-pyridyl 51 4-flavanyl 52 flavan-4-on -3-yl 53 flavon-3yl c 30 H 37 N 507 2

C 30 H 39 NO 753

C 30 36 NS 4 2 F 3

c 30 H 36 N 504 2 3

C 29 H 36 N 606 2

C 29 H 36 N 606 2

C 28 H 36 N 6 4 2

C 38 H 45 N 505 2

C 38 H 43 N 5 6 2

C 38 41 N 506 2

No R 6 R f

643.80

677.88

651.79

651.79

628, 76

628.76

584, 75

715.94

729, 92

727.90

78.83, 18, 26

87, 45

83, 06

83, 06

27,30

94, 25

82.12

82, 88

-198

132-133

153-154

184-185

-176

182-184

1 75-1 76

I.1 L Ml o.b -15-

Example 54

  Reaction of ampicillin with 4-flavanyl-isothiocyanate

  1007 mg (2.5 mmol) of ampic trihydrate are dissolved

  cillin in a mixture of 0.8 cm 3 of triethylamine and 5 cm 3 of anhydrous acetonitrile, 670 mg (2.5 mmol) of 4-flavanylisothiocyanate are added to the solution and the reaction mixture is discarded.

  the mixture at room temperature A crystalline precipitate

  White precipitate separates from the mixture. The precipitate is isolated by filtration, washed with a small amount of anhydrous acetonitrile and absolute ether and dried under vacuum. 1.55 g (86.47%) of the desired product is obtained; melting point: 171-172 ° C (dec), R f = 0.45 (in a 7-3: 1 mixture of

  benzene, ethyl acetate and glacial acetic acid).

  IR (K Br): 1770 cm-1 (lactam C = O) Analysis: Calculated: N = 9.8% Found: N = 9.68%, 9.75%

Example 55

  Reaction of cephalexin with phenyl iso-selenocyanate The reaction is carried out according to method a) to obtain the product having a Rf value of 0.36 (in a mixture

  7: 3: 1 toluene, ethyl acetate and formic acid).

  Analysis: Calcd for C 29 37 N 504 S Se (630.69):

C: 55.22%, H: 5.91%, N: 11.11%

  Found: C: 55.15%, H: 5.84%, N: 11.27% IR (K Br): 3350, 3010, 2960, 1765, 1720, 1680, 1660,

1520, 1500, 1310, 705 cm -1.

Example 56

  Preparation of trimethylammonium salt of 7- / alpha-

  (L-methylthioureido) 7-phenylacetamido-3-chloro-ceph-3-em

  4-carboxylic acid The compound is prepared according to the method e) Yield:

  88.2%; melting point: 127-12-9 C (dec).

  IR (K Br): 3270, 1773, 1680, 1617, 1558, 1540, 1345,

695 cm 1.

  Analysis: Calculated for C 23 H 32 Cl N 50452 (542.147) N: 12.92%, S: 11.83%, Cl: 6.54%; Found: N: 12.80%, S: 11.88%, Cl: 6.43%;

N: 12.85%, S: 12.02%, Cl: 6.46%.

Example 57

Method b)

  Preparation of triethylammonium salt of 6 beta-acid

  / D-2 - [(3- [2-phenyl-5,6-benzo-pyran-4-yl] -2-thioureido]

  2- / 4-hydroxyphenyl / T-acetamido 7-2,2-dimethyl-7-oxo-4-thia-

  1-azabicyclo [7-heptane-2-carboxylic acid A mixture of 0.8 g of pentachlorophenyl ester

  D-2- [3- (2-phenyl) -5,6-benzo-pyran-4-yl] -2-thio-acid

  ureido) -2- / 4-hydroxyphenyl / 7-acetic acid, 10 cm 3 of ethyl acetate, 0.23 g of 6-aminopenicillanic acid and 0.1 cm 3 of triethylamine is stirred at room temperature. 12 hours, then the mixture is evaporated and the product is crystallized The title compound is

obtained with a yield of 82%.

  IR: 3400, 1770, 1730, 1680, 1520 cm -1.

  Analysis: Calculated for C 38 H 47 N 50652 (727.96): N = 9.63%, S = 8.81% Found: N = 9.55%, S = 8.87%

N = 9.74%, S = 8.84%

Example 58

  Method b) 0.4 g of 7-ADCA is dissolved in 10 cm 3 of N, N-dimethyl formamide at 20 ° C. and 1.04 g (2 mmol) of N-phenylcarbamoyl-D-pentachlorophenyl ester are added. phenylglycine to the stirred mixture in several portions The mixture is stirred at 20 ° C. for 12 hours, after which it is poured into 100 cm 3 of ice water, the white crystalline substance which separates is isolated by filtration, washed with water and then crystallized from a mixture of dimethylformamide and water The crystals are isolated by filtration and the product is converted into its sodium salt, potassium or -17

  triethylammonium in a manner known in itself.

  The triethylammonium salt, obtained with a yield of 84% melts at 211213 ° C. IR 3400, 1765, 1710, 1680, 1520 cm. Analysis calculated for C 2 H 3 N 5 O S (567.73)

  C: 61.35H, H 6.57%, N 12.34%, S 6.65%

  Found C: 61.05%, H 6.55%, N: 12.23%, S 5.49

  C: 61.11%, 6.60% N N 12.19%, S 5.52%

Example 59

  Method c) 1.0 g (2.48 mmol) of picillin was dissolved in a mixture of 24.8 g of anhydrous acetonitrile and 2.48 g of

  triethylamine, and a resolution of 0.678 g of this 3-ethoxy-

  Carbonyl-4-chlorocarbonyl perhydro-1- (4-thiazine) in 3 cm 3 of toluene and 1 ml of triethylamine are added dropwise to the solution, and the mixture is stirred; O cool On

  stir the mixture for one hour, after which it is easy to

  difije at pH 2 with aquicultural acid at 2H,

  The acid mixture is treated with dichloromethane and the organics are combined, washed with water, dried and dried.

  The product is evaporated on sodium sulphate and evaporated to yield 100% of the desired product. IR = 3400, 1770, 1735, 11720, 16.72, 1.525 ° C. Ana lysis Calcu 1 lé for CH 4 NO -, S (651 z 86 i N 10, 75 S 9.83% Found N: 10.82%, S 9.899

N, 10.86, 9.85

Exe Mp'Le 60

  Preparation of 7-betal acid, / 2:, 2,4 / 4H-1-triazol-2-yl

  phenyl 7-acetamido-3-yl-3-carboxy

  0.56 g (10 mmol) of 4-amino

  1,2,4 (4H) -triazole in 20 cr 2 absolute dichloromethane and then 5.2 cm 3 of absolute triethylamine and 1.27 cm (10 mmol) of trimethylchlorosilane are added. The mixture is stirred at 20 ° C. C. for 15 minutes, then 0.76 cm 3 (10 mmol) of thiophosgene are introduced and stirring is continued for 30 minutes. The resulting mixture is filtered under a dry nitrogen atmosphere and the filtrate is added to a solution of 4 46 g (10 mmol) of pivaloyloxymethyl cephalexin ester in 40 cm 3 of dichloromethane. The mixture is stirred for one hour and then treated to give the title compound.

with a yield of 88%.

  IR (K Br): 3360, 3280, 3030, 2980, 1774, 1735, 1710, 1680, 1625, 1520, 1490, 1210, 1045, 715 cm. Analysis: Calculated for C 25 H 29 N 70652 (587.69): N: 16.68%, S: 10.91% Found: N: 16.55%, S: 11.12%

Example 61

  Preparation of triethylammonium salt of 6 beta-acid

  / 2-phenyl-2- (phénylthiouréido) 7-acetamido-penicillanic

  10 mmol (approximately 4 g) of amine trihydrate are dissolved in

  picillin at OC in a mixture of 7 cm 3 of triethylamine and 50 cm 3 of dimethylformamide and the solution is then reacted with an equimolar amount of phenyl mustard gasoline. When the mixture is worked up, 3.7 g of the compound are obtained. of the title as a primary product in a

  chromato-graphically pure state A quantity can be separated

  additional product by treating the mother liquor.

  Rf = 0.27 (in a 7: 3: 1 mixture of toluene, acetate

  ethyl and formic acid); m.p. 134-136 ° C.

-1

IR (K Br): 1788 cm (beta-lactam).

  1 H NMR (DMSO-d 6): 1.25 (t, 9H, -CH 2 CH 3), 1.54 (s, 2H, 2 Me), 1, 16 (s, 3H, 2H). a Me), 3.08 (6H, CH 2 -CH 3), 4.12 (s, 1H, C / 3H, 5.4-5, 6 (d + dd, 2H, C And 6.45 (d, J = 10 Hz, Ph-CH-CO-), 7.15-7.8 (m, 10H, 2 phenyl), 8, 07 (s, 1H), 8.84 (d, 1H, J = 9Hz, Nh), 9.3 (d, 1H,

  Ph-CH-NH-, J = 10Hz), 10.46 (s, 1H).

  The results of beta-lactamase inhibition of

  product are shown in Table 3.

Table 3

  Substance IC 5 (10-6 M) E. coli J 53 RP 4B cereus I.

Phenyl TEA salt

thioureido-benzyl

  penicillin 320 5000 Methicillin sulfone 1000 In a similar manner, the following compounds are prepared: a) triethylammonium salt of 1 (s) - acid oxide

  6 beta / 2-phenyl-2- (phenylthioureido) 7-acetamido penicillin

  lanic, b) triethylammonium salt of 1,1-dioxide of acid

  6 beta / 2-phenyl-2- (phenylthioureido) 7-acetamido penicillin

  lanic, (c) dicyclohexylammonium salt of (S) -oxide of acid

  7 beta- / 2-phenyl-2- (phenylthioureido) 7-acetamido-3-methyl-

  ceph-3-em-4-carboxylic acid, d) dicyclohexylammonium salt of 1,1-dioxide acid

  7 beta- / 2-phenyl-2- (phenylthioureido) 7-acetamido-3-methyl-

ceph-3-em-4-carboxylic acid

  e) Acetoxymethyl ester (7) beta (7)

  2-phenyl-2- (phenylthioureido) 7-acetamido-3-methyl-ceph-

  3-em-4-carboxylic acid, f) Benzoyloxymethyl acid ester 1,1-dioxide

  6 beta / 2-phenyl-2- (phenylthioureido) 7-acetamido penicillin

  lanique. The endpoints of beta-lactamase inhibition of phenylthio-ureido-benzylpenicillin TEA salt determined on certain isolated enzymes are indicated in

  Table 4 Values are given in units of mg / l.

2? 509311

-20-

Table 4

  Compound B cereus Aerobacter Ecoli S aureus cloacae 53 J-53 R 46 P Cl TEA salt of <1000 1000> 1000 <1000 phenylthioureido> 200 benzylpenicillin> 200 Acid sulfone

6 alpha-chloro

  penicillanic> 1000> 1000> 1000> 200 Sulfone of acid

6 alpha-bromo

  Penicillanic <5000 5000 <5000> 1000 Measurements were made using Nitrocéphine

as a substrate.

  The following examples illustrate the preparation of

pharmaceutical compositions.

Example 62

  Preparation of capsules for oral administration 250 mg of ampicillin trihydrate 250 mg are mixed

  7 beta - / (D- / alpha-phenylthio) sodium salt

  ureido /) - phenylacetamido 7-3-methyl-ceph-3-em-4-carboxylic acid with 10 mg of magnesium stearate and the mixture is used to fill a hard gelatin capsule of appropriate dimensions. The capsules are placed in vials which are it is sealed with a hood that is airtight and moisture-proof.

Example 63

  Preparation of a powder mixture for forming a syrup The following constituents are mixed together: Ampicillin trihydrate 5.0 g

  7 beta - / (D-alpha- / m-) sodium salt

  chlorophenylthioureido /) - phenylacetamido 7

  3-methyl-ceph-3-em-4-carboxylic acid 2.5 g Sodium saccharin salt 0.2 g Sodium citrate (anhydrous) 1.0 g Citric acid (anhydrous) 0.15 g Orange fragrance 1 0 g Glucose, supplement to 60.0 g This powder mixture is brought to a volume of 100 cm 3 with tap water or pure water for drinking

  just before use 5 cm 3 of the resulting syrup con-

hold 375 mg of antibiotics.

Example 64

  Injection powder ampoules Ampoules are filled under nitrogen and aseptic conditions, each containing 500 mg of cephazoline sodium salt and 250 mg or 500 mg of salt.

  6-beta- / (D- / 4-flavanyl / -thioureido)

  hydroxy-phenyl / -acdtamido / -2,2-dimréthyl-penam-3-carboxy-

  Light bulbs are closed with rubber discs equipped with aluminum retaining rings The powder mixture is mixed with a solvent for just injections

before use.

Example 65

  Pharmacological Studies and Results The majority of the compounds prepared according to the invention have an inhibitory effect on the Beta-Lactamase.

  Bacillus cereus 569 / H (an enzyme available in the

  merce) and partially purified beta-lactamases isolated from strains of E. coli and S. aureus to the same degree or even higher degree than clavulanic acid or dicloxacillin. Inhibition can also be examined photometrically in in vitro conditions, using Nitrocéphine as substrate / Punyiczki, M, Jaszberenyi, J Cs, Hernadi, F.

  MFT Publication 1977/1, pp. 71-81 (1978).

  The novel compounds synergistically enhance the activity of beta-lactam antibiotics sensitive to

  beta-lactamases known under in vitro conditions.

  The new compounds are potent antibacterial agents, as shown by the results of tests carried out

  on mice under in vivo conditions.

  Some of the compounds of the general formula (I) are

  also effective as antifungal agents.

  The results of the pharmacological tests are

summarized in Tables 5 to 8.

Table 5

  I 50 values (gmoles) of beta-inhibitory substances

  lactamase determined on various beta-lactamase enzymes Aerobacter compound E coli B cereus (N of the example) cloacae 53 J 53 RP 4

16,261.6 92.5 17.8

54,381.7 76.3 4894.1

255.4 226.8 2385.3

33,241.2 74.5 13.3

47,591.7 180.9 -

41,548.8 76.3 82.2

27,352.5 145.4 20.5

14,408.2 179.2 32.3

37 101.2 43.19 8.9

146.8 187.8 20.5

Cloxacillin 2773.3 165.8 1762.7

Sulbactam 2718.9 312.1 -

Table 6

  Endpoints of Inhibition of Various Beta-Lactamase Inhibitory Agents Measured on Isolated Enzymes Compound Endpoint of Inhibition (Inhibitor Concentration, g M) (N of B cereus S aureus E coli E coli + Aerobacter example) P Cl J 53 RP 4 D 53 R 46 cloacae 53 Dicloxacillin Sulbactam

> 5000

<0.32

> 5000

> 5000

> 5000

1.6 to I w l The us -24-

Table 7

  Activities of compounds in white mice after oral administration * Compound Dose Survivance mg / kg (treated / surviving mice) Cephalexin ceporin

Example 51

  Table 8 Activity of compounds in white mice after subcutaneous administration * Compound Dose Survivance mc / kcr (treated / surviving mice) Céporine

Example 51

  0.1 1.0 O, 0/1 1 0/9 / 10/2/10/10 Assays performed on groups of 10 animals, weighing 19-24 g Animals were infected with Staph aureus Smith (20 x LD 100 ip) and kept under observation during

72 hours.

  0.25 1.0, 0/4/9/10/0/10/10/10/10/10 -25-

Claims (9)

  A penicillin or cephalosporin derivative of the general formula (I), wherein A is a group of the general formula (a) or (b), X is a group of the formula -C (CH 3) 2-, - CH 2 -C (CH 3) =, -CH 2 -C (CH 2 O Ac) = or CH 2 -C (CH 2 Slet) =, and in the latter   Het formula is a heterocyclic group of 5 to 7 chains   saturated or unsaturated, containing from 1 to 4 nitrogen atoms and possibly   one or more of the other hetero-a Lomes, possibly   It is condensed with one or more phenyl groups and / or substituted by one or more alkyl, aralkyl, aryl, substituted aryl or substituted aralkyl groups. R 1 is a hydrogen atom, a C 14 alkyl group or a phenyl group. Currently, a substituent of a halogen, hydroxy, alkoxy or alkyl substituent, R 2 is a hydrogen atom, a C 4 -C 4 alkylamino group, or a phenyl group for the addition of a halo, hydroxy substituent. , alkoxy or alkyl, R and R each represent a hydrogen atom, a   C 1-4 alkyl group or a p 1 alkyl group bearing possibly   Alternatively, a hydroxy, alkoxy or alkyl substituent, Q is a doxygen, sulfur or selenium atom, R is a hydro, ene, a straight chain or branched C 4 1-4 alkyl group. a group of the general formula -COOR-, and in which formula R 5 is a C 1 -C 8 alkyl group, a benzyl group, a benzhydryl group or a phenyl group having a halo, hydroxy, alkoxy or alkyl, R 6 is a phenyl group optionally bearing one or more halo, C 16 alkyl, nitro, alkoxycarbonyl, trifluoromethyl, dialkylamino, hydroxy, carboxylic acid or sulphonic acid substituents, an alkyl group   C 1 -C 8 optionally substituted with an alkoxy substituent   Carbonyl, hydroxy, dialkylamino or alkoxy, a C 3 -C 8 cycloalkyl group, a C 26 alkenyl group, a   naphthyl group, a heteroaryl group, a heteroaryl group   a 3- to 8-membered cyclyl optionally fused with one or more phenyl groups and / or one or more substituents, or an adamantyl group, R 'is hydrogen, or R 6 and R 7 form, together with the atom adjacent nitrogen, a 4- to 8-membered heterocyclic group, unsubstituted or preferably substituted, containing one or more atoms   additional nitrogen, oxygen or sulfur and possibly   optionally condensed with one or more phenyl rings, Z is hydroxy, n is zero or one and t is zero, one or two, or a pharmacologically acceptable salt or an ester   biologically active of such a compound.   Compound of the general formula (I), wherein A is a group of the general formula (a) and R 1 2 3 6 7 8   R 2, R 3, R, R, R 8, Q Z, X, N and t are as defined in claim 1, or a pharmacologically acceptable salt or a biologically active ester of such a compound. A compound of the general formula (I) wherein R 1 is hydrogen, A is a group of the general formula (a), R is phenyl, R 3 and R 7 are hydrogen, n and t each represent zero, X is a group of the formula -CH 2 -C (CH 3) 2 -, Q is an oxygen atom and Z and R 6 are as defined in claim 1, or a salt pharmacologically acceptable or an ester   biologically active of such a compound.   -27- 4 Compound of the general formula (I), wherein 1 2 3 6 7   Q is a sulfur atom and R, R, R, R 6, R, A, X, Z, n and t are as defined in claim 3, or   a pharmacologically acceptable salt or a biological ester   gically active agent of such a compound. Compound of the general formula (I), wherein 1 2 -3   A is a group of the general formula (b) and R, R 2, R 3 6 7 8   R, R, R, Q, Z, X, N and t are as defined in claim 1, or a pharmacologically acceptable salt   or a biologically active ester of such a compound.   6 Compound of general formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IH), where R 10 is hydrogen or a group hydroxyl, R is a methyl group, -CH 2 O Ac, -CH 2 Py or -CH Het; R 2 and R 2 are halogen, alkyl, nitro, -COO-alkyl, -CF 3, 11 (alkyl) 2, -OH, -COOH or SO 2 OH; and   R 'represents one of groups (e) to (r).   Process for the preparation of a compound of the general formula (I), wherein A, R 1, R 2 R, R 4 R 6 RR, X, Z, Q, N and t are as defined in the claim 1, or a pharmacologically acceptable salt or a biologically active ester of such a compound, characterized in that a compound of general formula (II), wherein, R, R, R, X, Z, N and t are as defined   in claim 1, or a salt or a biological ester   The active ingredient of such a compound is reacted with a compound of the general formula (III), wherein B is a group of the general formula (c) or (d), R 6 is a trimethylsilyl group or a group R 6 as defined in claim 1 and R 7 'is a trimethylsilyl group or a group R as defined in claim 1, and Q   is as defined in claim 1.   Process for the preparation of a compound of the general formula (I), wherein A, R 1, R 2 R, R, R 4, R 6, R 7, R 8, X, Z, Q , N and t are as defined in claim 1, or a pharmacologically acceptable salt or a biologically active ester of such a compound, characterized in that a compound of the general formula (IV), in i 2 3 4 6 7 8 wherein A, R, R 2, R, R 4, R 6, R 7, R 8 Q and N are such   as defined in claim 1, Y is an oxy-   gene or sulfur and R 13 is a phenyl group bearing one or more halo substituents, a quinolyl group optionally carrying an alkyl, acyl or halo substituent, or an amidino group optionally carrying an alkyl or cycloalkyl substituent, is reacted with a compound of the general formula (V), wherein X, Z and t are as defined in claim 1, or   salt or a biologically active ester of such a compound.   9 Process for the preparation of a compound of the R 1 2 3 4 6   general formula (I), wherein A, R, R 2, R 3, R 4, R 6, R 7, R 8, X, Z, Q, N and t are as defined in claim 1, or a pharmacologically acceptable salt   or a biologically active ester of such a compound,   characterized in that a compound of the general formula (II), wherein R, R, R, R, X, Z, N and t are as defined   in claim 1, or a salt or a biological ester   the active compound of such a compound is reacted with a compound of the general formula (VI), wherein Q is as defined in claim 1, R 6 and R 7 are as defined in claim 7, is zero or one and 4 'R 4 represents the substituents listed in claim 1 to the definition of R 4, with the exception of hydrogen, and if appropriate a compound resulting from the general formula (I) is converted into a pharmacologically acceptable salt   or a biologically active ester.   Conventional pharmaceutical agent, a diluent and / or an auxiliary agent and optionally an antibiotic of known beta-lactam type.   Pharmaceutical composition characterized in that it contains as active agent a compound of the general formula (1) as defined in claim 1   or a pharniacologically acceptable salt or a biological ester   the active ingredient of such a compound, possibly in combination with   with a known beta-lactam antibiotic.   It process for the preparation of a pharmaceutical composition   characterized in that compound of the general formula (I) as defined in claim 1 or   pharmacologically acceptable salt or a bologic ester   active ingredient of such a compound is mixed with a vehicle