GB2101586A - beta -Lactam compounds and pharmaceutical compositions containing the same, and a process for the preparation thereof - Google Patents
beta -Lactam compounds and pharmaceutical compositions containing the same, and a process for the preparation thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
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Abstract
Ceph-3-em-4-carboxylic acid and 2,2-dimethyl-penam-3-carboxylic acid derivatives of the general formula (I), wherein: R<6>R<7>N- or R<6>R<7>-NR<4>-, X is -C(CH3)2-, -CH2-C(CH3)= -CH2-C(CH2OAc)= or -CH2-C(CH2SHet)=, Het is a 5-7 membered heterocyclic group containing 1-4 nitrogen atom(s) and optionally one or more other hetero atom(s), optionally condensed with one or more phenyl group(s) and/or substituted with one or more alkyl, aralkyl, aryl, substituted aryl or substituted aralkyl group(s), R<1> is hydrogen atom, a C1-4 alkyl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent, R<2> is hydrogen atom, a C1-4 alkyl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent, R<3> and R<8> each stand for hydrogen atom, a C1-4 alkyl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent, Q represents oxygen, sulfur or selenium atom, R<4> is hydrogen atom, a C1-4 alkyl group or a group -COOR<5>, R<5> being a C1-8 alkyl group, a benzyl group, a benzhydryl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent, R<6> is a phenyl group bearing optionally one or more halo, C1-6 alkyl, nitro, alkoxycarbonyl, trifluoromethyl, dialkylamino, hydroxy, carboxylic acid or sulfonic acid substituent(s), a C1-8 alkyl group optionally bearing an alkoxycarbonyl, hydroxyl, dialkylamino or alkoxy substituent, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a naphthyl group, a heteroaryl group, a 3-8 membered heterocyclyl group optionally condensed with one or more phenyl group(s) and/or bearing one or more substituent(s), or an adamantyl group, and R<7> is hydrogen, or R<6> and R<7> form, together with the adjacent nitrogen atom, a 4-8 membered, unsubstituted or substituted heterocyclic group optionally containing one or more additional nitrogen, oxygen or sulfur atom(s) and optionally condensed with one or more phenyl ring(s), Z is hydroxy group, n is zero or one, and t is zero, one or two, and their pharmacologically acceptable salts and biologically active esters possess strong antimicrobial and enzyme inhibiting, particularly antibacterial and beta -lactamase inhibiting effects.
Description
SPECIFICATION p-Lactam compounds and pharmaceutical compositions containing the same, and a process for the preparation thereof
The invention relates to new penicillin and cephalosporin derivatives with antibacterial and p- lactamase inhibiting effects, as well as to a process for the preparation thereof.
The literature reports on several p-lactam compounds possessing p-iactamase inhibiting effects {Lactamases (J. M. T. Hamilton-Miller, J. T. Smith, ed.) Academic Press, London, 1979]. The members of the isoxazolylpencillin group (oxacillin, cloxacillin, dicloxacillin, flucloxacillin) have, beside their p- lactamase inhibiting effects, significant antibacterial properties, too, which enables one to produce effective combinations (such as ampiclox).These compounds act, however, primarily on Gram-positive ,B-lactamases [Greenwood, D. and O'Grady, F.: Chemotherapy, 21,330 (1 975)]. Similar effects can be observed on nafcillin and quinacillin; both compounds possess, beside their p-lactamase inhibiting effects, valuable antibacterial activities, too. Some other p-lactam compounds, such as the monocyclic p-lactams, exert only p-lactamase inhibiting effects without any antibacterial activity (Belgian patent No. 766,534).
Several publications deal with the preparation of ureides, acylureides and related compounds starting from 6-amino-penicillanic acid or ampicillin [see e.g. Naito, T. et al.: J. Antibiotics (A) 18, 145 (1965); Nayler, J. H. C.: Adv. Drug Res., 7, (1973); Ger. Offen. 1,904,851; Ger. Offen. 1,770,620; Ger.
Offen. 1,929,997; US Pat. 3,479,339; Bodey, G. et al: Antimicrob. Ag. Chemother. 13, 14 (1978)].
These derivatives were examined only for their antibacterial effects. Although a broadening of the antibacterial spectrum towards Gram-negative microorganisms was observed with some compounds, none of them proved to be more effective than ampicillin.
The published German patent application No. 2,634,431 describes the preparation of compounds corresponding to the general formula (I). However, this publication
a) does not disclose compounds with penam skeleton,
b) does not disclose compounds wherein R6 and R7 represent substituted alkyl, aryl, heteroaryl, phenyl, substituted phenyl or heterocycyl groups,
c) relates only to thiourea derivatives,
d) relates only to compounds wherein X is a
type group,
e) does not disclose compounds with jB-lactamase inhibiting and synergistic effects, and
f) relates only to derivatives wherein t is always equal to zero.
A common disadvantage of the above compounds is that, although they have appropriately strong antibacterial effects and appropriately broad antibacterial spectra, they mostly retain the ,B- lactamase sensitivity of the starting molecules, thus they cannot be applied against resistant strains or should be used in combination with a p-lactamase inhibiting agent, such as clevulanic acid.
Now it has been found that the new ceph-3-em-4-carboxylic acid and 2,2-dimethyl-penam-3carboxylic acid derivatives corresponding to the general formula (I), wherein
A is a group of the general formula (a) or (b),
X is a group of the formula-C(CH3)2-,-CH2-C(CH3)=, -CH2-C(CH2OAc)= or -CH2 C(CH2SHet)=, and in the latter formula
Het is a saturated or unsaturated, 5-7 membered heterocyclic group containing 1-4 nitrogen atom(s) and optionally one or more other hetero atom(s), optionally condensed with one or more phenyl group(s) and/or substituted with one or more alkyl, aralkyl, aryl, substituted aryl or substituted aralkyl group(s), R1 is hydrogen atom, a C14 alkyl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent,
R2 is hydrogen atom, a C14 alkyl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent,
R3 and R8 each stand for hydrogen atom, a C14 alkyl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent,
Q represents oxygen, sulfur or selenium atom,
R4 is hydrogen atom, a straight-chained or branched C14 alkyl group or a group of the general formula -COOR5, and in this latter formula
R5 is a C18 alkyl group, a benzyl group, a benzhydryl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent,
R6 is a phenyl group bearing optionally one or more halo, C16 alkyl, nitro, alkoxycarbonyl, trifluoromethyl, dialkylamino, hydroxy, carboxylic acid or sulfonic acid substituent(s), a C18 alkyl group bearing an alkoxycarbonyl, hydroxy, dialkylamino or alkoxy substituent, a C38 cycloalkyl group, a C25 alkenyl group, a naphthyl group, a heteroaryl group, a 3-8 membered heterocyclyl group optionally condensed with one or more phenyl group(s) and/or bearing one or more substituent(s), or an adamantyl group, and
R7 is hydrogen, or
R6 and R7 form, together with the adjacent nitrogen atom, a 4-8 membered, unsubstituted or preferably substituted heterocyclic group optionally containing one or more additional nitrogen, oxygen or sulfur atom(s) and optionally condensed with one or more phenyl ring(s),
Z is hydroxy group,
n is zero or one, and
t is zero, one or two,
as well as the non-toxic, pharmacologically acceptable organic or mineral salts or biologically active esters thereof possess strong antimicrobial and enzyme inhibiting, particularly antibacterial and p-lactamase inhibiting, effects.
In substituent X the Het group represents preferably a pyrazolyl, imidazolyl, thiazoiyl, 1,2,3- triazolyl, 1 2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl or triazinyl group.
Of the biologically active esters those containing a group of the formula (e), (f), (g), (h), (i), (j), (k), (I), (m), (n) or (o) as esterifying group are preferred.
The new compounds of the general formula (I) can be prepared according to the invention by
a) reacting a compound of the general formula (II) with a compound of the general formula (III), b) reacting a compound of the general formula (V) with a compound of the general formula (IV), or
c) reacting a compound of the general formula (II) with a compound of the general formula (VI).
When cephalexin and 4-flavanyl-isothiocyanate are utilized as starting substances, the reaction can be performed according to method a), which produces compounds of the general formula (I) wherein R4 is hydrogen.
According to method a) of the invention a compound of the general formula (II), wherein R1, R2,
R3, R8, X, Z, t and n are as defined above, or a salt or a biologically active ester thereof is reacted with a compound of the general formula (III), wherein B is a group of the general formula (a) or (d). R8, is trimethylsilyl group or a group as defined at R6 above and R7' is trimethylsilyl group or a group as defined at R7 above. The reaction is performed in an aprotic solvent or a mixture of such solvents, at a temperature of 0 to 100 C, preferably at room temperature. The reaction can be performed with or without stirring the mixture.
Depending on the character of the starting substances, chlorinated aliphatic hydrocarbons, particularly 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 applied as reaction medium. The amount of the solvent(s) is selected so that the solution contains 3 to 30% of the starting substance of the general formula (II).
Depending on the reactivity of the compound of the general formula (III), the reaction proceeds within 5 minutes to 48 hours.
Method a) can be performed preferably so that e.g. 2-10 ml of dry acetonitrile, dimethyl formamide, dimethyl acetamide, ethyl acetate, butyl acetate, dioxane, tetrahydrofuran, diglyme or an appropriate mixture thereof, calculated for one gramm of the starting p-lactam compound, are utilized as solvent medium-, and if a free acid is applied as starting substance, 1-5 molar equivalents of a pharmacologically acceptable tertiary organic base, such as triethyl amine, ethyl diisopropyl amine, a
N,N-dialkylamino acid ester, etc., are also added to the reaction mixture.The resulting solution is filtered, if necessary, and then 1-3 molar equivalents of a compound of the general formula (III) are added to the solution (or filtrate) either as such or as a 350% solution formed with any of the above solvents or solvent mixtures. The reaction is performed at 0-1 000C, preferably at room temperature.
Depending on the characteristics of the starting substances and the solvent or solvent mixture, the end-product of the general formula (I) generally separates from the reaction mixture as a crystalline substance or sometimes as an oil. In some instances the reaction mixture should be evaporated to separate the product. The separated crystalline product is filtered off, washed with a mixture of the above solvents and an aliphatic ether if necessary, and dried at room temperature, optionally under vacuo. When the product separates as an oil, it is crystallized from an appropriate solvent.
The product obtained according to method a) of the invention can be purified further, if necessary-, so that the compound of the general formula (I) is dissolved in the minimum amount of water, the aqueous solution is extracted with a water-immiscible solvent, such as dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, butyl acetate, etc., then the aqueous phase is acidified with a calculated amount of a mineral 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 the general formula (I) is dried.
This method of purification, which is generally not necessary, yields highly pure products with high yields.
According to method b) of the invention a compound of the general formula (V), wherein the general symbols have the meanings defined above, or a salt or a biologically active ester thereof is reacted with a compound of the general formula (IV), wherein A, R', R2, R3, R8, 0 and n are as defined above, Y stands for oxygen or sulfur and R13 represents a phenyl group bearing one or more halo substituent(s), an unsubstituted or a substituted quinolyl group or a substituted amidino group. The reaction can be performed under the conditions discussed above in connection with 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 formulae the general symbols are as defined above. The reaction can be performed in a solvent medium, such as in an aliphatic ether, a ketone or a chlorinated hydrocarbon.
The new compounds according to the invention are valuable antibacterial agents with broad spectra of activity, and can also be applied as ,B-lactamase inhibiting agents in combination with p- lactamase sensitive semisynthetic penicillins or cephalosporins of broad antimicrobial spectra, to obtain particularly effective compositions. Thus e.g. when the new 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, combinations applicable even in the treatment of severe infections caused by resistant strains are obtained.
The new compounds can also be combined with aminoglycoside antibiotics, such as trobramycin, gentamycin or kanamycin.
In some instances the new compounds can also be applied as antifungal agents or as intermediates in the synthesis of other biologically active substances.
In some instances the new compounds can also be utilized as weight gain increasing additives in fodders of domestic animals, furthermore as preservatives in the paper, wood, leather and textile industry.
When applied as fodder additives, the new compounds can be introduced into the animal organisms according to the usual methods, in admixture with a fodder or fodder additive or added to the drinking water, whereupon the bacterial infections of the animals can be avoided and a better fodder utilization can be attained.
The invention is elucidated in detail by the- aid of the following non-limiting Examples.
Examples 1 to 53
Method a)
Preparation of ureathiourea and selenourea compounds
10 mmoles of the amino-p-iactam compound are dissolved in a mixture of 25 ml of abs.
acetonitrile and 3 ml of triethylamirte, and 10 mmoles of the appropriate isocyanate, isothiocyanate ar isoselenocyanate are added to the solution in one or more portions. The mixture is optionally stirred.
Depending 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 sometimes as an oil. When a crystalline substance is obtained, the crystals are filtered off and washed with dry acetonitrile or with a dry aliphatic ether.
When an oily substance is obtained, it is treated with a dry aliphatic ether, toluene, petroleum ether, hexane, heptane, light petrol or an appropriate mixture thereof to effect solidification, thereafter the product is 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 substance is dissolved in the minimum amount of water, the aqueous solution is washed in order to remove the traces of isocyanate, isothiocyanate or isoselenocyanate optionally present, then it is acidified with dilute hydrochloric, sulfuric or phosphoric acid, and extracted again with a water-immiscible aliphatic ester or a chlorinated solvent. The organic phase is separated, dried, and then the acid is precipitated as its salt either by using 2-ethylcapronic acid sodium or potassium salt or by treating the solution with an organic base, If the salt does not precipitate from the solution, the solvent is evaporated.
One proceeds similarly when az - or ,8-sulfoxide, a sulfone or an ester of the amino-p-lactam is applied as starting substance. Since the oxidized derivatives are less soluble in aliphatic esters and chlorinated hydrocarbons, sometimes a dipolar aprotic solvent or co-solvent should be applied as reaction medium.
The products prepared by the above method are listed in Tables 1 and 2.
Remarks to Tables 1 and 2
The elementary analysis data (C, H-, N, S and Hal) of the products were in good agreement with the calculated ones; the differences did not exceed 1% and were mostly below 0.4%.
Based on IR spectroscopic examinations, the thiourea compounds do not contain even traces of the isocyanate reactant and, as shown by the most intense maximum (lactam carbonyl at 1 765 1 772 cm-'), the p-lactarn ring is intact.
Some of the compounds were also subjected to mass spectrometry, the data observed were, however, non-informative due to the low volatility of the samples and the thermal decomposition. The measurements performed on samples rendered more volatile by silylation supported, however, the structures expected.
The 'H NMR spectroscopic examinations supported the structures expected. As shown by these spectra, no C-7 epimerization or ceph-3-em/ceph-2-em isomerization occurs with the compounds examined.
Table 1
Cephalexin-urea derivatives of the general formula (l); R=R =R7=hydrogen, R=phenyl,
n=t=zero, X=-CH2-C(CH3)=,O=oxygen,Z=OH.N(C2H5)3,A=a group of formula (a)
calculated
Analysis, % Ur spectrum,
Empirical Molecular Yield found lactam
No. R6 formual weight % M.p. C C H N S C=0, cm-1
1 methyl C24H35H5O5S 505.66 92.5 203--204 57.0 6.98 13.86 6.34 1765
56.15 6.82 13.72 6.39
56.77 6.88 13.69 6.30
2 3-methyl-phenyl C30H39N5O5S 581.75 94.3 202--204 61.93 6.75 12.04 5.51 1765
61.82 6.47 12.01 5.41
61.85 6.63 12.11 5.47
3 1-naphthyl C33H39N5O5S 617.76 89.1 207--209 64.16 6.36 11.34 5.19 1763
63.87 6.22 11.21 5.07
63.94 6.28 11.37 5.12
4 4-butyl C27H41N5O5S 547.74 96.2 amorph. 12.77 1765
12.72
5 methoxymethyl C25H37N5O5S 535.69 92.4 203 13.1 1765
13.0
6 ethoxycarbonyl- C27H39N5O7S 577.72 94.2 231-232 11.6 1770
methyl 11.75 Table 2
Cephalexin-thiourea derivatives of the general formula (I); R=R =R7=hydrogen, R2=phenyl,
n=t=zero, X=-CH2-C(CH3)=, Q=sulfur, Z=OHN(C2H5)3 A=a group of formula (a)
Empirical Molecular Yield
No.RG formula weight % M.P. C R1
7 methyl C24H36N5O4S2 521.69 34.61 128-130 0.22
8 ethyl C25H37N5O4S2 535.72 93.82 110-111 0.26
9 isopropyl C26H39N504S2 549.75 80.00 127-128 0.26
10 n-butyl C27H41N5O4S2 563.78 81.59 130-131 0.29
11 tert-butyl C27H41N5O4S2 563.48 92.85 123-124 0.31
12 -CH2CH2OH C2H37N5O5S2 551.72 88.22 174-175 13 allyl C26H37NsO4S2 547.74 84.15 154-155 14 cyclohexyl C29H43N5O4S2 589.83 95.63 126-127 0.40
15 -CH(CH3-(CH2)3N(CH3)2 C30H48N8O4S2 620.86 92.17 amorph.
16 phenyl C28H37N8O4S2 583:78 95.74 185-186 0.39
17 benzyl C3OH39Nso4S2 597.81 45.22 171-172 0.44
18 benzoyl C3OH37N4OsS2 611.79 91.20 142-143 19 phenoxyacetyl C31H39N5O6S2 641.82 95.60 116-117 0.43
20 1-naphthyl C33H39N5O4S2 633.84 75.70 182-183 0.40
21 3-fluorophenyl C29H36N6O4S2F 601.77 94.85 180-182
22 4-fluorophenyl C29H36N5O4S2F 601.77 87.74 138-140 23 2-chlorophenyl C29H36N5O4S2Cl 618.23 64.10 137-138 0.38
24 3-chlorophenyl C29N36N5O4S2Cl 618.23 78.62 168-170 0.38
25 4-chlorophenyl C29H36N5O4S2Cl 618.23 100.00 142-143 0.40
26 2,5-dichlorophenyl C29H36N5O4S2Cl2 652.68 84.16 189-190 0.43
27 2,6-dichlorophenyl C29H3sN504S2CI2 652.68 67.48 182-183 0.41
28 3,4-dichlorophenyl C29H35N5O4S2Cl2 652.68 92.55 amorph.
29 3,5-dichlorophenyl C29H36N5ORS2F3 652.68 87.15 177-178 30 2,4,6-trichlorophenyl C29H34N504S2CI3 687.14 88.23 182-183 31 3-bromophenyl C29H36N504S2Br 662.69 92.17 199-200 32 4-bromophenyl C29H36N504S2Br 662.69 84.44 amorph.
33 3-iodophenyl C29H36N504S2l 709.68 76.28 161-163 34 4-iodophenyl C29H36N6O6S2 709.68 92.16 amorph.
35 2-methylphenyl C3OH39N5o4S2 597.80 84.25 amorph.
36 3-methylphenyl C30H39N5O4S2 597.80 76.95 179
37 4-methylphenyl C30H39N5O4S2 597.80 85.42 167-168 38 2,4,6-trimethylphenyl C32H43N504S2 625.86 38.33 163-164 0.47
39 2-methyl-6-ethylphenyl C32H43N504S2 625.86 81.46 103-104 0.38
40 2,6-diethylphenyl C33H34N5O4S2 639.87 85.93 113-114 0.38
41 4-diethylaminophenyl C33H36N8O4S2 654.89 77.25 165-167 42 2-methyl-4-diethyl- C34H48N804S2 668.91 80.13 amorph.
aminophenyl
43 4-carboxyphenyl C30H37N5O6S2 627.80 91.96 161
44 3-hydroxy-4-carboxyphenyl C3oH37N5o7S2 643.80 78.83 143
45 2-methyl-4-sulfonylphenyl C30H35N5O7S3 677.88 85.18 195-198 46 2-trifluoromethylphenyl C30H36N5O4S2F3 651.79 95.26
47 3-trifluoromethylphenyl C30H36N5O4S2F3 651.79 87.45 146
48 3-nitrophenyl C29H36N6O6S2 628.76 83.06 132-133 49 4-nitrophenyl C29H36N6O6S2 628.76 83.06 153-154
50 4-pyridyl C28H36N604S2 584.75 27.30 184-185
51 4-flavanyl C38H45N5O5S2 715.94 94.25 175-176 52 flavan-4-on-3-yl C3sH43N506S2 729.92 82.12 182-184 53 flavon-3-yl C38H4,N506S2 727.90 82.88 175-176 Example 54
Reaction of ampicillin with 4-flavanyl-isothiocyanate
1007 mg (2.5 mmoles) of ampicillin trihydrate are dissolved in a mixture of 0.8 ml of triethyl amine and 5 ml of dry acetonitrile, 670 mg (2.5 mmoles) of 4-flavanyl-isothiocyanate are added to the solution, and the mixture is allowed to stand at room temperature. A white, crystalline precipitate separates from the mixture. The precipitate is filtered off, washed with a small amount of dry acetonitrile and abs. either, and dried in vacuo. 1.55 g (86.47%) of the desired product are obtained; m.p.: 171-1 720C (dec.), R,=0.45 (in a 7:3:1 mixture of benzene, ethyl acetate and glacial acetic acid).
IR (KBr): 1770 cm-l (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 performed according to Method a) to obtain the product with an Rf value of 0.36 (in a 7:3:1 mixture of toluene, ethyl acetate and formic acid).
Analysis:
calculated for
C29H37N5O4SSe(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-(α-(1-methylthloureido)]-phenylacetamido-3-chloro-ceph-3-em-4-carboxylic acid triethylammonium salt
The compound is prepared according to Method a).
Yield: 88.2%; m.p.: 127-129 C (dec.)
IR(KBr); 3270, 1773, 1680, 1617, 1558 1540, 1345, 695 cm-1
Analysis:
calculated for C23H32CIN504S2 (542.147):
N: 12.92%, S: 11.83%, CI: 6.54%; found:
N: 12.80%, S: 11.88%, Cl: 6.43%;
N: 12.85%, S: T2.02, CI: 6.46%.
Example 57
Method b)
Preparation of 6ss-[D-2-[(3-/2-phenyl-5,6-benzo-pyran-4-yl/-2-thioureido)-2-/4-hydroxyphenyl/]acetamido]-2,2-di-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxybic acid triethylammonium salt
A mixture of 0.8 g of D-2-[(3-/2-phenyl-5,8-benzopyran-4-yl/-2-thioureido)-2-/4- hydroxyphenyl/]-acetic acid pentachlorophenyl ester, 10 ml of ethyl acetate, 0.23 g of 6aminopenicillanic acid and 0.1 ml of triethyl amine is stirred at room temperature for 12 hours, thereafter 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 C38H47NsO6S2 (727.96):
N=9.63%, S=8.81%;
found: N=9.55S, S=8.87%; N=9.74%, S=8.8456.
Example 58
Method b) 0,4 g of 7-ADCA are dissolved in 10 ml of N,N-dimethyl formamide at 200 C, and 1.04 g (2 mmoles) of N-phenylcarbamoyl-D-phenylglycine pentachlorophenyl ester are added to the stirred mixture in several portions. The mixture is stirred at 200C for 12 hours, thereafter poured onto 100 ml of ice water, the-separated white, crystalline substance is filtered off, washed with water, and then crystallized from a mixture of dimethyl formamide and water. The crystals are filtered off, and the product is converted into its sodium, potassium or triethyl ammonium salt in a manner known per se.
The triethyl ammonium salt, obtained with a yield of 84%, melts at 211-21 30C. IR: 3400, 1765,1710,1680,1520 cm-'.
Analysis:
calculated for C29H37N5OsS (567.73):
C: 61.35%, H: 6.57%, N: 12.34%, S 5.65%;
found:
C: 61.05%, H: 6.55%, N: 12.23%, S: 5.49%; C: 61.11%, H: 6.60%, N: 12.19%, S; 5.52%.
Example 59
Method c)
1.0 g (2.48 mmoles) of ampicillin is dissolved in a mixture of 24.8 ml of dry acetonitrile and 2.48 ml of triethyl amine, and a solution of 0.678 g of 3-ethoxycargbonyl-4-chloro-carbonyl-perhydro-1,4- thiazine in 3 ml of toluene and 1 ml of triethyl amine is added dropwise to the stirred solution under cooling. The mixture is stirred for one hour, thereafter acidified to pH=2 with 2 n aqueous hydrochloric acid, the acidic mixture is extracted with dichloromethane, the organic phases are combined, washed with water, dried over sodium sulfate, and then evaporated. The product is crystallized from abs. ether.
0.82 g (60.1 %) of the desired product are obtained; IR=3400, 1770, 1735, 1720, 1672, 1525 cm-'.
Analysis:
calculated for C30H4sNsO7S2 (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 7ss-[2-(1,2,4/4H/-triazol-4-yl)-2-phenyl]-acetamido-3-methyl-ceph-3-em-4 carboxylic acid
0.56 g (10 mmoles) of 4-amino-i ,2,4(4H)-triazole are suspended in 20 ml of abs.
dichloromethane, and then 5.2 ml of abs. triethyl amine and 1.27 ml (10 mmoles) of trimethylchlorosilane are added. The mixture is stirred at 200C for 15 minutes, thereafter 0.76 ml (10 mmoles) of thiophosgene are introduced, and stirring is continued for 30 minutes. The resulting mixture is filtered under dry nitrogen atmosphere, and the filtrate is added to a solution of 4.46 g (10 mmoles) of cephalexin pivaloyloxymethyl ester in 40 ml of dichloromethane. The mixture is stirred for one hour and then processed to obtain the title compound with a yield of 88%.
lR(KBr):3360,3280,3030,2980, 1774, 1735, 1710, 1680, 1625, 1520, 1490, 1210, 1045, 75 cm-1.
Analysis:
calculated for C2sH2gN706S2 (587.69):
N: 16.68%, S: 10.91%;
found:
N: 16.55%, S:11.12%.
Example 61
Preparation of 6,B-[2-phenyl-2-(phenyithioureido)]-acetamido-pencillanic acid triethylammonium salt
10 mmoles (about 4 g) of ampicillin trihydrate are dissolved at 0 C in a mixture of 7 ml of triethyl amine and 50 ml of dimethyl formamide, and then reacted with an equimolar amount of phenyl mustard oil. When processing the mixture 3.7 g of the title compound are obtained as primary product in chromatographically pure state. A further amount of the product can be separated by processing the mother liquor. Rf=0.27 (in a 7:3:1 mixture of toluene, ethyl acetate and formic acid); m.p.: 134136 C. IR (KBr): 1788 cm-1 (ss-lactam).
'H NMR (DMSO-d6): 1.25 (t, 9H, -CH2CH3), 1.54 (s, 3H, 2 Me), 1.16 (s, 3H, 2α Me), 3.08 (6H, CH2-CH3), 4.12 (s, 1 H, C/3/-H), 5.4-5.6 (d+dd, 2H, C151 and C/6/-H), 6.45 (d, J=10 Hz,
7.15-7.8( (m, 1 OH, 2 phenyl), 8.07 (s, 1 H), 8.84 (d, 1 H, J=9 Hz, NH), 9.3 (d, 1 H,
J=10 Hz), 10.46 (s,1 H).
The ,B-lactamase inhibition data of the product are listed in Table 3.
Table 3 IC50 (10-5M) Substance E. coliJ53 RP4 B. cereus I.
Phenylthioureido-benzyl
penicillin TEA salt 320 5000
Methicillin sulfone - 1000
Similarly are prepared the following compounds:
a) 6p-[2-phenyl-2-(phenylthioureido)]-acetamido-pencillanic acid-1 (S)-oxide triethylammonium salt,
b) 6ss-[2-phenyl-2-(phenylthioureido)]-acetamido-pencillanic acid-1,1-dioxide triethylammonium salt,
c) 7P-[2-ph enyl-2-(phenylthiou reido)]-acetamido-3-methyl-ceph-3-em-4-carboxylic acid-1 (S)oxide dicyclohexylammonium salt,
d) 7ss-[2-phenyl-2-(phenylthioureido)]-acetamido-3-methyl-ceph-3-em-4-carboxylic acid-1,1dioxide dicyclohexylammonium salt,
e) 7ss-[2-phenyl-2-(phenylthloureido)]-aceta mido-3-methyl-ceph-3-em-4-carboxylic acidacetoxymethyl ester 1(S)-oxide, f) 6A-[2-phenyl-2-(phenylthioureido)]-acetamido-pe ncillanic acid-benzoyloxymethyl ester- 1,1 dioxide.
The p-lactamase inhibition end-points of phenylthioureido-benzylpenicillin TEA salt determined on some isolated enzymes are listed in Table 4. The values are given in mg/l units.
Table 4
Aerobacter E. coli S. aureus
Compound B. cereus cloacae 53 J-53 R46+ PCI
Phenylthioureido- < 1000 1000 > 1000 < 1000
benzylpencillin TEA salt > 200 > 200 6a-Chloropencillanic acidsulfon > 1000 > 1000 > 1000 > 200 6cr-Bromopencillanic acid sulfon < 5000 5000 < 5000 > 1000 +The measurements were performed by utilizing Nitrocephin as substrate.
The following examples illustrate the preparation of pharmaceutical compositions.
Example 62
Preparation of capsules for oral administration
250 mg of ampicillin trihydrate and 250 mg of 7ss-[(D-/α-phenylthioureido/)-phenylacetamido]- 3-methyl-ceph-3-em-4-carboxylic acid sodium salt are admixed with 10 mg of magnesium stearate, and the mixture is filled into a hard gelatine capsule of appropriate size. The capsules are placed into vials and stoppered with an air- and humidity-tight plastic cap.
Example 63
Preparation of a powder mixture for making syrup
The following components are admixed with each other: Ampiciliin trihydrate 5.0 g 7p-[(D--/m-Chlorophenylthioureido/)-phenyl-aceta mido]-3-methyl- ceph-3-em-4-carboxylic acid sodium salt 2.5 g
Sacharin sodium salt 0.2 g
Sodium citrate (anhydrous) 1.0 g Citric acid (anhydrous) 0.15 g Orange flavour 1.0
Glucose q.s. ad 60.0 g This powder mixture is filled up to 100 ml with tap water or pure drinking water just prior to use.
5 ml of the resulting syrup contains 375 mg of antibiotics.
Example 64
Powder ampoulles for injection purposes
500 mg of cephazolin sodium salt and 250 mg or 500 mg of 6ss-[(D-/4-flavanyl/-thioureido)-4/hydroxy-pheny/-acetamido]-2,2-dimethyl-penam-3-carboxylic acid sodium salt are filled into each of the ampoulles under nitrogen atmosphere and aseptic conditions. The ampoulles are closed with rubber discs equipped with aluminium fixing rings. The powder mixture is admixed with a solvent for injection purposes just before use.
Example 65
Pharmacological studies and results
The majority of the compounds prepared according to the invention exert an inhibiting effect on
Bacillus ceraus 569/H ss-lactamase (a commercially available enzyme) and on the partially pyrified sslactamases isolated from E. coli and S. aureaus strains of the same or even higher degree as clevulanic acid or dicloxacillin. The inhibition can also be examined photometrically under in vitro conditions, utilizing Nitrocephin as substrate [Punyiczki, M., Jászberényi, J. Cs., Hernádi, F.: MFT Publication 1977/1, pp.71-81(1978)].
The new compounds synergistically increase the activities of known p-lactamase sensitive p- lactam antibiotics under in vitro conditions.
The new compounds are potent antibacterial agents, as demonstrated by the results of the tests performed 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 5 150(,umole) values of ,B-lactamase inhibiting substances determined on various p-lactamase enzymes
Compound Aerobacter E. coli (No. of example) cloacae 53 J53 RP4 B. cereus
16 261.6 92.5 17.8
54 381.7 76.3 4894.1
60 255.4 226.8 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
35 146.8 187.8 20.5
Cloxacillin 2773.3 165.8 1762.7
Sulbactam 2718.9 312.1
Table 6
Inhibition end-points of various ,l3-lactamase inhibiting agents measured on isolated enzymes
Inhibition end-point (inhibitor concentration, HM) Compound S. aureus E. coli E. coli Aerobacter (No. of example) B. cercus PCl J53RP34 J53 R46+ cloacae 53
4 200 1000 5000 > 5000 5000
54 > 5000 1000 1000 40 200
51 40 - - 1000
16 < 0.32 200 1000 > 5000 1000
Dicloxacillin 200 1000 1000 > 5000 5000
Sulbactam 200 200 40 1.6 8
Table 7
Activities of the compounds on white mice after oral administration'
Dosis Survival
Compound mg/kg treated/survived
Cephalexin 1 10/4
5 10/9
10 10/10
Ceporin 0.25 10/0
1.0 10/10
5.0 10/10
Example 51 10 10/10
40 10/10
100 10/10
Table 8
Activities of the compounds on white mice after subcutaneous administration'
Dosis Survival
Compound mg/kg treated/survived
Ceporin 0.1 10/1
1.0 10/9
10.0 10/10
Example 51 10 10/2
40 10/10
100 10/10
'Tests performed on groups of 10 animals, weighing 19-24 g. The animals were infected with
Staph. aureus Smitch (20xLD100 i.p.) and maintained under observation for 72 hours.
Claims (9)
1. 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(CH3)2, -CH2-C(CH3)=, -CH2-C(CH2OAc)= or -CH2- C(CH2SHet)=, and in the latter formula Het is a saturated or unsaturated, 5-7 membered heterocyclic group containing 1 4 nitrogen atom(s) and optionally one or more other hetero atom(s), optionally condensed with one or more phenyl group(s) and/or substitued with one or more alkyl, aralkyl, aryl, substituted aryl or substituted aralkyl group(s),
R' is hydrogen atom, a C14 alkyl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent,
R2 is hydrogen atom, a C14 alkyl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent,
R3 and R8 each stand for hydrogen atom, a C14 alkyl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent,
Q represents oxygen, sulfur on selenium atom,
R4 is hydrogen atom, a straight-chained or branched C1-4 alkyl group or a group of the general formula -COOR5, and in this latter formula R6 is a C18 alkyl group, a benzyl group, a benzhydryl group or a phenyl group bearing optionally a halo, hydroxy, alkoxy or alkyl substituent,
R6 is a phenyl group bearing optionally one or more halo, Cie alkyl, nitro, alkoxycarbonyl, trifluoromethyl, dialkylamino, hydroxy, carboxylic acid or sulfonic acid substituent(s), a C18 alkyl group bearing optionally an alkoxycarbonyl, hydroxy, dialkylamino or alkoxy substituent, a C3s cycloalkyl group, a C26 alkenyl group, a naphthyl group, a heteroaryl group, a 3-8 membered heterocyclyl group optionally condensed with one or more phenyl group(s) and/or bearing one or more substituent(s), or an adamantyl group,
R7 is hydrogen, or
R6 and R7 form, together with the adjacent nitrogen atom, a 4-8 membered, unsubstituted or preferably substituted heterocyclic group optionally containing one or more additional nitrogen, oxygen or sulfur atom(s) and optionally condensed with one or more phenyl ring(s),
Z is hydroxy group,
n is zero or one, and
t is zero, one or two
or a pharmacologically acceptable salt or biologically active ester thereof.
2. A compound of the general formula (I), wherein A is a group of the general formula (a) and R1,
R2, R3, Re, R7, R8, Q, Z, X, n and t are as defined in claim 1, or a pharmacologically acceptable salt or biologically active ester thereof.
3. A compound of the general formula (I), wherein R1 is hydrogen,
A is a group of the general formula (a),
R2 is phenyl
R3 and R7 are hydrogen atoms,
n and t each stand for zero,
X is a group of the formula H2-C(CH3)2-, Q is oxygen atom, and
Z and R6 are as defined in claim 1,
or a pharmacologically acceptable salt or biologically active eSter thereof.
4. A compound of the general formula (I), wherein Q is sulfur atom and R', R2, R3, R6, R7, A, X, Z, n and t are as defined in claim 3, or a pharmacologically acceptable salt or biologically active ester thereof.
5. A compound of the general formula (I), wherein A is a group of the general formula (b) and R1,
R2, R3, Re, R7, Re, Q, Z, X, n and t are as defined in claim 1 , or a pharmacologically acceptable salt or biologically active ester thereof.
6. A compound of the general formula (IA), (IB), (IC), (ID), (IE), (IF), (IG) or (lH), wherein R'O is hydrogen or hydroxyl;
R9 is methyl, CH20Ac, -CH2Py+ or -CH2SHet; R" and R12 are halogen, alkyl, nitro, C0O-alkyl, -CF3-N(alkyl)2, -OH, -COOH, -SO2OH; and
R' represents one of the groups(e) to (r).
7. A process for the preparation of a compound of the general formula (I), wherein A, R', R2, R3,
R4, R6, R7, R8, 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 the general formula (it), wherein R', R2, R3, R8, 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 the general formula (III), wherein B is a group of the general formula (c) or (d), Re, is trimethylsilyl group or an Re group as defined in claim 1 and R7, is trimethylsilyl group or an R7 group as defined in claim 1, and Q is as defined in claim 1, or
b) a compound of the general formula (IV), wherein A, R1, R2, R3, R4, Re, R7 R8, Q and n are as defined in claim 1 , Y is oxygen or sulfur atom, and R'3 is a phenyl group bearing one or more halo substituent(s), a quinolyl group bearing optionally an alkyl, acyl, or halo substituent, or an amidino group bearing optionally 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 a salt or a biologically active ester thereof, or
c) a compound of the general formula (II), wherein R', R2, R3, R8, 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 the general formula (VI), wherein Q is as defined in claim 1, R6' and R7' are as defined in point a) above, m is zero or one and R4' represents the substituents listed in claim 1 at the definition of R4 except for hydrogen,
and, if desired, a resulting compound of the general formula (I) is converted into its pharmacologically acceptable salt or biologically active ester.
8. A pharmaceutical composition characterized by containing as active agent a compound of the general formula (I) as defined in claim 1 or a pharmacologically acceptable salt or biologically active ester thereof, optionally in combination with a known /3-lactam type antibiotic.
9. A process for the preparation of a pharmaceutical composition, characterized in that a compound of the general formula (I) as defined in claim 1 or a pharmacologically acceptable salt or biologically active ester thereof is admixed with a conventional pharmaceutical carrier, diluent and/or auxiliary agent and optionally with a known -lactam type antibiotic.
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AU (1) | AU8321282A (en) |
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BG (1) | BG37227A1 (en) |
DE (1) | DE3215941A1 (en) |
DK (1) | DK198282A (en) |
ES (1) | ES511884A0 (en) |
FI (1) | FI821551L (en) |
FR (1) | FR2509311A1 (en) |
GB (1) | GB2101586A (en) |
GR (1) | GR78166B (en) |
IL (1) | IL65602A0 (en) |
IT (1) | IT1156467B (en) |
NL (1) | NL8201810A (en) |
NO (1) | NO821456L (en) |
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AU577105B2 (en) * | 1985-04-02 | 1988-09-15 | T.P.O. :Pharmachim: | Acylaminic penicillin derivatives |
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GB1476312A (en) * | 1974-06-03 | 1977-06-10 | Beecham Group Ltd | Penicillins and cephalosporins |
CA1074298A (en) * | 1974-09-20 | 1980-03-25 | E.R. Squibb And Sons | 3-heterothio-7-ureido cephalosporins |
CA1075679A (en) * | 1975-07-30 | 1980-04-15 | E.R. Squibb And Sons | 3-heterothio-7-thioureido cephalosporins |
JPS5239694A (en) * | 1975-08-29 | 1977-03-28 | Toyama Chem Co Ltd | Producing novel penicillins and cephalosporins |
US4063019A (en) * | 1976-03-30 | 1977-12-13 | E. R. Squibb & Sons, Inc. | [[[(2,4-Dioxo-1-imidazolidinyl)amino]carbonyl]amino]-acetylcephalosporin derivatives |
PT67170B (en) * | 1976-11-06 | 1979-03-21 | Merck Patent Gmbh | LACTAME METHOD FOR THE PRODUCTION THEREOF AND MEDIUM CONTAINING THESE COMPOUNDS |
ES477520A1 (en) * | 1978-02-25 | 1979-06-01 | Thomae Gmbh Dr K | Penicillins, their salts, process for their preparation and pharmaceutical compositions containing them. |
DE2828261A1 (en) * | 1978-06-28 | 1980-01-10 | Thomae Gmbh Dr K | NEW PENICILLINE, ITS SALTS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
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- 1982-04-26 IL IL65602A patent/IL65602A0/en unknown
- 1982-04-28 SE SE8202674A patent/SE8202674L/en not_active Application Discontinuation
- 1982-04-29 DE DE19823215941 patent/DE3215941A1/en not_active Withdrawn
- 1982-05-03 BG BG8256468A patent/BG37227A1/en unknown
- 1982-05-03 ES ES511884A patent/ES511884A0/en active Granted
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- 1982-05-03 FI FI821551A patent/FI821551L/en not_active Application Discontinuation
- 1982-05-03 FR FR8207659A patent/FR2509311A1/en not_active Withdrawn
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BE893057A (en) | 1982-08-30 |
FI821551A0 (en) | 1982-05-03 |
DK198282A (en) | 1982-11-05 |
BG37227A1 (en) | 1985-04-15 |
FI821551L (en) | 1982-11-05 |
ES511884A0 (en) | 1983-08-16 |
GR78166B (en) | 1984-09-26 |
SE8202674L (en) | 1982-11-05 |
FR2509311A1 (en) | 1983-01-14 |
DE3215941A1 (en) | 1983-05-05 |
JPS5813590A (en) | 1983-01-26 |
IL65602A0 (en) | 1982-07-30 |
NO821456L (en) | 1982-11-05 |
NL8201810A (en) | 1982-12-01 |
IT8267577A0 (en) | 1982-05-03 |
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