Substituted derivatives isothiazol-pyridone of azetidine and pharmaceutical composition based on them

 

(57) Abstract:

Usage: as drugs with antimicrobial activity. The inventive zameshannye derivatives isothiazol-pyridinethiol f-ly I or its tautomers f-crystals II possessing antibacterial activity, and a pharmaceutical composition having antimicrobial activity, containing the active principle and a pharmaceutically acceptable carrier, while it contains as active principle derived f-ly I in the amount of 50-100 mg per unit dose. Connection structure of f-crystals I and II: 2 C. p. f-crystals, 6 PL.

The invention relates to new azetidinone derived isothiazol-pyridone: 2,3,4,9-tetrahydroindazole[5,4-b]China - in-3,4-dione, 2,3,4,9-tetrahydrothieno [5,4-b] [1,8]-naphthiridine-3,4-dione, 1,2,8,9-tetrahydro-7H-isothiazol-[4',5',5,6]pyrido [1,2,3-de]benzoxazine-7,8-dione and its salts.

Compounds according to the invention can be used in the pharmaceutical industry as intermediates and for obtaining medicines. Isothiazol-naphthiridine and isothiazol-quinoline known from European patent ER, isothiazol-pyrido-benzoxazines known from the patent ER, but in none of these cases, there are no examples svodnyy isothiazol-naphthiridine, isothiazol-quinoline and isothiazol-pyridobenzoxazine that are the subject of the invention possess good antimicrobial activity.

Compounds according to the invention have a General formula I

which can also be written in tautomatically form II

N where a nitrogen atom or a carbon atom with attached hydrogen atom of the C-H or a carbon atom attached with a halogen With-X, in the latter case, X represents an atom of bromine, chlorine or fluorine; R1alkyl or lower cycloalkyl radical, a lower halogenated, aryl radical or aryl radical, substituted by one or more fluorine atoms; R2and R7the same or different represent a hydrogen atom or a lower alkyl radical; R3, R5, R6identical or different denote hydrogen atom, lower alkyl radical, aminoalkyl radical, alkylamino radical, acylaminoalkyl radical; R4a hydrogen atom, a lower alkyl radical, a hydroxyl radical, amino radical, aminoalkylsilyl radical, alkylamino radical, dialkylamino radical, nitrogen-containing geterotsiklicheskikh radical, which may be a loop containing from three to six chain links, acylaminoalkyl RA is their halogen, radical, arylsulfonate, radical, alkylsulfonate, radical, carboxamide, which may be substituted or not substituted on the nitrogen, or a cyano radical; R8a hydrogen atom, a nitro radical, an amino radical or substituted amino;

A and R1can together form a bond, represented by the group-CH2-CH2-R9- or C-O-CH2-CHR9-, in which R9represents a hydrogen atom or a lower alkyl radical, in the latter case, there is a chiral center configuration R or s

Azetidinone alternates depending on the number, nature and position of substituents can have up to three chiral centers, each of them with the R configuration or s

The stereochemistry of the products that are the subject of the invention was determined by the stereochemistry of the starting products. By selection of stereoisomerism each of the original products you can get all the possible stereoisomers, and in the case where the reaction product is stereoisomeric mixture, the components can be separated and their configuration can be determined by known methods. New derivatives of General formula I can be obtained, in accordance with the invention, the following method, namely by reaction of a halogen atom, preferably chlorine or fluorine with azetidinol (trimethylaluminum) of General formula IV

in which R2, R3, R4, R5, R6, R7have the specified values.

The reaction is carried out in the presence of an appropriate solvent, for example dimethylsulfoxide, dimethylformamide, pyridine, trialkylamine, as for example, triethylamine, chlormethine, chloroform, acetonitrile, or ethers, such as tetrahydrofuran or dioxane, or mixtures of these solvents.

The most suitable temperatures vary from room temperature up to the temperature of the return of the refrigerator solvent, and the reaction time from 1 to 24 hours

Heterocyclic compounds of General formula III, which can be used as starting products for producing compounds in accordance with the invention, are described, for example, D. T. W. Chu, P. B. Fernandes, A. Claiborne, L. Chen. Pernet. Drugs Exp. Chim. Res. 14, 6, 379, 1988.

Compounds of General formula IV, which are also source products for producing compounds according to the invention of General formula I are known or can be synthesized according to method A. Anderson, R. Lok, J. Org. Chem. 1972, 37, 3953 or R. Higgins, N. Cromwell, J. Heterocycl. Chem. 1971, 8, 1059 or N. Cromwell, B. Philips, Chem. Rews. 1979, 79, 331.

Azetidine the chiral centers, different stereoisomers can be obtained or by asymmetric synthesis, or by various methods of separation, according to the methods known in organic chemistry.

Compounds of General formula I and their physiologically acceptable salts, such as salts of inorganic acids, for example hydrochloric, or organic acids, such as toluensulfonate or methylsulfonate, preferably introduced in the form of pharmaceutical compositions.

In the following examples describes the obtaining of new derivatives in accordance with the invention. Will be described also forms application.

P R I m e R 1. 9-cyclopropyl-6-fluoro-7-(3-amino-1-azetidine)-2,3,4,9-the - tradititional [5,4-b]quinoline-3,4-dione.

Within 2 hours at the reflux withstand a mixture of 140 mg (0.475 µm) 9-cyclopropyl-6,7-debtor-2,3,4,9-tetrahydrothieno [5,4-b]quinoline-3,4-diode, 300 mg (2 µm) dichlorhydrate 3-aminoacridine and 1 ml of triethylamine in 5 ml of pyridine and 5 ml of dimethyl sulfoxide. Filtered, washed with water and ethanol, and spend hot drying and obtain 102 mg of 9-cyclopropyl-6-fluoro-7-(3-amino-1-azetidine)-2,3,4, 9-tetrahydrothieno [5,4-b]quinoline-3,4-dione, so pl. 270aboutWith (d).

Spectroscopic data: 1H, NMR, (DMSO-d6-ATFA), : 8,42 (SS="ptx2">

P R I m m e R 2. 9-cyclopropyl-6-fluoro-7-(3-methylamino-1-azetidine)-2,3,4,9-tetrahedralization olol [5,4-b]quinoline-3,4-dione.

For 1.5 h at the reflux withstand a mixture of 500 mg (1.7 µm) 9-cyclopropyl-6,7-debtor-2,3,4,9-tetrahedrite - thiazole [5,4-b]quinoline-3,4-dione, 750 mg (3.4 µm) of the hydrochloride of 3-(triptorelin-N-methyl)azetidine and 1.2 ml of triethylamine in 10 ml of pyridine and 10 ml of DMSO, filtered, washed with water and ethanol, and spend hot drying, obtain 430 mg of 9-cyclopropyl-6-fluoro-7-(N-methyl-3-trift - aracetamol-1-azetidine)-2,3,4,9 - tetrahydrothieno [5,4-b] quinoline-3,4-dione with so pl. 284-290aboutC, which is then hydrolized by heating with 10% soda for 2 hours was Filtered, washed with water and ethanol, and spend hot drying and obtain 340 mg of 9-cyclopropyl-6-fluoro-7-(3-methylamino-1-azetidine)-2,3,4,9-tetrahydro-ittia angry [5,4-b] quinoline-3,4-dione, with a melting point 270aboutWith (d).

Spectroscopic data: 1H NMR, , (DMSO-d6-ATFA): which 9.22 (e, 2H), 7,71 (d, 1H, J 13 Hz), for 6.81 (d, 1H, J 6 Hz), 4,35 (m, 4H), of 3.45 (m, 1H), 2,64 (s, 3H), of 1.29 (m, 4H).

IR (KBr): 1629, 1588, 1497, 1431 cm-1.

P R I m e R 3. 9-cyclopropyl-6-fluoro-7-(3-dimethylamino-1-azetidine)-2, 3,4,9-tetrahydrooxazolo [5,4-b] quinoline-3,4-dione.

aboutWith (d). Spectroscopic data: 1H NMR (DMSO-d6-ATFA), : of 7.70 (d, 1H, J 13 Hz), 6,77 (d, 1H, J 7 Hz), 4,34 (m, 4H), 3.43 points (m, 2H), and 2.83 (s, 6N), of 1.20 (m, 4H).

IR (KBr): 1640, 1612, 1501 cm-1.

P R I m e R 5. 9-cyclopropyl-6-fluoro-7-(TRANS-3-amino-2-methyl-1-azeti - dinyl)-2,3,4,9 - tetrahydrothieno [5,4-b]quinoline-3,4-dione.

Within 2 hours at the reflux withstand a mixture of 150 mg (0.51 µm) 9-cyclopropyl-6,7-debtor-2,3,4,9-then it is carbonated - tosociety [5,4-b]quinoline-3,4-dione, 300 mg (1.9 µm) dichlorhydrate TRANS-3-amino-2-methylaziridine and 1 ml of triethylamine in 5 ml of pyridine and 5 ml of dimethyl sulfoxide. Filtered, washed with water and ethanol, and spend hot drying and obtain 105 mg of 9-cyclopropyl-6-fluoro-7-(TRANS-3-amino-2-methyl-1-azetidine)-2,3,4,9 - tetrahydrothieno [5,4-b] quinoline-3,4-dione, melting point 264-267aboutC.

Spectroscopies the 4N).

IR (KBr): 1628, 1592, 1486 cm-1.

P R I m e R 9. d) Receiving 9-cyclopropyl-6-fluoro-7-(3-amino-3-methyl-1-azetidin - yl)-2,3,4,9 - tetrahydrooxazolo[5,4-b]quinoline-3-4-dione.

For 2 h at the reflux withstand a mixture of 90 mg (0.3 µm) 9-cyclopropyl-6,7-debtor-2,3,4,9-tetrahydro - isothiazole[5,4-b]quinoline-3,4-dione, 200 mg (1.25 µm) dichlorhydrate 3-amino-3-methylaziridine and 1 ml of triethylamine in 5 ml of pyridine and 5 ml of dimethyl sulfoxide. Filtered, washed with water and ethanol, and spend hot drying and receive 70 mg of 9-cyclopropyl-6-fluoro-7-(3-amino-3-methyl-1-azetidine)- 2,3,4,9-tetrahydrooxazolo[5,4-b]quinoline-3,4-dione, so pl. 297-302aboutC.

Spectroscopic data of 1H NMR, , (DMSO-d6-ATFA): 8,50 (e, 2H), 7,72 (d, 1H J 13 Hz), 6,79 (d, 1H, J 7 Hz), is 4.21 (m, 4H), of 3.45 (m, 1H), 1,64 (s, 3H), 1,25 (m, 4H).

IR (KBr): 1629, 1592, 1492 cm-1.

b) Receiving methylsulfonate 9-cyclopropyl-6-fluoro-7-(3-amino-3-methyl-1-azeti - dinyl)-2,3,4,9 - tetrahydrothieno [5,4-b]quinoline-3,4-dione.

Make a suspension of 60 mg (0,17 µm) 9-cyclopropyl-6-fluoro-7-(3-amino-3-methyl-1-azetidine)-2,3,4,9 - tetrahydrooxazolo[5,4-b]quinoline-3,4-dione in 10 ml of methanol and add an excess of metasulphate acid. Stirred for 15 min, filtered, washed with methanol, conduct picascia data: 1H NMR, , (DMSO-d6-ATFA): 8,44 (e, 2H), a 7.62 (d, 1H, J 13 Hz), 6,72 (d, 1H, J 7 Hz), 4.16 the (m, 4H), 3.43 points (m, 4H), of 2.50 (s, 3H), 1,60 (s, 3H), of 1.20 (m, 4H).

IR (KBr): 1638, 1617, 1498 cm-1.

P R I m e R 10. 9-cyclopropyl-6-fluoro-7-(3-methylamino-3-methyl-1-AZE - tidine)-2,3,4,9 - tetrahydrothieno [5,4-b]quinoline-3,4-dione. According to the method, which is identical to that described in example 2, get 9-cyclopropyl-6-fluoro-7-(N-methyl-3-triptoreline-3-me - Teal-1 - azetidine)-2,3,4,9-tetrahydrothieno [5,4-b] quinoline-3,4-dione with a melting point 286-290aboutWith that hydrolized by heating with 10% soda for 2 hours, get 9-cyclopropyl-6-fluoro-7-(3-methylamino-3-methyl-1-AZE - tidine)-2,3,4,9 - tetrahydrothieno [5,4-b]quinoline-3,4-dione with a melting point 300aboutC.

Spectroscopic data: 1H-NMR, , (DMSO-d6-ATFA): 9,39 (e, 2H), 7,80 (d, 1H, J 13 Hz), 6.90 to (d, 1H, J 6 Hz), 4,28 (m, 4H), 3.46 in (m, 1H), 2,70 (s, 3H), 1.69 in (s, 3H), 1,22 (m, 4H).

IR (KBR): 1625, 1597, 1495, 1474, 1428, 1385 cm-1.

P R I m e R 22. 9-cyclopropyl-6-fluoro-7-(3-ethylamino-1-azetidine)-2, 3,4,9-tetrahydrothieno [5,4-b]quinoline-3,4-dione.

The method is completely similar to the founded in example 2, get 9-cyclopropyl-6-fluoro-7-(N-ethyl-3-triptycene - to-1-azetines)-2,3,4,9-tetrahydrozoline - sooi for 2 h, get 9-cyclopropyl-6-fluoro-7-(3-ethylamino-1-azetidine)-2,3,4,9 - tetrahydrothieno [5,4-b] quinoline-3,4-dione with a melting point 231-236aboutC. Spectroscopic data: 1H-NMR, , (DMSO-d6-ATFA): 9,39 (e, 2H), 7,69 (d, 1H, J 13 Hz), to 6.80 (d, 1H, J 6 Hz), the 4.29 (m, 4H); 3.43 points (m, 1H), 3,03 (m, 2H), 1,31 (m, 7H).

IR (KBr): 1628, 1601, 1492, 1472 cm-1.

P R I m e R 29. 9-cyclopropyl-6,8-debtor-7-(TRANS-3-amino-2-methyl-1-azetidine)-2,3,4,9 - tetrahydrothieno[5,4-b]quinoline-3,4-dione.

Within 2 hours and maintained at the reflux mixture of 125 mg (0.4 µm) 9-cyclopropyl-6,7,8-Cryptor-2,3,4,9-Tetra - hydrosocial[5,4-b]quinoline - 3,4-dione, 128 mg (0.8 µm) dichlorhydrate TRANS-2-methyl-3-aminoacridine and 0.34 ml of triethylamine in 4 ml of pyridine and 4 ml of dimethyl sulfoxide. Filtered, washed with water and ethanol, and spend hot drying and obtain 93 mg of 9-cyclopropyl-6,8-debtor-7-(TRANS-3-amino-2-methyl-1-azetidine)-2,3,4,9 - tetrahydrothieno[5,4-b] quinoline-3,4-dione with a melting point 268-270aboutC.

Spectroscopic data: 1H-NMR, , (DMSO-d6-ATFA): 8,35 (e, 3H), 7,66 (d, 1H, J 13 Hz), 4,70 (m, 2H), 4,10 (m, 1H), 3,78 (m, 2H), 1,53 (d, 3H, J 6 Hz) and 1.15 (m, 4H).

IR (KBr): 1623, 1608, 1605, 1465, 1424 cm-1.

P R I m e R 33. a) Receiving 9-cyclopropyl-6,8-debtor-7-(3-amino-3-methyl-1-incubated mixture of 250 mg (0.8 µm) 9-cyclopropyl-6,7,8-Cryptor-2,3,4,9-Tetra - hydrosocial [5,4-b]quinoline - 3,4-dione, 255 mg (1.6 µm) dichlorhydrate 3-methyl-3-aminoacridine and 0.6 ml of triethylamine in 10 ml of pyridine, and then evaporated in vacuo, add a mixture of ethanol with water, filtered and washed. Get 0,225 g 9-cyclopropyl-6,8-debtor-7-(3-amino-3-meth - yl-1-azetidine)-2,3,4,9 - tetrahydrothieno[5,4-b]quinoline, 3,4-dione, so pl. 294-300aboutC.

Spectroscopic data:

IR (KBr): 1630, 1602, 1469 cm-1.

b) Receiving methylsulfonate 9-cyclopropyl-6,8-debtor-7-(3-amino-3-methyl-1 - azetidine)-2,3,4,9 - tetrahydrothieno [5,4-b]quinoline-3,4-dione.

Make a suspension of 120 mg (0.32 µm) 9-cyclopropyl-6,8-debtor-7- (3-amino-3-methyl-1-azetidine)-2,3,4,9-tetrahydrozoline - angry [5,4-b] quinoline-3,4-dione in 10 ml of methanol and add an excess of methylsulfonic acid. Stirred for 15 min, filtered, washed with methanol, and spend hot drying receive 120 mg of the above salt, melting point 248-253aboutC.

Spectroscopic data: 1H NMR, , (DMSO-d6-ATFA): 8,40 (e, 2H), a 7.62 (d, 1H, J 12 Hz), 4,35 (m, 4H), 3,70 (m, 1H), 2,50 (s, 3H), 1.55V (s, 1H), 1,07 (m, 4H).

IR (KBr): 1648, 1619, 1468 cm-1.

Using as starting product 9-cyclopropyl-6-fluoro-2,3,4,9-tetrahydrothieno [5,4-b]quinoline-3,4-dione, but working as described in examples 1, 3 the Il-6,7-debtor-2,3,4,9-tetrahydrothieno [5,4-b][1,8]quinoline-3,4-dione, the method of example 33 receive the products of examples 25 to 48 (table. 1); if used as a source of product 9-cyclopropyl-6,7-debtor-2,3,4,9-tetrahydrothieno [5,4-b] [1,8] naphthiridine-3,4-dione, according to the method of example 5, you can get the products from 49 to 72 (table. 1 and 2); if used as starting product 1-methyl-4,5-debtor-1,2,8,9-tragida-7H-isothiazol[4',5'; 5,6']pyrido[1,2,3 de] [1,4]benzoxazine-7,8-dione, prepared as in example 5, the products of examples 73-96.

Biological activity

Pharmacological antimicrobial activity of these compounds was investigated in accordance with the references.

Pharmacological antimicrobial activity (G. L. Daguet, Y. A. Chabpect, techniques en bacteriologie, Vol. 3. Flammation Medecine Sciences, Paris 1972; W. B. Hugo et. A. D. Rusell, Pharmacentical, Microbiology, Blackwell Scientific Publications, London, 1977.

Culture medium and solvent:

antibiotic agar No. 1 (Oxoid CM327)

the broth tripton soy (Oxoid CM 129)

saline Ringer 1/4 (Oxoid Br52)

agar dextrose (BBL11165)

Microorganisms:

Bacillus subtilis ATCC 6633

Citrobacter freundii ATCCC 112606

Enterobacter aerogenes ATCC 15038

Enterobacter cloacae ATCC 23355

Bacillus cereus ATCC 1178

Escherichia coli ATCC 10799

Escherichia coli ATCC 23559

Klebsiella pneumoniae ATCC 10031

Proteus vulgaris ATCC 8427

Morgs have been screaming. morganii ATratia marcescens ATCC 13880

Shigella flexnerii ATCC 12022

Staphylococcus epidermis ATCC 155-1

Staphylococcus epidermis ATCC 25178

Streptococcus faecalis ATCC 10541

Getting vaccinations.

Each of the microorganisms seeded stroke in tubes with antibiotikum agar 1 and incubated for 20 h at 37aboutC. Then take a loop of culture and sown in the broth tripton soy, kept in the incubator for 20 h at 37aboutC. the resulting culture was diluted to 1/4 physiological ringer's solution, so to get the standard suspension 10-10ufc/ml for each organism.

Cooking environment containing derivatives of General formula 1. On the basis of 100 μg/ml solution of each product is dissolved in dextrosol agar, previously melted and maintained at a temperature of 50aboutWith by serial dilution to obtain the following concentrations: 64-32-16-8-4-2-1-0,5-0,25-0,125 mcg derived/ml of medium.

Then each concentration of each environment are placed in a Petri dish of 10 cm diameter, 10 ml of medium in each Cup and as many cups as microorganisms for testing.

After cooling medium into cups seeded, rate of 0.4 ml grafting environment for one Cup. Stretch loop Dahlskog and collect what is shown in the table. 3-6. Activity of compounds in-vitro compared with the activity of norfloxacin. Concentrations are given in µg/ml.

Norfloxacin described in Drugs of the Future" 1982, 7(8), and has the formula

< / BR>
The applicant has also conducted a comparative pytania new compounds with known and loved by the structure of the connection Ciprofloxin, (see the Merck Handbook, page 360). The comparison was carried out bacteriological tests with different types of microorganisms. The results are shown in table. 3-6. As follows from the table. 3-6 new compounds show an increase antibacterial activity compared to the known compound.

The new compounds according to the invention belong to the category of low-toxic products.

In the treatment of people dose is determined depending on the susceptibility of infectious strain, taken from nature connection and method of reception. The usual dose is 0,200-300 mg per kg of body weight per day. Derivatives in accordance with the invention are produced in the form of tablets, solutions or suspensions or in the form of pills.

As an example two herbal forms of derivatives in accordance with the invention.

An example of a formula tablets, mg: the Connection with Omnia 50 Stearate 3 Weight tablets 300

An example of a formula pills, mg: Connection example 5 100

Polyoxyethylene the glycerides 185 Glycerinated 15

Excipient: Qty gelatin sufficient to 300

1. Substituted derivatives isothiazol-pyridone of azetidine General formula I

< / BR>
where A carbon with attached hydrogen C H or a carbon attached to the halogen C X, where X is bromine, chlorine or fluorine;

R1lower cycloalkenyl radical;

R2and R7hydrogen;

R3, R5and R6the same or different, hydrogen or a lower alkyl radical;

R4hydroxyl, amine, aminoalkyl, alkylamino, dialkylamino, acylaminoalkyl radical;

R8hydrogen

possessing antimicrobial activity,

or their tautomers General formula II

< / BR>
where A, R1R8have the specified values.

2. Pharmaceutical composition based derivatives isothiazol-pyridone of azetidine that have antimicrobial action, containing the active principle and a pharmaceutically acceptable carrier, while it contains as active principle derived the General formula I in a quantity of 50 to 100 mg per unit dose.

 

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19 cl, 39 ex

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