The method of obtaining the compounds cafema or their acid additive salts


C07D501/06 - Acylation of 7-aminocephalosporanic acid

 

(57) Abstract:

The invention relates to heterocyclic substances, in particular method of obtaining new compounds cafema General formula I, where R1- carboxy(lower)alkyl or esterified carboxy(lower)alkyl; R2is lower alkyl or hydroxyalkyl, R3- NH2, lower alkanolamine or carbamoylating, R4-H, alkyl, or acid-agents, additive salts with antimicrobial activity that can be used in medicine. Goal - the creation of new active substances of the specified class. Synthesis of lead from the corresponding derivatives of 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-carboxymethylamino)acetamido]-3 - chloromethyl-3-cefem-4-carboxylic acid and substituted pyrazole in the environment of N,N-dimethylformamide at room temperature. The new compounds inhibit pathogenic microorganisms at a concentration of 0.1 - 0.2 mg/ml, single dose of 50 - 2000 mg daily doses up to 4000 mg 1 tab.

The invention concerns a method of obtaining biologically active substances, namely method of obtaining new compounds cafema or their acid additive salts exhibiting antimicrobial activity.

This property suggests the possibility of which may find application in medicine.

The aim of the invention is the creation of new connections cafema containing both thiadiazolyl and pyrazol substituents exhibiting improved antimicrobial activity.

P R I m e R 1. 1-Methyl-5-uneedapart (1.4 g) is added to a solution of 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-carboxy-1 - methylethoxy) acetamido] -3-chloromethyl-3-cefem-4-carboxylic acid triptorelin (SYN-isomer) (1.24 g) in N, N-dimethyl - formamide (13 ml) and the mixture is stirred at room temperature for 4 h, the Reaction mixture was poured into ethyl acetate (100 ml). The precipitate was separated by filtration and sequentially washed with ethyl acetate and diisopropyl ether, the solid residue dissolved in water (30 ml) and adjusted pH to 2.0 with 10% hydrochloric acid. The solution is subjected to chromatography on a column of macroporous non-ionic adsorption resin "Diaion HP-20" and elute 30% aqueous solution of methyl alcohol. The fractions containing the target compound is separated, concentrated in vacuo and lyophilized obtaining 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-carboxy-1-methylethoxy) acetamido] -3-(2-methyl-3-ureido-1-pyrazolo)methyl-3-cefem-4 - carboxylate (SYN-isomer) (0.12 g).

IR spectrum (Nujol): 3300 (broad), 1770, 1680, 1570 cm-1.

The J = 5 Hz/, 5,27/2H, broad singlet/, 5,85 1H, doublet, J = 5 Hz/, 6,75/1H, doublet, J = 3 Hz/, 8,10 /1H, doublet, J = 3 Hz/.

P R I m m e R 2. Analogously to example 1 to obtain 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-carboxymethylamino] - 3-(4-moramide-2-methyl-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer).

IR spectrum (Nujol): 3300, 1765, 1665, 1605 cm-1.

NMR spectrum (D2O ): 3,18 and 3,51 (2H, AB-quadruplet, J = 18 Hz), 4.09 to (3H, singlet), 4,63 (2H, singlet), 5,22 and 5,46 (2H, AB quadruplet, J = 15 Hz), 5,23 (1H, doublet, J = 5 Hz), 5,86 (1H, doublet, J = 5 Hz), of 8.25 (1H, singlet), at 8.36 (1H, singlet), 8,43 (1H, singlet).

P R I m e R 3. Analogously to example 1 to obtain 7-[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-carboxymethylamino] -3-(3-formamido-2-methyl-1-pyrazolo) methyl-3-cefem-4-carboxylate (SYN-isomer).

IR spectrum (Nujol): 3300, 1760, 1660, 1580 cm-1.

AMC-range (D2O ): 3,13 and 3,44 (2H, AB quadruplet, J = 18 Hz), 3,91 (3H, singlet), of 4.67 (2H, singlet), to 5.21 (1H, doublet, J = 5 Hz) 5,22 and 4,43 (2H, AB quadruplet, J = 15 Hz), to 5.85 (1H, doublet, J = 5 Hz), 6.82 and 6,92 (1H, each doublet, J = 3 Hz), 8,15 (1H, doublet, J = 3 Hz), to 8.40 (1H, singlet).

P R I m e R 4. Analogously to example 1 to obtain 7-[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-carboxymethylamino] -3-(3-formamido-2,4-dimethyl-1-pyrazolo) methyl-3-cefem-4-carboxylate (si (2H, AV quadruplet, J = 18 Hz), 3,83 (3H, singlet), 4,70 (2H, singlet), 5,18 and 5,43 (2H, AB quadruplet, J = 15 Hz), 5,24 (1H, doublet, J = 5 Hz), by 5.87 (1H, doublet, J = 5 Hz), with 8.05 (1H, singlet), at 8.36 (1H, singlet).

P R I m e R 5. Analogously to example 1 to obtain 7-[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-carboxymethylamino] -3-(3-amino-2-methyl-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer).

IR spectrum (Nujol): 3300, 1760, 1660, 1590 cm-1.

NMR spectrum (D2O ): a 3.06 and 3.33 (2H, AB quadruplet, J = 18 Hz), 3,63 (3H, singlet), 4,60 (2H, singlet), 4,93 and to 5.21 (2H, AB quadruplet, J = 15 Hz), 5,16 (1H, doublet, J = 5 Hz), of 5.83 (1H, doublet, J = 5 Hz), 5,88 (1H, doublet, J = 3 Hz), 7,78 (1H, doublet, J =3 Hz).

P R I m e R 6. Analogously to example 1 to obtain 7-[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-carboxymethylamino] -3-(3-amino-2,4-dimethyl-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer).

IR spectrum (Nujol): 3350, 1770, 1660, 1600 cm-1.

NMR (D2O : of 1.93 (3H, singlet), 3,06 and 3.30 (2H, AB quadruplet, J =18 Hz), to 3.64 (3H, singlet), of 4.67 (2H, singlet), 4,88 and 5,19 (2H, AB quadruplet, J = 15 Hz), 5,18 (1H, doublet, J = 5 Hz), of 5.84 (1H, doublet, J = 5 Hz), 7,66 (1H, singlet).

P R I m e R 7. Analogously to example 1 to obtain 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-tert-butoxycarbonyl-1 methylethoxy)acetamido]-3-(3-amino-2-methyl-1-pyrazole the CLASS="ptx2">

NMR spectrum (D2O ): 1,45 (S, singlet), 1,57 (6N, singlet), 3,09 and 3,37 (2H, AB quadruplet, J = 18 Hz), to 3.67 (3H, singlet), 4,98 and at 5.27 (2H, AB quadruplet, J = 15 Hz), to 5.21 (1H, doublet, J = 5 Hz), 5,86 (1H, doublet, J = 5 Hz), of 5.92 (1H, doublet, J = 3 Hz), a 7.85 (1H, doublet, J = 3 Hz).

P R I m e R 8. Analogously to example 1 to obtain 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-tert-butoxycarbonyl-1 methylethoxy) acetamido] -3-(3-amino-2,4 - dimethyl-1-pyrazolo) methyl-3-cefem-4-carboxylate trihydrochloride (SYN-isomer).

IR spectrum (Nujol): 3300, 1780, 1650 cm-1.

NMR spectrum (D2O ): 1,42 (N, singlet), 1,47 (6N, singlet), of 1.93 (3H, singlet), 3,32 (2H, broad singlet), to 3.67 (3H, singlet), is 5.18 (2H, broad singlet), with 5.22 (1H, doublet, J = 5 Hz), 5,90 (1H, double doublet, J = 8 Hz), of 7.90 (1H, singer), to 9.45 (1H, doublet, J = 8 Hz).

P R I m e R 9. Analogously to example 1 to obtain 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-carboxy-1 - methylethoxy)acetamido]-3-(3-amino-2-methyl-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer).

IR spectrum (Nujol): 3325, 1770, 1650, 1630, 1590 cm-1.

NMR-spectrum (DHSO-d6, ): 1.52m (6N, singlet), 3,19 and 3,37 (2H, AB quadruplet, J = 18 Hz), 3,66 (3H, singlet), equal to 4.97 and 5.25 (2H, AB quadruplet, J = 15 Hz), 5,20 (1H, doublet, J = 5 Hz), of 5.84 (1H, doublet, J = 5 Hz), 5,91 (1H, doublet, J = 3 Hz), 7,82 (1H, doublet, J = 3 Hz).

P R-3-(3-amino-2,4-dimethyl-1-pyrazolo)-methyl-3-cefem-4 - carboxylate (SYN-isomer).

IR spectrum (Nujol): 3320, 3180, 1760, 1650, 1595 cm-1.

NMR spectrum (D2O ): 1,60 (6N, singlet), a 1.96 (3H, singlet), 3,10 and 3,37 (2H, AB quadruplet, J = 18 Hz), 3,68 (3H, singlet), 4,92 and 5,23 (2H, AB quadruplet, J = 15 Hz), with 5.22 (1H, doublet, J = 5 Hz), 5,86 (1H, doublet, J = 5 Hz); to 7.68 (1H, singlet).

P R I m e R 11. Analogously to example 1 to obtain 7 -[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxy) acetamido]-3-(2-methyl-3-formamido-1-pyrazolo)methyl-3-cefem-4 - carboxylate (SYN-isomer).

IR spectrum (Nujol): of 3,200-3,300, 1760, 1580 cm-1.

NMR-spectrum /DMSOd6, /: 1,46 /6N, singlet/, 3,05-3,37 (2H, multiplet), 3,91 (6N, singlet), 4,90-to 5.57 (2H, multiplet), is 5.06 (1H, doublet, J = 5,71 (1H, double doublet, J = 5.3 Hz), 6,91 (1H, doublet, J = 3 Hz), 8,02-of 8.27 (2H, broad singlet), to 8.34 (1H, doublet, J = 3 Hz), 8,56 (1H, singlet), 9,46 (1H, doublet, J = =8 Hz).

P R I m e R 12. Analogously to example 1 to obtain 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-carboxy-1-methylethoxy) acetamido]-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolo]-methyl-3 - cefem-4-carboxylate (SYN-isomer).

IR spectrum (Nujol): 3300, 1765, 1640 cm-1.

NMR spectrum (D2O ): 1,58 (6N, singlet), 3,10 and of 3.43 (2H, AB - quadruplet, J = 18 Hz), 3,78-of 3.97 (2H, multiplet), 4.26 deaths-of 4.46 (2H, multiplet), of 5.15 (2H, broad singlet), of 5.26 (1H, doublet), J = 5 Hz), by 5.87 (1H, doublet, J = 5 Hz), 5,97 (diazol-3-yl)-2-(1-carboxy-1 - methylethoxy)acetamido] -3-(3-acetamido-2-methyl-1-pyrazolo) methyl-3-cefem-4-carboxylate (SYN-isomer).

IR spectrum (Nujol): 3300, 1775, 1670 cm-1.

NMR spectrum (D2O ): 1,56 (6N, singlet), 2,31 (3H, singlet), 3,20 and a 3.50 (2H, AB quadruplet, J = 18 Hz), 8,93 (3H, singlet), 5,23 and 5.47 (2H, AB quadruplet, J = 15 Hz), 5,26 (1H, doublet, J = 5 Hz), 5,88 (1H, doublet, J = 5 Hz), to 6.88 (1H, doublet, J = 3 Hz), 8,19 (1H, doublet, J =3 Hz).

P R I m e R 14. To N,N-dimethylformamide (231,6 ml) is added 7 -[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxy) acetamido] -3-(3-amino-2-methyl-1-pyrazolo)methyl-3-cefem-4 - carboxylate (SYN-isomer) (38,6 g) at room temperature. The mixture is stirred at this temperature for 2 h and the resulting precipitate was separated by filtration to obtain bis(N, N-dimethylformamide) MES (47,3 g) 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-carboxy-1 - methylethoxy)acetamido] -3-(3-amino-2-methyl-1-pyrazolo)- methyl-3 - cefem-4-carboxylate (SYN-isomer).

IR spectrum (Nujol): 3280, 3130, 1775, 1670, 1580 cm-1.

NMR spectrum (D2O + NaHCO3),: 1,53 (6N, singlet), 2,86 (6N, singlet), 3,01 (6N, singlet), 3,10 and to 3.36 (2H, AB quadruplet, J = 18 Hz), 3,66 (3H, singlet), 4,96 and 5,23 (2H, AB quadruplet, J = 15 Hz), with 5.22 (1H, doublet, J = 5 Hz), to 5.85 (1H, doublet, J = 5 Hz), of 5.92 (1H, doublet, J = 3 Hz), 7,83 (1H, doublet, J = 3 Hz), to $ 7.91 (2H, singlet).

P R I m e R 15. To a solution of 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-carboxy-1 - maternal acid (2M, 1.0 ml) are added ethanol. After stirring the solution for 1.0 h, the crystals are separated by filtration, washed with a mixture of water and ethanol (1: 5), then ethanol and dried over pjatiokisi phosphorus obtaining salts of sulfuric acid (480 mg) 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-carboxy-1-methylethoxy) acetamido] -3-(3-amino-2-methyl-1-pyrazolyl) methyl-3-cefem-4-carboxylate (SYN-isomer).

Melting point 194-197aboutC.

IR spectrum (Nujol): 3320, 3200, 3060, 1770, 1720, 1655, 1590, 1545 cm-1.

NMR spectrum (D2O ): 1,50 (6N, singlet), 3,33, of 3.13 (2H, AB quadruplet, J = 18 Hz), the 3.65 (3H, singlet), 5,20 (1H, doublet, J = 5 Hz), 5,22, to 4.98 (2H, AB quadruplet, J = 14 Hz), of 5.83 (1H, doublet, J =5 Hz), of 5.92 (1H, doublet, J = 3 Hz), 7,80 (1H, doublet, J = 3 Hz).

P R I m e R 16. Triperoxonane acid (7 ml) is added dropwise to a suspension of 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-tert-butoxycarbonyl-1 - methyl-1-methylethoxy) acetamido] -3-(3-amino-2 - methyl-1-pyrazolo) methyl-3-cefem-4-carboxylate of trihydrochloride (3.8 g) and anisole (3.5 ml) in methylene chloride (10 ml) at room temperature. After stirring at the same temperature for 4 h, the mixture was poured into diisopropyl ether (800 ml) and the resulting precipitate was separated by filtration. The precipitate is dissolved in water (100 ml) and the solution n is the her on a column of macroporous non-ionic adsorption resin "Diaion HP-20". Target product elute with 5% aqueous solution of isopropyl alcohol and lyophilized obtaining 7 -[2-(5-amino-1,2,4-thiadiazole-3-yl)-2-(1-carboxy-1 - methylethoxy) acetamido] -3-(3-amino-2-methyl-1-pyrazolo)methyl-3-cefem-4 - carboxylate (SYN-isomer) (515 mg).

The compounds of formula 1 and pharmaceutically acceptable salts of these compounds exhibit antimicrobial activity, inhibiting the growth of a wide class of pathogens, including gram-positive and grammatically microorganisms.

Below presents data on the test MIC (minimum inhibition concentration) of some compounds of the invention.

Test method.

In vitro antibacterial activity was determined by the method of double dilution agar plates, as described below.

One drop of the culture of the test strain obtained during the night in broth trypticase soybean (106viable cells per ml) was applied to extract agar hearts (1H - agar) containing certain concentrations of the test compounds and the minimum inhibition concentration (MIC) was expressed in units of micrograms/ml after incubation at 37aboutWith over 20 am

Tested sedimental-3-cefem-4-carboxylate (SYN-isomer) (Compound A).

7-[2-(5-Amino-1,2,4-thiadiazole-3 - yl)-2 - carboxymethylamino] -3-(3-formamido-2-methyl-1-pyrazolo)methyl-3-cefem-4-carboxylate (SYN-isomer) (Compound).

7-[2-(5-Amino-1,2,4-thiadiazole-3 - yl)-2-(1-carboxy-1-methylethoxy) acetamido] -3-(3-amino-2-methyl-1-pyrazolo)methyl-3-CE-FEM-4-carboxylate (SYN-isomer) (Connection With.

The test results presented in the table.

The dose of the compounds of formula 1 can vary from 1 mg to 4000 mg or more to a single patient. The average single dose of 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, 2000 mg of the compounds of formula 1 for the treatment of diseases caused by infection with pathogenic microorganisms.

The method of obtaining the compounds cafema General formula I

CONHR3< / BR>
where R1- carboxy(lower)alkyl or esterified carboxy(lower)alkyl;

R2- lower alkyl or hydroxy(lower)alkyl;

R3- amino group, a lower alkanolamine or carbamoylating;

R4is hydrogen or lower alkyl,

or their acid additive salts, characterized in that the compound of General formula II

CONH

where R1has the specified values,

Y is halogen,

or its salt is subjected to interaction with oedipustraumes with obtaining the compounds of formula I or its acid salt additive, and if necessary, the compound of formula I, where R1- esterified carboxy(lower)alkyl, remove carboxyamide group to obtain the compounds of formula I, where R1- carboxy(lower)alkyl, or an acid additive salt.

 

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