HU219347B - 10,11,12,13-tetrahydro-desmycosin derivatives and pharmaceutical compositions containing 4'-deoxy-10,11,12,13-tetrahydro-desmycosin - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention relates to 10,11,12,13-tetrahydrodemicosin derivatives of formula (I) and their salts with pharmaceutically acceptable inorganic or organic acids. In formula (1), R is oxygen or two ethoxy groups, R1 is tetramethylsilyl or hydrogen, and R2 is hydrogen or iodo, or hydroxy or methylsulphonyloxy, with the proviso that when R is O and R 1 is H, then R 2 is other than hydroxy. Among the compounds of formula (1), 4'-deoxy-10,11,12,13-tetrahydro-demicosin has antibiotic activity, the other intermediates. ŕ

Description

The present invention relates to 10,11,12,13-tetrahydro-demicosine derivatives of the general formula (I), and in particular to the pharmacologically active 4'-deoxy-10,11,12,13-tetrahydrodemicosine and pharmaceutical compositions containing this compound. More particularly, the invention relates to 10,11,12,13-tetrahydro-demicosine derivatives of formula (I), and in particular to the novel 4'-deoxy-10,11,12,13-tetrahydro-demicosine of formula (I) and pharmaceutically acceptable acid addition salts thereof. salts thereof and pharmaceutical compositions containing such compounds.

Demicosin is a 16-membered macrolide antibiotic prepared by hydrolysis of mycose at the C-4'-position of the parent antibiotic tylosin (Hamill, R.L., 1961, Antibiotics and Chemotherapy, 11,328).

10,11,12,13-Tetrahydrodemicosine can be prepared by the catalytic hydrogenation of demicosin as described in German Patent Specification 272 304 or European Patent Application 201 089 corresponding to European Patent Application Publication Number 287 082.

It is also known that 4'-deoxy demicosin can be prepared in a series of reactions in which reactive groups which are not involved in the reaction are pre-selectively deprotected and then deprotected after the desired target reaction is carried out.

For example, J. Antibiot. 34, 1381 (1981), Tanaka, A., et al., Describe a process for the preparation of 4'-deoxy demicosin by acetylation of demicosin at C-2 'and C-4' positions followed by C-3- tetrahydrofurazinization at positions 4 and 4, followed by methanolysis of the acetyl groups at positions C-2 'and 4', selective sulfonylation at the C-4 'position and subsequent replacement of the iodine atom with tin. it is cleaved using tributyl hydride and finally the tetrahydrofuranyl and acetyl protecting groups are removed by hydrolysis. 40

US 4,421,911 discloses a method for the preparation of 4'-deoxy-demicosin by selectively acetylating tylosin at the C-2 'position, hydrolyzing mycarose, acetylating the resulting demicosin at the C-4' position, They are sulfonated at the C-4 'position, the sulfonyl group is replaced with iodine, the C-4' position is deacetylated, the iodine atom is removed with tin tributyl hydride, and the C-2 'position is subjected to hydrolysis. 50

J. Antibiot., 42, 903 (1989), Imalai, A., et al., Describe a method for the preparation of 19-deformyl-4'-demicosin by deforming tylosin in the presence of Wilkinson's catalyst followed by C-3,2 '. - and the hydroxyl groups at the 4 ' -55 position are silylated, sulfonated at the C-4 'position, replaced with iodine by the sulfonyl group, reduced with iodine tributyl hydride and subjected to hydrolysis. 60

Thus, according to the state of the art, the 4'-deoxy-10,11,12,13-tetrahydro-demicosine of formula (I), the acid addition salts of this compound with inorganic or organic acids, and the (la) - (le) ) are novel compounds, i.e., have not been described in the prior art.

Accordingly, the present invention relates to novel 10,11,12,13-tetrahydrodemicosine derivatives of the general formula (I) and, in particular, to the novel 4'-deoxy-10,11,12,13-tetrahydro-demicosine of the formula I and its pharmaceutically and salts thereof with acceptable organic or inorganic acids. In the general formula (1)

R is oxygen or two ethoxy groups,

R ¹ is trimethylsilyl or hydrogen; and

R ² is hydrogen, iodine, or hydroxy or methylsulfonyloxy, provided that when R is oxygen and R ¹ is hydrogen, then R ² is other than hydroxy.

Intermediates represented by the general formula (1) include the following compounds:

(Ia) R = (OC ₂ H ₅ ) ₂ , R 1 = H, R ² = OH (1b) R = (OC ₂ H ₅ ) ₂ , R 1 = Si (CH ₃ ) ₃ , R ² = O H (1c) R = (OC ₂ H ₅ ) ₂ , R 1 = Si (CH ₃ ) ₃ , (ld) R = (OC ₂ H ₅ ) ₂ , R 1 = Si (CH ₃ ) ₃ (le) R == O, R 1 = H;

R ² = OSO ₂ CH ₃

R ² = I

R ² = I

In the preparation of the compounds of the invention, 10,11,12,13-tetrahydrodemicosine of the formula is acetalized in ethanol with an equimolar amount of p-toluenesulfonic acid. The end of the reaction was determined by thin layer chromatography (TLC, B) as eluent. After completion of the reaction, the reaction mixture is partially neutralized with triethylamine. The reaction mixture was then concentrated to a quarter of its original volume and saturated aqueous sodium bicarbonate was added. After extraction with chloroform from the extract

10,11,12,13-Tetrahydro-demicosin diethyl acetal can be isolated, i.e. the compound of formula (Ia) wherein R is two ethoxy groups, R ¹ is hydrogen and R ² is hydroxy. Compound (Ia) is then subjected to selective silylation at positions C-3,2 'and 4' using 6-8 molar equivalents of trimethylchlorosilane in the presence of a tertiary organic amine such as pyridine, triethylamine or dimethylaniline. in a solvent such as dichloromethane, dichloroethane or chloroform at 0-5 ° C. The completion of the reaction was monitored by thin layer chromatography using a solvent mixture (A) as described below. A mixture of water and ice was added to the reaction mixture, followed by extraction with chloroform at pH 8-9. Thus, the 3,2 ', 4' -tri (O-trimethylsilyl) -10,11,12,13-tetrahydro-demicosin diethyl acetal can be isolated, i.e. the compound of formula (Ib) wherein R is

GB 219,347 Β ethoxy group, ^R1 represents a trimethylsilyl group, and R ² is hydroxy. The crude product (Ib) is then dissolved in pyridine and sulfonated at the C-4 'position using 5-7 molar equivalents of methanesulfonyl chloride at -5 to + 15 ° C. The completion of the reaction is also monitored by thin layer chromatography using a solvent mixture of formula A as described below. A mixture of water and ice was added to the reaction mixture, and the pH was adjusted to between 9 and 9.5. At this time, 4 '- (methanesulfonyl) -3,2', 4 '-tri (O-trimethylsilyl) -10,11,12,13-tetrahydro-demicosin-diethyl-acetal, i.e. the compound represented by the formula (Ic), is precipitated. two ethoxy group, ^R1 represents a trimethylsilyl group, and R ² is a methyl-sulfonyloxy group. The wet precipitate was dissolved in chloroform and a saturated sodium chloride solution was added to the resulting solution. After drying the extract and evaporating the solvent under reduced pressure, the product (Ic) thus obtained is immediately converted to the corresponding 4'-iodine derivative by dissolving it in an anhydrous inert solvent, followed by 4-6 molar equivalents of an alkali metal iodide. We are added. The resulting reaction mixture is stirred at elevated temperature, up to the boiling point of the reaction mixture, until the starting material, as determined by TLC, is eluted using the solvent mixture C as described below. For example, dimethoxyethane or methyl ethyl ketone may be used as the inert solvent, while potassium iodide, sodium iodide or lithium iodide may be used as the alkali metal iodide. The reaction mixture was concentrated and, after addition of water and ice, extracted with chloroform at pH 9-9.5. The combined extracts were worked up by treating with 10% w / w aqueous sodium thiosulfate and then evaporating under reduced pressure. This gives 4'-deoxy-4'-iodo-3,2 ', 4' -tris (O-trimethylsilyl) -10,11,12,13-tetrahydro-demicosin-diethyl-acetal, i.e. the compound (Id), wherein two R is ethoxy, R ¹ is a trimethylsilyl group and R ² is iodo. Hydrolysis of the protecting group of the 4'-iodine derivative (Id) is carried out in a mixture of 50% acetonitrile and 0.2N hydrochloric acid. The hydrolysis proceeds at room temperature. The end of the reaction was determined by thin layer chromatography, using solvent mixtures A and B as described below, as eluent. The pH is then adjusted to 9 to 9.5 and then extracted to give 4'-deoxy-4'-iodo-10,11,12,13-tetrahydro-demicosine, a compound of the formula (Ic) wherein R R ¹ is hydrogen and R ² is iodo. The crude product thus obtained is then purified by column chromatography on silica gel using a solvent mixture of formula A or C as described below. When using the solvent mixture of the _Rf 0.85 Fractions were collected and concentrated under reduced pressure. The resulting yellow amorphous product was dissolved in anhydrous ethanol and the resulting solution was removed in the presence of a catalytic amount of 5 to 10 weight percent palladium on carbon (0.1 to 2.0 weight percent) in the presence of a catalytic amount of 0.1 to 0.2 MPa. with hydrogen gas at room temperature for 2 to 8 hours. The reduction time was determined by thin layer chromatography using a solvent mixture of formula A or C as described below as the eluent. After removal of the catalyst by filtration, the filtrate is treated with twice the volume of water and extracted at pH 8-9. The extract was washed with brine and then concentrated under reduced pressure. This gives 4'-deoxy-10,11,12,13-tetrahydro-demicosine as a white crystalline product, i.e. the target compound of formula (I).

The acid addition salts of 4'-deoxy-10,11,12,13-tetrahydro-demicosine can be prepared by treating 4'-deoxy-10,11,12,13-tetrahydro-demicosine with at least 1 molar equivalent of an inorganic or organic acid, such as hydrogen, in an inert solvent. chloride, sulfuric acid, phosphoric acid, acetic acid, propionic acid, citric acid or tartaric acid. Separation of the salt formed can be achieved by precipitating with a suitable solvent (in which the salt is insoluble) or, more often, by lyophilization. 4'-Deoxy-10,11,12,13-tetrahydro-demicosine and its acid addition salts have valuable antibacterial activity. The results of our in vitro studies are shown in Figures I and II. Tables 1 to 4, comparing with the parent antibiotic tylosin and its 10,11,12,13-tetrahydro derivatives.

The results show that 4'-deoxy-10,11,12,13-tetrahydro-demicosin can be used as an antibiotic in the treatment of various infectious diseases in the form of conventional pharmaceutical preparations.

Table I

In vitro antibacterial activity on Sarcina lutea strain ATCC 9341

Test compound U / mg tylosin 883 10,11,12,13-tetrahydro-tylosine 1138 10,11,12,13-Tetrahidrodemikozin 1118 4 '-Deoxy-10,11,12,13-tetrahydro- desmycosin 1358

For the preparation of the novel 10,11,12,13-tetrahydrodemicosine derivatives of the present invention, the following solvent mixtures were used for silica gel thin-layer chromatography:

The solvent mixture is 90: 9: 1.5 by volume = methylene chloride, methanol and concentrated ammonium hydroxide;

Solvent mixture B = 85: 10: 5 by volume ethyl acetate: methanol: concentrated ammonium hydroxide;

Solvent mixture C = benzene: acetone = 4: 1 (v / v).

HU 219 347 Β

II. spreadsheet

Minimum inhibition concentration (MIC value), mcg / mL Micro-organism I II Sarcina lutea ATCC 9341 0.39 0.39 Mycroc. pyogenic. Castle. St. aureaus ATCC 6538 0.78 0.09 Strep. b. hem. THE 0.05 0.05 Strep. b. hem. B 3.12 3.12 Strep. pyogenic. animal is 0.19 0.05 Pasteurella hem. L-314 12.50 6.25 Pasteurella multocida L-315 12.50 3.12 MicroCal. flavus ATCC 10240 0.78 0.05

I = 10,11,12,13-tetrahidrodemikozin

II = 4'-deoxy-1,11,12,13-tetrahydro-demicosine

The following examples are intended to illustrate the invention.

Example 1

10,11,12,13-Tetrahydro-demicosine diethyl acetal (Ia)

Dissolve 10,11,12,13-tetrahydro-demicosin (50 g, 64.4 mmol) in anhydrous ethanol (500 mL) and add p-toluenesulfonic acid monohydrate (12.5 g, 65 mmol). The reaction mixture was stirred at room temperature for 2 hours and then triethylamine (6 ml) was added. Subsequently, the volume of the reaction mixture was reduced to 1/4 by evaporation of the ethanol under reduced pressure. Saturated sodium bicarbonate solution (700 ml) was added to the residue, followed by extraction with chloroform (2 x 100 ml).

The combined extracts were dried over potassium carbonate and evaporated under reduced pressure. This gave 50.9 g (93%) of the title compound as a dry residue, having R _r of 0.30 when using solvent mixture A and 0.50 when using solvent mixture B.

IR (Kbr) cm -1: 3480, 2970, 1720, 1460,

1380, 1265, 1170, 1085, 1060, 1010, 960.

1 H-NMR (CDCl 3) ppm: 3.61 (3H, 3 'OCH _{3 -} ), 3.56 (2H, 20-OCH ₂ -), 3.50 (3H, 2' OCH ₃ ), 3.45 (2H , 20OCH ₂ -), 2.49 [6H, N _{(CH3) 2]} • 3C-NMR (CDCl₃) ppm 215.07 (C-9), 172.52 (Cl),

105.31 (C-1 '), 102.31 (C-20), 100.62 (Cl'), 61.80 (20-OCH ₂ -), 61.63 (3 'OCH ₃ ), 60.62 ( 20-O-CH ₂ -),

59.31 (2 ”OCH ₃ ).

Example 2

3,2 ', 4 Tri (O-trimethylsilyl) -10,11,12,13-tetrahydrodemicosine diethyl acetal (1b)

In a mixture of 200 ml of anhydrous methylene chloride and 7.8 ml (96.6 mmol) of anhydrous pyridine was dissolved 10 g (11.7 mmol) of 10,11,12,13-tetrahydro-demicosin diethylacetal and then The resulting solution was cooled to 0 ° C and then trimethyl chlorosilane (11 mL, 84 mmol) was added dropwise. The reaction mixture was stirred at 5 ° C for 2 hours and then poured into 400 ml of ice-water. The pH of the resulting aqueous mixture was adjusted to 9 by the addition of concentrated ammonium hydroxide solution and extracted twice with 100 ml of chloroform. The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous potassium carbonate and concentrated under reduced pressure. to yield the title compound (96%) 12.0 g, a value for _Rf of 0.75 in the solvent system.

IR (Kbr) cm -1: 2970, 1730, 1460, 1380,

1265, 1255, 1170, 1100, 1085, 1060, 1010, 970, 885, 842, 755.

1 H-NMR (CDCl ₃ ) ppm: 3.59 (5H, 3 "OCH ₃ , 20OCH ₂ -), 3.51 (5H, 2" OCH ₃ , 20-OCH ₂ -), 2.52 [6H, N (CH ₃ ) ₇ ] 0.17 [27H, 3x x Si (CH ₃ ) ₃ ],

Example 3 '- (Methanesulfonyl) -3,2', 4-tri (O-trimethylsilyl) 10,11,12,13-tetrahydrodemicosine diethyl acetal (Ic)

12 g (11.25 mmol) of intermediate (1b) are dissolved in 100 ml of pyridine and 5.2 ml (67 mmol) of methanesulfonyl chloride are added to the resulting solution after cooling to 10 ° C. While cooling, the resulting reaction mixture was stirred for four hours and then poured into 1500 ml of ice water. The resulting aqueous mixture was adjusted to pH 9 with concentrated ammonium hydroxide solution. After 30 minutes, the precipitate was collected by filtration and immediately dissolved in 100 ml of chloroform. The resulting solution was washed thoroughly with a saturated sodium chloride solution, dried over magnesium sulfate and evaporated. To afford the title compound in an amount of 12.1 g (94%) of a dry residue, of which _Rf value of 0.90 for category A solvent.

IR (Kbr) cm -1: 2970, 1730, 1460, 1380,

1360,1265,1255,1170,

1100,1085,1060,965, 885, 842.755.

1 H-NMR (CDCl ₃ ) ppm: 3.59 (5H, 3 "OCH ₃ , 20OCH ₂ -), 3.51 (5H, 2" OCH ₃ , 20-OCH ₂ -), 3.15 (3H, SO ₂ -CH ₃ ), 2.54 and 2.49 [6H, N (CH ₃ ) ₂ ], 0.16 [27H, 3xSi (CH ₃ ) j],

Example 4 '-Deoxy-4' -iodo-3,2 ', 4' -tris (O-trimethylsilyl) 10,11,12,13-tetrahydrodemicosine diethyl acetal (Id)

12 g (10.5 mmol) of Ic are dissolved in 120 ml of methyl ethyl ketone and 7.8 g (52 mmol) of sodium iodide are added. The resulting reaction mixture was heated under gentle reflux for 2 hours and then concentrated to one tenth of its volume by evaporation of the solvent under reduced pressure. Chloroform (100 mL) and water (200 mL) were added to the resulting residue

Adjust the pH of the resulting mixture to 9 with base. The phases are separated and the organic phase is washed twice with 100 ml of 10% sodium thiosulfate solution each time. Concentration under reduced pressure gave 11.22 g (90.9%) of the title compound as a yellow compound having an Rf of 0.95 when using solvent mixture A and 0.85 when using solvent mixture C.

IR (Kbr) cm -1: 2970, 1725, 1460, 1380,

1265,1255,1170,1100,

1085,1060,965,885, 842, 755.

1 H-NMR (CDCl 3) ppm: 3.59 (5H, 3 'OCH ₃ , 20OCH ₂ -), 3.50 (5H, 2' OCH ₃ , 20-OCH ₂ -), 2.54 and 2.49 [ 6H, N (CH ₃ ) ₂ ]

0.16 [27H, 3xSi (CH ₃ ) ₃ ].

Example 5

4'-Deoxy-4'-iodo-10,11,12,13-tetrahydro-demicosin (le) In a mixture of 110 ml of acetonitrile and 110 ml of 0.2 N hydrochloric acid was dissolved 11 g (9.3 mmol) of (Id), and the resulting solution was stirred at room temperature for 2 hours. The pH of the reaction mixture is then adjusted to 9 by addition of solid sodium bicarbonate. The mixture was extracted twice with chloroform (60-60 ml), and the combined extracts were washed with saturated sodium bicarbonate solution and concentrated under reduced pressure to give 7.3 g (88.6%) of crude product which was dissolved in a small amount of methylene chloride. The resulting solution is a trademark of Silk Gel 60, a US company Merck,

The column was subjected to chromatography on a column of 70-230 mesh silica gel eluting with the solvent mixture A. The fractions were then evaporated to a TLC of 0.85 using TLC. 3.44 g (55%) of the title compound are chromatographically pure with an Rf of 0.30 when using solvent mixture C.

IR (Kbr) cm -1: 3480, 2970, 1720, 1460,

1380,1260,1170,1085,

1060.960.

1 H-NMR (CDCl ₃ ) ppm: 9.67 (1H, 20-CHO),

3.61 (3H, 3 "OCH ₃ ),

2.49 (3H, 2 'OCH ₃ ), 2.58 and 2.56 [6H, N (CH ₃ ) ₂ ], ³ C-NMR (CDCl ₃ ) ppm: 214.68 (C-9),

202.60 (C-20),

172.35 (Cl), 61.63 (3 "OCH ₃ ), 59.43 (2" OCH ₃ ), 30.70 (C-4 ').

Example 6 '-Deoxy-10,11,12,13-tetrahydrodemicosine (If)

Procedure A: Compound (le) (1 g, 1.1 mmol) was dissolved in anhydrous ethanol and 0.2 g of a palladium-on-carbon catalyst was added. The reaction mixture was hydrogenated at 0.2 mPas for 2 hours. The catalyst was filtered off and the ethanol was removed from the filtrate under reduced pressure. To the resulting oily product was added water (100 mL) and the aqueous mixture was extracted with chloroform at pH 8.5. The extract was dried over anhydrous potassium carbonate and then concentrated under reduced pressure. 0.73 g (85.9%) of the title compound is obtained in the form of a white crystalline material having an Rf of 0.35 when using solvent mixture A and an M ⁺ of mass spectrum activity of 759. IR (Kbr) cm -1: 3480, 2970, 1720, 1460,

1380,1260,1170,1085,

1060.960.

1 H-NMR (CDCl ₃ ) ppm: 9.67 (1H, 20-CHO), 3.62 (3H, 3 'OCH ₃ ), 3.50 (3H, 2' OCH ₃ ), 2.26 [6H .

N (CH ₃ ) ₂ ] 1.25 (1H, 4 '),

1.18 (1H, 4 ').

³ C-NMR (CDCl ₃ ) ppm: 214.79 (C-9),

202.99 (C-20),

172.47 (Cl), 61.74 (3 "OCH ₃ ), 59.43 (2" OCH ₃ ), 28.27 (C-4 ').

Procedure B Compound (le) (1 g, 1.1 mmol) was dissolved in anhydrous ethanol and 0.1 g of 5% palladium-on-carbon was added. The resulting reaction mixture was then hydrogenated at 0.1 MPa at room temperature for 8 hours. After the hydrogenation is complete, the catalyst is isolated by filtration and the product is isolated as described in Process A above. Thus, a product is obtained which has the same characteristics as those obtained in Process A above.

Claims (8)

PATENT CLAIMS 10,11,12,13-Tetrahydrodemicosine derivatives of the formula (I) and their pharmaceutically acceptable inorganic or organic acid salts, wherein R is oxygen or two ethoxy groups, R * is independently trimethylsilyl or hydrogen; and R ² is hydrogen or iodine, or hydroxy or methylsulfonyloxy, provided that when R is oxygen and all three R * are hydrogen, then R ² is other than hydroxy. 2. The compound of formula 1 according to claim 1, which is 10,11,12,13-tetrahydrodemicosin diethyl acetal. The compound of formula (1) according to claim 1 which is 3,2 ', 4' -tris (O-trimethylsilyl) 10,11,12,13-tetrahydrodemicosine diethyl acetal. 4. The compound of formula (1) according to claim 1 which is 4 '- (methanesulfonyl) -3,2', 4 '-tri (O5). HU 219 347 Β Trimethylsilyl-10,11,12,13-tetrahydrodemicosin diethyl acetal. 5. The compound of formula (I) according to claim 1 which is 4'-deoxy-4'-iodo-3,2 ', 4' -tris (o-trimethylsilyl) -10,11,12,13-tetrahydrodemicosine. di-ethylacetal. 6. The compound of formula (I) according to claim 1, which is 4'-deoxy-4'-iodo-10,11,12,13-tetrahydrodemicosine. 7. The compound of formula (1) according to claim 1 which is 4'-deoxy-10,11,12,13-tetrahydrodemicosine. 8. A pharmaceutical composition having an antibacterial activity comprising 4'-deoxy-10,11,12,13-tetrahydro-demicosine or a pharmaceutically acceptable salt thereof with an pharmaceutically acceptable carrier and / or excipient as active ingredient.