DE2355790A1 - NEW MONOESTERS FROM ROSAMICIN - Google Patents

Description

5 Cologne 1, EJEICHMANNHAUS Cologne, 7th 11.73 AvK / IM Scherico Ltd., Lucerne / Switzerland .

New monoesters of rosamicin
This invention relates to 3-monoesters of rosamicin and to processes for their preparation from 3,2'-diesters of the antibiotic by solvolysis, as well as to pharmaceutical preparations which contain said 3-monoesters.

The novel compounds of this invention are derivatives of the antibiotic 67-69 ² I-, which is described in Belgian patent specification No. 761,922 (granted date: July 21, 1972).

ι: s Received after the Belgian patent was granted

the antibiotic is called rosamicin. Thus the names antibiotic 67-694 and rosamicin are synonyms. Rosamicin can be produced by a rosamicin producing strain of Micromonospora rosaria, which is also described in the above-mentioned patent. ".. ■

Rosamicin forms monoesters under mild acylation conditions in position 2%. Under stronger conditions it forms 5 * 2 '° Diester. Such diesters are commonly known hydrolysis conditions subject, one or more reactions occur sln "such as the splitting off of both acyl groups, whereby the antibiotic which is not aoyliortfc is obtained, hydrolysis d-jr-Laktongruppisri-rig des Aeglykon ^ was su Gf ^ connection siu openeiB Ring leads, splitting off of the glycoside ^ gruppieriir, s and more general

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«AD. ORIGINAL

Breakdown of the aglycon. In general, two or more of the aforementioned reactions occur simultaneously, resulting in one
Large number of undesirable by-products. None of the
known conditions of hydrolysis represent a method which is suitable for the preparation of the desired 3-monoester. The new process of this invention describes a simple way of obtaining the J5 monoesters of rosamicin, which were previously unpreparable.

The new compounds of this invention are 3-monoesters of rosamicin with the area formula

N (CHs) ₂

3.7

O acyl

and the acid addition salts thereof. The acyl group can derived from monohasic or dibasic alkane carbons Mijr @ iv Älkenkarbonsäuren, Cycloalkankarbonshuren, Ärylkarbon-

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acids, arylalkane carboxylic acids or heterocyclic carboxylic acids, the aryl, arylalkane and heterocyclic Carboxylic acids can be substituted by nitro, halogen, lower alkyl or lower alkoxy »

The abovementioned aliphatic carboxylic acids, in particular the alkane carboxylic acids, can contain up to 18 carbon atoms. Acids that can be used well are those containing 2-10 carbon atoms, especially 2-5. The Cycloalkankarboxylic Acids Which Can Be Well Used contain 4-11 carbon atoms. In the above aryl and arylalkane carboxylic acids, the aryl group can be, for example, phenyl and the alkyl group in the arylalkane carboxylic acids Lower alkyl. Usually those heterocyclic carboxylic acids are used in which the cyclic group 5 or β contains ring atoms, especially those that are a heteroatom (e.g. sulfur or oxygen) and which are unsaturated. The groups "lower alkyl" and "lower igaikoxy" mentioned above

usually

have been mentioned contain / 1-8 carbon atoms, in particular 1-4 carbon atoms. The term "halogen" includes Fluorine, chlorine, bromine and iodine. Examples of acids from which the acyl group can be derived are acetic acid, propionic acid, Butyric acid, pivalic acid, valeric acid, hexanoic acid,

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Octanoic acid, decanoic acid, stearic acid ,. Succinic acid, maleic acid, Glutaric acid, malonic acid, cyclopropyl carboxylic acid, adamantane carboxylic acid. Benzoic acid, phthalic acid, phenylacetic acid, nicotinic acid, furan carboxylic acids or the like, including of the isomers of the acids such as, for example, isobutyric acid.

new The compounds of this invention can by a / method be prepared, the selective solvolysis of a 3> 2'-diester of rosamicin, the diester in one Medium that is a water-miscible organic solvent, preferably a lower alcohol or mixture this solvent contains up to $ 50 water until the ester group in position 2 'is selectively removed, and isolating the 3-monoester from said medium.

Under the selective solvolysis of this invention, the 2'-ester group becomes removed without splitting the lactone ring or any cause another degradation reaction or rearrangement of the macrostructure of the antibiotic. The ester group in position 2 'of the starting material can be defined like the esters group in position J5. The ester groups in position 3 and 2 ' can be identical or different from one another.

-5-409820 / 1 196

The solvolysis of this invention can be carried out in water-miscible organic solvents are carried out, such as for example. wise in ethers, especially cyclic ethers, ketones, tertiary lower alkyl amides and preferably, lower ones Alcohols. Examples of such solvents are dioxane, Tetrahydrofuran, acetone, methyl ethyl ketone, dimethylformamide, Methanol, ethanol, propanol and the like. In cases where the reaction is carried out in a solvent that is not a lower alcohol becomes about 5 to about 50 Vol. $ Water added to the reaction medium. In cases where the reaction is carried out in "lower alcohols" must Water not added, but the addition of up to $ 50 Water, preferably about $ 20. usually facilitates that Solvolysis. . The reaction can take place at temperatures of about 0 C to about 100 C, preferably at reflux temperature the reaction medium or a lower alcohol such as methanol, be performed. Room temperature is also appropriate in many cases. The reaction takes place at these temperatures about 15 minutes. In. the lower temperature ranges the conversion takes about 72 hours; A preferred one. Carrying out the reaction consists in carrying out the reaction in a medium composed of lower alcohol, water and the 'exists ^ at the reflux temperature of the alcohol

ORfGiNAL -6-

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for about 120 minutes. It is noteworthy that under the conditions described above, the solvolysis only progresses to the 3-monoester and essentially none Rosamicin is produced.

Many methods are known for observing the course of solvolysis. Among them, thin layer chromatography and mass spectrum analysis are preferred. During the course of the solvolysis, samples of the reaction mixture are taken at suitable intervals, diluted with a water-immiscible solvent, such as, for example, with ethyl acetate, toluene or the like, washed with water, dried and thin-layer chromatography on silica gel in a suitable solvent system, such as chloroform. ^ Methanol in a volume ratio of 9:!, Subjected. For comparison, samples of the starting material (the jSjS'-diester) of rosamicin and the corresponding 2'-monoester are also chromatographed. Disappearance of the spot of the 3,2'-diester of the test plate associated with the occurrence of a material whose Wanderungsjge is different ^ speed from that of the applied compounds and slower (more polar) than that of the j, diesters, "indicates that the reaction has essentially ended.

-7-

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f III «

Isolating the j5 monoester can be done after a large number be done by well known methods. For example Isolation can be carried out by diluting the reaction medium with water, then not with one with water miscible solvent extracted and the solvent removed by distillation. When using this method the solvent is preferably removed in vacuo. Another approach is to use the products of this invention to isolate by concentrating the reaction mixture to a residue or to a crystalline mass. Other Methods can also be used provided that they are sufficiently mild that no significant degradation of the 3-monoesters occurs.

Acid addition salts of the 25-monoesters can be prepared according to known Methods are made. The classic method involves treating the solution of the ester in a non-reactive one organic solvent, such as alcohol, with a stoichiometric amount of acid (or a small Excess of the same), followed by the precipitation of the acid addition salt by adding a precipitant, such as ethyl ether, for example. which is particularly useful. Examples of suitable acids for the production of the above

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Salts are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, propionic acid, maleic acid, benzoic acid, tartaric acid, Monopotassium phosphoric acid and the like.

The compounds of this invention show substantial in vitro antibacterial activity against pathogenic species of gram positive and gram negative microorganisms. The gram positive group of pathogenic microorganisms includes, for example, the species Staphylococcus, Streptococcus, Bacillus and Diplococcus. Examples of the gram-negative group are the species Proteus, Pseudomonas, Escherichia and Klebsiella. The compounds can be used to inhibit or destroy sensitive microorganisms, for example in spi-

at

valleys, especially toilet facilities and / for contamination especially objects at risk, such as examination tables, bathtubs, wash basins, examination instruments and the same. The antibacterial agents are of particular value when used in conjunction with soap solutions and detergents can be used for cleaning the contaminated surfaces.

The compounds of this invention also exhibit substantial in vivo antibacterial activity. So they can for them

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Treatment of mammals used to feel with ■ '·
borrowed microorganisms / are infected. For example, rosamicin-3-propionate has a PD ^ ₀ (mg / kg) in male CP-I mice against a number of strains of Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli of 2.5-25, 25 and / 50, when administered subcutaneously one hour after intraperitoneal infection, untreated infected mice usually die 18-24 hours after infection. The treated surviving mice are counted.

The acute intraperitoneal and subcutaneous toxicity of rosami 3-propionate, expressed in LDc ₀ ', determined on CF-I mice using standard methods, is 550 mg / kg and 750 mg / kg, respectively.

When used in vivo, the compounds of this invention can be administered topically, orally or parenterally, preferably mixed with suitable pharmaceutical excipients. Even though the exact dose for administration depends on many factors, such as the degree and the dangerousness of the Infection, the susceptibility of the infecting organisms to the antibiotic and the individual characteristics of the mammal being treated, it is generally preferred to use the antibiotic in amounts from about 5 mg to about 20 mg

-10-

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per kg of body weight per day, divided into 2 to 4 equal doses. If necessary, larger or smaller doses can be administered, the exact therapy is left to the judgment of the treating person.

The compounds of this invention can be brought into forms suitable for pharmaceutical administration. This can be achieved by mixing the active ingredients with pharmaceutical carriers or excipients. she can be administered externally, parenterally, orally or rectally. They can be external in the form of both hydrophilic as well as hydrophobic ointments are administered, in the form of lotions that are aqueous, non-aqueous or Can be emulsions, or in the form of creams. Examples of suitable carriers are gelatin, lactose, talc, Stearic acid, acacia, gum or cellulose material, polyalkylene glycols, Vaseline, disintegrating agents such as corn or starch, lubricants or lubricants such as for example magnesium stearate, calcium carbonate, aromatic water, benzyl alcohol, syrup, pharmaceutical glues, elixirs, Colorants, tinctures, extracts, oils, sterile water or isotonic saline solution, condoms such as methyl paraben, Propyl paraben, benzoic acid, and non-toxic antimicrobial agents.

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/ au

The diesters used in the following examples (starting

^: will,

materials) can be manufactured / as it is in the above Belgian Patent No. 761,922.

example 1 Rosamicin - ^ - propionate primary potassium phosphate

A. ■ Rosamicin-3-propionate

4.6 g of rosamicin-3,2'-dipropionate are dissolved in 40 ml of a Mixture - consisting of 52 ml of methanol and 8 ml of water. The resulting solution is heated to reflux temperature for about 2 hours, evaporated under reduced pressure to a residue consisting of rosamicin-jS-propionate,

M.p. 95-95 ° C, [α] ί? ⁶ - 20 ° ethyl alcohol, λ ^M ® ^0H 240 nm,

υ max

S = 13.200.

B. Rosamicin propionate primary potassium phosphate

Dissolve 10, 7 potassium primary phosphate mg in 10 ml of water and adding 50 mg Rosamicin-3-propionate, the mixture is stirred for about one hour at room temperature (about 25 ⁰ C) and the solution filtered to separate small amounts of insoluble material , freeze-dried the piltrate and receives primary potassium phosphate from Rosamiein - ^ - propionate, m.p. 98-104 ° C,

. -12-

4 G ί 3 2 C

ή ^β - 15.2 (water, C = 0.3). λ * ^ ° ^Η 238 nm, ^ 13,000.

Other non-toxic pharmaceutically acceptable acid addition salts of rosamicin-3-monoesters can be prepared analogously to Example IB described above. Examples of such Salts are those made with hydrochloric acid, sulfuric acid, citric acid, Acetic acid, propionic acid, tartaric acid, maleic acid, benzoic acid, cyclopropane carboxylic acid, adamantane carboxylic acid and the like can be produced.

Example 2 Rosamicin-3-acetate

185 mg of rosamicin 3,2'-diacetate are dissolved in 8 ^ 0 ml of 80% aqueous methanol and leave the solution at room temperature Stand for four hours, evaporate to a residue, dissolve the residue in chloroform, filter through 1.5 g Silica gel and evaporate to a residue in vacuo. The residue is dissolved in chloroform and crystallized from chloroform-hexane and the compound is obtained this example in the form of a chloroform solvate, m.p. 108-110 C. It is crystallized from chloroform-hexane and

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/ 3

dries in vacuo at 60 C, making the solvent-free Product of this example. M.p. 145-1 ^ 7 C,

Example 3 Rosamicin 3-benzoate

A solution consisting of 40 mg of rosamicin 3,2'-dibenzoate in one ml of 80% aqueous methanol is allowed to stand at room temperature for 40 hours, evaporated to a residue under reduced pressure, the residue is dissolved in methanol and the solution is poured into 'Ice water. The resulting precipitate is isolated by filtration, washed with water and dried to give the compound of this example. M.p. 111-115 ° C, mass spectrum M. ⁺ 685.

Example 4 Rosamicin-3-valerate A: Rosamicin-2'-acetate-3-valerate

The solution of 623 mg rosamicin-2'-acetate and Q, 5 ml is stirred Valeric anhydride in 10 ml of pyridine at room temperature

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for 24 hours, evaporated to a residue under reduced pressure and the residue was taken up in ammonium hydroxide. The mixture obtained is extracted with ethyl acetate and the extracts are washed with sodium bicarbonate and water. The organic solution is evaporated to a residue and the diester is obtained with a melting point of 85-86 ° C., mass spectrum M. ⁺ 707.

B: rosamicin-3-valerate

A solution of 625 mg of the product from stage A is stirred

watery

in 20 ml of 75% methanol at room temperature for 4 hours. The solvent is replaced by ethyl acetate, washed with sodium bicarbonate solution and evaporated to a residue a. The rosamicin-3-valerate obtained has a melting point of 1O4-1O5 ° C, [α] !? - 39 ° (0.3 # ethanol).

Example 5 Rosamicin-3-propionate

A: Dissolve 35 mg of rosamicin 3.2'-dipropionate in 0.5 ml aqueous methanol and the solution is left to stand at room temperature for 8 hours, the solution evaporates under reduced pressure

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Js

a residue consisting of the compound of this example.

B: Dissolve 5 mg of rosamicin 3,2′-dipropionate in 0.5 ml of 95% Aethanoi, leaves the solution at about 25 ° C for 72 hours stand, evaporated under reduced pressure to a residue and obtained rosamicin J-propionate.

C: Dissolve 10 mg of rosamicin 3 2-dipropionate in 0.5 ml of a Solvent mixture consisting of 80 # tetrahydrofuran and 20 $ Water, leaves the solution at about 25 ° C Stand for about 72 hours, evaporate under reduced pressure on a residue and receives rosamicin 3-propionate.

D: Repeat procedure C using a mixed solvent used from $ 80 acetone and $ 20 water.

Example 6 '■ ^;

Rosamicin -3- propionate.- .. - ...-

Dissolve 5 mg of rosamicin 3.2; - propionate in 0.5 ml of methanol, lets the solution stand at room temperature for 1§ hours, concentrated the solution in a vacuum to a residue and receives rosamicin-3-propionate, melting point 93-95 ° C.

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Claims (1)

/ 6 Expectations Process for the preparation of 3-monoesters of rosamicin, which are derived from carboxylic acids, characterized in that a 3j2-diester of rosamicin in one Medium containing a water-miscible organic solvent solvolyzes until the 2'-ester group is selectively removed and that the monoester thus obtained is isolated in free form or in the form of its acid addition salt. 2. The method according to claim 1, characterized in that the medium is a lower alcohol. 3. The method according to claim 1, characterized in that that the medium contains 5-50 $ water. 4. The method according to claim 3 » characterized in that the medium contains $ 20 water. 5. The method according to any one of claims 1, 3 and 4, characterized characterized in that the medium consists of a lower alcohol and water. -17-4098 20/1198 6. The method according to any one of claims 1 * 3 and 4, characterized characterized in that the medium consists of a ketone and water. 7. The method according to any one of claims 1, 3 and 4, characterized characterized that the medium consists of ether and water. 8. The method according to any one of claims 1 to T _3, characterized in that the solvolysis is carried out at a temperature between 0 ⁰ C and approximately 100 ⁰ C. 9. The method according to claim 8, characterized in that the temperature is the reflux temperature of the reaction medium. 10. The method according to claim 8, characterized in that that the temperature is room temperature. 11. The method according to any one of claims 1 to 10, characterized characterized that you can get a 3.2 * -diester of Rosamiein as Starting material used in which the ester group in position 3 is derived from a monobasic or dibasic -18-409820 / 1196 it Alkaharboxylic acid, alkenecarboxylic acid, cycloalkanecarboxylic acid, arylcarboxylic acid, arylalkanecarboxylic acid or a hetero.-cyelic acid Carboxylic acid, the aryl, arylalkane and heterocyclic carboxylic acid by nitro, halogen, lower alkyl or Lower alkoxy can be substituted. 12. The method according to claim 11, characterized in that a starting material is used in which the ester group in position 2 ^{1 is defined} like the ester group in position j5. 15. The method according to claim 11 or 12, characterized in that that the aryl group of the ester group is phenyl. 14. The method according to any one of claims 11 to Γ5, characterized characterized in that the ester group is in position 3 of benzoic acid is derived. 15. The method according to claim 11 or 12, characterized in that that the ester group in position 3 of an alkane carboxylic acid is derived with up to 18 carbon atoms. -19-409820 / 119 16. The method according to claim 15, characterized in that that the acid contains 2 to 5 carbon atoms. 17. The method according to claim 16, characterized in that that the acid is propionic acid. 18. The method according to claim l6, characterized in that the acid is acetic acid. 19. The method according to claim 16, characterized in that that the acid is valeric acid. 20. The method according to claim 11 or 12, characterized in that the ester group in position / is derived from a heterocyclic carboxylic acid in which the cyclic group contains 5 or 6 ring atoms. 21. The method according to any one of claims 1 to 20, characterized characterized that one has the 3-monoester in the form of his primary potassium phosphate isolated. 22. 3-monoester of rosamicin with the area formula -20- ·.
409 8 207 1196 ΔΟΌΌ I CJU HO N (CH ₃ I ₂ O. Acyl and acid addition salts thereof in which the acyl group is derived is of a monobasic or dibasic alkane carboxylic acid, Alkene carboxylic acid, cycloalkane carboxylic acid, aryl carboxylic acid, Arylalkane carboxylic acid or a heterocyclic carboxylic acid, the aryl, arylalkane and heterocyclic carboxylic acid may be substituted by nitro, halogen, lower alkyl or lower alkoxy. ■ 22. The compound of claim 22, wherein the aryl group is the Acyl group is phenyl. 24. A compound according to claim 22 or 23, wherein the acyl group is the eenzoyl group. -21-.
409820/1196 The compound of claim 22, wherein the acyl group is an alkanoyl group of up to 18 carbon atoms. 26. The compound of claim 25 wherein the alkanoyl group contains 2 to 5 carbon atoms. 27. The compound of claim 26, wherein the alkanoyl group Is propionyl. 28. The compound of claim 26 wherein the alkanoyl group is acetyl. 29. The compound of claim 26 wherein the alkanoyl group is valeryl. 50.. A compound of Claim 22 wherein the acyl group is derived from a heterocyclic carboxylic acid wherein the cyclic group contains 5 or 6 ring atoms. A compound according to any one of claims 22 to J> 0 in the form of primary potassium phosphate. -22-409820 / 1196 52. Pharmaceutical preparation with antibacterial Activity containing a compound as an active ingredient, such as it is defined in any one of claims 21 to ^ 1 together with a pharmaceutical carrier or excipient. -23- 409820/1196