CH630086A5 - Process for the preparation of thienamycin sulphoxide and process for the preparation of thienamycin sulphone - Google Patents

Description

The present invention relates to a method for producing thienamycin sulfoxide and a method for producing thienamycin sulfone.

The process according to the invention for the preparation of thienamycin sulfoxide of structural formula I

sce2cs2nk2

COOH

II

sce2ch2nh2 cooh and the non-toxic, pharmaceutically acceptable salts thereof, is characterized in that thienamycin of structural formula II

There is generally an ongoing need for new antibiotics. Unfortunately, there is generally no static efficacy for a given antibiotic, since continued widespread use of any such antibiotic results in selectively resistant strains of pathogens. The known antibiotics also have the disadvantage, for example, that they are only effective against certain types of microorganisms. 65 Accordingly, new antibiotics are generally constantly being sought.

It has surprisingly been found that the compounds which can be prepared according to the invention are, for example

630086

Antibiotics are broad spectrum and are useful for animal and human therapy and in inanimate systems.

It is therefore the object of the present invention to provide a new class of antibiotics which have the basic core structure I "given above. These antibiotics are usually active against a broad range of pathogens which, for example, both gram-positive bacteria such as S aureus, S. pyogenes and B. subtilis, as well as gram-negative bacteria such as E. coli, Proteus morganii and Klebsiella.

The compounds which can be prepared according to the invention are expediently prepared by mild oxidation of thienamycin in accordance with the following reaction scheme:

10th

ch2ch2nh2

cooh

V

[0]

(0) n r-SCK ^^ Ni ^ cooh

15

20th

25th

30th

35

40

The above reaction scheme shows that the sulfoxide (n = 1) is obtained quantitatively when 1 equiv. Oxidizing agent, [O], is used. In contrast, 2 equiv. used, the sulfone form is obtained (n = 2). There are no restrictions on the exact identity of the oxidizing agent. Suitable oxidizing agents are e.g. Peracids such as m-chloroperbenzoic acid and peracetic acid. Other exemplary oxidants are potassium permanganate, hydrogen peroxide and ozone. There are normally also no restrictions with regard to the reaction solvent. Any solvent which is inert or substantially inert in the course of the reaction and which effectively solubilizes the thienamycin substrate is usually suitable. Examples of suitable solvents for the oxidation are tetrahydrofuran, methylene chloride and water. Typically, the reaction is carried out at a temperature of about 0 to about 50 ° C for a period of a few minutes to 1 hour for the sulfoxide and 1 to 6 hours for the sulfone.

The compounds which can be produced according to the invention are generally valuable antibiotics which are active against various gram-negative and gram-positive bacteria. Accordingly, they are used, for example, in human and veterinary medicine and in inanimate systems. The compounds that can be produced according to the invention can thus be used as antibacterial drugs for the treatment of gram-positive or gram-negative

55

60

65

infections caused, e.g. against Sta-phylococcus aureus, Escherichia or Escheria coli, Klebsiella pneumoniae, Bacillus subtilis, Salmonella typhosa, Pseudomonas and Bacterium proteus. The antibacterial compounds which can be produced according to the invention can furthermore be used as additives for animal feed, for the preservation of foods or feed and as disinfectants. For example, they can be used in aqueous preparations in concentrations ranging from 0.1 to 100 parts of antibiotic per million parts of solution to destroy and inhibit the growth of harmful bacteria on medical and dental devices and devices and as bactericides in industrial applications, e.g. in water-based paints and in the white water of paper mills to inhibit the growth of harmful bacteria.

The products which can be produced according to the invention can be used alone or in a mixture as an active ingredient in any type of pharmaceutical preparation. These antibiotics and their corresponding pharmaceutically acceptable salts can be used in capsule form or as tablets, powders or liquid solutions or as suspensions or elixirs. They can be administered orally, intravenously or intramuscularly. Such pharmaceutically acceptable forms are generally produced by methods known per se.

The preparations are preferably produced in the form of forms suitable for absorption by the gastrointestinal tract. Tablets and capsules for oral administration can be in unit dosage forms and can be conventional excipients or diluents such as binders, e.g. Syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; Fillers, e.g. Lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Lubricants, e.g. Magnesium stearate, talc, polyethylene glycol, silicon dioxide; Disintegrant e.g. Potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets can be coated by methods known per se. Oral liquid preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or they can be dry products for reconstitution with water or other suitable excipients before use. Such liquid preparations can include conventional additives such as suspending agents, e.g. Sorbitol, syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, or hydrogenated, edible oils, e.g. Almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; Preservatives, e.g. Methyl or propyl p-hydroxy benzoate or sorbic acid. Suppositories are common sup-positoria raw materials, e.g. Cocoa butter or other glyce ride.

The preparations for injection can be prepared in unit dose form in ampoules or in containers containing several doses with added preservatives. The preparations can be in the form of suspensions, solutions, emulsions in oily or aqueous vehicles, and they can contain formulating agents such as suspending agents, stabilizers and / or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable carrier, e.g. sterile, pyrogen-free water, before use.

The preparations can also be in suitable forms for absorption through the mucous membranes of the nose

630 086

and the neck or bronchial tissues, and they may conveniently be in the form of powder, liquid sprays or inhalants, lozenges, throat brushing agents, etc. For the medication of the eyes and ears, the preparations can be in the form of individual capsules, in liquid or semi-solid form, or they can be used as drops. Topical applications can be present in hydrophobic or hydrophilic bases as ointments, creams, lotions, brushing agents or powders.

In addition to a carrier, the preparations can contain other constituents, such as stabilizers, binders, anti-oxidants, preservatives, lubricants, suspending agents, viscosity agents or flavoring agents or flavorings and similar compounds. To produce a broader spectrum of antibiotic activity, the preparations can additionally contain other active ingredients.

For veterinary medicine, the preparations can e.g. as intramammary preparations, either in long-acting or fast-acting raw materials.

The dose to be administered usually largely depends on the condition of the subject to be treated and the weight of the host, the route and frequency of administration. The parenteral route is preferred for generalized infections and the oral route is preferred for intestinal infections. Generally, a daily oral dose will be from about 15 to about 600 mg of active ingredient / kg body weight of the subject in one or more applications per day. A preferred daily dose for adult humans is in the range of about 80 to 120 mg active ingredient / kg body weight.

The administrations can be in several unit dose forms, e.g. in solid or liquid, orally edible dosage forms. The formulations may contain 0.1 to about 99% active ingredient as a unit dose in liquid or solid form, with the preferred range being about 10 to 60%. The formulations will generally contain from about 15 to about 1500 mg of active ingredient. However, it is generally preferred to use a dose in the range of about 250 to 1000 mg. For parenteral administration, the unit dose usually contains the pure compounds in slightly acidified, sterile water solution or in the form of a soluble powder intended for dissolution.

The following examples illustrate the invention.

example 1

Production of thienamycin sulfoxide

Step A: Preparation of 0, N-bis-trimethylsilyl-thiena-mycin-trimethylsilyl ester, Th (TMS) 3

- sch2ce2nh (tks)

coo (tms)

36.7 mg (0.135 mmol) of thienamycin are suspended in 20 ml of tetra-hydrofuran (THF) under a nitrogen atmosphere and concentrated to 5 ml. 0.5 ml of hexamethyldisilazane and 150 ml of trimethylchlorosilazane are added. The mixture is reacted for 20 minutes at 25 ° C. with vigorous stirring. The suspension is then centrifuged to remove ammonium chloride. The supernatant liquid is evaporated to an oil under a stream of nitrogen 0, N-bis-tri-methylsilylthienamycin trimethylsilyl-lo ester is obtained.

Step B: Preparation of Thienamycin Sulfoxide

(TMS = trimethylsilyl)

ch2ch2nh2

cooh

25th

The Th (TMS) 3 from stage A is dissolved in 3 ml of tetrahydrofuran and treated with a solution of 23.4 mg of m-chloroperbenzoic acid in 1 ml of tetrahydrofuran. The reaction solution is evaporated to dryness and the residue is thus dissolved in 5 ml of 0, in sodium phosphate buffer (pH 7.0) and kept at 5 ° C. for 24 hours to remove the trimethylsilyl protective groups. The resulting solution contains thienamycin sulfoxide and has an absorption maximum at 282 nm. It is evaporated to dryness, giving the desired product, thienamycin sulfoxide.

If you work as described in Example 1, but use 2 equiv. m-chloroperbenzoic acid (46.8 mg) instead of 1 equiv. of Example 1, so you get thienamycin sulfone.

40

Example 2

45 Production of thienamycin sulfoxide

A solution of 36.7 mg (0.135 mmol) of thienamycin in 2 ml of water is cooled to 5 ° C. and treated with a solution of 26.2 mg of the sodium salt of m-chloroperbenzoic acid. The mixture is stirred until the oxidation agent is consumed (negative test with KJ starch test paper). The reaction mixture is acidified to a pH of 3 with dilute hydrochloric acid and extracted with three 4 ml portions of ether to remove m-chloroperbenzoic acid. The aqueous phase is neutralized to a pH of 7 with dilute sodium hydroxide. The salts are removed from the aqueous phase by passing the aqueous phase through a column of 50 ml of XAD resin and eluting with distilled water. The fractions containing the thienamycin sulfoxide are collected and 60 freeze-dried. A residue of thienamycin sulfoxide is obtained.

B

Claims (2)

630086 PATENT CLAIMS 1. Process for the preparation of thienamycin sulfoxide of structural formula I sce2ch2nh2 cooh and the non-toxic, pharmaceutically acceptable salts thereof, characterized in that thienamycin of structural formula II SCH2ce2NE2 GOOH ii OH O -N- ■ sch2ch2nh2 COOH II oxidized and compound obtained optionally converted into the non-toxic, pharmaceutically acceptable salts. 10 The process according to the invention for the preparation of thienamycin sulfone of structural formula I ' CO) 2 f SCE „, CH„ ÏTH- oxidized and compound obtained optionally converted into the non-toxic, pharmaceutically acceptable salts. 2. Process for the preparation of thienamycin sulfone of structural formula I ' i ' 20 and the non-toxic, pharmaceutically acceptable salts thereof, is characterized in that thienamycin sulfoxide of structural formula I is prepared as described above and the compound obtained is further oxidized and the compound thus obtained is optionally converted into the non-toxic, 25 pharmaceutically acceptable salts. Experience has shown that thienamycin sulfoxide (I ", n = 1) and thienamycin sulfone (I", n = 2) and their pharmaceutically acceptable salts are useful antibiotics. sce2ch2nh2 cooh * sce2ck2ne2 COOH I " and the non-toxic, pharmaceutically acceptable salts thereof, characterized in that thienamycinsul- 40 (n = 1 or 2) oxide of structural formula I is prepared by the process according to claim 1 and the compound obtained is further oxidized and the compound thus obtained is optionally not converted into the compound -toxic, pharmaceutically acceptable salts. Thienamycin is described, for example, in DT-PS 2 552 638 (P 25 52 638.9, corresponding to US Ser. Patent Application No. 526 992, filed on November 25, 1974). Thiena-45 mycin is used as the starting material in the preparation of the compounds which can be prepared according to the invention. Thienamycin has the following structural formula (II):