NO821456L - PROCEDURE FOR THE PREPARATION OF BETA-LACTAMES. - Google Patents

Description

This invention relates to new penicillin and cephalosporin derivatives with antibacterial and 3-lactamase-inhibiting effect, as well as a method for their production.

The literature indicates several 3-lactam compounds exhibiting 3-lactamase inhibitory effects [p<->Lactamases (J.M.T. Hamilton-Miller, J.T. Smith, ed.), Academic Press, London, 1979]. The members of the isoxazolylpenicillin group (oxacillin, cloxacillin, dicloxacillin, flucloxacillin) have, in addition to their 3-lactamase-inhibiting action, significant antibacterial properties which enable the preparation of effective combinations (such as ampiclox). However, these compounds act primarily on Gram-positive 3-lactamases [Greenwood, d. and 0<*->Grådy, F.: Chemotherapy, 21, 330 (1975)]. A similar effect can be observed for nafcillin and quinacillin; both compounds exhibit, in addition to their 3-lactamase inhibitory effect, valuable antibacterial activity. Certain other 3-lactam compounds, such as the monocyclic 3-lactams, exhibit only [3-lactamase-inhibiting effect without any antibacterial activity (Belgian Patent Document No. 766,534). ;Several publications - concern the production of ureides, acylureides and related compounds from 6-amino-penicillinic acid or ampicillin [see e.g. Naito, T. et al.: J. Antibiotics (A) 18, 145 (1965)]; Nayler, J. H. C.: Adv. Drug Res., 1_, 1 (1973); Ger. Open. 1,904,851; Ger. Open. 1,770,620; Ger. Open. 1,929,997; US Patent 3,479,339; ;Bodey, G. et al: Antimicrob. Ag. Chemother...13, 14 (19 78)]. These derivatives were only investigated for their antibacterial effect. Although an extension of the antibacterial spectrum against Gram-negative microorganisms was observed with some compounds, none of them proved to be more effective than ampicillin. ;Published German patent application 2 634 431 describes the preparation of compounds corresponding to general formula I. This publication ;a) does not describe compounds with a penne skeleton,;6 7 ;b) does not describe compounds in which R and R denote substituted alkyl, aryl, heteroaryl, phenyl , substituted ;phenyl or heterocyclyl groups,;c) relates only to thiourea derivatives,;d) relates only to compounds in which X is a type group, e) does not describe compounds with 3-lactamase inhibitory and synergistic effects, and ;f) relates only to derivatives in which t is always equal null.;A common disadvantage of the above-mentioned compounds is that, although they have a suitably strong antibacterial effect and a suitably broad antibacterial spectrum, for the most part they retain the 3-lactamase sensitivity of the starting molecule, and thus they cannot be used against resistant strains or must be used in combination with a 3-lactamase inhibitor such as clevulanic acid. It has now been found that the new ceph-3-em-4-carboxylic acid and 2,2-dimethyl-penam-3-carboxylic acid derivatives corresponding to general formula I in which A is a group of general formula (a) or (b), X is a group of the formula -C(CH3)2-, -C<H>2<->C(CH3)=, -CH2-C(CH2OAc)=- or -CH2~C(CH2 <S>Het)=, and in which the latter compound Het denotes a saturated or unsaturated, 5-7-membered heterocyclic group: containing 1-4 nitrogen atoms and optionally with one or more other heteroatoms, optionally condensed with one or more phenyl groups and/ or substituted with one or more alkyl, aralkyl, aryl, substituted aryl or substituted aralkyl groups, ;R"*" is a hydrogen atom, a 'C^_^ alkyl group or a phenyl group which optionally carries a halogen, hydroxy, alkoxy or alkyl substituent,

R 2 is a hydrogen atom, a C1-4 alkyl group or a phenyl group which optionally carries a halogen, hydroxy, alkoxy or alkyl substituent,

R 3 and R 8 each denote a hydrogen atom, a C 1-4 alkyl group or a phenyl group which optionally carries a halogen, hydroxy, alkoxy or alkyl substituent,

Q denotes oxygen, sulfur or selenium atom,

R 4 denotes a hydrogen atom, a straight-chain or branched C 4 alkyl group or a group of general formula -COOR^, and in this latter formula R 4 denotes a C 4 alkyl group, a benzyl group, a benzhydryl group or a phenyl group which optionally carries a halogen, hydroxy, alkoxy or alkyl substituent,

R is a phenyl group which optionally carries one or more halogen, C₁₋ alkyl, nitro, alkoxycarbonyl, trifluorophenyl, dialkylamino, hydroxy, carboxylic acid or sulfonic acid substituents, a C₋₋₋ alkyl group bearing an alkoxycarbonyl, hydroxy, dialkylamino or alkoxy substituent, a C 1-8 cycloalkyl group, a C 2-8 alkenyl group, a naphthyl group,

a heteroaryl group, a 3-8-membered heterocyclyl group optionally condensed with one or more phenyl groups and/or bearing one or more substituents, or an adamantyl group, and

7

R is hydrogen, or

R 6 and R 7 together with the adjacent nitrogen atom form a 4-^8-membered, unsubstituted or preferably substituted heterocyclic group optionally containing one or more additional nitrogen>oxygen or sulfur atoms, and optionally condensed with one or more phenyl rings,

Z is a hydroxy group,

n is zero or one, and

t is zero, one or two,

as well as non-toxic, pharmacologically acceptable organic or inorganic salts or biologically active esters thereof, exhibit strong antimicrobial and enzyme-inhibiting, preferably anti-bacterial and 3-lactamase-inhibiting effects.

In the substituent X, the Het group preferably denotes a pyrazolyl, imidazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl or triazinyl group.

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

The new compounds of general formula I can be prepared according to the invention by

a) reacting a compound of general formula II with a compound of general formula III, b) reacting a compound of general formula V with a compound of general formula IV, or c) reacting a compound of general formula II with a compound of general formula VI. When cephalexin and 4-flavanyl isothiocyanate are used as starting compounds, the reaction can be carried out according to method a), which gives compounds of general formula I in which R 4 is hydrogen.

According to method a) a compound of general formula II in which R<1>, R<2>, R3, R8, X, Z, t and n are as defined above, or a salt of a biologically active ester thereof, is reacted with a compound of general formula III in which B is a group of general formula (a) or (d), R g is trimethylsilyl group or a group as defined by R c above,

and R 7' is a trimethylsilyl group or a group as defined by R 7 above. The reaction is carried out in an aprotic solvent or a mixture of such solvents, at a temperature of from 0 to 100° C, preferably at room temperature. The reaction can be carried out with frequent stirring of the mixture.

Depending on the nature of the starting compounds, chlorinated aliphatic hydrocarbons, in particular dichloromethane, dichloroethane or chloroform, aliphatic ethers such as di-n-butyl ether, tetrahydrofuran or dioxane, or other aprotic solvents, preferably acetonitrile or ethyl acetate, or mixtures thereof, can be used as reaction medium. The amount of the solvents is chosen so that the solution contains 3 to 30% of the starting compounds of general formula II.

Depending on the reactivity of the compound of general formula III, the reaction proceeds within. 5 minutes to 48 hours.

Method a) can preferably be carried out so that, for example, 2 - 10 ml of dry acetonitrile, dimethylformamide, dimethylacetamide, ethyl acetate, butyl acetate, dioxane, tetrahydrofuran, diglyme or a suitable mixture thereof, calculated for 1 gram of the 3-lactam starting compound, is used as the solution medium, and if a free acid is used as starting compound, 1-5 molar equivalents of a pharmacologically acceptable tertiary organic base such as triethylamine, ethyldiisopropylamine, an N,N-dialkylamino acid ester, are also added to the reaction mixture. The resulting solution is filtered if necessary, whereupon 1-3 molar equivalents of a compound of formula III is added to the solution (or filtrate), either as such or as a 30-50% solution formed with any of the above solvents or solvent mixtures. The reaction is carried out at 0 - 100° C, preferably at room temperature. Depending on the characteristics of the starting compounds and the solvent or solvent mixture, the final product of general formula I generally separates from the reaction mixture as a crystalline substance or sometimes as an oil.

In some cases, the reaction mixture should be evaporated to separate the product. The separated crystalline product is filtered off, washed with a mixture of the above-mentioned solvents and an aliphatic ether if necessary, and dried at room temperature, possibly under vacuum. When the product is separated as an oil, it is crystallized from a suitable solvent.

The product obtained according to method a) can be further purified if necessary, so that the compound of general formula I is dissolved in a minimal amount of water, the aqueous solution is extracted with a water-immiscible solvent such as dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, butyl acetate, etc., after which the aqueous phase is acidified with a calculated amount of an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, and the aqueous-acidic phase is extracted again with a water-immiscible organic solvent. The organic phase is treated with a calculated amount of a pharmacologically acceptable salt-forming agent and then evaporated. The resulting purified solid product of general formula I is dried.

This purification method, which is generally not necessary, gives products of very high purity and with high yields.

According to method b), a compound of general formula V in which the general symbols have the meanings given above, or a salt or a biologically active ester thereof, is reacted with a compound of general formula IV. where A,

in 2 3 8

R, R , R , R , Q and n are as defined above, Y denotes

13

oxygen or sulfur and R denotes a phenyl group bearing one or more halogen substituents, an unsubstituted or substituted quinolyl group or a substituted amidino group. The reaction can be carried out under the conditions discussed above in connection with method a).

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

The new compounds are valuable antibacterial agents with broad spectrums of activity, and can also be used as (3-lactamase-inhibiting agents in combination with (3-lactamase-sensitive semi-synthetic penicillins or cephalosporins with broad antimicrobial spectra, forming particularly effective preparations. When thus the new compounds are combined with ampicillin, carbenicillin, amoxycillin, ticar-cillin, azlocillin, cephalexin, cephaloglycine, cephradine, cephalchlor, cephadroxyl etc. in a ratio of 3:1 to 1:8, combinations are obtained which are useful even in treatment of serious infections caused by resistant strains.

The new compounds can also be combined with amino-glycoside antibiotics. such as trobramycin, gentamycin or kanamycin.

In some cases, the new compounds can also be used as antifungal agents or as intermediates in the production of other biologically active substances.

In some cases, the new compounds can also be used as weight-increasing additives in feed for livestock, and furthermore as preservatives in the paper, wood, leather and textile industries.

When the new compounds are used as preparations, they can be introduced into the animal organism by usual methods, mixed with a feed or feed additive or added to drinking water, whereupon the bacterial infections in the animals can be avoided and a better utilization can be achieved.

The invention is further illustrated in the following examples.

Example 1 to 53

Method a)

Production of urea, thiourea and selenurea compounds

10 mmol of the amino-3-lactam compound were dissolved in a mixture of 25 ml of absolute acetonitrile and 3 ml of triethyl- . amine, and 10 mmol of the appropriate isocyanate, isothiocyanate or isoselencyanate was added to the solution in one or more portions. The mixture was optionally stirred. Dependent on

the reactivity of the isocyanate reactant, the product separates from the mixture within 5 minutes to 24 - 48 hours as a crystalline solid, or occasionally as an oil. When a crystalline substance was obtained, the crystals were filtered off and washed with dry acetonitrile or with a dry aliphatic ether. When an oily substance was obtained, this was treated with a dry aliphatic ether, toluene, petroleum ether, hexane, heptane, light petrol or a suitable mixture thereof, to effect solidification, after which the product was filtered off and dried.

When the resulting compound is not sufficiently pure, as shown by thin-layer chromatography, it can be purified as follows: The impure compound is dissolved in the minimal amount of water, the aqueous solution is washed to remove traces of isocyanate, isothiocyanate or isoselencyanate that may be present present, and then acidified with dilute hydrochloric acid, sulfuric acid or phosphoric acid, and extracted again with a water-immiscible aliphatic ester or a chlorinated solvent. The organic phase is separated, dried, after which the acid is precipitated as its salt either by using 2-ethylcaproic acid sodium or potassium salt, or by treating the solution with an organic base. If the salt is not released from the solution, the solvent evaporates.

One proceeds in a similar way when an α- or 3-sulfoxide, a sulfone or an ester of the amino-3~lactam is used as starting compound. As the oxidized derivatives are less soluble in aliphatic esters and chlorinated hydrocarbons, a dipolar aprotic solvent or co-solvent can sometimes be used as reaction medium.

The products produced by the above method are listed in Tables 1 and 2.

Notes to Tables 1 and 2:

Elemental analysis data (C, H, N, S and Hal) for the products were in good agreement with the calculated values; the difference did not exceed 1% and was in most cases below 0.4%.

Based on IR spectroscopic investigations, the thiourea compounds did not contain traces of the isocyanate reactant, and, as shown by the strongest maximum (lactam carbonyl at 1765-1772 cm ), the fl-lactam ring was intact.

Some of the compounds were also subjected to mass spectrometry, however, the observed data were non-informative due to the low volatility of the samples and thermal decomposition. However, the measurements carried out on samples made more volatile by silylation supported the expected structures.

The H NMR spectroscopic investigations substantiated the expected structures. As shown by these spectra, no C-7 epimerization or ceph-3-em/ceph-2-em isomerization took place with the investigated compounds.

Example 54

Reaction of ampicillin with 4-flavanyl isothiocyanate

1007 mg (2.5 mmol) of ampicillin trihydrate was dissolved in a mixture of 0.8 ml of triethylamine and 5 ml of dry acetonitrile, 670 mg (2.5 mmol) of 4-flavanyl isothiocyanate were added to the solution, and the mixture was allowed to stand at room temperature. A white, crystalline precipitate separated from the mixture. The precipitate was filtered off, washed with a small amount of dry acetonitrile and absolute ether, and was dried in vacuo. 1.55 g (86.47%) of the desired product was obtained, m.p. 171 - 172° C (decomposition), Rf = 0.45 (in a 7:3:1 mixture of benzene,

-1

ethyl acetate and glacial acetic acid). IR (KBr): 1770 cm (lactam C=0) Analysis: Calculated: N = 9.8%

Found : N = 9.68%, 9.75%

Example 55

Reaction of cephalexin with phenyl iso-selencyanate

The reaction was carried out according to Method a) forming the product with an R^ value of 0.36 (in a 7:3:1 mixture of toluene, ethyl acetate and formic acid).

Analysis: Calculated for C29<H3>7<N5>04SSe (630.69):

C 55.22% H 5.91% N 11.11%

Found : C 55.15% H 5.84% N 11.27%

IR (KBr): 3350, 3010, 2960, 1765, 1720, 1680, 1660, 1520, 1500, 1310, 705 cm"<1>.

Example 56

Preparation of 7-[a-(1-methylthioureido)]-phenylethamido-3-chloro-ceph-3-em-4-carboxylic acid triethylammonium salt

The compound was prepared according to Method a). Yield: 88.2%, m.p. 127 - 129° C (decomposition).

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

695 cm<1>.

Analysis: Calculated for C^H^CINjO^j (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 63-[D-2-[(3-(2-phenyl-5-,6-benzo-pyran-4-yl)-2-thioureido)-2-[4-hydroxyphenyl)]-acetamido]- 2 , 2- dimethyl- 7-oxo- 4- thia- l- azabicyclo[ 3, 2 , 0] heptane- 2- carboxylic acid- triethyl-ammonium salt

A mixture of 0.8 g of D-2-[(3-(2-phenyl-5,6-benzo-pyran-4-yl)-2-thioureido)-2-[4-hydroxyphenyl]]-acetic acid pentachlorophenyl ester , 10 ml of ethyl acetate, 0.23 g of 6-aminopenicillanic acid and 0.1 ml of triethylamine were stirred at room temperature for 12 hours, then the mixture was evaporated and the product crystallized. The title compound was obtained with a yield of 82%.

IR: 3400,.1770, 1730, 1680, 1520 cm"<1.>

Analysis: Calculated for C3<gH>47<N>506<S>2(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 was dissolved in 10 ml of N,N-dimethylformamide at 20°C, and 1.04 g (2 mmol) of N-phenylcarbamoyl-D-phenylglycine-pentachlorophenyl ester was added to the stirred mixture over several portions. The mixture was stirred at 20° C. for 12 hours, then poured into 100 ml of ice water, the precipitated white crystalline material was filtered off, washed with water and then crystallized from a mixture of dimethylformamide and water. The crystals were filtered off and the product was converted to its sodium, potassium or triethylammonium salt in known manner.

The triethylammonium salt, obtained with a yield of 84%, melts at 211 - 213° C. IR: 3400, 1765, 1710, 1680, 1520 cm"<1>.

Analysis: Calculated for C^H^N^O^S (567.73):

C 61.35% H 6.57 N 12.34% S 5.65%

Found : C 61.11% H 6.55 N 12.23 4 S 5.49%

C 61.11% H 6.60% N 12.19% S 5.52%

Example 59

Method c)

1.0 g (2.48 mmol) of ampicillin was dissolved in a mixture of 24.8 ml of dry acetonitrile and 2.48 ml of triethylamine, and a solution of 0.678 g of 3-ethoxycarbonyl-4-chlorocarbonyl-perhydro-1,4- thiazine in 3 ml of toluene and 1 ml of triethylamine was added dropwise to the stirred solution while cooling. The mixture was stirred for 1 hour, then acidified to pH = 2 with 2N aqueous hydrochloric acid, the acidic mixture was extracted with dichloromethane, the organic phases were combined, washed with water, dried over sodium sulfate and then evaporated. The product was crystallized from absolute ether. 0.82 g (60.1%) of the desired product was obtained; IR = 3400, 1770, 1735, 1720, 1672, 1525 cm"<1>.

Analysis: Calculated for C3qH45N5C>7S2 (651.86):

N 10.75% S 9.83%

Found : N 10.82% S 9.89%

N 10.86% S 9.85%

Example 60

Preparation of 7p-[2-(1,2,4(4H)-triazol-4-yl)-2-phenyl]-acetamido-3-methyl-ceph-3-em-4-carboxylic acid

0.56 g (10 mmol) of 4-amino-1,2,4(4H)-triazole was suspended in 20 ml of absolute dichloromethane, and then 5.2 ml of absolute triethylamine and 1.27 ml (10 mmol) of trimethyl- chlorosilane added. The mixture was stirred at 20°C for 15 minutes, then 0.76 mL (10 mmol) of thiophosgene was introduced, and stirring was continued for 30 minutes. The resulting mixture was filtered under a dry nitrogen atmosphere, and the filtrate was added to a solution of 4.46 g (10 mmol) of cephalexin pivaloyloxymethyl ester in 40 ml of dichloromethane. The mixture was stirred for 1 hour and then worked up to give the title compound in 88% yield.

IR (KBr): 3360, 3280, 3030, 2980, 1774, 1735, 1710, 1680, 1625, 1520, 1490, 1210, 1045, 715 cm"<1>.

Analysis: Calculated for C25H29N7°6S2(587'69):

N 16.68% S 10.91%

Found : N 16.55% S 11.12%

Example 61

Preparation of 63-[2-phenyl-2-(phenylthioureiod)]-acetamido-penicillanic acid-triethylammonium salt 10 mmol (approx. 4 g) of ampicillin trihydrate was dissolved at 0° C in a mixture of 7 ml of triethylamine and 50 ml of dimethylformamide, and then reacted with an equimolar amount of phenyl mustard oil. When working up the mixture, 3.7 g of the title compound was obtained as primary product in the chromatographic state. A further quantity of the product can be separated by working up the mother liquor.. R f = 0.27 (in a 7:3:1 mixture of toluene, ethyl acetate and formic acid); sm.p.

134 - 136° C IR (KBr): 1788 cm"<1>(3-lactam).

<1>H NMR (DMSO-d6): 1.25 (t, ?H, -CH2C<H>3), 1.54 (s, 3H, 23 Me), 1.16 (s, 3H, 2a Me ), 3.08 (6H, CH2-GH3), 4.12 (s, 1H, C(3)-H), 5.4 - 5.6 (d + dd, 2H, C(5)and C( 6)-H), 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 = 9 Hz, NH), 9.3 (d, 1H, Ph-CH-NH-,

J = 10 Hz) , 10.46 (s, 1H) .

3-lactamase inhibitory data of the product are listed in Table. 3.

In a similar manner, the following compounds were prepared: a) 6β-[2-phenyl-2-(phenylthioureido)]-acetamido-penicillanic acid-1(S)-oxyd-triethylammonium salt, b) 63-[2-phenyl-2- (phenylthioureido)]-acetamido-penicillanic acid-1,1-dioxyd-triethylammonium salt, c) 73- [ 2-phenyl-2-(phenylthioureido).] - acetamido-3-methyl-cef-3-em-4 -carboxylic acid-1(S)-oxyd-dicyclohexylammonium-salt, d) 73-[2-phenyl-2-(phenylthioureido)]-acetamido-3-methyl-cef-3-em-4-aryloxylic acid-1, 1- dioxyd-dicyclohexylammonium salt, e; 73-[2-phenyl-2-iphenylthioureido]-acetamido-3-methyl-cef-3-em-4-carboxylic acid acetoxymethyl ester (1(S)-oxyd, f) 63-[2-phenyl-2-( phenylthioureido)N-acetamido-penicillanic acid-ben2oyloxymethylester-1,1-dioxyd. 3-lactamase inhibitory endpoints of phenylthioureido-benzylpenicillin TEA salt determined on individual isolated enzymes are listed in Table 4. Values are given in mg/l units.

The following examples illustrate the preparation of pharmaceutical preparations.

Example 62

Preparation of capsules for oral administration

250 mg of ampicillin trihydrate and 250 mg of 73-[(D-(α-phenylthioureido))-phenylacetamido]-3-methyl-cef-3-em-4-carboxylic acid sodium salt were mixed with 10 mg of magnesium stearate and the mixture was filled in a hard gelatin capsule of suitable size.The capsules were placed in ampoules and closed with an air- and moisture-tight plastic stopper.

Example 6 3

Preparation of a powder mixture for the preparation of syrup The following components were mixed together:

This powder mixture was filled up with 100 ml of tap water or clean drinking water just before use. 5 ml of the resulting syrup contains 375 mg of antibiotics.

Example 64

Powder ampoules for injection purposes

500 mg cefazolin sodium salt. and 250 mg or 500 mg 63-[(D-(4-flavanyl)-thioureido)-[4-hydroxyphenyl)-acetamido]-2,2-dimethyl-penam-3-carboxylic acid sodium salt was filled into each of the ampoules under a nitrogen atmosphere and under aseptic conditions. The ampoules were closed with rubber washers fitted with aluminium-minium fasteners. The powder mixture was mixed with a solvent for injection purposes just before use.

Example 65

Pharmacological investigations and results

The majority of the compounds produced according to the invention exhibit an inhibitory effect on Bacillus cereus 569/H 3-lactamase (a commercially available enzyme) and on partially purified 3-lactamases isolated from E. coli and S. aureus strains to the same or even higher degree than clevulanic acid or dicloxacillin. The inhibition can also be examined photometrically under in vitro conditions, using nitrocefin as substrate [Punyiczki, M., Jåszberényi, J. Cs., Hernådi, F.: MFT Publication 1977/1, pp. 71-81 (198) ]..

The new compounds synergistically increase the activity of known 3-lactamase-sensitive 3-lactam antibiotics under in vitro conditions.

The new compounds are powerful antibacterial agents as demonstrated by the results of tests performed on mice under in vivo conditions.

Some of the compounds of general formula I are also effective as antifungal agents.

The results of. the pharmacological tests are listed in Tables 5-8.

Claims (7)

1. Penicillin or cephalosporin derivative.of general formula I wherein A is a group of general formula (a) or (b) , X is a group of formula -CfCH^^-/ -CH2-C (CH3) =, -CH2 -C(CH2 OAc)= or -CH2~ C(CH2 SHet)=, and in which the latter formula Het is a saturated or unsaturated, 5-7 membered heterocyclic group containing. 1-4 nitrogen atoms and optionally one or more other heteroatoms, optionally condensed with one or more phenyl groups and/or substituted with one or more alkyl, aralkyl, aryl, substituted aryl or substituted aralkyl groups, R 1 is hydrogen, a C 1 -4 alkyl group or a phenyl group which optionally carries a halogen, hydroxy, alkoxy or alkyl substituent, R 2 is hydrogen, a C 1 -3 alkyl group or a phenyl group which optionally carries a halogen, hydroxy, alkoxy or alkyl substituent, R 3 and R 8 each represent hydrogen, a C 1 - 4 alkyl group or a phenyl group which optionally carries a halogen, hydroxy, alkoxy or alkyl substituent, Q denotes oxygen, sulfur or selenium, R 4 denotes hydrogen, a straight chain or carbonized C,_4 alkyl group or a group of general formula -COOR 5 , and in the latter formula R 1 is a C 1 -6 alkyl group, a benzyl group, a benzhydryl group. or a phenyl group which optionally carries a halogen, hydroxy, alkoxy or alkyl substituent, R^ is a phenyl group which optionally carries one or more halogen, C 1 -g alkyl, nitro, alkoxycarbonyl, trifluoromethyl, dialkylamino, hydroxy, carboxylic acid or sulfonic acid substituent, a C 1 -g alkyl group which optionally carries an alkoxycarbonyl, hydroxy, dialkylamino or alkoxy substituent, a C 1 -Q cycloalkyl group, a C 2 -g alkenyl group, a naphthyl group, a heteroaryl group, a 3-8 membered heterocyclic group optionally .condensed with one or more phenyl groups and/or bearing one or more substituents, or an adamantyl group, R 7 is hydrogen or R 6 and R 7 together with the adjacent nitrogen atom form a 4-8 membered, unsubstituted or preferably substituted heterocyclic group optionally containing one or more additional nitrogen, oxygen or sulfur atoms and optionally condensed with one or more phenyl rings, Z is a hydroxy group, n is zero or one, and t is zero, one or two, . or a pharmaceutically acceptable salt or biologically active. ester thereof. 2. Compound of general formula I, characterized in that A is a group of general formula (a) and I O T z: - J o R, R, R, R, R, R, Q, Z, X, others as defined in claim 1, or a pharmacologically acceptable salt or biologically active ester thereof. 3. Compound of general formula I, characterized in that R <1> is hydrogen, A is a group of general formula (a), 2 R is phenyl, 3 7 R and R are hydrogen atoms, n and t each denote zero, X is a group of formula -CH2-C (CH-j) 2~' Q is an oxygen atom, and Z and R^ are as defined in claim 1, or a pharmacologically acceptable salt or biologically active ester thereof. 4. Compound of general formula .ly.' characterized in that Q is a sulfur atom and R1, R <2> , R3, R^, R^, A, X, Z, n and t are as defined in claim 3, or a pharmacologically acceptable salt or biologically active ester thereof. 5. Compound of general formula I, characterized in that A is a group of general formula (b) and R1, R2, R3, R6, R7, R8, Q, Z, X, n and t are as defined in claim 1, or a pharmacologically active salt or biologically active ester thereof. 6. Compound of general formula (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (IH), characterized in that R1^ is hydrogen or hydroxy1, R is methyl, -CH2 OAc, -CH?Py or -CH2 SHet, 11 12 R and R are halogen, alkyl, nitro, -COO-alkyl, -CF^, -N(alk<y>l)2 , -OH, -COOH, -SO2<O>H, and R' denotes one of the groups (e) to (r). 7. Process for the preparation of a compound of general formula I, wherein A, R <1> , 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 biologically active ester thereof, characterized in that a) a compound of general formula II in which R 1 , R 2 , R 3 , R 8 , X, Z, n and t are as defined in claim 1, or a salt or a biologically active ester thereof, is reacted with a compound of general formula III in which B is a group of general formula (c) or (d), R 6 1 is trimethylsilyl group or 6 7' an R group as defined in claim 1, and R is trimethylsilyl group or an R 7 group as defined in claim 1, and Q is as defined in claim 1, or b) a compound of general formula IV in which A, R , 2 3 4 6 7 8 R , R , R , R , R , R , Q and n are as defined in claim 1, Y 13 is oxygen or a sulfur atom and R is a phenyl group bearing one or more halogen substituents, a quinolyl group optionally bearing an alkyl, acyl or halogen substituent, or an amidino group optionally bearing an alkyl or cycloalkyl substituent, is reacted with a compound of general formula V, in which X , Z and t are as defined in claim 1, or a salt or a biologically active ester thereof, or c) a compound of general formula II in which R 1 , R 2 , R 3 , R<8> , X, Z, others which defined, in claim 1, or a salt or a biologically active ester thereof, is reacted with a compound of general formula VI in which Q is as defined in claim 1, R 6 1 and R is as defined in point ..a), m is zero or one and R 4 1 denotes the substituents specified in claim 1 for the definition of R 4 excluding hydrogen, and if desired, that a resulting compound of general formula I is converted into its pharmacologically acceptable salt or biologically active ester.