DD239795A5 - PROCESS FOR PREPARING SUBSTITUTED 4-BENZYL-PIPERAZINYL COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of substituted 4-benzyl-piperazinyl compounds having high antibiotic, in particular antituberkulöser efficacy for use as medicaments. The aim of the invention is the provision of new substituted 4-benzyl-piperazinyl derivatives having a longer duration of action. According to the invention, novel substituted rifamycin compounds of the formula are prepared, in particular 3-W-rifamycin SV and S compounds, wherein W is a piperazin-1-yl radical of the formula (II) in which R1 and R2 are C (1-4 ) Alkyl and R3, R4 and R5 are hydrogen or C (1-4) -alkyl, or R2 together with R3 or R3 together with R4 optionally substituted by C (1-4) -alkyl substituted buta-1,3-diene 1,4-ylene, trimethylene or tetramethylene, in which case R1, R4 and R5 or R1, R2 and R5 denote hydrogen or C (1-4) -alkyl, and their salts. Formulas (I A), (I B), (II)

Description

R ¹ . R ⁵

into the 4-position of the piperazine radical, and, if desired, converting a compound of the formula (IA) and / or (IB) obtained into another compound of the formula (IA) and / or (IB), and / or a salt obtainable according to the invention into the free compound or into a salt and / or a free compound obtainable according to the method in a salt and optionally the compounds prepared by this process with at least one pharmaceutical excipient by non-chemical processes to pharmaceutical compositions.

2. A process according to item 1, characterized in that a compound of the formula (IA) or (IB) in which W is the radical of the formula II in which R ¹ and R ^{2 are} C (1-4) -alkyl, R ^{4 is} hydrogen or C (1-4) -alkyl and R ³ and R ^{6 are} hydrogen, or wherein R ² and R ³ together or R ³ and R ⁴ together are buta-1,3-dien-1,4-ylene, trimethylene or tetramethylene and R ¹ , R ⁴ and R ⁶ or R ¹ , R ² and R ^{5 are} hydrogen, or a salt thereof.

3. The method according to item 1, characterized in that a compound of formula (IA) in which the radical W has the formula II, wherein R ¹ and R ^{2 is} Cd-4) alkyl, R ^{4 is} hydrogen or C (1 -4) alkyl and R ³ and R ^{5 are} hydrogen, or wherein R ² and R ³ together or R ³ and R ⁴ together are buta-1,3-dien-1,4-ylene and R ¹ , R ⁴ and R ^s and R ¹ , R ² and R ^B denote hydrogen, or a salt thereof.

4. The method according to item 1, characterized in that one produces 3- [4- (2,6-dimethyl-4-tert-butyl-benzyl) piperazin-1-yl] -rifamycin SV.

5. The method according to item 1, characterized in that 3- [4- (2,4,6-trimethyl-benzyl) piperazin-1-yl] -rifamycin SV is prepared.

6. Process according to item 1, characterized in that 3- [4- (1-naphthylmethyl) -piperazin-1-yl] -rifamycin SV is prepared.

7. Process according to any one of items 1 to 6, characterized in that the compounds are prepared in the form of a pharmaceutically acceptable salt thereof.

Field of application of the invention

bie invention relates to a process for the preparation of new derivatives of rifamycin SV and S with high antibiotic, especially antituberculosis efficacy. These are substituted in the 3-position by a substituted piperazin-1-yl radical rifamycin compounds of the formula

CH-COO

V CO CH_

XH OH OH I ³

³ I » I

(IA)

- J -

Cn_ CH-. w · · ·

I ³ I ³ I ³

CH ₃ COO

CH-O

OH OH 3 0Hg

ι '"ti 1

(IB)

wherein W is a piperazin-1-yl radical of the formula

R ¹ R ⁵

R R

in which R ¹ and R ^{2 are} C (1-4) -alkyl and R ³ , R ⁴ and R ^{B are} hydrogen or C (1-4) -alkyl, or R ² together with R ³ or R ³ together with R ⁴ optionally substituted by C (1-4) alkyl substituted buta-1,3-dien-1,4-ylene, trimethylene or tetramethylene, wherein R ¹ , R ⁴ and R ^B or R ¹ , R ² and R ^{B is} hydrogen or C (1-4) alkyl, and their salts.

The invention further relates to processes for the preparation of the compounds of formulas IA and IB and their salts, pharmaceutical preparations containing them and the use of these compounds and preparations.

Due to the very close relationship between the 1,4-quinone and 1,4-hydroquinone form (corresponding to rifamycin S and -SV) and the ease with which the two forms merge into one another, where not specifically stated otherwise both forms included in the subject invention, but the SV-form (IA) is considered to be the preferred one.

Characteristic of known technical solutions

Rifamycin is one of the best agents for the treatment of tuberculous infections. In some cases, its short residence time in the organism is a major disadvantage.

The 3- (4-benzyl-piperazin-1-yl) -rifamycin disclosed in US Pat. No. 4,005,777 surpasses rifamycin by about three times in terms of antituberculosis activity but is hardly superior in long-term activity.

Object of the invention

The aim of the invention is the provision of new substituted 4-benzyl-piperazinyl compounds having a strong antibiotic, in particular antituberculosis effect and a long duration of action.

Explanation of the essence of the invention

The invention has for its object to find new substituted 4-benzyl-piperazinyl derivatives having the desired properties and methods for their Hersteliung.

According to the invention, compounds of the formulas (IA) or (IB) are prepared.

The C (1-4) alkyl are, for. For example, ethyl, propyl, i-propyl, n-butyl, isobutyl or tert-butyl, but especially methyl.

A preferred subject of the present invention are the compounds of the formula (IA) and (IB) in which W is the radical of the formula II wherein R ¹ and R ^{2 are} C (1-4) -alkyl, in particular methyl, R ⁴ Is hydrogen or C (1-4) -alkyl, for example methyl or tert-butyl, and R ³ and R ^{6 are} hydrogen, or in which R ² and R ³ together or R ³ and R ⁴ together are buta-1,3-diene -

-4- 139 / SfD

1,4-ylene, trimethylene or tetramethylene and R ¹ , R ⁴ and R ⁵ or R ¹ , R ² and R ^{6 are} hydrogen, and salts, especially pharmaceutically acceptable salts thereof.

In the first place, the invention relates to compounds of the formula IA, in which the radical W has the formula II, in which R ¹ and R ^{2 are} C (1-4) -alkyl, in particular methyl, R ^{4 is} hydrogen or C (1-4) - Alkyl, e.g. As methyl or tert-butyl, and R ³ and R ^{5 are} hydrogen, or wherein in particular R ² and R ³ together, further R ³ and R ⁴ together are buta-1,3-dien-1,4-ylene and R ¹ , R ⁴ and R ⁵ or R ¹ , R ² and R ⁶ denote hydrogen, and salts, especially pharmaceutically acceptable salts thereof. 3- (piperazin-1-yl) -rifamycins S and SV substituted in the 4-position of the piperazin-1-yl radical have already been described. So z. No. 4,250,777 at column 4, lines 3-24, such rifamycin derivatives are mentioned, in which inter alia in this 4-position an unsubstituted or substituted hydrocarbon radical may be present, which C (1 -) -lower alkyl or mono- or dihydroxy-lower alkyl or lower alkoxy, carbalkoxy, phenyl or phenyl-lower alkyl. Benzyl- and 1- or 2-phenylethyl derivatives which may be substituted in the aromatic part by one or more radicals, inter alia by alkyl having 1-6 C atoms, are mentioned as derivatives having such substituents. Substituted 3- (4-benzyl-piperazin-1-yl) -rifamycins SV and S having substituents of the last-mentioned type are disclosed in particular in Example 77 of said US patent, according to the table obtained in this example in addition to the 3- (4 -Benzylpiperazin-1-yl) -rifamycin SV the 3- [4- (p-methylbenzyl) -piperazin-1-yl] -rifamycin SV, 3- [4- (o-methylbenzyl) -piperazin-1-yl) - rifamycin SV, 3- [4- (m-methylbenzyl) -piperazin-1-yl] -rifamycin SV, 3- [4- (p-isopropylbenzyl) -piperazin-1-yl] -rifamycin SV, 3- [4- (2,3-dimethylbenzyl) -piperazin-1-yl] -rifamycin SV and 3- [4- (p-tert-butylbenzyl) -piperazinyl] -rifamycin SV. All of these compounds have a very good antituberculosis effect, as shown in mice or rats infected with Mycobacterium bovis. In these tests, they have ED ₆₀ values which correspond approximately to those of the known antituberculous agent rifampicin.

Although rifampicin is one of the best agents for the treatment of tuberculous infections, in some cases its relatively short residence time in the organism is a major drawback. The provision of active ingredients which, compared to rifampicin, would have approximately the same but prolonged action against tuberculosis infections is therefore one of the most urgent tasks in this field. Also, the above-cited 3- (4-benzylpiperazin-1-yl) -rifamycins described in US Pat. No. 4,005,777 do not have the desired advantage: they surpass rifampicin, as already mentioned above, in terms of antituberculous activity in vivo by about threefold, but are hardly superior in terms of long-term effect. '.

In contrast, it has now been found that the novel compounds according to the present invention are surprisingly distinguished not only by a good antituberculous activity, which corresponds approximately to that of rifampicin, but also in particular by a significantly increased residence time in the organism.

The differences between the prior art compounds and the novel compounds of the present invention can be demonstrated by the data set forth in Table I. From the table it is clear that in compounds A and B, the residence time of the drug in the organism is significantly longer than the rifampicin or compounds 1 to 4 of the US Patent 4005077th This is particularly clear when comparing the benzyl in the triple methylated compound A. of the present invention with the monosubstituted analogues of said US patent, d. H. the three monomethylbenzyl derivatives (compounds 1 to 3) on the one hand, and a benzyl derivative with a larger alkyl substituent, d. H. 3- (4-isopropyl-piperazinyl-1-yl) -rifamycin SV (Compound 4), on the other hand. Such, in relation to the

Table I.

Antituberculous activity and pharmacokinetic behavior of the novel and some previously known active ingredients

Effect against ^ED 50 po (mg / kg) Pharmacokinetics C (c) max (mc g / ml) rat C (c) max (mc g / ml) 3- (4-R-Piperaziri-l- Mycobacterium 1.4 2.69 t / 2 (b) (h) 1.32 yl) -rifamycin SV tuberculosis 1.4 3.39 86 - TB H-R 3 ν 1.2 2.28 - - R MIC (a) (mcg / ral) 1.5 mouse 1.81 - - 1. o-methyl-benzyl 0.001 1.0 t / 2 (b) (h) 1.20 - - 2. m-methylbenzyl 0.0003 1.0 22.9 1.40 - - 3. p-methyl-benzyl 0.0001 4 11.9 2.95 - 1.51 4. p-isopropylbenzyl 0,003 3 11.5 1.88 / "- 450 1.12 5. Isobutyl 0.0001 5.9 20.4 2.48 111 1.39 6. 2-methyl-allyl 0.0003 12.0 3.8 A. 2,4,6-trimethylbenzyl 0,003 21.0 For example, 1-naphthyl-methyl 0.0003 47.4 Standard: Rifampicin 0,003 48.5 6

(a) minimum inhibitory concentration (1 meg = 1.10 g)

(b) t / 2 = elimination half-life (h = 1 hour)

(c) C = maximum concentration in plasma (1 meg = 1.10 g)

Max

Pharmacokinetics superior efficacy show compounds A and B according to the invention but not only against the said, under the general term 3- (4-benzyl-piperazin-1-yl) -rifamycin SV and S falling compounds described in US Patent 4005077, column 4, Lines 3 to 24, but also in general compared to other 3-piperazinylrifamyeins, such as the 3- (4-isobutyl-piperazin-1-yl) -rifamycin SV (compound 5) and the 3- (4-methyl-piperazine- 1-yl) -rifamycin SV (compound 6).

The novel compounds of the present invention also have a surprisingly high activity against other mycobacteria, in particular against atypical mycobacteria, which have recently been increasingly found to be pathogenic microorganisms in AIDS patients and are considered an immediate cause of death in these patients have shown that compounds A and B according to the invention multiply exceed the antimicrobial activity in vitro exhibited by rifampicin in relation to a number of atypical mycobacteria. This high efficiency is particularly pronounced in group c, d. H. in non-photochromogenic microorganisms, which are among the most dangerous pathogens in AIDS diseases.

Table II

 Efficacy (MIC) against atypical mycobacteria.

microorganism Photochromogene: 181 MIC m mcg / ml Verb. B rifampicin (Mycobacterium) känsasii K 367 653 Verb. A a) Scotochromogene: 546 0,015 0.25 M. 550 0,015 b) 551 0.06 1 M. 0.03 0.5 1 M. ,1 0.03 0.25 M. 0.03 c) scrofulaceum K 1166 1 64 M. xenopei K 716 0.5 0,125 0.5 M. aquae K 1165 0.03 0.25 2 0,125 1 16 0,125 1 8th Nonphotochromogene: 0.25 1 1 avium K 536 0.25 intracellular K K K K "Ir _k

MIC = minimum inhibitory concentration (1 meg = 1.10 g)

The novel compounds of the present invention have good antibacterial properties also against others,

especially gram-positive microorganisms. Thus they show in the vitrc experiment against staphylococci, such as

Staphylococcus aureus K1098, and confer inhibitory effects via streptococci, such as Streptococcus pyogenes Aronson K1129

from about 0.005 ^ g / ml. In in vivo experiment, z. B. against the aforementioned Staphylococcus, the compounds of

at doses (ED ₆₀ ) above about 1 mg / kg, both subcutaneously and orally.

In this case, the compounds according to the present invention have a wide therapeutic range by using a

have significant toxicity only at high doses, such as on the order of 5000mg / kg.

The new compounds can therefore be used as a remedy, primarily for the treatment of tuberculous and AIDS infections,

but also from other infections, such. B. leprosy, or those caused by pyogenic bacteria such. Staphylococci,

caused to be used.

The novel compounds of the formulas IA and IB can be prepared in a manner known per se! e.g. by

a) a 3-R _o -Rifamycin S, wherein R _{0 is} hydrogen or halogen, with an amine of the formula HW (Hl) or

b) an N'-unsubstituted 3-piperazinylrifamycin S or -rifamycin SV with a compound containing the remainder of the formula

(IV)

into the 4-position of the piperazine radical, and, if desired, converting a compound of the formula (IA) and / or (IB) obtained into another compound of the formula (IA) and / or (IB), and / or a salt obtainable according to the process is converted into a salt into the free compound or into another salt and / or a free compound obtainable in accordance with the process. '

The reaction of rifamycin S (R ₀ = hydrogen) with the amine of formula III can in a conventional manner, such. B. in DE-PS 1670377, performed. Thus, it is convenient to use an excess of amine (about 5-10 moles). The reaction is z. In a hydroxy-free organic solvent, preferably of low polarity, such as

a halogenated aliphatic hydrocarbon such as methylene chloride or chloroform, an ester or ether such as ethyl acetate, butyl acetate, amyl acetate, cellosolve or tetrahydrofuran, and primarily in dioxane, and preferably at room temperature or, e.g. B. at a slow rate, at elevated temperature, for. B. between room temperature and 100 ⁰ C, performed. The course of the reaction can be monitored by thin-layer chromatography.

In general, this process variant forms a mixture of the desired reaction product in the quinone and the hydroquinone form. Preferably, this mixture is standardized, as described in more detail below, by reducing only the hydroquinone form (derivative of rifamycin SV) or by oxidation only the quinone form (derivative of rifamycin S) is formed.

As 3-halo-rifamycin S, in particular the 3-bromo-rifamycin S can be used in addition to 3-chloro and 3-iodo-rifamycin S (cf DE-PS 2,548,128). The replacement of the halogen atom with the rest of the amine of formula III is usually carried out in an inert solvent, especially in an ether such as tetrahydrofuran, dioxane or in a halogenated aliphatic hydrocarbon such as chloroform, dichloromethane or 1,2-dichloroethane, or an aromatic hydrocarbon such as benzene or toluene, wherein the reaction is preferably carried out at temperatures between 0 ° C to 100 ⁰ C; see. also DE-OS 2847427.

In process variant b), reactive esters of the corresponding alcohol, in particular compounds of the formula, are used as the reagent for introducing the radical of the formula IV

R ¹ R ⁵ * '.

X-CH ₂ - // ^ -R ⁴ (V),

wherein X is the radical of a strong inorganic or organic acid, such as the radical of a halogen, such as hydrochloric, hydrobromic or hydroiodic acid, an oxygen-containing inorganic acid, such as sulfuric acid, phosphoric acid, phosphorous acid, silica, sulfurous acid, or a Halogensulfuric acid, such as fluorosulfonic acid, or an organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid.z. B. a lower alkane sulfonic acid or an optionally, for. B. by lower alkyl or nitro-substituted benzenesulfonic acid. X is in particular chlorine, bromine or iodine, furthermore methanesulphonyloxy or p-toluenesulphonyloxy. / j

The reaction is preferably carried out in the presence of a base, in particular a strongly basic, non-nucleophilic, tertiary amine, in particular a corresponding sterically hindered, aliphatic and / or araliphatic amine, such as tri-lower alkyl-amine, for. B. the so-called Hünig base, ie ethyl diisopropylamine. In this case, the rifamycin compound and the alkylating agent is used in equimolar amounts, wherein the base is preferably added in an equimolar ratio. _N.

The isolation of the reaction product from a reaction mixture obtainable according to the process is carried out in a manner known per se, for. By diluting with water, and / or optionally neutralizing with an aqueous acid such as an inorganic or organic acid, e.g. As a mineral acid or, advantageously, citric acid, and adding a water-immiscible solvent such. B. a chlorinated hydrocarbon, for. As chloroform or methylene chloride, wherein the reaction product passes into the organic phase, from which it in the usual manner, for. Example, by drying, evaporation of the solvent and crystallization and / or chromatography of the residue or other, conventional purification methods can be obtained in pure form.

The starting materials for the process variants described are known and can be prepared in a manner known per se. So z. B. the starting material to be used 3-Piperazinylrifamycin SV are obtained by the process described in DE-PS 1676377 from rifamycin S and piperazine with subsequent reduction of the product with ascorbic acid.

The process product can be obtained in the hydroquinone form of the formula IA or in the quinone form of the formula IB or, in particular the product of the process modification a), in the form of a mixture of the two. The two forms can be converted into each other in a manner known per se or a mixture of the two into one of the two uniform forms. The conversion of a quinone of the formula IB obtainable by the process into the corresponding hydroquinone of the formula IA or a hydroquinone of the formula IA obtainable in accordance with the process into a quinone of the formula IB, or the standardization of a mixture of the two compound types by means of reduction or oxidation, can be carried out according to or advantageously before isolation of the desired product. The reduction may be accomplished by treatment with one, especially one suitable for reducing a quinone to the corresponding hydroquinone. Reducing agent, w <an alkali metal, z. As sodium dithionite or hydrosulfite. Zinc and acetic acid, or preferably with ascorbic acid ^r "oxidation by treating with one, especially one suitable for the conversion of hydroquinone to the corresponding quinone oxidant, such as atmospheric oxygen, hydrogen peroxide, alkali metal, eg potassium, -ferricyanid, a persulfate, e.g. The quinones are usually violet-red colored compounds, while the hydroquinones are usually yellow-colored and crystallize more readily.

The compounds of the present invention may form salts, especially acid addition salts, and primarily pharmaceutically acceptable acid addition salts with inorganic or organic acids; such are u.a. Halogen, e.g. Chloric and hydrobromic acids, sulfuric acid, phosphoric acid, nitric acid or perchloric acid, or aliphatic, acyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, and tartaric acids. , Citric, fumaric, maleic, hydroxymalein, oxalic, pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic, p -aminosalicylic, embonic, methanesulfonic,

Äthansulfon-, Hydroxyäthansulfon-, Äthylecisulfon-, halobenzene-sulfone, toluenesulfone, naphthalenesulfonic or sulfanilic acid, methionine, tryptophan, lysine or arginine, and ascorbic acid. Hydrochihone compounds of the type of formula IA may also be salts with bases, e.g. B. alkali metal, such as sodium salts.

The salts can be prepared in a conventional manner, for. B. by treatment with an appropriate acid for salt formation or with a base, for. With the desired base, such as ammonia or an organic amine, or a corresponding metal, such as alkali metal hydroxide, carbonate or bicarbonate, or with a suitable ion exchange agent.

Compounds of the present invention may also contain internal salts, e.g. B. by conventional acido-basic titration to the neutral point or to the isoelectric point, or, z. Example, by treating with suitable quaternizing agents, such as reactive esters of lower alkanols with strong acids such as hydrohalic acid, sulfuric acid or strong organic sulfonic acids, forming quaternary ammonium salts.

These or other salts of the new compounds, such as. As the picrates, can also serve to purify the compounds obtained by converting the free compounds into salts, these separated and in turn the free compounds gains from the salts. As a result of the close relationship between the compounds in free form and in the form of their salts, the corresponding salts are to be understood in the preceding and following among the free compounds as appropriate and appropriate.

The invention also relates to those embodiments of the method, according to which one starts from an available at any stage of the process as an intermediate compound and performs the missing steps or a starting material in the form of a derivative, for. As salt, used or forms under the reaction conditions. '

In the methods of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable.

In view of the pharmacological properties of the novel compounds described above, the present invention also encompasses the use of the active compounds according to the invention, alone, for. B. together with excipients, or in combination with other drugs, especially antibiotics or chemotherapeutic agents, as agents for the treatment of infections, especially those caused by tubercle bacilli, atypical mycobacteria, especially those of AIDS diseases, as well as by bacteria and especially cocci such mentioned, both as a remedy, as well as a disinfectant. When used as a remedy, the active compounds of the invention are administered in therapeutically effective amounts, preferably in the form of pharmaceutical preparations together with conventional pharmaceutical excipients or excipients. This z. B. to warm-blooded animals with a body weight of about 70 kg depending on species, body weight, age and individual condition, and depending on the mode of administration and especially depending on the sensitivity of the pathogen, daily doses of about 50 to 3000 mg in acute cases may be exceeded several times administered. Analogously, the invention also includes the corresponding method for medical treatment. , . '. ..

The invention further relates to pharmaceutical preparations containing the compounds of the present invention as active ingredients, and to processes for their preparation.

The pharmaceutical preparations according to the invention are, for. B. to those for enteral, such as peroral or rectal, as well as for parenteral administration to warm-blooded animals. Corresponding dosage unit forms, in particular for peroral administration, eg. As dragees, tablets or capsules, preferably contain from about 50 to about 500 mg, in particular from about 100 to about 300 mg of the active ingredients together with pharmaceutically acceptable carriers or excipients.

Suitable carriers are in particular fillers, such as sugars, for. As lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, eg. Tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch pastes using e.g. Corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and / or, if desired, disintegrants such as the above-mentioned starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow regulators and lubricants, eg. For example, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragoe cores may be provided with suitable, optionally gastric juice-resistant coatings, which include concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, Z ₁ . As for the identification or labeling of different doses of active ingredients, be attached.

Other orally applicable pharmaceutical preparations are gelatine capsules, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can be the active ingredient in the form of granules, eg. B. in admixture with fillers, such as lactose, binders, such as starches and / or lubricants, such as talc or magnesium stearate, and optionally of stabilizers, lh soft capsules, the active ingredient is preferably in suitable liquids / such as fatty oils, paraffin oil or liquid Polyäthytenglykolen, dissolved or suspended, wherein stabilizers may also be supplied. , -

As rectally applicable pharmaceutical preparations come z. As suppositories into consideration, which consist of a combination of the active ingredient with a suppository base. As suppository base are z. As natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkenols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a matrix may also be used; as basic materials come z. As liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question. For parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, ι. As a water-soluble salt, or aqueous injection suspensions, which viscosity-increasing substances z. As sodium carboxymethylcellulose, sorbitol and / or dextran and optionally stabilizers. In this case, the active ingredient, optionally together with excipients, also be in the form of a lyophilisate and be brought into solution prior to parenteral administration by the addition of suitable solvents.

-9- £ 39 / ss

The pharmaceutical preparations of the present invention can be prepared in a manner known per se, for. Example by means of conventional mixing, granulation, coating, solution or lyophilization process. Thus, one can obtain pharmaceutical preparations for oral use by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and the mixture or granules, if desired or necessary, after addition of suitable Hilfsstoffert, processed into tablets or dragee cores ,

embodiment

The following examples illustrate the invention described above, but do not limit its scope in any way. Temperatures are given in degrees centigrade.

Example 1: A solution of 5 g of 3-bromo-rifamycin S in 50 ml of tetrahydrofuran is mixed with 3 g of 1- (2,6-dimethyl-4-tert-butyl-benzyl) -piperazine and allowed to stand at 20 ⁰ C for 30 minutes. The mixture is then acidified by adding aqueous citric acid solution and the reaction product is taken up in methylene chloride. After drying and evaporation of the methylene chloride extract leaves behind a dark colored residue; it is dissolved in methanol and added dropwise aqueous ascorbic acid. 3- [4- (2,6-dimethyl-4-tert-butyl-benzyl) -piperazin-1-yl] -rifamycin SV precipitates in the form of yellow-colored crystals, mp. 260 ⁰ C.

EXAMPLE 2 In analogy to Example 1, 3 g of 3-bromorifamycin S are reacted with 3 g of 1- (2,4,6-trimethylbenzyl) -piperazine to give the 3- [4- (2,4,6 Trimethyl-benzyl) -piperazin-1-yl] -rifamycin SV in yellow crystals, m.p. 178X-181 ⁰ C (partially with decomposition).

To prepare the sodium salt of this compound, equivalent amounts of 3- [4- (2,4,6-trimethyl-benzyl) -piperazin-1-yl] -rifamycin SV and sodium bicarbonate are dissolved in a mixture of dioxane and water, and the solution is lyophilized.

EXAMPLE 3 In analogy to Example 1, 3 g of 3-bromorifamycin S are reacted with 3 g of 1- (1-naphthylmethyl) -piperazine to give 3-I4- (1-naphthylmethyl) -piperazin-1-yl] -rifamycin SV in yellow crystals, mp 177 ° C-178 °. The preparation of the sodium salt is carried out in an analogous manner as described in Example 2.

Example 4: Capsules containing 250 mg of 3- [4- (2,4,6-trimethyl-benzyl) -piperazin-1-yl] -rifamcine SV can be prepared as follows:

Composition (for 1000 capsules):

3- [4- (2,4,6-trimethyl-benzyl) -piperazin-1-yl] -rifamycin SV 250.0 g

Cornstarch 50.0 g

Polyvinylpyrrolidone 15.0 g

Magnesium stearate 5.0 g

Ethanol q.s.

The active ingredient and the corn starch are mixed and moistened with a solution of polyvinylpyrrolidone in 50 g of ethanol.

The wet mass is forced through a sieve with a mesh size of 3mm and dried at 45 ° C. The dry granules are sieved through a sieve with a mesh size of 1 mm and mixed with 5 g of magnesium stearate. The mixture is filled into 0.320g portions in size 0 capsules.

Claims (2)

Invention claim: 1. Process for the preparation of compounds of the formulas CH, 0 ³ v CH, CH, CH, I ³ I ³ I ³ OH OH CH_OH ³ I co OH I NH HI O-C CO OH CH. or CH COO (IA) CH, CH. CH, CH_O OH OH ·, CH_OH L ³ ^! " H CO CH. NH ι ι κ O-C CO CH. (IB) where W is a piperazin-1-yl radical of the formula ►Ν Ν »""" (II) -2- Z39 in which R ¹ and R ^{2 are} C (1-4) -alkyl and R ³ , R ⁴ and R ^{5 are} hydrogen or C (1-4) -alkyl, or R ² together with R ³ or R ³ together with R ^{4 is} optionally substituted by C (1-4) alkyl substituted buta-1,3-dien-1,4-ylene, trimethylene or tetramethylene, in which case R ¹ , R ⁴ and R ⁶ or R ¹ , R ² and R ^{6 is} hydrogen or C (1-4) -alkyl, and their salts and, where appropriate, their pharmaceutical preparation form, characterized in that a) a 3-R _D -rifamycin S, wherein R _{0 is} hydrogen or halogen, is reacted with an amine of the formula HW (III), or b) an N'-unsubstituted piperazinylrifamycin S or -rifamycin SV with a compound containing the remainder of the formula