New polycyclic derivatives phthalazine and their application

 

(57) Abstract:

The invention relates to novel polycyclic phthalazine, in particular disubstituted moderatelysized (10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphthalen-[1,2-g] -phthalazine formula I, in which R1represents a residue of the formula -(CR4R5)n-SDA or-Ph(R6)(SDA), where R4and R5denote N, n denotes the number of 1-4, R6represents N and Y represents OR7where R7represents H or (C1-C10)alkyl, or alkali metal ion or ammonium ion; R2and R3denote hydrogen, and salts, esters and Amida compounds of formula I. Proposed according to the invention compounds are effective against strains of gram-positive bacteria, especially against multi-drug resistant staphylococci (MRSA), and also against resistant to glycopeptides, such as vancomycin, enterococci and can therefore be used to manufacture possessing antibacterial effect of drugs. Also proposed drug with antibacterial effect, containing a compound of formula I together with physiologically acceptable auxiliary substances is lickilicky derived phthalazine, in particular 2-carboxyethyl - and 2-carboxyethylgermanium moderatelysized (10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphthalen- [1,2-g]-phthalazine), and their salts, esters and Amida. These compounds are having a strong antibacterial activity, especially against gram-positive, particularly against multi-drug resistant staphylococci (MRSA) and resistant enterococci, a substance that can be used to combat infectious diseases in humans and animals. These compounds are suitable for preparing various pharmaceutical compositions and their uses.

These compounds are the first representatives of an unknown up to the present time cyclic system, namely naphthacene-[1,2-g] - phthalazine. They are derived maturerealasslatinas, respectively madurakavi acid (lactone) can be derived from Actinomadura rubra using biotechnological methods (W. Fleck, D. G. Strauss, J. Meyer, Zeitschrift Allgem. Mikrobiol. 18, p. 368-398 (1978) Structure of maturerealasslatinas (formula II) opened Paulus and his colleagues (E. F. Paulus, K. Dornberger, W. Werner, D. Fenske, Acta Cryst. (1994) C50, 2064-2067). By itself, maturegalaxies has only insufficient neposlednee time gained fame primarily benyamini and primitine as antifungal substance, causing intense interest (cf. T. Oki in "Recent Progress in Antifungal Chemotherapy", Ed. by N. Jamaguchi, G. S. Kobayachi, H. Takahashi, Marcel Dekker, Inc., New York, Basel, Hong Kong, 1992, page 38).

The basis of the invention was based on the task to get disubstituted, in particular 2-carboxyethyl - and 2-carboxyethylidene maturefilipina (10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphthalen- [1,2-g] -phthalazine) and their corresponding salts, esters and amides, and to offer their application. The purpose of creating new connections is expanding the range of actions have antibacterial efficacy, particularly against gram-negative bacteria, especially against multi-drug resistant staphylococci. To solve this problem, the new compounds are particularly suitable because favorably with the currently known antibiotics and anti-infective funds lack inherent to the last of these significant shortcomings, such as lack of effectiveness against resistant strains of bacteria (W. Witte, S. Braulke, D. Heuck, C. Cuny. "Analysis of nosocomial outbreaks with multiply and methicillin resistent staphylococcus aureus (MRSA) in Germany: implications for hospital hygiene", Infection 22, (1994), Annex 2, 128-134; G. M. Eliopulos. "Increasing problems in therapy of enterococcal infection", which authorized new polycyclic phthalazine formula I

< / BR>
in which R1denotes carboxyethyl or carboxyethyl, and R2and R3independently of one another denote hydrogen or acyl, and salts, esters and Amida compounds of formula I, provided that R1has a value other than optionally substituted carboxyphenyl, if R3represents C1-C8alkanoyl.

In the context of the present description, the term alkyl (including when it is part of other groups, such as in alkoxy or carboxyamide) denotes1-C10alkyl, unbranched or branched, preferably1-C4alkyl, and under the term aryl residue (as well as under any of the following aryl residues or including in this term the group, as, for example, in aralkyl) refers to a substituted or unsubstituted aryl, primarily corresponding phenyl, substituents which may be IT, O-alkyl, O-aryl, halogen, alkyl, aryl. Acyl in the context of the present invention represents the first1-C8alkanoyl,1-C8alkoxycarbonyl, aroyl, first of all, benzoyl or substituted benzoyl (where the substituents are identical to those in the substituted aryl), and optional saadati R1are, for example, residues of formula -(CR4R5)n-COY or

< / BR>
where R4and R5can represent H, alkyl, aryl or substituted aryl, n denotes the number of 1-4, R6denotes H, alkyl, HE alkoxy in the o-, m - and p-position, COY in the o-, m - and p-position, a Y may represent OR7where R denotes H, alkyl, aryl or substituted aryl, an ion of an alkali metal such as Na+or+or ammonium ion (NaH4+accordingly ion mono-, di - or trialkylamine or N - methyl-D-glutaminovuyu salt), or Y may represent NR8R9where R8and/or R9denote H, alkyl, aryl or substituted aryl or aralkyl. In the case of asymmetric C-atoms corresponding D - and L-forms, enantiomers and diastereoisomers, as well as the racemate, respectively, mixtures of enantiomers and diastereomers are also the object of the invention.

In a particularly preferred compounds of the formula I R1represents a carboxy-C1-C4alkyl or C1-C4alkoxycarbonyl-C1-C4alkyl or carboxyphenyl,

and R2and R3represent hydrogen, where the carboxyl group in free Compounds according to the invention receive, for example, due to the fact that maturegalaxies, respectively Muranovo acid (3,9,11,14,15-pentahydroxy-10-methyl-7-methoxy-1,8,13-trioxo-1,3,5,6,8,13-hexahydropyrazino[1,2-f]benzothieno) formulas II

< / BR>
subjected to interaction with hydrazinonicotinamide acids or hydrazinonicotinamide acids, respectively, with esters and inorganic salts of these acids, optionally in the form of their salts. The reaction is carried out using suitable for such purposes solvents, such as glacial acetic acid. The reaction temperature is usually equal to the boiling temperature of the solvent, and the duration of the reaction may take up to several hours.

Obtained according to the invention the compounds of formula I may be transferred by known techniques into other compounds of formula I. Thus, in particular, the compounds of the formula I with Y denoting O-alkyl, by alkaline saponification, for example, using 2M sodium hydroxide and subsequent acidification, for example, 2M hydrochloric acid can be converted into the corresponding acid (formula I, where Y refers to IT). On the other hand, the compounds of formula I, where R2accordingly, R3denote H, due to allievate phenolic Oh is, R3denote H, respectively, acyl (for example, -CO-alkyl, -COO-alkyl)] . This operation is carried out according to conventional methods of acylation of phenolic Oh-groups, for example using an acid anhydride (for example, acetanhydride, respectively, anhydride propionic acid) or by using the ether Harborview acid (for example, methyl ether of Harborview acid) in an alkaline solution, for example in 2M caustic soda or tetrahydrofuran/triethylamine. The reaction temperature may be in the range from -20 to +20oC.

The resulting compound with Y denoting IT can be converted by conventional methods into the corresponding salts, where Y denotes OR7and R7can be an alkali metal ion (such as Na, K) or ammonium ion (NH4, ion mono-, di - or trialkylamine, for example ion triethylamine or ion N-methyl-D-glucamine. Purification of the synthesized compounds can be made by conventional methods (for example, by recrystallization or by column chromatography).

Obtained according to the invention, the compounds inhibit the growth of bacteria, especially gram-negative bacteria, in particular multi-drug resistant staphylococci, the effective activity against resistant chinolone Staphylococcus, and against multi-drug resistant TB, including those resistant to glycopeptides, such as vancomycin-resistant, hospital strains (MRSA).

When tested by the method of microdesmidae in broth according to DIN 58940 (part 8) compounds were investigated for their minimum inhibitory concentration (MIC) against the following bacterial strains:

Staphylococcus aureus strains 8325-4 (susceptible strain of Staphylococcus aureus, which is the typical representative of its genus), NCTC 6571 (receptive international reference strain), 108/83 ("old" MRSA without resistance chinolone), 134/94 ("new" MRSA with resistance to chinolone), Staph. epidermidis CCM 2124 (susceptible control strain) Enteroococcus faecium 70/90 (strain resistant to vancomycin) and 64/3 (susceptible strain). For comparison purposes, in parallel experiments explored, though different in their structure, the following substances: vancomycin, teicoplanin and ciprofloxacin.

The results of the antibacterial testing are presented in the table. As shown by these results, obtained according to the invention substance in its effectiveness against some strains of bacteria significantly higher than those of comparative inhibition substances and capable espessially properties suitable for use as medicines to treat bacterial infections, first of all the infections caused by multidrug resistant staphylococci. Diseases of this type are the compounds of formula 1 can be used either as such or with physiologically acceptable excipients or carriers, and possible in principle all conventional pharmacological uses and physiologically acceptable dosage. Prescribed drugs, for example, for oral or parenteral administration, such as intravenous.

Used in the following examples, the abbreviations have the following meanings:

TLC - thin layer chromatography,

THF is tetrahydrofuran,

GHUR - liquid chromatography high-resolution,

min - min,

tPLthe melting point

MS - mass spectrometry,

NMR - nuclear magnetic resonance.

Example 1.

Substance 1.

2-(4-Carboxyphenyl)moderately (2-(4-carboxyphenyl-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo - 1,2,6,7,9,14-hexahydronaphthalen-[1,2-g] -phthalazine), formula I, where R denotes 4-carboxyphenyl, R2, R3denote H, C33H22N2ABOUT10(606,54)

A mixture of 100 mg (0.2 mmole) of maturerealasslatinas (80%) and 50 of the refrigerator. The obtained red crystals were washed simple ether. The substance was purified twice by preparative TLC (ready plates Si 60, 1 mm Merck, eluent CH2Cl2/CH3OH 9: 1), was dissolved in THF, filtered and precipitated with petroleum ether. Yield 78 mg (63% of theory), tPL>350oWith that purity according GHUR (Eurospher, acetonitrile/ water 3: 2) to 94.7%. t = 9,4 min, TLC (aluminium foil Si 60 Merck), eluent CH2Cl2/CH3HE 9:1), Rf=0,77, FAB-MC (3NBA) [M+H]+: m/z = found 607,1.

1H-NMR (DMSO-D6): d (ppm million) = 14,1, 13,6 12,98, and 11.2 (4H, s, 10-, 12-, 15-, 16-IT), and 8.6 (1H, s, 4-CH), 7.3 and 7.5 (a 2x1H, s, 5-CH and 13-CH), 7,8 7,83, 8,08, 8,12 (4H, 2-phenylene), 3,85 (3H, s, 8-OCH), 2,1 (3H, s, 11 CH3).

Example 2.

Substance 2.

2-Ethoxycarbonylmethylene (10,12,15,16-tetrahydroxy-8-methoxy-2-ethoxycarbonylmethyl-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphthalen-[1,2-g] -phthalazine), formula I, where R1denotes CH2COOC2H5, R2, R3denote WITH30H24N2ABOUT10(572,53).

A mixture of 1 g madurakavi acid (97%) (2 mmole) and 400 mg of the hydrochloride of ethyl ether hydrazinolysis acid (2.5 mmole) was boiled in 20 ml of glacial acetic acid at peremeshivaniem acid and then recrystallized from glacial acetic acid. In this way received light red crystals with tPL324-325oC (decomposition), the output of 622 mg (54% of theory), purity according GHUR (Nucleosil RP 18, acetonitrile/water 3:2) 98,14%, t=10,45 min, TLC (aluminium foil Si 60 Merck): butyl acetate/glacial acetic acid 4:1, Rf= 0,87.

FAB-MC (3NBA) [M+H]+: m/z = found 573,1.

1H-NMR (DMSO-D6) d (part./million): 14,07, 13,56, 12,77, 11,18 (4xH, s, 10-, 12-, 15 - and 16-HE), and 8.50 (1H, s, 4-CH), 7,40 and 7,28 (2H, s, 5-CH and 13-CH), equal to 4.97 (2H, s, NCH2), 4,15-of 4.25 (2H, q, CH2ethyl), 3,81 (3H, s, 8-och3), of 2.08 (3H, s, 10-CH3), 1,20 were 1,268 (3H, t, CH3ethyl).

Example 3.

Substance 3.

2-Carboximetilkrahmala (10,12,15,16-tetrahydroxy-8-methoxy-2-carboxymethyl-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydropyrazino[1,2-g]-phthalazine), formula I, where R1denotes CH2COOH, R2, R3denote H, C28H20N2ABOUT10(544,47).

570 mg (1 mmol) 2-arbetarskyddsstyrelsen (substance 2) maintained in 35 ml of 2M sodium hydroxide in one day. Then was acidified using 2M hydrochloric acid. The obtained red crystals were purified by recrystallization or by boiling in glacial acetic acid, respectively, by dissolving in tetrahydrofuran and eadsne GHUR (Nucleosil RP 18, acetonitrile/water 3:2) and 99.8%, t = 0,87 min, TLC (aluminium foil Si 60 Merck): butyl acetate/ glacial acetic acid 4:1, Rf= 0,31.

FAB-MC (3NBA) [M+H]+: m/z = found 545,0.

1H-NMR (CDCl3) d (part./million): 14,0, 13,5, 12,8, 11,2 (4H, s, 10-, 12-, 15 - and 16-HE), 8,42 (1H, s, 4-CH), a 7.2 and 7.3 (2H, s, 5-CH and 13-CH), a 3.9 (3H, s, 7-och3), of 2.9 and 2.5 (2x2H, s, 6 - and 7-CH2), and 2.1 (3H, s, 10-CH3).

13C-NMR (l3) 28 C-atoms d (part./million): 187,66 and 185,54 (quinone group), 169,0 (2-COOH), 61,04 (och3), 52,30 (NCH2), 29,21 and 22,21 (6 - and 7-CH2). 8,17 (11-CH3).

13C-NMR, DEPT 135: d (part./million): 139,44 (CH=N) 114,19, 106,06 (2xArH), 60,79 (8-och3), 52,04 (NCH2), 29,05, 21,96 (2xCH2), 7,92 (11-CH3).

Of the substance 3 by adding an amine, such as triethylamine or N-methyl-D-glucamine, in an appropriate solvent, such as tetrahydrofuran, can be obtained a water-soluble salt of trialkylamine, for example salt triethylamine or salt of N-methyl-D-glucamine.

Example 4.

Substance 4.

2-(D, L-a-carboxypropyl)moderately (10,12,15,16-tetrahydroxy-8-methoxy-2-(D, L-a-carboxypropyl)-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-hexahydronaphthalen-[1,2-g] -phthalazine), formula 1, where R1denotes the D,L-a-carboxypropylbetaine and 0.52 g (4.4 mmole) of D, L-a-hydrazinolysis acid was boiled in 50 ml of glacial acetic acid for 2 hours under reflux. The obtained dark red crystals after standing overnight was filtered using a vacuum filter, washed with simple ether and recrystallized from glacial acetic acid. Yield: 1.8 g (76% of theory), tPL225-230oC (decomposition), purity according GHUR (RP 18 Eurospher 100 C7, acetonitrile/water 3:2 + 0,05% triperoxonane acid) 99,6%, t = a 13.3 min, TLC (aluminium foil Si 60 Merck): butyl acetate/glacial acetic acid 4:1, Rf= 0,79.

FAB-MC (3NBA) [M+H]+: m/z = found RUB 573.4.

1H-NMR (DMSO-D6) d (part./million): 14,1, 13,6, 12,9, 11,3 (4H, s, 10, 12, 15 and 16), and 8.5 (1H, s, 4-CH), 7.2 and 7.4 (2H, s, 5-CH and 13-CH), 5,3 (1H, d, NCH), a 3.9 (3H, s, 7-och3), and 2.0 (3H, s, 10-CH3), and 0.9 (3H, s, CH3Alif.).

13C-NMR (DMSO-D6) DEPT 135: d (part./million): 29,48, 22,43, 22,22 (HSN2).

1. Polycyclic derivatives phthalazine General formula I

< / BR>
in which R1represents a residue of the formula

(CR4R5)n-COY

or

< / BR>
where R4and R5denote H;

n denotes the number of 1-4;

R6denotes H;

Y denotes OR7where R7 and R3represent hydrogen;

and salts, esters and amides of compounds of formula I.

2. The compounds of formula I on p. 1, where R1represents a carboxy-C1-C4alkyl or C1-C4alkoxycarbonyl-C1-C4alkyl or carboxyphenyl, and R2and R3denote hydrogen, and a carboxyl group in free form or in salt form.

3. The compounds of formula I under item 1 in the form of salts.

4. The compounds of formula I on p. 1, where R7denotes ion trialkylamine or ion N-methyl-D-glucamine.

5. Connection on p. 1 representing 2-carboximetilkrahmala and its salts under item 1.

6. Drug, possess antibacterial action, containing the compound of the formula I according to any one of paragraphs.1-5 together with physiologically acceptable excipients or carriers.

 

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25 cl, 1 tbl, 11 ex

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EFFECT: higher efficiency of complex therapy.

2 ex

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