FI66386B - FRAMEWORK FOR THE REQUIREMENT OF THERAPEUTIC MEASURES OF MONEY DERIVATIVES - Google Patents

Abstract

Urethane derivatives of the formula <IMAGE> wherein R<1> is aryl, alkylaryl, haloaryl, nitroaryl, alkoxyaryl, aryloxyaryl acylaryl, alkyl, cycloalkyl, arylalkyl, haloarylalkyl or arylcycloalkyl and R<2> is methyl or ethyl, and their pharmaceutically acceptable salts. Moreover, the manufacture of the above urethane derivatives as well as compositions containing same. Also the use of these derivatives for the treatment or prophylaxis of diseases and to promote animal growth.

Description

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4βΓφ ^ ^ utlAggningsskmpt 66386 + ¾¾¾ C (45) v34 ^ ^ (51) / following».a.3 C 07 D 493/10 FINLAND — FINLAND (*> 793705 (M) Hilfrnl — Ml — Awatoil — 26.11.79 ( 23) AHnflM — Glklfkatadaf 26.11.79 (41) ΎιΛλ Htodal — Mvtt rf — rti 30.05.80 PMaitti · ja rekbfearlhallltH · ΜβΜΛύφ *** jt hMLMkata · j.u ____

Patent and regulatory proceedings ™ Amein oct «Urria» »> Jitiw <29.06.84 (31X33X31) fyy4« ty WO * ». leWprtrte 29.11.78 05-09-79, 20.09.79 USA (US) 964564, 72818 77415 (71) F. Hoffmann-La Roche 6 Co. Aktiengesel1schaft, Grenzacherstrasse 124-184, Basel, Switzerland-Switzerland (CH) (72) Chao-Min Liu, Cedar Grove, NJ, John Westley, Cedar Grove, NJ, USA (74) Oy Koister Ab (54) Method The present invention relates to a process for the preparation of therapeutically valuable monensin derivatives of the following formula: The present invention relates to a process for the preparation of therapeutically valuable monensin derivatives of the formula

Me Me

Mp '' O ^ * · θ / (t

1 k J H R2 H 0_ / I

RWO ^ ° H

OH

2 66386 wherein R is phenyl, 4-halophenyl, p-tolyl, 4-nitrophenyl, 4-phenoxyphenyl, n-butyl, cyclohexyl, phenethyl, 4-bromophenethyl or 2-phenylcyclopropyl, and R is methyl or ethyl, and for the preparation of their pharmaceutically acceptable salts.

The symbol Me used in formula I denotes a methyl group. The new monensin derivatives and their salts act as antibacterial agents; furthermore, they are coccidiostats and can also be used in the treatment of hypertension, malaria and porcine rubella.

New monensin derivatives are made by giving to monensin! A or B, i.e. a compound of formula y »^» fr tfr ^ Me 'Ό' / ^^ 0 '' · VsO,

Me ^ XOpH J ^ OH

HO--

? H

2 wherein R is methyl (monensin B) or ethyl (monensin A), or a salt thereof, to react with an isocyanate of formula

R 2 -NCO III

where R is as defined above.

Monensin A is described in J. Am. Chem. Soc. 189 (1967) 5737-9 and monensin B in Antimicrobial Agents and Chemotherapy-1967 (1968) 363-368.

Preferably a salt of the starting compound of formula II, in particular a sodium salt, is used. The isocyanate of formula III is preferably added in a small excess, e.g. about 10% excess, in order to optimize the formation of the mono-derivative. The reaction is preferably carried out in an inert solvent such as a chlorinated hydrocarbon, e.g. carbon tetrachloride, methylene chloride or chloroform; in diethyl ether, ethyl acetate. | v 3 66386, or in an aromatic hydrocarbon solvent such as benzene or toluene. The reaction temperature is not critical, but is between about 0 ° C and the boiling point of the reaction mixture, preferably the reaction is carried out at room temperature.

The monensin derivatives of formula I are polyether antibiotics and form a number of pharmaceutically acceptable salts. These salts are prepared according to methods known per se from the free acid form of antibiotics, for example by washing the free acid in solution with a suitable base or a suitable salt. Examples of such pharmaceutically acceptable basic salt-forming agents include alkali metal bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkaline earth metal bases such as calcium hydroxide and barium hydroxide, and ammonium hydroxide. Alkali or alkaline earth metal salts which can be used for the preparation of pharmaceutically acceptable salts of the monensin derivatives of the formula I are, for example, carbonates, bicarbonates and sulphates.

Examples of organic bases which can form pharmaceutically tolerable salts with the monensin derivatives of formula I are lower alkylamines or primary, secondary or tertiary hydroxy-lower alkylamines, such as e.g. ethylamine, isopropylamine, diethylamine, methylamine, methylamine and diethanolamine.

A highly preferred amine is N-methylglucamine. The salts of N-methylglucamine are particularly valuable due to their water solubility and, as a result, the compounds can be used for parenteral administration.

The antibiotic activity of the monensin derivatives prepared according to the invention is shown in Table 1 below.

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It was further found that the monensin! Derivatives prepared according to the invention, as well as their pharmaceutically tolerable salts, have anticoccidial activity against the microorganism Eimeria tenella.

The experiment was performed as follows: 10 chickens were used as a weight control and 10 chickens as an infected control. The test substance was administered 48 hours before infection. 1 g of the test substance was mixed in a mechanical mixer with the required amount of chicken food to achieve the desired dosage. The infection consisted of approximately 200,000 spore vesicles of the malaria plasmod, administered orally by pipette. The experiment lasted 11 days, after which the surviving animals were examined for coarse intestinal lesions by necropsy. The number of surviving animals and the number of colonic lesions were determined. The results are expressed as “mean rate of infection.” With a mean rate of infection of less than 2.5, the dose was considered to be significantly effective.

The results are shown in Table 2.

8 66386

Table 2

Anti-coccidiosis effect of monensin urethanes (added to the diet of Elmer tenella-infected chickens)

Dosage Average

Compound in the diet degree of infection _EE * _

Non-infectious, untreated control none 0.0

Infected, untreated control none 3.0

Monensin! A, 4-nitrophenylurethane 75 0.5

Monensin! A, 4-bromophenylurethane 75 0.7

Monensin A, phenylurethane 75 0.9

Monensin A, 4-chlorophenylurethane 65 0.8

Monensin A, 4-methylphenylurethane 75 1.1

Monensin A, 4-iodophenylurethane 125 0.1

Monensin A, 4-fluorophenylurethane 125 1.0

Monensin A, cyclohexylurethane 125 0.8 9 66386

The monensin derivatives prepared according to the invention also have an effect on Treponema hyodysenteriae. The corresponding minimum inhibitory concentrations for urethane derivatives are:

Compound concentration (pq / ml)

Monensin B, phenethylurethane 2.0

Monensin A, 4-bromophenylurethane 0.4

Monensin B, (R) -1-phenylethyl urethane 0.4

Monensin A, phenethylurethane 0.4

Monensin A, phenylurethane 0.08 to 0.4

Monensin A, 4-chlorophenylurethane 0.08

Monensin B, (S) -1-phenylethyl urethane 0.4

Monensin A, cyclohexylurethane 0.4

Monensin A, 2- (phenyl) -cyclopropylurethane 0.4

Monensin A, 4-fluorophenylurethane 0.08

The experimental method for obtaining an effect against Treponema hyodysenteriae, the causative agent of rubella, is based on inoculating blood agar plates with 2 or 4-fold dilutions of monensin derivatives at 10-fold dilutions of T. hyodysentriae. After incubation for 48 hours at 42 ° C in an anaerobic atmosphere, minimum inhibitory concentrations are obtained at the lowest concentration of compound that most completely inhibits the most diluted planting of each T. hyodysentriae strain.

By administering the monensin derivatives prepared in accordance with the invention (hereinafter referred to as "antibiotics"), ketosis is prevented or ameliorated: at the same time, food utilization is improved. Ketosis is caused by the delayed formation of propionate. The currently recommended method of treatment is based on the administration of propionic acid or nutrients which preferably produce propionate. It is evident that the beneficial formation of propionate when ingested conventional nutrients reduces the incidence of ketosis.

10 66386

As stated above, oral administration of the antibiotic provides a beneficial change in propionate production relative to acetate in the rumen. As a result, it can be expected that the same treatment will similarly affect monogastric animals that subject the fibrous plant material to fermentation in the cecum, as a beneficial change in propionate / acetate ratio can be expected to occur after oral administration of the antibiotic. Horses, pigs, and rabbits are examples of animals that digest some of their food by fermenting it in the colon.

Determination of Liquid Fatty Acid Production Cattle that have been surgically modified to insert a stent into the rumen are used as a source of rumen fluid. Samples of rumen fluid are obtained using a rumen cannula (connecting tube). The animal is fed twice a day with a mixture of 80% concentrate (mainly yellow corn, soybean oil meal and alpha meal) and 20% hay. The pöt-sludge is sieved through 4 layers of nettle slag in a 4-liter container and stored in a carbon dioxide atmosphere. To 2000 ml of ice-cold aqueous buffer solution having the following composition

Na 2 HPO 4 0.316 g / l MgSO 4 0.112 KH-PO. 0.152 CaCl- 0.038 2 4 2

NaHCO 3 2,260 FeSO 4 .7H 2 O 0.008

NaCl 0.375 ZnSO4.7H2O 0.004 KCl 0.375 CuSO4.5H2O 0.002 is added 1000 ml of the rumen fluid obtained above.

The buffered rumen fluid thus placed is placed in a 4-liter separation funnel. Carbon dioxide is introduced into the liquid to provide anaerobic conditions.

A 250 ml Erlenmeyer flask is used for each fermentation. To each flask was added 1 g of a mixture of 80% finely ground concentrate and 20% alfalfa feed. The flasks to be used as controls contain 1.07 g of mixture (80% finely ground concentrate wire and 20% alfalfa feed). Place 1 ml of a solution of the test substance in a suitable solvent in each flask and allow to stand for 0/5 - 1 hour. Each compound is tested in duplicate at a concentration of 50 ppm. Solvents without test compound are placed in control flasks. Monensin (10 and 50 ppm) is used as a positive control in all fermentation experiments.

80 g of buffered rumen fluid is added to each flask containing the test compound and 85.93 g is added to control flasks. The flasks are in each case fitted with a gas trap and allowed to stand at room temperature until all the flasks have been completed.

A 6 ml sample is taken from all control flasks ("zero time" samples). Place the flasks in a water bath at 38 ° C? the germination time and gas collection from the fermentation start 10 min later. Incubate the flasks for 4 hours with shaking (90 times per minute).

Each of the fermentation gas is measured by sampling a half-hour intervals. A suitable device is described in Trei et al., J. Anim. Sci., 30, 825 1970.

The rumen is poured into 25 x 150 mm glass tubes and allowed to stand for 15 minutes in an ice bath to separate the coarse material. To 2 ml of 25% (w / v) metaphosphoric acid in a 13 ml centrifuge tube add 6 ml of rumen fluid. Each tube is sealed and mixed thoroughly. The tubes are allowed to stand in an ice bath for 30 minutes and finally centrifuged for 10 minutes at 16,000 rpm. To 4 ml of the remaining solution is finally added 1 ml of internal standard (0.25% 2-methylvaleric acid). The resulting mixture is filtered through a 0.22 μm filter using a 5 ml syringe. The filtrate is sealed in 1 ml glass tubes with Teflon stoppers.

Each tube from the different fermentations is analyzed for liquid fatty acids.

The results are shown in the following table.

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The compounds of formula I wherein R is phenyl, 4-halophenyl or 4-nitrophenyl, and their pharmaceutically tolerable salts, act as oral antimalarial agents. This effect is illustrated by the following activities against the malaria agent Plasmodium berghei in mice:

ED_. mg / kg orally DU

Compound given_

Monensin A, 4-chlorophenylurethane 2,3

Monensin A, phenylurethane 4

Monensin A, 4-bromophenylurethane 15-20

The compounds of formula I and their pharmaceutically tolerable salts act as antihypertensive drugs when administered orally. This effect is explained in the following table 4: S '14 66386 ex M e 1 3 5 rt - + i 5 o »3 5 t (1) X £ 5 ^ 0 ff'O'ooocncNfN x: 2 s Ji cooor ~ r ^ r ^ oooo -h 5J G 4- »~ 4— 4— Tt — T- Jj

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The monensin derivatives of formula I have a better therapeutic index than monensin A, as shown in Table 5 below.

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Example 1

Preparation of 4-bromophenylurethane from monensin A.

Monensin A (free acid) 10 mmol (6.89 g) to Monensin! Hydrate A is dissolved in 100 ml of benzene. To this solution is added an excess (11 mmol) of 4-bromophenyl isocyanate in an equal volume of benzene, and the reaction mixture is stirred at room temperature. The reaction is monitored by thin layer chromatography (silica gel column, eluting with ethyl acetate-n-hexane-ethanol (80: 20: 2) developing vanillin-phosphoric acid).

After one week, the reaction mixture is washed with 0.5 N hydrochloric acid, water and saturated sodium carbonate solution, and finally with more water. The benzene solution is dried over sodium sulfate and evaporated to dryness under reduced pressure to give an amorphous solid. Crystallized from acetonitrile to give the 4-bromophenylurethane sodium salt of Monensin A; mp. 201-203 ° C; Δ <+ Jo = + 65.3 ° (CHCl 3, C = 1%).

Elemental analysis: Calculated for C 28 H 19 O 2 NBrNa 2α (891.87) C 57.90, H 7.46, N 1.57 and Br 8.96%

Found: C 58.57, H 7.36, N 1.23 and Br 8.90%

Example 2

Preparation of 4-bromophenylurethane monensin A from the sodium salt of monensin Starting from 5 g of the sodium salt of monensin A (7 mmol) and 2 g of 4-bromophenyl isocyanate, the reaction is allowed to proceed as in Example 1. After thin layer chromatographic analysis, the reaction is complete after 2 days. Proceed in the same manner as in Example 1 to give 4-bromophenylurethane of monensin A.

28 66386

Example 3

In a manner similar to that described in Examples 1 and 2, the following compounds are obtained using the corresponding isocyanate:

Compound Melting point (° C) Optical rotation _ _ C * D (°) _

Monensin A, methyl urethane 191-193

Monensin A, 4-bromophenethylurethane 201-203

Monensin B, (R) -1-phenylethylurethane 89-93

Monensin A, phenylurethane 199-210

Monensin A, 4-chlorophenylurethane 199-207

Monensin B, (S) -1-phenylethylurethane 116-120

Monensin A, cyclohexylurethane 110-123

Monensin A, 2- (phenyl) -cyclopropylurethane 119-124

Monensin A, 4-fluorophenylurethane 199-223

Monensin A, 4-nitrophenylurethane 189-192 +104/7 (1%, CH 2 CN)

Monensin A, 4-methylphenylurethane 330 +59.6 (1%, CHCl 3)

Monensin A, 4-iodophenylurethane 203-206 +67.6 (1%, CHCl 3)

Monensin A, n-butylurethane + 59.2 (1%, CHCl 3)

Monensin A, 4-phenoxyphenylurethane 210-213 + 67.9 (1%, CHCl 3)

Claims (5)

21 66386 A process for the preparation of therapeutically valuable monensin derivatives of the formula M 'Me Me / νθ0 <Α x HRR, HNOCO + 7 \> H OH wherein R 1 is phenyl, 4-halophenyl, p-tolyl, 4-nitrophenyl, 4-phenoxyphenyl, n-butyl, cyclohexyl, phenethyl, 2,4-bromophenethyl or 2-phenylcyclopropyl, and R is methyl or ethyl, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula Me Me Me Me O. 0 ^ / \ .Me / \ 1 y-Λ ^ Me / SMe Me οο2η \ Χ _7 \ oh 11: where OH 2 where R is methyl or ethyl is reacted with an isocyanate of formula R1-NCO III where R ^ means the same as above. Process for the preparation of compounds according to Claim 1, in which R 1 is phenyl, p-tolyl, 4-halo-phenylphenyl, 4-nitrophenyl, 4-phenoxyphenyl or 2-phenylcyclopropyl, characterized in that the correspondingly substituted Isocyanate according to III. A method according to claim 1 for the preparation of compounds. for which R is phenyl, p-tolyl, or 4-halophenyl, characterized in that the correspondingly substituted isocyanate of the formula III is used. Process for the preparation of compounds according to one of Claims 1 to 3, in which R is ethyl, characterized in that it is starting from a correspondingly substituted starting compound of the formula II in which R 1 has the same meaning as in Claim 1. Process for the preparation of compounds according to Claims 3 and 4, in which R is 4-bromophenyl and R is ethyl, characterized in that the starting compounds of the formulas II and III are substituted, respectively. 23 66386