HU194251B - Process for preparing novel penicillin derivatives and pharmaceuticals comprising such active substance - Google Patents

Abstract

Penicillin derivs. of formula (I) are new where R is a gp. of formula (II), (III) or (IV); R3 = H, lower alkyl, lower alkoxycarbonyl or phenyl; R4, R5 and R6 each = H, lower alkyl, halogen or lower alkoxy; A = -O- or -N(lower alkyl)-; n = 0 or 1; R1 = H or OH; and R2 = H, alkali metal or carboxy protecting gp. - 32 cpds. (I) are specifically claimed e.g. Na salt of 6-(4-methyl-isocoumarin -3-carboxamido)-2,2 -dimethyl-penam-3 -carboxylic acid, Na salt of 6-(7,8-dimethoxy -isocoumarin-3-carboxamido) -2,2-dimethyl-penam -3-carboxylic acid, Na salt of 6-(N-(2-methyl-1(2H) -phthalazinone-4-carbonyl) -2R-2-aminophenylacetamido) -2,2-dimethyl-penam-3 carboxylic acid and corresp. methyl esters. - Prepn. of (I) is also claimed and comprises reacting cpd. (V) with RCOZ in solvent where X = H or trialkylsily; Y = metal or ammonium cation or trialkylsilyl; and Z = -O-CO-Alk or halogen. Solvent is e.g. acetone, THF, DMF, DMSO, CH2Cl2, etc.

Description

The present invention relates to penicillin derivatives for pharmaceutical use.

Penicillin derivatives in which the amino group of ampicillin is acylated with isocoumarin-3-carboxylic acids (Bulgarian Patent No. 34532) and l (2H) -phthalazinone-4-carboxylic acids (Japanese Patent Application No. 78.73593) are known, which compounds are Ps. Aeruginosa. are effective.

The present invention relates to novel penicillin derivatives having high antimicrobial activity against Gram-positive and Gram-negative microorganisms.

The novel adl-amine penicillin antibiotics of the present invention are represented by formula (I)

R is (RA (R 1), (R _c ) wherein

R ₃ is hydrogen, C 1-4 alkyl, C 1-4 alkoxycarbonyl, or phenyl,

R ₄ is hydrogen,

R _s and R ₆ is hydrogen, C 1-4 alkoxy,

A is oxygen or N- (C 1 -C 4) alkyl, n is 0 or 1,

R 1 is hydrogen,

R ₂ is hydrogen, alkali metal or C 1-4 alkyl.

Acid addition salts of compounds of formula I are also included within the scope of the invention.

Compounds of formula (I) are prepared by reacting a compound of formula (II) wherein R and n are as defined in formula (I),

X is hydrogen or trialkylsilyl; and

Y is a metal ion, an ammonium or a trialkylsilyl group with a compound of formula III wherein

R is as defined for formula (I) and

Z is -O-CO-Alk or halogen.

The acylating agents of formula (III) are derived from 4-methyl-3-carboxy-iso-coumarin and 7,8-dimethoxy-3-carboxy-iso-coumarin according to U.S. Pat. or 4-methoxycarbonyl-3-carboxyisoquoumarin as described in S. Spassov, I. Atanassova, M. Haimova (Org. Magn. Resonance, 1983, in press). (VH Belgaonkar, RN Usgaonkar, Chem. Ind. (London), 1974, 954) or 2-methyl-4-carboxy-1 (2H) -isoquinoline (VJ1 Belgaonkar, RN Usgaonkar, Tetrahedron Letters, 1975). (44) 3849) or 2-methyl-4-carboxyl-1 (2H) -phthalazinone (AN Kost, S. Eartheák, K. Grabljauskas, Khim. Farm. Zhumal, 1, (3), 43 (1967)).

The acylation of the amino group of the penam derivatives can be carried out as described for the acylation of beta-lactam antibiotics (GA, Weinberg, LN. Petruljanis, EJa. Lukevitz, Khim. Geteroziklitchnih soedinenij, 1982, No. 2, 147). The condensation of the penam derivatives and the derivatives of formula III is carried out in anhydrous or aqueous organic solvent medium in the presence of a weak organic or inorganic base such as hydrogen chloride binder at a temperature of -20 to 20 ° C.

When an aqueous organic solvent is used, the solvent may be acetone, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide. The acylation in the anhydrous medium is preferably carried out in a water immiscible organic solvent such as chlorinated hydrocarbon (chloroform, methylene chloride).

Hydrochloric acid binders include weak organic or inorganic bases such as sodium bicarbonate, Ν, Ν-dimethylaniline, triethylamine, pyridine and the like. They can be used.

In the case of acylation in anhydrous medium, 6-anno-polypeptide acid and its alpha-amino derivative are added in the form of the N, O bis-trialkylsilyl derivative.

Silylation is carried out in anhydrous organic solvent. Suitable silylating agents are trialkyl chlorosilanes, hexamethyldisilazane, N, O-bis-trimethylsilylacetamide, Ν, Ν-bis-trimethylsilylurea, or a mixture of hexamethyldisilazane and trimethylchlorosilazane.

Depending on their properties, the final products are recovered from the reaction mixture as follows: the metal salts are obtained from the reaction mixture by extracting the organic solvent with sodium hydrogencarbonate and then lyophilizing the organic solvent or using appropriate precipitating agents such as sodium acetate, etc with the help of it.

The compounds thus prepared exhibit in vitro activity against the following pathogenic bacteria: Staph. aureus, E. coli, Ps. aeruginosa, P. vulgaris.

The invention is illustrated by the following examples, which are not intended to limit the invention in any way.

Example 1

Sodium salt of 6- (4'-methylisocoumarin-3'-carboxamido) -2-dimethyl-penam-3-carboxylic acid (Compound 1) mole (216 mg) 6-anno-penidylanoic acid and 023 ml (1.1 mmol) hexamethyldisilazane and 15.0 mL of methylene chloride are heated to reflux. The reaction mixture was cooled to -5 ° C, and then 1 mmol (0.14 mL) of triethylamine was added, followed by the addition of a solid acid chloride, which was treated in portions with 1 mmol (2.04 mg) of 4-methylisocoumarin-3- carboxylic acid and 3.0 ml of thionyl chloride. The cooling was stopped and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo at 40 ° C. Ethyl acetate (10 mL) was added to the residue and the mixture was cooled to -5 ° C. Water (2.0 mL) was added and the solution was acidified to pH = 2 with concentrated hydrochloric acid. The two phases were separated and, after drying, the organic phase was poured into an equal volume of a saturated alcoholic sodium acetate solution. The precipitated sodium salt is filtered off and washed with acetone. 290 mg (68%) of product are obtained. 178-181, "decomposes).

IR spectrum (nujol, cm @ -1): 1600 (CO), 1650 (CO, amide), 1730 (OH, lactone) Inflexion point at 1780 (CO, beta-lactam), 3400 (NH).

Table 1

194/251

2-7.pdda

The following compounds were prepared from 216 mg of aminopenidylllanoic acid as in Example 1; 5

Example Compound Name Yield Op. (° C) IR Spectrum (nujol, cm ^-1 )% (decomposed)

2. Sodium salt of 6- (7'3'-dimethoxy-4-isoquoumarin-3'-carboxamido) -2,2-dimethyl-penamine-3-carboxylic acid 64 212-214 1560 (COO '), 1690 (CO, amide), 1770-wide (C0, lactone, CO, beta-lactam), 3300 (NH) 3. Sodium salt of 6- (4'-methoxycarbonyl-3'-carboxamido) -2,2-dimethyl-penam-3-carboxylic acid 61 176-178 1580 (COO), 1650 (CO 2 mid), 1700 (CO, ester), 1760 broad, inflection point, 1780 (CO, lactone, CO, beta-lactam), 3400 (NH) _? 1590 (COO ^- ), 1660 (CO, amide), 1720 (CO, lactone), 1780 (CO, beta-lactam), 3400 (NH) 4. Sodium salt of 6- (isocoumarin 4'-carboxamido) -2,2-dimethyl-penam-3-carboxylic acid 59 195-199 5. Sodium salt of 6- (3'-methylisocoumarin-4'-carboxamido) -2,2-dimethyl-penamic-4-carboxylic acid 65 220-222 1580 (COO '), 1660-ac (CO, amide), 1750-wide (CO, lactone, CO, beta-lactam, 3400 NH) 6. Sodium salt of 6- (2'-methyl-1 '(2Ή) 4-hydroxy-4'-carboxamido) -2,2-dimethyl-penam-3-carboxylic acid 61 218-220 1600 (COO '), 1660 (CO), 1780 (CO, beta-lactam), 3400 (NH) 7. Sodium salt of 6-1,2'-methyl-1 '(2' H) -phthalazinone-4'-carboxamido] -2,2-dimethyl-penam-3-carboxylic acid 64 205-210 1600 (COO), 1640 and 1660 (CO, amide), 1780 (CO, beta-lactam), 3400 (NH)

8-17. PDDA

The compounds listed in Table 2 were prepared from 349 mg (1 mmol) of an) picillin in the same manner as in Example 1, using the procedure described in Table 2.

Table 2

Example Compound name 'number

Yield: m.p. (° C) IR (nujol, cm ^-1 ) (%) (decomposition)

8. Sodium salt of 6- [N- (4'-methylisocoumarin-3'-58-carbonyl) -2R-2-aminophenylacetamido] -2,2-dimethyl-penam-3-carboxylic acid

9. Sodium 6-N- (7'3 * -dimethoxy-1-isoocoumarin · 60 -3 '-carbonyl-2R-2-aminophenyl) -cetanedrido-J-22-dimethyl-pen-3-carbonazole

134-138 1600 (COO '), 1660 (CO.amid) / 1730 (CO, lactone), 1780 (CO, beta-lactam), 3300 (NH); _Z iodometric activity 1023,

U / mg (content: 96.1%)

228-230 1570 (COO), 1680 (CO, amide),

1780 (broad, CO, lactone and CO, metric activity: 860.72 U / mg (content: 87.5%)

2, Table continued

Example Number of compound name

Yield: m.p. (° C) IR (nujol, cm ^-1 ) (%) (decomposition)

10. Sodium salt of 6- [N- (4'-methoxycarbonyl-isoquo-58-marin-3'-carbonyl) -2R-2-aminophenylacetamido] -22-dimethylpenam-3-carboxylic acid

11. 6- [N- (isoquoumarin-4'-carbonyl) · 60

-2R-2-Aminophenylacetamido] -2-dimethyl-penam-3-carboxylic acid sodium salt

12. 6- (N- (3'-Methyl-isoquoumarin-4'-58)

-carbonyl) -2 R-2-aminophenylacetamido] -2,2-dimethyl-penam-3-carboxylic acid sodium salt

13. 6- [N- (2'-Methyl-1 '(2'H) -isoquinoline-61 -4'-carbonyl) -2R-2-amino-phenylacetamido] -2-di-methyl -pen-3-carboxylic acid sodium salt

14. 6- [N- (2-Methyl-1 '- (2U) -phthalazine-4'-carbonyl) -2R-2-amino-1-phenylacetamido] -2-2-dimethyl-penam Sodium salt of -3-carboxylic acid

15. 6- [N- (2 ', 4'-Dimethyl-1' - (2H) -iso-)

Sodium salt of -quinolinone -3-carbonyl) -2R-2-aminophenylacetamido] -2-dimethylpenepen-3-carboxylic acid

16. 6- [N- (4'-phenyl-isoquoumarin-3'- 68)

-carbonyl) -2R-2-aminophenylacetamidooj-2 2-dimethylpentamine-3-carboxylic acid sodium salt

195-200 1580 (COO '), 1680 (wide, CO, amide), 1750 wide, inflection point: 1780 (CO, ester, lactone and beta-lactam) 3340 (NH). Iodometric activity: 90524 U / mg ( content: 91.7%)

220-224 1600 (COO '), 2660 (CO, amide), 1780 (CO, beta-lactam), 3300 (NH)

186-190 1590 (COO '), 1670 (CO, amide), 1750 - wide, inflection point at 1780 (8CO, lactone, CO, beta-lactam), 3400 (NH)

235-240 1590 (COO '), 1660 (CO, amide), 1770 (CO, beta-lactam), 3400 (NH)

218-222 1590 (COO '), 1680 - wide CO, amide, 1780 (CO, beta-lactam), 3400 (NH)

17. 6- [N- (2'-Methyl-4'-phenyl-1 '- (2H) -65)

Sodium salt of isoquinoline ol-3 '-carbonyl) -2R-2aminophenylacetamido [beta] -22-dimethylpenamine-3-carboxylic acid

245-248 1600 (COO '), 1650 (CO, amide), 1780 (CO, beta-lactam), 3400 (NH), iodometric activity: 1009, 12 U / mg (content: 913%).

210-212 1650 (C0, amide). 1710 (CO, lactone), 1780 (CO, beta-lactam),? 3UU (NH), iodometric activity: 985, 55-U / mg content: 92.9%

215-217 1660 (CO 2), 1780 (CO, beta-lactam, 3300 (NH)). Iodometric activity: 938.83 U / mg (content: 96.4%).

Example 18; 50

Methyl 6- (4 '-Meyl-iso-isocholine-3' -bromooxido) -22-dimethyl-penamecarboxylic acid (18)

6-Aminopenicillanic acid (216 mg, 1 mmol) was acylated with acid chloride from 1-mmol (104 mg) of 4-methylisocoumarin-55 -3-carboxylic acid and treated with the reaction mixture as in Example 1. A solution of diazomethane in ether was added to the dried ethyl acetate solution. After 2 hours, the solvent was evaporated in vacuo and the residue was crystallized from isopropanol. Yield: 260 mg (63%). M.p.

161-162 ^Ö C.

IR (nujol, cm ^-1 ): 1680 (CO, amide), 1730 (CO, lactone and CO, ester), 1800 (CO, beta-lactam), 3430 (NH).

¹ H-NMR (acetone-d _e ), 100 MHz, delta; 1, 52 and 1.68 (2x311), all s, C (Cl ₁₃ ) j /, 2.64 (s, 3H, CH ₃ ), 3.67 (s, 3H, OCH 3), 4.48 (s , 1H, 3-H), 5.6-5, 9 (m, 5-H and 6-H), 7.6-8.0 (3 aromatic R), 8) -83 (m, 8- HésNH).

Analysis for C H _{0 0} N i _e O S O: N = 6.7% 3% S <= 7.68; found: . Ν% = 6β0, S% = 8.01 (41638).

194 051

Example 19

6- (7'O'-Dimethoxy-isoquoumarin-3'-carboxamido) -2-O-dimethyl-penam-3-carboxylic acid methyl ester (19)

Prepared in the same manner as in Example 18 using 1 mmol (216 mg) of 6-aminopenidylanoic acid and 1 mmol (250 mg) of 70-dimethoxyisocoumarin-34-carboxylic acid. The yield was 300 mg (65%). M.p. 83-85 ° C (after recrystallization from isopropanol).

IR spectrum (chloroform), cm ^-1 : 1690 (CO, amide), 1750 - broad (CO, lacion and CO, ester), 1800 (CO, beta-lactam), 3440 (N11).

1 H NMR Spectrum (100 MHz, DMCO-d ₆ ), delta 1.42 and 1.62 (2x3H, all s, CH 2 Cl 2), 3.68 (s, 3H, OCH 3), 3.76 (s, 3H). , OC ₃ ), 3.86 (s, 3H, COOCH ₃ ),

4.44 (s, 1H, 3-H), 50-5.7 (m, 2H, 5-H and 6-H), 7080 (in, 3 aromatic H), 8.6 (m, 1H, D) ₂ O).

Analysis for C ₂ | H ₁₂ N ₂ O on the basis _{of this} S Calculated: N% = 6.06, S% = 602; Found: N, 50.50; S, 7.72 (462.40).

Example 20

6- (4'-Methoxycarbonyl-isoquoumarin-3'-carboxamido) -20-dimethyl-penam-3-carboxylic acid methyl ester (20)

The title compound was prepared as described in Example 18 using 1 mmol (216 mg) of 4-methoxycarbonylisocoumarin-3-carboxylic acid. Yield: 280 mg (63%). 85-87 ° C (after recrystallization from isopropanol).

IR (CHCl₃), cm ^4: 1680 (CO, amide), 1740 (CO, ester CO deltadakton), 1790 (CO.bétadaktám), 3400 (NH).

1 H-Nuclear Magnetic Resonance Spectrum (80 MHz, CDCl ₃ ), δ 101 and 1.72 / (2x3H, all s, 6H, C (CH ₃ ) ₂ ), 3.78 (s, 3H, COOCH ₃ ), δ , 02 (s, 3H, COOCH ₃ ), 400 (s, 1H,

3-H), 5.4-6.0 (m, 2H, 5-H and 6), 70-8.0 (m, 3-aromatic H and NH), 80-80 (m, 1H, 8-H). ).

Analysis for C ₂ H ₂₀ N ₂ O _e Sképlet: Calculated: C% = 54.78, H% = 408% N 6 O9; Found: C, 54.16; H, 602; N, 602.

Example 21

6- (Isocoumarin-4'-carboxamido) -2-O-dimethyl-penam-3-carboxylic acid methyl ester (21)

The title compound was prepared as described in Example 18 using 1 mmol (216 mg) of 6-aminopenidylanoic acid and 1 mmol (190 mg) of 4-carboxyisocoumarin. Yield: 253 mg (63%). 89-92 ° C (after recrystallization from isopropanol).

IR Nujol, cm ^-1): 1690 (CO, amide), 1740 br (CO deltadakton, CO, ester), 1800 (CO.bétadaktám), 3400 (NH).

¹ H-Nuclear Magnetic Resonance Spectrum (acetone-d ₄ , 100 MHz), δ 1.48 and 1.64 / 2c 3 H, all s, C 1 H 2 O 3, 3.76 (s, 3H, OCH 3), 4.40 (» , 1H, 3-H), 5.6-50 (5-H, 6-H, m), 70-80 (m, 5-aromatic H and NH).

Elemental analysis based on the formula Ci »HisN ₂ O _í SH ₂ O:

N, 6.66; S, 7.61.

Found: N, 609; S, 7.45. (42,007)

Example 22

Methyl 6- (3 '-methyl-isoquoumarin-carboxamido) -2-dimethyl-penam-34-carboxylic acid (22)

The title compound was prepared as described in Example 18 using 1 mmol (216 mg) of 6-aminopenylillanoic acid and 1 mmol (204 mg) of 3-methyl-4-carboxydocoumarin. Yield: 250 mg (60%). M.p. 88-92 ° C (after recrystallization from isopropanol).

IR spectrum (chloroform), cm ^-1 : 1690 (CO, amide), 1740 (CO, lactone and CO, ester), 1790 (CO, beta-lactam), 3400 (NH).

1 H NMR (acetone-d ₆ , 100 MHz), delta 1.44 and 106 / 2x3H, all s, C (CH ₃ ) ₂ /, 202 (s, 3H, OCH ₃ ), 3.68 (s, 3H, OCl ₃ ), 406 (delta, 1H, 3-H),

5.6-50 (in, 2H, 5-H and 6-H, dd, J _{5 6} = 40Hz, dd, D ₂ O), 7.1-80 (m, 4 aromatic H and NH).

Elemental analysis for C ₂ oH _{2 U} N ₂ O ₆ S calculated:% N = 6.73, S% = 7.68 found: N% = 6.63, S% = 702 (41608).

Example 23

Methyl 6 (2 '-Methyl-1 (2H) -isoquinalinone 4' -carboxamido) -2-O-dimethyl-penam-3-carboxylic acid (23)

The title compound was prepared as in Example 18 using 1 mmol (216 mg) of 6-aminopenylcillanoic acid and 1 mmol (203 mg) of 2-inethyl-1 (2H) 4-isoquinobnone-4-carboxylic acid. Yield: 245 mg (59%). 118-122 ° C (after recrystallization from isopropanol).

IR (chloroform, cm '): 1660 (CO, amide), 1740 (CO, ester), 1790 (CO. Beta.-lactam), 3400 (NH).

1 H NMR (acetone-d ₆ , 100 MHz): 1.44 and 1.60 / 2x3H for all s, C (CH ₃ ) ₂ /, 302 (s, 3H, NCH ₃ ), 3.72 (s, 3H, OCH ₃ ), 4.40 (s, 1H, 3-H),

5.6-50 (ni, 2H, 5-H and 6-H), 70-8.4 (m, 5 aromatic H and NH).

Mass Spectrum M / E: 415 (M ⁺ ).

C ₂₀ H ₂ N ₃ O _s S (41509)

Example 24

6- (2 '-Meyl-1' (2 'H) -Phthalazine on 4' -carboxamido) -2-O-methyl-pen-3-carboxylic acid methyl ester (24)

The title compound was prepared as described in Example 18 using 1 mmol (216 mg) of 6-aminopenidylanoic acid and 1 mmol (204 mg) of 2-methyl-1 (2H) -phthalazinone-4-carboxylic acid; yield 270 mg (65%). 98-100 ° C (after recrystallization from isopropanol).

IR (chloroform, cm @ ^-1 ): 1670 broad (CO, amide), 1750 (CO, ester), 1800 (CO, beta4-lactam), 3400 (NH).

¹ Η-NMR (acetone-d _e, 100 MHz) delta: 1.48 and 1.64 (2x3H, each s, C / ₂ 1 _CH3), 3.72 (delta, 3H, NCH _3), 3 , 74 (s, 3H, OCH ₃ ), 4.44 (s, 1H, 3-H),

(After replacement of O m, 2H, 5-H, 6-H, J, _e = 40 Hz, dd, D ₂₎ from 5.6 to 50, 7, (> - 70 (m, 3 aromatic H) .

8.1-80 (m, 1H, 8-H), 8.7-80 (m, 1H, NH). Analysis Ci9H OJS ₄ oN ₂ O: Calculated: N% = 13.46, S% = 7.68;

Found: N% 13/08, S% 7,79 (41608).

25-32. example

From 349 mg of ampicillil, the compounds listed in Table 3 were prepared as described in Example 15.

Table 4 illustrates the efficacy of the 194251 compounds of the present invention. Some of the antibiotics have the broad spectrum of activity shown in Table 5. The MICs in Tables 4 and 5 represent the minimum growth inhibitory concentration.

Table 3

Example Compound Yield Mp. (° C) IR cm * Analysis number (%) 25. 6- [N- (4'-Methyl-2 H-Coumarin-3'- 60 118-120 (chloroform) ♦ calculated • carbonyl) -2 R-2-amine offenyl - 1660 (CO, amide) "found -ace tamido] -2 2 -dimethyl -penam- 1730-wide (CO, Cjg Hj 7N3O7S -3-Carboxylic acid methyl ester (25) lak ton and CO, north (549.52) square), 1790 (CÓ, beta ♦ N7.65 lactam), 3400 (NH) «Ν721 ♦ S5.82 ♦♦ S 6.11 26. 6- [N- (7'0'-Dimethoxyisocoumarin-3 ^5- carbonyl> 2R-2-aminophenyl) 63 130-132 (chloroform) Cl 0 Hl qN ^ Oo S 1680 (CO, amide), (593.30) -acetamido J-2,2-dimethyl-penam 3 _r 1740green (CO, ♦ N, 7.06 methyl carboxylic acid (26) ester, CO lakion), ♦ S5.38 1800 CO beta «Ν 6.94 lactam), 3400 (NH) S 6.14 27. 6- [N- (4'-methoxycarbonylisocouma- 62 143-145 (Nujol) Cj 9 Hj 7N3O9S -rin-3, -carbonyl) -2R-2-amine-phenyl- 1680 (CO, amide), (593.10) acetamido] -2,2-dimethyl-penam-3- 1730-wide (CO, ♦ N, 7.08 methyl carboxylic acid (27) ester and lactone) ⁺ S5.39 1790 (CO, beta »N 720 lactam, 3400 (NH) -S5.54 28. 6- [N-Physocoumarin 4 'Carbonyl) - 63 103-105 (chloroform) C ₂₇ H _JS N ₃ O ₇ SH ₃ C -2R-2-amino o-phenylacetamido] -di - 1680 (CO, amide) (553.51) pen am-3-k or onsa v-methyl ester (2 8) 1740 broad N7.59 + (CO.lactone and CO, + S5,48 ester) 1800 (CO, «Ν729 lactam) 3400 (NH) «S5,63 29. 6- (N- (3'-Methyl-isoquoumarin-4'- 60 104-108 (chloroform) CjeH ₂₇ N ₃ O ₇ S -carbonyl) -2R-2-aminophenyl- 1680 (CO, amide), (54952) • ace tamido], 2 2 -di methyl - 1740-wide (CO, ♦ N, 7.65 -pen-3-carboxylic acid methyl - lactone and CO ester), ♦ S5.82 ester (29) 1790 (CO, beta «Ν 7.26 lactam), 3400 (NH) «S554 30. 6- [N- (2'-methyl-r (2'H) 4zokino- 57 140-143 (Nujol) CisHjgNg O _e S Unon4'-butoxycarbonyl) -2R-2-amino- 1660 (C0. Amide). (54854) phenylacetamido] -2 2-dinyl 1740 (C0, ester), ♦ N 1021 penam-3-carboxylic acid methyl 1790 (CO, beta ♦ S5.84 ester support), 3300 (NH) «Ν 9.87 31. 6- (N- (2'-methyl-1 '(2H> phthalate) 62 118-120 (chloroform) Cl 7 Hl 7N, OftS azin is 4 '-carbonyl) -2R-2 - 1670 broad (54,953) -aminophenyl-ace tamido] -22- (CO.amid), 1740 MS: • dlmethyl -pen am-3-carboxylic acid- (CO, ester), 1810 M / E: 5490 (M *) methyl ester (31) (CO, beta-lactam), 3400 (NH) 32. 6-ίΝ <2 ', 4 · -ιϋηιβ «1-1 · (2Ή) - 75 139-141 (Nujol) Cj »H ₃₀ N ₄ O _e S -isokin ol is -3'-arbonil> 2 R- 1650 broad (56,256) Aniinofenil -2-acetamido] -22- (CO.amid), 1730 ♦ N 996 di methi, -pen am-3-carboxylic acid- (CO, ester), 1790 S5.69 + methyl methyl ester (32) (CO, beta-lactam), «Ν9.81 3300 (NH) S 6.15

MIC (ml / kg) against microorganism strain

195 251

4, Table

Compound Ps. Aeruginosa 2 P. vulgaris 10 Staph. aureus 31 P. mirabiiis 171 E. coli II-012S Compound (2) 100  100 12.5 100 100 Compound (3) 100 100 12.5 100 100 Compound (4) 100 100 12.5 100 100 Compound (8) 625 100 3.1 3.1 3.1 Compound (9) 12.5 100 12.5 12.5 12.5 Compound (10) 12.5 100 12.5 12.5 12.5 Compound (11) 100 100 3.1 625 25 (Compound 12) 100 100 100 100 25 Compound (13) 100 100 100 100 100 Compound (14) 50 100 12 123 2.5 Compound (5) 100 625 100 100 100 Compound (1) 100 625 100 100 100 Compound (6) 100 625 100 100 100 Compound (7) 100 625 100 100 100

Table 5

Ps. Aeruginosa Vl.pneu- En te ro. E.coli bacter Pjnirabilis

38 632 634 635 665 671 Compound (8) 625 625 25 Compound (9) 625 625 25 25 Compound (10) 12.5 12 ^ 5 25 25

moma

597,576,640,626,669,667,660,661,662

12.5 12.5 3.1 12.5 12.5 12.5 50 50 12.5

625 625 2.1550 50 50 12.5

Claims (34)

PATENT CLAIMS A process for the preparation of a novel antibiotic of formula (I): R (R ') (R b) (R _c) of formula wherein R 1 is hydrogen, C 1-4 alkyl, C 1-4 alkoxycarbonyl, or phenyl; R ₄ is hydrogen, R 1, R ₆ are hydrogen, or C 1-4 alkoxy, A is oxygen or N-C 14 alkyl, n is 0 or 1, R 1 is hydrogen and R 1 is hydrogen, alkali metal or C 1 -C 4 alkyl, characterized in that e is a compound of formula II wherein R and n are as defined in the scope, X is hydrogen or trialkylsilyl, and Y is a metal ion, an ammonium or a trialkylsilyl 4U - with a compound of formula III wherein R is given by and Z is -O-CO-Alk or halogen. 2. A process according to claim 1 for the preparation of the sodium salt of 6- (4'-methyl-isoquoumarin-3'-carbocamido) -22-methylmethyl-penam-3-carboxylic acid, wherein the appropriate starting materials are used. The process according to claim 1 for the preparation of the sodium salt of 6- (7'JB'-dimethoxy-50-isoquumerine-3'-carboxamido> 224-methyl-penam-3-carboxylic acid, characterized in that appropriate starting materials are used. The process of claim 1, 6- (4'-methoxycarbonyl-isoquoumarin-3'-carboxamido) -22-dimethyl-55. for the preparation of the sodium salt of -penam-3-carboxylic acid, characterized in that suitable starting materials are used. 5. A process according to claim 1 for the preparation of the sodium salt of 6- (isoquoumarin-4'-carboxamido) -2-dimethylpenepen-3-carboxylic acid, characterized in that appropriate starting materials are used. 6. A process according to claim 1 for the preparation of the sodium salt of 6 / 3'-methyl-4-coumarin 4 '-carboxamido) -2 2-dimethyl-pen-3-carboxylic acid, wherein the appropriate starting materials are used. 7. A process according to claim 1 for the preparation of the sodium salt of 6-1,2'-methyl-1 '/ 2H) 4-isoquinolinone 4'-carboxylamido] -2,2-dimethyl-penam-3-carboxylic acid, using appropriate starting materials. The process according to claim 1 for the preparation of the sodium salt of 6 / 2'-methyl-1 '/ 2H-phthalazinone 4'-carboxamido) -2,2-dimethyl-amine-3-carboxylic acid, characterized in that: suitable starting materials are used. 9. A process according to claim 1 for the preparation of the sodium salt of 6- [N / 4'-methylisocoumarin-3'-carbonyl) -2R-aninophenylacetamido] -22-dinethyl-penam-3-carboxylic acid, suitable starting materials are used. A process according to claim 1 for the preparation of the sodium salt of 6- [N / 7 ', 4'-dimethoxy-isoquumarin-3'-carbonyl) -2R-2-aminophenylacetamido] -22-dimethyl-penam-3-carboxylic acid. , characterized in that appropriate starting materials are used. The process of claim 1, 6- [N- (4'-methoxycarbonylisocoumarin-3'-carbonyl) -2R-2-aminophenylacetamido] -2-dimethyl-penam-3 -carboxylic acid, characterized in that appropriate starting materials are used. The process according to claim 1 for the preparation of the sodium salt of 6- [N / isoquumarin 4,4-carbonyl) -2R-2-amine-phenylacetamido] -2-dimethyl-penam-3-carboxylic acid, characterized in that the appropriate starting materials are used. employed. 13. A process according to claim 1 for the preparation of the sodium salt of 6- [N / 3'-methyl4-isoquinoline-4'-carbonyl) -2R-2-aminophenylacetamido] -22-dimethyl-penam-3-carboxylic acid, which comprises using appropriate starting materials. . The process according to claim 1 for the preparation of the sodium salt of 6- [N-2'-methyl-1 '/ 2'] 4-isoquinolinone-4'4-carbonyl) -2R-2-aminophenylacetamido] -2-dimethyl-penam-3-carboxylic acid. , characterized in that appropriate starting materials are used. The process of claim 1, 6- [N- (2'-methyl-1 '/ 2H) -phthalazinone-4'-carbonyl) -2R-2-aminophenylacetamido] -2-2-dimethyl-penam-3k. characterized in that the appropriate starting materials are used. 16. A process according to claim 1 for the preparation of the methyl ester of 6 / 4'-methyl4-coumarin-3'-arboxamido) -2,2-dimethylpenam-3-carboxylic acid, wherein the appropriate starting materials are used. 17. A process according to claim 1 for the preparation of the methyl ester of 6,7'3'-dimethoxyphenyl-4'-coumarin-3'4-carboxamido) -224-methyl-penam-34-carboxylic acid, wherein the appropriate starting materials are used. 18. A process according to claim 1 for the preparation of the methyl ester of 6 / 4'-matoxycarbonyl-4'-coumarin-3'-carboxamido) -2-dimethyl-penam-3-carboxylic acid, wherein the appropriate starting materials are used. 19. A process according to claim 1 for the preparation of the methyl ester of 6-isocoumarin-4'-carboxamido) -22-dimethyl-penam-3-carboxylic acid, characterized in that appropriate starting materials are used. A process according to claim 1 for the preparation of the aryl acid methyl ester of 6β, 3'-methyl-14Socoumarin-4'-carboxamido) -2-dimethyl-penam-3-k, using appropriate starting materials. 21. A process according to claim 1 for the preparation of the methyl ester of 6- [2'-methyl-1/2 'H) -phthalazinone 4'-carboxamido] -2-dimethyl-penicarboxylic acid using appropriate starting materials. 22. A process according to claim 1 for the preparation of the methyl ester of 6- [2'-methyl-1 '(2H) -phthalazinone-4'-carboxamido-2-dimethyl-pen-4-carboxylic acid, using appropriate starting materials. 23. A process according to claim 1 for the preparation of the methyl ester of 6- [N / 4'-methylisocoumarin-3'-carbonyl) -2R-2-aminophenylacetamido] -22-dimethyl-penam-34-carboxylic acid, starting materials are used. 24. The process of claim 1 for the preparation of the methyl ester of 6-N- (7'3'-dimethoxy-isoquoumarin-3'-carbonyl) -2R-2-aminophenylacetamido] -2-dimethyl-penam-3-carboxylic acid, by using appropriate starting materials. 25. A process according to claim 1 for the preparation of the methyl ester of 6- [N- (4'-methoxycarbonyl-iso-coumarin-3'-carbonyl-2R-amino-4-phenylacetamido] -22-dimethyl-penam-3-carboxylic acid, suitable starting materials are used. 26. A process according to claim 1 for the preparation of the methyl ester of 6- [N- (isoquoumarin-4'4-carbonyl) -2R-2-aminophenylacetamido] -22-dimethyl-penam-3-carboxylic acid, using appropriate starting materials. 27. A process according to claim 1 for the preparation of the methyl ester of 6- [N- (3'-methyl-4-isoquoumarin-4'-carbonyl) -2R-2-aminophenylacetamido] -2-dimethyl-pentam-3,4-one. suitable starting materials are used. 28. A process according to claim 1 for the preparation of the methyl esters of 6- [N- (2'-methyl-1 '(2?) 4-chloro-4'-carbonyl) -2R-2-aminophenylacetamido] -22-dimethyl-penam-34-carboxylic acid. characterized in that suitable starting materials are used. 29. The process of claim 1, 6- [N- (2'-methyl-1 '(2'H) -phthalazinone-4'-carbonyl) -2R-2-aminophenylacetamido] -22-dimethyl-penam-3- wherein the appropriate starting materials are used. 30. The method of claim 1, 6- [N- (2 ', 4'-dimethyl-1' (2 ') -isoquinolinone -3'-4-carbonyl) -2R-2-aminophenylacetamido] -2-dimethylpentene am-3 carboxylic acid methyl ester, characterized in that suitable starting materials are used. The process of claim 1, wherein the methyl ester of 6- [N / 2 ', 4'-dimethyl-r (2H) 4-isoquinolinone-3'4carbonyl] -2R-2-aminophenylacetamido] -22-dimethyl-penam-3-carboxylic acid is present. characterized in that suitable starting materials are used. ., 32. The method of claim 1, which is 6- [N- (4'-phenylisocoumarin-3'4carbonyl) -2R-2-aminophenylacetamido] -81 -22-dimethyl-penam-3-carboxylic acid, characterized in that the appropriate starting materials are used. 33. The method of claim 1, 6- [N- (2'-methyl-4'-phenyl-1 '(2H-isoquinolinone-3'-carbonyl) -2R-2-amino-phenylacetamidol-2 2-dimethyl- penic acid carboxylic acid, characterized in that suitable starting materials are used 34. A process for the preparation of a pharmaceutical composition comprising the compound of formula (I) according to claim 1 wherein R, R 1, R 1, n are as defined in claim 1, with one or more pharmaceutically acceptable inert carriers and / or or mixed with an excipient and formulated into a pharmaceutical composition.