FI60198C - FREQUENCY REQUIREMENT FOR THERAPEUTIC THERAPEUTIC PLEUROMUTILINER - Google Patents

Description

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Wa [b] (11> utlAggninosskiupt 60190 C Patent granted 10 12 1931 <4S) Patent meddelat ^ ^ (51) Kv.ik.3 / int.a.3 0 07 C 149 A3 * C 07 D 295/08 ENGLISH - FINLAND (21) FSMnttlhak «mu · - PttmtaMBknlng 79 ^ 060 (22) Haksmlspilvl —AmBknlngtdag 27 * 12.79 '' (23) Alkupilvl — GHtlgh« t * dag 26.09.72 (41) Interpreters slipped - Blivtt off «Kili 27.12.79 __ _ *, (44) Date of issue of the Niktivlktlptnon | a kuL | - ""

Patent · och registrarstyralsan 'Amakan uth * d och utUkrlftM published 31.08.8l (32) (33) (31) P) Trt «« y sweiksu * —Begird prieritat 05.10.71 05.10.71, 25.05.72, 25.05.72, 25.05.72 Switzerland-Switzerland (CH) 11 + 1 + 50/71 »11 + 1 + 51/71 7738/72, 7739/72, 77 ^ 0/72 (71) Sandoz AG., Basel, Switzerland-Switzerland ( CH) (72) Helmut Egger, Vienna, Hellmut Reinshagen, Vienna, Austria-Austria (AT) (7 * +) Oy Kolster Ab (51+) Method for the preparation of new therapeutically useful pleuromutilins - Förfarande för framställning av nya therapeutikisk an-vändbara pleuromil (62) Share! la separated from application 261 + 5/72 (patent 58635) - /

Avdelad frän ansökan 261 + 5/72 (patent 58635)

The present invention relates to a process for the preparation of novel pleuromocilines of the general formula ^ 2

Γ = ζ \ 0- (CH9) -N

o-co-ch2-s -A 2 n \ r 0 CH3 ^^ v - '3; (3 ch3 oh with ethyl or vinyl, n is an integer from 2 to 5, 2,601,98 and R3 either denote alkyl groups having 1 to 5 carbon atoms or together with an adjacent nitrogen atom form a piperidino group, and acid addition salts and quaternary salts of these compounds. to prepare salts.

According to the invention, these novel pleuromutilins of the formula I and their acid addition salts and quaternary salts are obtained in such a way that the compound of the formula II

/ = 5K0H

O-CO-CH 2 -S // 0 1_I J / R 1 n χ /, ch 3 oh wherein is as defined above, is reacted with a compound of formula III

A- (CH2) n-N2 III

wherein n, R 2 and R 3 are as defined above, and A is an acid residue of a reactive ester, after which the resulting pleuromutilin of formula I is optionally converted into an acid addition salt or a quaternary salt.

The process may be carried out, for example, by dissolving a compound of formula II in an inert solvent, e.g. an aliphatic ketone such as ethyl methyl ketone, or a lower alcohol such as methanol or ethanol, then adding a compound of formula III and reacting the reaction mixture, optionally with a base, e.g. alkali metal carbonate. , such as potassium carbonate. The reaction takes place from room temperature to the boiling point of the reaction mixture and takes 2 to 20 hours.

The corresponding quaternary salts can be obtained from the compounds of the formula I by methods known per se.

The compounds of the formula I, their pharmacologically acceptable acid addition salts and quaternary salts, while having very low toxic, interesting biological, in particular antimicrobial, properties, and can therefore be used as medicaments. They have an inhibitory effect on bacteria, which has been found in in vitro (agar plate) and in vivo (mouse experiments) studies using different bacterial strains. This inhibitory effect was determined in a concentration range of about 0.00 to 3.00-5 .mu.g / ml. In particular, the inhibitory effect on mycoplasma has been studied, and a clear inhibitory effect was found above the range of about 0.008-2.5 μg / ml. As a result, the compounds obtained according to the invention can be used as bactericidal solid antibiotics.

The compounds of the formula I and, if appropriate, their water-soluble, physiologically acceptable salts, alone or in suitable dosage forms together with inorganic or organic pharmacologically inert excipients can be used as medicaments. They are used, for example, as ingredients in capsules and injection or instillation preparations which contain a sufficient amount of active substance to obtain an optimal blood count, i.e. about 10-500 mg per capsule.

The starting materials of formula II can be prepared by reacting a compound of formula IV with 0-C0-CH2-O-SO9-Rr

y __ / "CH3 IV

CH 'oh wherein R 1 is as defined above and R 1 is an alkyl or aryl group to react with a compound of formula V

Me_s ~ ö 0H

where Me is an alkali metal atom. The process is carried out, for example, by reacting compounds of formula IV with a compound of formula V in an inert, water-miscible solvent, e.g. a lower aliphatic ketone such as acetone or methyl ethyl ketone, or a lower alcohol such as methanol or ethanol, optionally also water or water-miscible in the presence of an inert organic solvent, e.g. dimethylformamide, the reaction temperature being between 20 and 60 °, but preferably between 20 and 50 °.

Starting compounds of formula IVa 60198 4 O. C/O. CII0 · O «S09. R c o c »3 ruc ^ .c" ° ai>

CH3 OH

in which the formula has the same meaning as above, are known. Starting compounds of the formula IVb O.CO.CH .O.SO, .R O CU, 1 λ .5> —r.

CH3 oh · having the same meaning as above can be prepared so that U) a compound of formula VI

O.CO.CH-OH

O CH, 1 2 »Γ r rcll3xi

J - J J .C? HS

CII3 Ol was reacted with a compound of formula

a-so2-r5 VII

wherein A and R are as defined above, or P is a reduced compound of formula IVa.

The reaction according to the process can be carried out in an inert solvent, e.g. an aromatic hydrocarbon such as toluene or benzene, but preferably at the same time as a non-fatal solvent, e.g. pyridine. As the fluffy compound of formula VII, e.g. p-toluenesulfochloride can be added. The reaction can be carried out, for example, at a temperature between -15 and -10 ° C and takes 2-4 hours.

The hydrogenation of a compound of formula IVa according to the process is conveniently carried out under the influence of hydrogen in the presence of a hydrogenation catalyst, using e.g. a palladium or platinum carbon catalyst in an inert solvent, e.g. ethyl acetate, and at room temperature.

Pharmacological tests and their results

Method: Determination of the minimum effective concentration by the dilution method (dilution factor 0,5); Medium: Modified Bakos broth (without phenol red)

Culture time: 48 hours / 37 ° C in a tube, then transferred to agar and a solution containing the test compound was added and monitored for 48 hours (at 37 ° C).

The compounds tested, the test organisms used and the results obtained are shown in Tables I and II.

Table I. Minimum effective concentration (pg / ml) of the compounds according to the invention 14-deoxy-14- / 1+ -14-deoxy-14 {4-tetracycline- · · (2-diethylamino- [3- (N-piperidino) - hydrochloride 1 organism ethoxy) phenylmerpropoxy / phenylcapto / acetoxymercapto and acetoxynutilin mutilin

ATCC

M. hominis 14152 0.00078 0.00156 3.125 M. gallisepticum 19610 0.003 0.00156 0.78 M. sp. ISR, - 0.31 0.62 6.25 M. Hyorhinis 17981 0.156 0.156 6.25

Table II. V lowest effective concentration of reference compound (jpg / ml)

Microorganism 14-deoxy-14-p-hydroxyphenyl-tetracycline-mercaptoacetoxyrrutilium hydrochloride

ATCC

M. hominis 14152 3.9 3.12 M. gallisepticum 19610 1.95 3.12 M. sp. IRj 15,625 12.5

The results show that the reference compound (DE-OS 2 036 027, Example 16) has almost the same activity as tetracycline hydrochloride 11a, that the new compounds have a significantly better activity.

The following examples illustrate the invention. Temperatures are shown in degrees Celsius.

* Ά L. ’6 60198

Example 1 .: 14-Deoxy-14- [4- (2-diethylaminoethoxy) phenyl] mercapto] acetoxymutilin 960 mg of 14-deoxy-14- (4-hydroxyphenylmercapto) acetoxymutilin are dissolved in 20 ml of anhydrous methanol, then 120 mg of sodium methoxide are added. and evaporated to dryness in vacuo. The evaporation residue is dissolved in a mixture of 4 ml of water and 20 ml of xylene, to which are added 360 mg of diethylaminoethyl chloride hydrochloride and 420 mg of potassium carbonate and refluxed for 8 hours at a bath temperature of 150 °. The xylene layer is then washed five times with water, the combined aqueous phases are extracted once with ethyl acetate and the combined organic phases are evaporated in vacuo. The residue is dissolved in 10 ml of methylene chloride and converted into the hydrochloride with 0.6 ml of an ethereal solution of 5.8% hydrogen chloride. The solvent is removed in vacuo and the precipitate is dissolved in 6 ml of methanol, diluted with 30 ml of distilled water and then extracted six times with a total of 80 ml of ether. The thus purified aqueous hydrochloride solution is evaporated in vacuo at a bath temperature of about 30 °. In the thin layer chromatogram, the silica pogel G is a compound of the uniform system examined with chloroform / methanol (1: 2). The foamy product is dried in vacuo with potassium hydroxide. The softening point of the hydrochloride was 88-93 ° C.

Example 2: 14-Deoxy-14- [4- (2-diethylaminoethoxy) phenyl-mercapto] acetoxydihydromutilin a) 14-Deoxy-14-tosyloxyacetoxydihydromutilin Method * (:

To a solution of 8.86 g of dihydropleuromutilin in 30 ml of dry pyridine at -15 ° is added 6.10 g of p-toluenesulfochloride in one portion with vigorous stirring, then stirred for 2 hours at -15 ° and then for a further 1 hour at -15 °. 0 °. The mixture is then poured into ice water and the product is dissolved in methylene chloride. The organic phase is washed while cooling first with ice water and then with saturated sodium hydrogen carbonate solution. Dry over sodium sulfate and evaporate to dryness to give a uniform product with a softening point of 78-80 ° by thin layer chromatography.

7 601 98

Method / ¾: 0.53 g of 14-deoxy-14-tosyloxyacetoxymutilin are hydrogenated in 10 ml of ethyl acetate, with 0.10 g of 10% palladium on carbon as a catalyst, at atmospheric pressure and at room temperature. The calculated amount of hydrogen has elapsed after about 1 hour. The solution is separated from the catalyst by filtration and evaporated to dryness in vacuo. The softening point of the obtained product is 78-80 °.

b) 14-Deoxy-14- (4-hydroxyphenylmercapto) acetoxydydromutilin 6.00 g of 14-deoxy-14-tosyloxyacetoxide hydromutilin are dissolved in 15 ml of ethyl methyl ketone. To this solution is added 1.60 g of thiohydroquinone under nitrogen. A solution of 0.35 g of sodium in 25 ml of anhydrous ethanol is then added dropwise with ice-cooling and stirring, followed by stirring for a further 5 hours at room temperature. Work-up is carried out by adding 10% acetic acid (pH 4.5) to the reaction mixture and then evaporating in vacuo. The residue is dissolved in ethyl acetate, then water is added and extracted four times with ethyl acetate. The combined organic phases are washed once with water, dried over sodium sulfate and evaporated in vacuo. The compound crystallizes from chloroform-hexane, m.p. 191-194 ° C.

c) 14-Deoxy-14- [4- (2-diethylaminoethoxy) phenyl] mercapto-7-acetoxydihydromutilin

14-Deoxy-14- (4-hydroxyphenylmercapto) acetoxide hydromutilin is reacted with diethylaminoethyl chloride hydrochloride in analogy to the previous example to give 14-deoxy-14- / 4- (2-diethylaminoethoxy) phenylmercapto / acetoxy-dihydromutilin; hydrochloride softening point 88-92 ° C.

Example 3

In the same manner as in Example 1 and using the appropriate starting materials in corresponding amounts, the following compounds are obtained: a) 14-deoxy-14- {4- [3- (N-piperidino) propoxy] phenyl] mercapto-acetoxymutilin; a hydrochloride softening point of 105-110 ° C, and b) 14-deoxy-14- [2- (2-diethylaminoethoxy) phenyl] mercaptoacetoxymutilin; hydrochloride softening point 81-95 ° C.

The compound mentioned in b) is prepared as follows: 5.33 g of 14-deoxy-14-tosyloxyacetoxymutilin are reacted with 1.57 g of 2-mercaptophenol and 0.25 g of sodium in 10 ml of anhydrous ethanol as in Example 1. 2b is explained. The formed 14-deoxy-14- (2-hydroxyphenylmercatto) azetoxy-8 60198 mutilin is crystallized from chloroform; mp. 150-152 ° C. The resulting intermediate is reacted with diethylaminoethyl chloride hydrochloride in analogy to Example 3 to give 14-deoxy-14- [2- (2-diethylaminoethoxy) -phenyl] mercapto / acetoxymutilin.

Claims (2)

9 601 98 Claim: A process for the preparation of new therapeutically useful pleuromutilins of the general formula / R 20 O- (CH 9) -n ro -CH 2 -s = X CH0 J CH3 xoh having ethyl or vinyl, n is an integer from 2 to 5, and R1 either represents alkyl groups having 1 to 5 carbon atoms, or together with an adjacent nitrogen atom form a piperidine group, and acid addition salts and quaternary salts of these compounds, characterized in that the compound of formula II is O-O, O-O-CH2 ^ OH wherein R1 is reacted with a compound of formula III 601 98 10 / * 2 A- (CHO) -ΝΓ III 2 n \ R3 wherein n, R2 and are as defined above, and A is an acid residue of a reactive ester which the resulting pleuromutilin of formula I is converted, if desired, into an acid addition salt or a quaternary salt. t, k ''