NO880953L - 4-BENZYL-piperazinyl hydrazone. - Google Patents

Description

The object of the invention is new antivirally active hydrazones which derive from 1-amino-4-benzylpiperazine substituted in the phenyl ring as hydrazine component and 3-formylrifamycin SV or S, or one in positions 16, 17, 18, 19 and possibly also 28, 29 saturated analogues thereof, as aldehyde components, and which correspond to formula I

wherein Rif means a residue of partial formula wherein A-A-A-A buta-1,3-diene-1,4-diyl and X-X means vinylene or A-A-A-A means tetramethylene and X-X means ethylene or vinylene, and wherein W means a piperazinyl residue of partial formula

in that each of the residues R<1>, R<2>, R^, R4 and R<5> together with the neighboring residue can mean a 2-valent aliphatic hydrocarbon residue with 3-10 C atoms, which together with the corresponding two C -atoms of the central phenyl ring form an annulated 5- or 6-membered carbocyclic ring, the other residues being hydrogen or C1-C4-alkyl, and in which R<4>means a ^-c12<->

alkylphenyl or hydrogen, and R<1>, R<2>, R<3> and R<5> independently each means a C^-C^alkyl or hydrogen, at least one of all residues must be different from hydrogen, and their salts.

The invention also relates to methods for preparing the compounds of formula I, including their salts. Pharmaceutical preparations contain the compounds, and the use of the compounds and the preparations is also discussed.

Due to the very narrow relationship between the 1,4-quinone and 1,4-hydroquinone forms (corresponding to rifamycin-S and -SV) and the ease with which the two forms change into each other, wherever there is no specifically stated otherwise, both forms are included in the object of the invention, the SV form being however to be considered the preferred one.

Due to the very narrow relationship between the syn- and anti-configuration of the aldiminino double bond -CH=N-, no distinction is made between the different stereoisomeric hydrazones (as well as mixtures thereof), and -all forms are likewise included in the object of the invention.

When referring to the compounds according to the invention, the name "hydrazone" is given preference over alternative designations "aldiimide", as the former more accurately describes the chemical properties of this class of compounds.

In compounds of formula I in which in partial formula (W) each of the residues R*, R2, R<3>, R<4> and R<5> together with its neighboring residue can mean a divalent aliphatic hydrocarbon residue, with 3-10 C- atoms, which, together with the corresponding two C atoms of the central phenyl ring, form an annulated 5- or 6-membered carbocyclic ring, the other residues being hydrogen or C 1 -C 4 alkyl, e.g. the residues R<2> and R <3->orR<3>andR<4>, further R2 and. R<3>, as well as additionally R<4>and R<5>resp. R<1>and R5, resp. a corresponding divalent aliphatic hydrocarbon residue. ;A divalent aliphatic hydrocarbon residue with 3-10 C atoms is straight, further branched has 3 or 4 C atoms in a straight chain and may have one or two double bonds, and means especially buta-1,3-diene-1,4- diyl, further tri- or tetramethylene. The correspondingly formed fused ring may have one or more or two, C 1 -C 4 alkyl residues, and preferably be unsubstituted. As such an annelated ring, the benzo ring is particularly an unsubstituted one, particularly preferred. A C₁-C₂ alkyl is e.g. a linear alkyl, for example with 5-12 C atoms, and especially a C 1 -C 4 alkyl, such as ethyl, propyl, i-propyl, n-butyl, isobutyl or tert-butyl, primarily, however, methyl. A preferred object according to the invention is the compound of formula I, in which the residue W means the symbols R^ and R<2>, each independently a C^-C4-alkyl, R<3> and R<4> independently each hydrogen or C1- C4-alkyl, and R<4>means phenyl or C^-C]^-alkyl, or R<2>together with R<3>or R<3>together with R4 means a possibly with C^-C4- alkyl substituted buta-1,3-diene-1,4-diyl, trimethylene or tetramethylene, R<1> and R<5> together have one of these meanings, or each individually means hydrogen or C1-C4~alkyl, where R <4> or R<2> means hydrogen or C1-C4-alkyl and their salts. Particularly preferred are compounds of formula I, in which in the residue_W the symbols R-*- and R<2>each means methyl or if R<4>means phenyl, also means hydrogen,R<4>means hydrogenphenyl, linear C5-Ci2~< alkyl or C1-C4 alkyl, especially methyl or tert-butyl, and R<3> and R<5> are hydrogen, and in which the symbols R<2> and R<3> together or R3 and R <4>together means buta-1,3-diene-1,4-diyl, R^ and R<5>mean either together buta-1,3-dien-1,4-diyl or each individually hydrogen or methyl, and R<4> or R<2> means hydrogen, as well as salts, especially pharmaceutically usable salts thereof.

In particular, the invention relates to compounds of formula I in which Rif means the residue [Rif SV] in which X-X preferably means the vinylene and A-A-A-A means buta-1,3-diene-1,4-diyl or tetramethylene, and in the residue W the symbols R-1- and R<2>C1-C4-alkyl, especially methyl, R<4>means hydrogen or C^-C^-alkyl, especially methyl or tert.-butyl, and R<3>and R<5>mean hydrogen, or in which the radicals R<2> and R<3> together further also R<3> and R<4> together mean buta-1,3-dien-1, 4-diyl, R-'- and R<5>mean either together buta-1,3-diene-1,4-diyl or each individually means hydrogen and R<4>resp. R<2> means hydrogen, or in which R<4> means phenyl and R<1>, R<2>, R<3> and R<5> independently means methyl or above all hydrogen, as well as their salts, especially pharma - sugarically usable salts with bases.

Among the compounds of formula I with the above-mentioned preferred meanings of Rif, those in which the residue W means 4-(2,4,6-trimethylbenzyl)-piperazinyl, 4-(2,6-dimethyl-4-tert) are to be highlighted above all. -butyl-benzyl)piperazinyl, 4-(1-naphthyl-methyl)-piperazinyl, 4-(2-naphthylmethyl)-piperazinyl, 4-(9-anthyrylmethyl)-piperazinyl and 4-(4-biphenylylmethyl)-piperazinyl. Other compounds of formula I which have these residues are also preferred.

Above all, the invention relates to the compounds mentioned in the description and especially in the examples.

In the 4-position of the piperazinyl residue, substituted hydrazones derived from 1-aminopiperazine with 3-formylrifamycin SV or S (not, however, with the corresponding 16, 17, 18, 19-tetrahydro- and 116,17,18,19,28,29-hexahydroanalogs) , was generally already taken into account. Thus, e.g., is described and protected. in US-PS 3,342,810 i.a. antimicrobially active derivatives of 3-formylrifamycin SV also hydrazones of partial formula =N-N(R2)R3, in which Rg and R3 (besides a number of individual meanings for each symbol), both together and together with the nitrogen atom mean a heterocyclic ring with 5-7 atoms. Apart from this definition in patent claim 6, no further characterization of the heterocyclic ring can be found in the description, only in example 9 are specific single compounds (including biological test data) listed in the table, column 3, compound III-XIV. Of these, highlighted in the further text (column 5 lines 64-75 and column 6 lines 30-45), hydrazones of 3-formylrifamycin-SV with l-amino-4-piperazine due to their outstanding antituberculosis action, and are specifically protected in claim 15. This compound has hitherto belonged under the generic name rifampicin to the leading therapeutics for combating tuberculosis. Hydrazones with a 1,4-benzyl-piperazinyl residue are only represented by 3-(4-benzyl-2,6-dimethylpiperazinyliminomethyl)-rifamycin SV, i.e. compounds with VIII in column 3, which, however, are neither mentioned in the description nor in the claims . The mentioned compounds have a very good antituberculosis effect as well as a clear antibacterial effect, and are therefore proposed in corresponding indications, especially as tuberculostatics for medical use. The possibility of some antiviral or antitumor effect of such compounds was not mentioned in any form or taken into consideration.

In contrast, it was now found that the initially defined new compounds of formula I are indeed also distinguished by the usual antituberculosis effect, moreover, surprisingly, they primarily inhibit the reverse transcriptase, one for retroviruses or the oncoronavirus (such as the RNS tumor and leukemia virus ) characteristic enzyme, retroviruses require this enzyme for their natural replication cycle [Baltimore: Nature, 226. 1209 (1970 ); and Temin and Mizutani: Nature, 226. 1211 (1970)].

The detection of diseases caused by retroviruses is based, for example, on on the following findings: Detection of type C retroviruses and their reverse transcriptase in humans takes place primarily in a T-cell leukemia, the virus was named human T-cell leukemia virus (HTLV-I). In additional T-cell leukemias and

-lymphomas, the same viruses and a corresponding one were found

retrovirus (HTLV-II) [Gallo: Cancer Surveys (Ed. Franks, Wyke and Weiss), vol. 3, pp. 113-160; Oxford Univ. Press. (1984)]. Finally, such a virus was also isolated in connection with the AIDS (Acquired Immune Deficiency Syndrome) disease. [Gottlieb et al., Morbid. Mortal. Weekly Rep., 30, 25 (1981); Friedman-Kien et al., Morbid Mortal. Weekly Rep., 30, 305

(1981); Gottlieb et al., New Eng. J. Med. 305, 1425 (1981); Masur: New Engl. Med., 305, 1439 (1981 ); CDC Task Force on Kaspoi's Sarcoma and Opportunistic Infections, New Engl. J. Med., 306. 248 (1982)]; these were initially designated HTLV-III or LAV [Essex et al., Science, 220, 859 (1983), Celmann et al., Science, 220, 862 (1982); Callo et al.; Science, 220. 868 (1983); Hirsch and Levy: Viruses in Human Malignancy and AIDS, ASC0/AACR Symposium, May 1984, Toronto]. The currently valid name for this group of viruses is HIV.

These retroviruses belonging to the HTLV family require the reverse transcriptase for the formation of a double-stranded DNA (provi-virus) which "integrates" into the cell cenome and can lead to the malignant transformation [Strayer and Gillespie, The Nature and Organization of Retroviral Genes in Animal Cells, Virology Monographs, Vol. 17 (Springer Ed., 1980)].

While after the induction of malignant leukemic lymphatic or tumorous neoplasms by retroversion a decrease in the reverse transcriptase and viruses HTLV-I and -II can be detected, and secondary oncogenes induced by these viruses control the replication of malignant cells, the virus is HIV, and the reverse transcriptase in AIDS not only detectable in the early stages, but also during the entire course of the disease. The ongoing infection and functional disturbances of immunocompetent T-helper cells finally lead to a breakdown of the immune system with a lethal outcome. It is assumed that an inhibition of the reverse transcriptase virus replication by positive enzyme and virus antigen detection [Beardsley: Nature, 311. 195- (1984)] in patients at risk, e.g. "homosexuals," affects the disease process. In the case of induction of leukemias and lymphomas by retroviruses (HTLV-I and HTLV-II) and possibly also retrovirus-induced sarcomas and mammary carcinomas, a prophylactic application should, on the other hand, be possible, provided that an easy and readily available diagnostic detection of such risk patients.

Also in connection with non-A and non-B hepatitis, the reverse transcriptase has been found as a specific enzyme in association with virus particles [Seto et al.: Lancet, 941 (1984)].

The compounds according to the invention can therefore find application for the prophylaxis and therapy of diseases where the reverse transcriptase is important, above all with the help of the type C retroviruses caused and co-caused malignant diseases, but also certain immune diseases and autoimmune diseases. As tumor diseases, retrovirus-induced leukaemias, lymphomas and lymphosarcomas, as well as possibly also osteosarcomas and mammary carcinomas, come first into consideration. Compounds according to the invention are also particularly suitable for relapse prophylaxis, after surgical therapy, radiation therapy or cytostatic or antimetabolic chemotherapy. As an immune disease, mention should be made of AIDS as an autoimmune disease, systemic Lupus erythematosus, where, according to recent findings, RNS tumor viruses also seem to play an important role [Dennman: Med., Biol. 53, 61 (1975); Panem et al., New England J. Med., 295, 470 (1976)].

Thereby, the compounds according to the invention have a large therapeutic range, as they have a clear toxicity only at high doses, e.g. in the order of 5000 mg/kg.

The new compounds can therefore be used as healing agents primarily for the treatment of infections caused by retroviruses such as e.g. AIDS viruses or viruses of the type HTLV-I or -II. The new compounds according to the invention of formula I (including their salts) can be prepared by with the help of general analogical procedures known per se, e.g. while

a) a 3-formylrifamycin of formula II

in which Rif has the above meaning and Z means a free or functional modified oxo group, is reacted with an N-aminopiperazine of formula III in which W has the above meaning, or

b) an N'-unsubstituted aminopiperazine-derived hydrazone of formula

wherein Rif has the above meaning, is reacted with a compound of formula V

wherein R<1>, R<2>, R<3>, R<4> and R<5> have the above meaning, and Y means the residue of a strong organic or inorganic acid,

and if desired when a compound of formula I in which the quinone form is desired, a compound of formula I present in the hydroquinone form is treated with an oxidizing agent and/or when a compound of formula I in which the hydroquinone form is desired, a compound present in the quinone form is treated with formula I with a reducing agent, and/or a compound of formula I present in free form, is transferred in a salt thereof, or a free compound of formula I is released from a salt thereof.

The reaction is an I formula II corresponding to 3-formylrifamycin or a reactive functional derivative thereof, with hydrazines of formula III, takes place in a manner known per se, e.g. according to the above-mentioned US-PS 3,342,810. In particular, 3-formylrifamycin SV or a partially saturated derivative thereof of formula II, in which Rif [Rif SV] has the above-mentioned meaning and Z means free oxo, and the N-aminopiperazine (III) react in approximately equimolar amounts (or a small excess thereof), and preferably in the presence of an organic solvent such as an alcohol, e.g. methanol, ethanol or isopropyl alcohol, an open-chain or cyclic ether, e.g. diethyl ether, 1,2-dimethoxy- or 1,2-diethoxyethane, tetrahydrofuran or dioxane, an aliphatic ester or amide, e.g. ethyl acetate, e.g. dimethylformamide, also dimethylsulfoxide and acetonitrile, or a mixture thereof, at temperatures of approx. -20° to approx. 70° C, preferably between the zero point and room temperature. The N-aminopyrazine component (III) can also be used in the form of an acid addition salt, and the base is first released in situ by adding a basic auxiliary substance such as an organic alkali metal salt, e.g. sodium or potassium acetate, or a tertiary organic base, such as a tertiary amine," e.g. triethylamine, N-methyl- or N-ethylpiperidine or N-methylmorpholine, or also heterocyclic aromatic base of the pyridine type and its homologues or quinoline. The aldehyde component of formula II can also exist in the form of a functional derivative, e.g. as an alkali metal salt of the hydroquinone form of the starting substance II with a free oxo group, or especially as a reactive derivative with a functionally modified aldehyde group, e.g. as a compound of formula II, in which Rif has the above meaning, in particular means [Rif S], and Z means oximino-, N-substituted imino-, unsubstituted or N-(mono- or di)-substituted hydrazono or semicarbazono group. of the imino and hydrazono group are monovalent hydrocarbon residues, each with a maximum of 8 C atoms, such as in particular alkyl or cycloalkyl residues with a maximum of 7 C atoms, phenyl or benzyl, or analogous divalent residues, such as together with nitrogen the enatom forms a saturated monocyclic heterocycle with 5-7 ring members, and possibly contains an additional heteroatom such as oxygen, sulphur(II) nitrogen, and single nitrogen substituted with C^-C4~alkyl in the ring. Preferred are such substituents and their combinations which give easily volatile amines or hydrazines, especially those with a boiling point at normal or reduced pressure of a maximum of 60°C, methyl having a particular advantage. When using such a derivative and the aldehyde component (II), one also works in a manner known per se analogously to the method discussed for free aldehyde. When component (II) is then used as a salt of a base, it is advantageous to adjust the reaction mixture to a neutral reaction, e.g. by using the second component (of N-aminopiperazine III) in the form of an acid addition salt, or also by careful addition of an acid, such as a carboxylic acid, e.g. acetic acid. When aldehyde component II is used in the form of a derivative with a functionally modified aldehyde group, one can conveniently work in a larger excess of hydrazine component (III), which then simultaneously serves as a solvent. The reaction conditions, above all temperature and pressure, are thereby set so that the volatile reaction products (e.g. amines or hydrazines with formula ZH2) which are released by the exchange reaction from the starting material (II) are removed from the reaction mixture by distillation. Appropriately, the pressure is reduced so that the temperature during distillation does not exceed approx. 60°C, preferably about 40°C. However, under similar conditions, the exchange can also be carried out in an inert organic solvent such as one of the above, e.g. dimethyl sulfoxide.

The compounds used as starting materials are either known or available by usual standard procedures from synthetic organic chemistry. Thus, the N-substituted N-aminopiperazines of formula III can e.g. is obtained by nitrosation, (e.g. by means of in situ liberated nitric acid or nitrogen dioxide N2O4) of the corresponding singly substituted piperazine, with formula HW, in which W has the above-mentioned meaning, and subsequent usual reduction when the nitrosamine formed, e.g. e.g. by means of a complex hydrin, such as lithium aluminum hydride in particular, or by catalytic hydrogenation.

The monosubstituted piperazines of formula HW are prepared, if they are not already known, in a general manner known per se, whereby piperazine or a derivative thereof protected by one of its nitrogen atoms is reacted with an equimolar amount of a reactive functional derivative of a corresponding benzyl alcohol, e.g. a compound of the above-mentioned formula V in which Y and R^ - R^ have the above-mentioned meaning, and the possibly present protecting group is cleaved off. As protecting groups, all common protecting groups known in particular from peptide chemistry can be used, e.g. solvolytically or hydrogenolytically cleavable protective groups, such as tert.-butyloxycarbonyl (BOC) or benzyloxycarbonyl, as their cleavage takes place according to known general methods. The reaction with the reagent V is also carried out in a generally known manner, e.g. as discussed below in method variant b).

The 3-formylrifamycin compounds used as starting material are already known, compare e.g. the aforementioned US-PS 3,342,810 or available as known, e.g. general methods mentioned in this patent. In this way Introduce e.g. advantageously the 3-formyl group in compounds with an already partially saturated basic structure, i.e. in the corresponding tetrahydro- and hexahydrorifamycin derivatives. These again you get e.g. from similarly known 3-aminomethylrifamycins with saturation of the double bonds taking place in a manner known per se, especially under generally known reaction conditions of catalytic hydrogenation using conventional hydrogenating agents. Thus, one works with hydrogen gas at normal or elevated pressure under conditions of heterogeneous or homogeneous catalysis. As catalysts for the former, finely divided metals, e.g. Raney metals such as Raney nickel or noble metals, such as palladium, platinum or rhodium, which may be distributed on a carrier such as calcium carbonate or barium sulphate. For homogeneous catalysis, particularly complex rhodium compounds are used, e.g. tris-(triphenylphosphine )-rhodium(I ) chloride. The conditions can be modified so that a less reactive isolated 28,29-double bond is not co-reduced, e.g. interrupts the hydrogenationf by consuming two equivalents of hydrogen, and isolates the resulting 16,17,18,19-tetrahydro derivative, in particular a milder catalyst can be used for this purpose, such as e.g. palladium on a support, e.g. activated carbon or calcium carbonate, as the reaction under normal pressure and room temperature spontaneously stops when two equivalents are consumed. When using stronger catalysts, e.g. platinum, especially in the in situ as platinum oxide-reduced form, the hydrogenation can be continued until saturation of all three double bonds, which under normal conditions leads to spontaneous cessation of the hydrogenation, and to the formation of the corresponding 16,17,18,19,28,29 -hexahydro derivatives.

According to their nature, the hydrogenation leads to the formation of an asymmetry center at C(16) and thus to the mixture of epimers that differ from each other by the steric arrangement of the C(30) methyl placed at C(16). Due to the very difficult and wasteful separation of the epimer by physical methods, the resulting epimer mixture is usually considered to be used as a uniform process product. As the partially saturated starting materials at one stage or another of their preparation require an analogous hydrogenation of their unsaturated base compounds which gives one epimer mixture, all the 16,17,18,19-tetrahydro- and 16,17,18,19,28 mentioned here are ,29-hexahydrorifamycin compounds in general, when nothing else is expressly stated, also to be considered a mixture of both C(16) epimeric forms. The novel arrangement of the double bonds in the 16,17,- 18,19-, 28,29 position corresponds to that of unsaturated rifamycin compounds of natural origin.

In process variant b) a compound of formula V in which Y is e.g. means the residue of a halogen such as chloro, bromic or iodohydrogen acid, an oxygen-containing inorganic acid such as sulfuric acid, phosphoric acid, silicic acid, or a halogen sulfonic acid such as fluorosulfonic acid, or an organic sulfonic acid such as an aliphatic or aromatic sulfonic acid, e.g. . a lower alkanesulfonic acid, or a possibly e.g. with lower alkyl or nitro substituted benzenesulfonic acid. Y means in particular chlorine or bromine, further methanesulfonyloxy or p-touenesulfonyloxy.

The reaction preferably takes place in the presence of a base, especially of a strongly basic non-nucleophilic, tertiary amine, especially a corresponding sterically hindered aliphatic and/or araliphatic amine, such as trilower alkylamine, e.g. ethyl diisopropylamine. Thereby, the rifamycin compounds of the alkylating agent are used in equimolar amounts, the base also being preferably added in an equimolar ratio. The reaction is usually carried out in an organic solvent, such as in particular an ether (e.g. one of the above) or a chlorinated aliphatic hydrocarbon (e.g. chloroform or dichloromethane), or in suitable mixtures thereof. The reaction temperature is usually 0-70°C, working at atmospheric pressure.

The starting compounds of formula V are generally known, or can be prepared analogously to the known ones, e.g. by halogen-methylation of a correspondingly substituted benzene derivative, or by introducing the above-mentioned group Y by exchange, against hydroxide, in a correspondingly substituted benzyl alcohol. The starting substances with formula IV are obtained by condensation of the corresponding 3-formylrifamycins with formula II, with N-aminopiperazine, according to the above-mentioned method variant a).

The isolation of the reaction product from a reaction mixture obtained according to the invention takes place in a manner known per se, e.g. by dilution with water, and/or possibly by neutralization with the aqueous acid, such as an inorganic or organic acid, e.g. a mineral acid, or advantageously citric acid, and the addition of a water-immiscible solvent, e.g. a chlorinated hydrocarbon, e.g. chloroform or methylene chloride, the reaction product passing to the organic phase, from which it can be obtained in the usual way by drying, evaporation of the solvent, and crystallization, and/or chromatography of the residue, or other usual purification methods in pure form.

As already mentioned above, the process products obtained according to the invention can be transferred to other process products according to the invention.

As the process products are obtained both in the hydroquinone form with formula I [Rif SV] and in the quinone form with formula I [Rif S] , or a mixture of the two forms is obtained, they can then be transferred in a manner known per se into each other, resp. . a mixture of the two into one of both uniform form. Thereby, the conversion of a quinone obtained according to the method with formula I [Rif SV] resp. a Hydroquinone of formula I [Rif SV] obtained according to the method to a quinone of formula I [Rif S] or the compatibility of a mixture of the two types of compounds is carried out by means of reduction or oxidation, after or advantageously before the isolation of the desired product. The reduction can be carried out by treatment with a reducing agent suitable for the reduction of a quinone or corresponding hydroquinone, such as an alkali metal, e.g. sodium dithionide or -hydrosulphide, zinc and acetic acid, or preferably with ascorbic acid, the oxidation by treatment with an oxidizing agent suitable for converting a hydroquinone into the corresponding quinone, such as atmospheric oxygen, hydrogen peroxide, alkali metal, e.g. potassium ferrocyanide, a persulphate, e.g. ammonium persulfate, furthermore also manganese dioxide, as the oxidation is preferably carried out under basic conditions. The quinones are mostly violet-red to black-colored compounds, while the hydroquinones are usually colored light, e.g. yellow to red, and are better crystallizable.

The compounds produced according to the invention can form salts, particularly acid addition salts and primarily pharmaceutically usable acid addition salts, with inorganic or organic acids, such are i.a. halogen, e.g. hydrochloric and bromic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid, or aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glucolic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, hydroxymaleic acid . , further methionine, tryptophan, lysine or arginine, as well as ascorbic acid. Hydroquinone compounds of the type with formula I [Rif SV] can also form salts with bases, e.g. alkali metal, such as sodium salts.

The salt formation, which, if desired, is to carry out and release the basic forms of the compounds of formula I from their salts, also takes place in a generally known and usual way. Thus hydroquinones of formula I [Rif SV] are transferred into corresponding salts with bases, above all alkali metal salts by treatment with a corresponding base, especially in an alkaline reacting compound such as hydroxide carbonate or bicarbonate, the salts can be converted into free hydroquinone compounds with acidification, e.g. .ex. by inorganic acids, such as especially halogenated hydrogen acids. Alkaline reacting final substances, e.g. the quinones of formula I [Rif S] can be converted into their acid addition salts, e.g. by treatment with an acid suitable for salt formation such as one of the above; conversely, upon treatment with basic reacting agents such as inorganic hydroxides, carbonates or bicarbonates or organic bases and ion exchangers, such a basic basic form of a compound of formula I, [Rif S] is released.

Compounds produced according to the invention can also form internal salts, e.g. by normal acid-base titration to the neutral point, resp. to the isoelectric point.

The salts of the new compounds can also serve to purify the compounds formed, as the free compounds are transferred to the salts and separated, and from these again the free compounds are produced. Due to the narrow relationship between the compounds in free form and in the form of their salts, in the foregoing and the following, free compounds may also possibly mean the corresponding salts.

The invention also relates to the embodiments of the method according to which one starts from a compound obtained as an intermediate in one or another step of the method and carries out the missing steps, or uses a starting substance in the form of a derivative, e.g. salt, or forms it under the reaction conditions.

In the method according to the invention, such starting materials are preferably used which lead to the initially and particularly valuable compounds mentioned.

In view of the above-mentioned pharmacological properties of the new compounds, the present invention also encompasses the use of the active substances according to the invention alone, possibly together with excipients or in combination with other active substances, especially (for the production of) antibiotics or chemotherapeutics, which agent for the treatment of diseases where, as mentioned above, the reverse transcriptase is important, namely both prophylactically and curatively, when used as a healing agent, the active substances according to the invention are administered prophylactically or curative effective amounts, preferably in the form of pharmaceutical compositions together with usual pharmaceutical carrier materials or excipients. Thus, e.g. on warm-blooded animals with a body weight of approx. 70 kg, depending on the species, body weight, age and individual condition, as well as depending on the method of application, and especially depending on the respective sensitivity of the pathogen, daily doses of approx. 50-1000 mg, which in acute cases can also be exceeded several times. Consequently, the invention also includes a corresponding method for the medical treatment of warm-blooded animals, above all humans.

Pharmaceutical compositions contain the compounds according to the invention as active substances, and methods for producing these compositions are also discussed. The industrial production of the active substance is also discussed.

In the case of the pharmaceutical compositions, it concerns e.g. if such for enteral such as peroral or rectal, as well as for parenteral administration on warm-blooded animals. Corresponding dosage unit forms, especially for oral administration, e.g. dragees, tablets or capsules, preferably contain from approx. 50 to 500 mg, especially from approx. 100 to 300 mg of the active substance, together with pharmaceutically usable carriers and auxiliary substances.

Suitable carriers are especially fillers such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch pastes, (using e.g. corn, wheat, rice or potato starch), gelatins, tragacanthfff, methyl cellulose and/or, if desired, explosives, such as the above-mentioned starches, further carboxymethyl starches, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Aids are primarily flow regulating and lubricating agents, e.g. silicic acid, thallium, stearlic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. The Dragee cores can be equipped with suitable, possibly gastric salt-resistant, covers. uses concentrated sugar solutions that may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycols and/or titanium dioxide, or varnish solutions in suitable organic solvents or solvent mixtures, or for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate . Dyes or pigments can be added to the tablets or dragon covers, e.g. for the identification or characterization of different active substance doses.

Furthermore, orally usable pharmaceutical preparations or injectable capsules of gelatin, as well as soft closed capsules of gelatin and an active agent such as glycerol or sorbitol. The injectable capsules can contain the active substance in the form of a granule, e.g. in a mixture with fillers, such as lactose, binding agents such as starches and/or lubricants as well as talc or magnesium stearate, and possibly stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as fatty oils, paraffin oils or liquid polyethylene glycols, as stabilizers may also be added.

As rectally applicable pharmaceutical preparations, there are e.g. considering suppositories which consist of a combination of the active substance with a suppository base. As a suppository base material, it is suitable, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used which contain a combination of the active substance with a base material. As base materials there are e.g. namely liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration, aqueous solutions of a water-soluble form of the active substance, e.g. a water-soluble salt or aqueous injection suspensions, which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran, and possibly stabilizers. Thereby, the active substance, possibly together with the excipients, can also be present in the form of a lyophilisate and dissolved before parenteral administration by adding suitable solvents.

The pharmaceutical mixtures can be prepared in a manner known per se, e.g. using conventional mixing, granulation-coating, dissolution, and lyophilization methods. Thus, pharmaceutical preparations for oral use can be obtained by combining the active substance with solid carriers, granulating a formed mixture, possibly and processing the mixture or the granulate if desired or necessary, or the addition of suitable excipients for tablets or dragee cores.

The invention will be explained in more detail with the help of some examples, where the temperatures are indicated in "C.

Example I.

3- formvl- 16. 17. 18, 19- tetrahydrorifamycin SV.

To a solution of 2.4 g of tetrahydrorifamycin S in 25 ml of THF (tetrahydrofuran), 1.21 g of manganese dioxide, 1.5 ml of tert-butylazomethine and 0.34 ml of tert-butylamine are added in order. The violet solution is stirred for 18 hours at 50°C, then filtered over diatomaceous earth, concentrated to 15 ml and mixed with 2.3 g of ascorbic acid and 10 ml of 16# aqueous sulfuric acid. The solution is stirred for 3 hours at 45°C, cooled to 5°C, mixed with water, and extracted at pH 3.5 three times with ethyl acetate. The organic phases are washed with water, dried and evaporated. Chromatography of the crude product on silica gel and crystallization from acetone-ether-petroleum ether gives 3-formyl-16,17,18,19-tetraphydrorifamycin SV (16-epimer mixture) with m.p. 215-220'C. Mass spectrum: m/z = 729 (M<+>) corresponding to formula C38<H>52NO23.

360 MHz-^H-NMR (CDCI3): 10.5 ppm (-CH=0) [olefinic protons shifted to right field],<13>C-NMR (CDCI3): 191.94 (-CH-0), 42.18 (C-16), 35.74 C-19), 30-62 C-18), 20.38 (C-17) ppm.

Example 2.

3- formvl- 16. 17. 18. 19. 28. 29- hexahvdrorifamvcin SV.

Analogously to example 1, 4.5 g of 16,17,18,19,28,-29-hexahydrorifamycin S is prepared in 50 ml of THF, 2.25 g of methane dioxide, 2.8 ml of tert.butylazomethine, 1.2 ml of tert .-butylamine, 1.9 g of ascorbic acid, and 20 ml of 16^-ig aqueous H2SO43-formyl-16,17,18,19,28,29-hexahydrorifamycin Sv (16-epimer mixture), m.p. 148-151"C. Mass spectrum m/z = 731, corresponding to the formula C38<H>53N013- 360MHz-<1>H-NMR (CD3OD): 10.-50 ppm (-CH-0)

[olefinic protons missing],<13>C-NMR (CD3OD): 19.4.60 (-CH=0), 66.49 (C-29), 44.48 (C-16), 36.16 ( C-19), 32.50 (C-18), 31.02 (C-28), 22.97 (C-17) ppm.

Example 3.

3-f4-(2.4.6-trimethylbenzyl)-plperazinylaminomethyl]-rifamycln SV.

For a solution of 5 g of 3-formylrifamycin SV in 100 ml. 2 g of 1-amino-4-(2,4,6-trimethylbenzyl)-piperazine are added to THF. The dark red reaction solution is stirred for 10 minutes at room temperature, and then concentrated in vacuo. The concentrate is washed with water and extracted at pH 3.5 with methylene chloride. The organic phase is dried over Na2SO4 and evaporated. The residue is crystallized from ether-hexane, obtaining red crystals of m.p. 161-168°C (under decomposition). Mass spectrum: m/z = 939 (M-H)<+>, corresponding general formula<C>52<H>68N4°12-<13>C-NMR (CDCl3): 134.70 (-C-N-N); 137.89 (2C), 136.52, 131.11, 128.95 (2C) (aromat. C); 56.95 On-COCHC2); 51.31, 50.63 (2C) (piperazinyl-C) ppm.

A. Sodium salt.

To prepare the sodium salt, equivalent amounts of 3-[4-(2,4,6-trimethylbenzyl)-ipierazinyliminomethyl]-rifamycin SV and sodium bicarbonate are dissolved in - a mixture of dioxane and water, and the solution is lyophilized.

B. 3- f4-(2, 4, 6- trimethylbenzyl)- ipierazinyliminomethyl1 - rifamycln S (oxidase. ion to quinone).

A solution of 2 g of 3-[4-(2,4,6-trimethylbenzyl)-ipyrazinylIminomethyl]-ribamycin SV in 50 ml of methylene chloride is stirred well with 4 g of powdered manganese dioxide at room temperature, until According to thin layer chromatography (DC) of the starting material has disappeared. The solid parts are filtered off and the filtrate is evaporated to dryness. 2 g of the title compound of the S series is obtained as an amorphous blue-black solid, without a sharp melting point.

Mass spectrum m/z = 937 (M-H)<+>corresponding sum formula<C>52<H>66<N>4°12-

C. Preparation of the starting material.

The 1-amino-4-(2,4,6-trimethylbenzyl)-piperazine used as starting material can be prepared as follows:

a) Benzylation of piperazine.

To a solution of 25.3 g of piperazine hexahydrate in 100 ml

ethanol, add 20 g of 2,4,6-trimethylbenzyl chloride, dissolved in 50 ml of ethanol. The solution is heated overnight below reflux temperature. After cooling, alcohol is removed under vacuum. The residue is suspended in 100 ml of 2N NaOH, and extracted with methylene chloride. The combined organic extracts are dried and evaporated. The crystalline residue (26 g) is distilled in high vacuum. The oily distillate (12 g) solidifies to colorless crystals of N-(2,4,6-trimethylbenzyl)-piperazine, m.p. 103-104°C.

Mass spectrum: m/z = 218 (M<+>), corresponding to the formula <C>14<H>22<N>2-

b) Nitroses ring:

An aqueous solution of 5.86 g of N-(2,4,6-trimethylbenzyl)piperazine is brought at 5°C with concentrated hydrochloric acid to pH 1.1, and treated while cooling at 0-5°C dropwise with a solution of 3.8 g of sodium nitrite in 5 ml of water, stirred for a further 2 hours at 5-10° C, and set with approx. 58 ml of aqueous 2N solution of caustic soda to pH 13. The reaction mixture is extracted with 3 portions of 80 ml each of ethyl acetate, and the combined organic solutions are dried with sodium sulphate and evaporated. The oily residue is used without purification for the next step.

c) Reduction:

To a stirred suspension of 1.71 g of lithium aluminum hydride in 150 ml of tetrahydrofuran is added dropwise at reflux temperature a solution of 6.76 g of crude 1-nitroso-4-(2,4,6-trimethylbenzyl)-piperazine (prepared according to step b)) in 30 ml of tetrahydrofuran. The reaction mixture is stirred for a further 3 hours at room temperature, mixed under ice-cooling with 10 ml of aqueous 2N sodium hydroxide solution and then with 10 ml of water, and stirred for a further 2 hours at room temperature. The precipitate is removed by suction and the nut is washed with warm isopropyl alcohol. The filtrate (as well as the isopropyl alcohol portion) evaporated in vacuum gives the desired 1-amino-(2,4,6-trimethylbenzyl)-piperazine as a slightly yellow oil in a purity sufficient for the above-mentioned hydrazone formation.

In an analogous way, the following four substituted N-amino-piperazines can also be prepared in process steps a-c, starting from the corresponding halide (chloride or bromide), which are further used as raw product. 1-amino-4-(1-naphthylmethyl)-piperazine; 1-amino-4,(2,6-dimethyl-4-tert-butylbenzyl)-piperazine; 1-amino-4-(4-biphenylylmethyl)-piperazine; 1-amino-4-(4-tert-butylbenzyl)-piperazine; 1-amino-4-(9-anthrylmethyl)-piperazine; 1-amino-4-(2,3-dimethylbenzyl)-piperazine; 1-amino-4-(2,4-dimethylbenzyl)-piperazine; 1-amino-4-(2,5-dimethylbenzyl)-piperazine; 1-amino-4-(2,6-dimethylbenzyl)-piperazine; 1-amino-4-(3,4-dimethylbenzyl)-piperazine and 1-amino-4-(3,5-dimethylbenzyl)-piperazine.

Example 4.

3-[4-(2,4,6-trimethylbenzyl)-piperazinyliminomethyl]-16,17,18,19-tetrahydro-rifamycin SV.

To a solution of 0.3 g of 3-formyl-16,17,18,19-tetrahydro-rifamycin SV in 20 ml of THF is added 0.12 g of 1-amino-4-(2,4,6-trimethylbenzyl)-piperazine . The dark red reaction solution is stirred for 10 minutes at room temperature, and then concentrated. The concentrate is mixed with water and extracted at pH 3.5 with methylene chloride id. The organic phase is dried with Na2SO4 and evaporated. The residue is crystallized from ether-petroleum ether. The title compound formed decomposes by melting point determination in wide temperature limits above 100°C. Mass spectrum: m/z = 943 (M-H)+, corresponding to general formula C52<H>72<N>4°12- 360-MHz-NMR (CDC13): 8.17 (CH=N); 3.53 (N-CH2): olefinic H-17, 18, 19 absent, 6.85 (2 aromatic protons) ppm.

<13>C-NMR (CDCl 3 ): 134.13 (CH=N); 138.04 (2C), 136.70, 131.19, 129.11 (2C) (aromat. C); 57.07 (N-CH 2 ), 51.59 (2C); 51.26 (2C) (piperidyl-C); 43.85 (C-16); 35.53 (C-19); 31.40 (C-18); 21.45 (C-17) ppm.

A. Sodium salt.

To prepare the sodium salt, equivalent amounts of 3-[4-(2,4,6-trimethylbenzyl)-piperazinyliminomethyl]-16,17,18, 19-tetrahydrorifamycin SV and sodium bicarbonate are dissolved in a mixture of dioxane and water, and the solution is lyophilized.

B. 3-[4-(2,4,6-trimethylbenzyl)-piperazinyliminomethyl]-16,17,18,19-tetrahydro-rifamycin S (oxidation to quinone).

A solution of 2 g of the hydroquinone compound prepared in the main example in 50 ml of methanol is mixed with 10 ml of a 10% solution of ferricyanide in 10% sodium bicarbonate solution and stirred intensely for 5 minutes. It is then carefully acidified with a 10% citric acid solution to pH 3.5, and the aqueous phase is extracted 3 times with methylene chloride. The organic phase is dried and evaporated. 2 g of the title compound are obtained as a blue-black solid without a sharp melting point. Mass spectrum: m/z = 941 (M-H)<+>corresponding to the formula C52<H>70<N>4<O>12.

Example 5.

3-[4-(2,4,6-trimethylbenzyl)-piperazinyliminomethyl]-16,17,18,19,28,29-hexahydrorifamycin SV.

To a solution of 0.3 g of 3-formyl-16,17,18,19,28,29-hexahydrorifamycin SV in 20 ml of THF is added 0.12 g of 1-amino-4-(2,4,6-trimethylbenzyl) -piperazine. The dark red reaction solution is stirred for 30 minutes at room temperature and concentrated in vacuo. The concentrate is mixed with water and extracted at pH 3.5 with methylene chloride. The organic phase is dried over Na2SO4 and evaporated. The residue is crystallized from ether-petroleum ether, the resulting title compound melts with cleavage in a wide temperature range above 125 0 C. Mass spectrum: m/z = 945 (M-H)<+>, corresponding to the general formula C52<H>74<N>4°12- 260 -MHz-NMR (CDCl3)<:>8.20 (CH=N-), 8.85 (2 aromatic, protons), 3.55 (N-CH2-), olefinic H-17,18,19,28 ,29 , missing, ppm.<13>C-NMR (CDCl3); 134.53 (-CH-N); 138.66 (2C), 137.31, 131.77, 129.62 (2C) (aromat. C); 56.04 (N-CH 2 ), 51.78 (2C) (piperidyl-C); 65.91 (C-29); 44.49 (C-16; 37.05 (C-19); 31.90 (C-18); 30.12 (C-28); 22.79 (C-17) ppm.

Sodium salt.

To prepare the sodium salt, equivalent amounts of the title compound are dissolved in sodium bicarbonate in a mixture of dioxane and water, and the solution is lyophilized.

Example 6.

3-[4-(4-biphenylmethyl)-piperazinyliminomethyl]-rifamycin SV.

To a solution of 1 g of 3-formylrifamycin SV in 30 ml of THF is added 0.5 g of 1-amino-4-(4-biphenylylmethyl)-piperazine. The dark red reaction solution is stirred for 10 minutes at room temperature and concentrated in vacuo. The concentrate is mixed with water and extracted at pH 3.5 with methylene chloride. The organic phase is dried with Na2SO4 and evaporated. The residue is crystallized from acetone-ether-hexane, obtaining red crystals of m.p. 164-167°C during decomposition. Mass spectrum: m/z = 974 (M<+>), corresponding to the formula C55<H>55<N>4O22• 360-NHz-<1>H-NMR (CDCl3): 8.21 (-CH-N) 7 .3-7.7 (aromatic, proton);

3.62 CN-CH2-) ppm.<13>C-NMR (CDCl3): 134.28 (CH-N-); 140.82, 140.31, 136.83, 129.41 (2C), 128.77 (2C), 127.29, 127.06 (4C), (aromat. C); 62.26 (CH 2 -10; 51.82 (2C), 50.45 (2C), piperidyl-C) ppm.

Sodium salt.

To prepare the sodium salt, equivalent amounts of the title compound and sodium bicarbonate are dissolved in a mixture of dioxane and H 2 O and the solution is lyophilized.

Example 7.

3-[4-(4-biphenylylmethyl)-piperazinyliminomethyl]-16,17,18,19-tetrahydro-rifamycin SV.

54 mg of 1-amino-4-(4-aminobiphenylylmethyl)-piperazine is added to a solution of 0.1 g of 3-formyl-16,17,18,19-tetrahydrorifamycin SV in 10 ml of THF. The dark red reaction solution is stirred for 16 minutes at room temperature and concentrated in vacuo. The concentrate is mixed with water and extracted at pH 3.5 with methylene chloride. The organic phase is dried with Na2SC>4 and evaporated. The residue is precipitated from ether-hexane. The amorphous title compound formed has the following physical data:

Mass spectrum: m/z = 978 (M<+>) corresponding sum formula<C>55<H>70<N>4°12'360-MHz-NMR (CDCl3)<:>8.20 (-CH=N) , 7.3-7.7 (aromatic, protons); 3.6"5 (N-CH2) ppm; olefinic 17,18,19 protons missing.<13>C-NMR (CDCl3): 134.20 (-CH=N-); 140.85, 140.36 , 136.90, 129.40 (2C), 128.80 (2C), 127.30, 127.10 (4C) (aromat. C); 62.24 (^N-CH2-); 52.10 ( 2C), - 50.98 (2C)

(piperazinyl-C); 43.93 (C-16); 36.59 (C-19); 31.48 (C-18); 21.47 (C-17) ppm.

Natrlum salt.

To prepare the sodium salt, equivalent amounts of the title compound and sodium hydrogen carbonate are dissolved in a mixture of dioxane and water, and the solution is lyophilized.

Example 8.

3-[4-(4-biphenylylmethyl)-piperazinyliminomethyl]-16,17,18,19,28,29-hexahydrorifamycin SV.

To a solution of 0.1 g of 3-formyl-16,17,18,19,28,29-hexahydrorifamycin SV in 10 ml of THF is added 54 mg of 1-amino-4-(4-biphenylylmethyl)-piperazine. The dark red reaction solution is stirred for 10 minutes at room temperature and concentrated in vacuo. The concentrate is mixed with water and extracted at pH 3.5 with methylene chloride. The organic phase is dried with Na2SO4 and evaporated. The residue is precipitated from ether/hexane, giving the title compound in amorphous form.

Mass spectrum: m/z = 980 (M<+>), corresponding to general formula C55<H>72N4°12>360-MHz-NMR (CDCl3): 8.21 (-CH-N-); 7.3-7.7 (aromatic, proton); 3.65 CN-CH2)PPm5olefinic H-17,18,19,28, 29 missing. 13 C-NMR (CDCl3): 140.85, 140.31 (2C), 136.91, 129.42 (2C), 128.80 (2C), 127.50, 127.10 (4C) (aromat. C); 65.26 (C-29); 62.26 (~N-CH 2 ); 52.18 (2C), 50.92 (2C)

(piperazinyl-C); 43.94 (C-10); 36.49 (C-19); 31.40 (C-18), 29.57 C-28) (C-17) ppm.

Natrlum salt.

To prepare the sodium salt, equivalent amounts of the title compound and sodium bicarbonate are dissolved in a mixture of dioxane and water, and the solution is lyophilized.

Example 9

3-[4-(2,6-dimethyl-4-tert.-butyl-benzyl)-piperazinyl iminomethyl]-rifamycin SV.

To a solution of 1 g of 3-formylrifamycin SV in 20 ml of THF is added 0.94 g of 1-amino-4-(2,6-dimethyl-4-tert-butyl-benzyl)-piperazine. The dark red reaction solution is stirred for 60 minutes at room temperature and evaporated to dryness. The crude product is mixed with water and extracted at pH 3.5 with methylene chloride. The organic phase is dried with Na2SO4 and evaporated. The residue is crystallized from ether-petroleum ether, obtaining red crystals of the title compound with m.p. 171-174°C during decomposition.

Mass spectrum: m/z = 982 (M<+>) corresponding sum formula

C52<H>74N4°12'360-MHz-1H-NMR-(CDCl3); 8.20 (-CH=N); 7.04 (2H, arom); 2.40 + 2.24 (2 arom. CH3), 1.32 (3 CH3 from tert.-butyl) ppm.<13>C-NMR (CDCl3): 124.00 (-CH=N); 149.81 (aromat. C); 137.51 (2C); 131.20, 125.15 (2C), 55.5 CIN-CH 2 ); 5.135 (2C); 50.67 (2C) (piperazinyl-C); 34.13 (tert-butyl); 31.27 (3C, tert-butyl) ppm.

Natrlum salt.

To prepare the sodium salt, equivalent amounts of the title compound and sodium bicarbonate are dissolved in a mixture of dioxane and water, and the solution is lyophilized.

Example 10.

3-[4-(1-Naphthylmethyl)-piperazinyliminomethyl]-rifamycin SV.

To a solution of 5 g of 3-formylrifamycin SV in 100 ml of THF is added 1.98 g of 1-amino-4-(1-naphthylmethyl)-piperazine. The dark red reaction solution is stirred for 10 minutes at room temperature and concentrated in vacuo. The concentrate is mixed with water and extracted at pH 3.5 with methylene chloride. The organic phase is dried with Na 2 SC 4 and evaporated. The residue is crystallized from ether, obtaining red crystals of the title compound with m.p. 165-169°C during cleavage.

Mass spectrum: m/z = 947 (M-H)~, corresponding to'sum formula<C>53<H>64N4°12-<13>C-NMR (CDCl3): 134.75 (CH=N-); 133.84, 133.33, 132.42, 129.34, 127.41, 125.70, k25.02, 124.62, 123.14 (10 naphthyl-C); 60.77 (N-CH 2 -); 51.88 (2C), 50.34 (2C) (piperazinyl-C) ppm.

The sodium salt.

To prepare the sodium salt, equivalent amounts of the title compound and sodium bicarbonate are dissolved in a mixture of dioxane and water and the solution is lyophilized.

Example II:

3-[4-(9-Anthrylmethyl)-piperazinyliminomethyl]-rifamycin SV.

To a solution of 1 g of 3-formylrifamycin SV in 20 ml of THF is added 0.85 g of 1-amino-4-(9-anthrylmethyl)-piperazine. The dark red reaction solution is stirred for 90 minutes at room temperature and concentrated in vacuo. The concentrate is mixed with water and extracted at pH 3.5 with methylene chloride. The organic phase is dried with Na2SO4 and evaporated. The residue is crystallized from acetone-ether-hexane, obtaining red crystals of the title compound with m.p. 168-173"C during cleavage.

Mass spectrum: m/z = 998 (M<+>), corresponding to formula C57<H>66<N>4<0>12, 360-MH-1H-NMR (CDC13); 8.37 (-GH-N-); 7.5 + 8.0 (aromatic, protons); 4.45 (N-CH2-)ppm.<13>C-NMR (CDCl3): 133.89 (-CH=N-); 131.13 (2C), 131.06 (2C), 129.06 (2C), 127.63, 125.47 (2C), 124.63 (2C), 124.54 (2C) (aromatic C); 53.52 (N-CH 2 -); 51.51 (2C), 50.29 (2C) (piperazinyl-C) ppm.

The sodium salt.

To prepare the sodium salt, equivalent amounts of the title compound and sodium bicarbonate are dissolved with a mixture of dioxane and water, and the solution is lyophilized.

Example 12.

3-[4-(9-anthrylmethyl)-piperazinyliminomethyl]-16,17,18,19-tetrahydrorifamycin SV.

To a solution of 0.2 g of 3-formyl-16,17,18,19-tetrahydrorifamycin SV in 10 ml of THF is added 160 mg of 1-amino-4-(9-anthryl-methyl)-piperazine. The dark red reaction solution is stirred for 10 minutes at room temperature and concentrated in vacuo. The concentrate is mixed with water and extracted at pH 3.5 with methylene chloride. The organic phase is dried with NaCl and evaporated. The residue is precipitated with ether-petroleum ether, whereby the title compound appears in amorphous form.

Mass spectrum: m/z = 1002 (M<+>), corresponding to formula C57<H>7oN4012, 360-MHz-1H-NMR (CDCl3): 8.48 (-CH=N-); 4.52 (-CH 2 ) ppm; olefinic H-17, H-18, H-19 missing.<13>C-NMR-CDCl3): 134.38 (-CH=N-); 131.46 (2C), 131.40 (2C), 128.86, 127.82, 125.78 (2C), 124.95 (2C), 124.83 (2C) (aromat. C); 53.84 (N-CH 2 -); 52.05 (2C), 51.17 (2C) (piperazinyl-C); 45.90 (C-16); 31.40 (C-17); 21.44 (C-18); 36.54 (C-19) ppm.

The sodium salt.

To prepare the sodium salt, equivalent amounts of the title compound are dissolved in sodium bicarbonate in a mixture of dioxane and water, and the solution is lyophilized.

Example 13.

Analogous to example 3, the following hydrazones are obtained by reacting 3-formylrifamycin SV with correspondingly substituted 1-amino-4-benzylpiperazines at the phenyl ring: 3-[4-(4-methylbenzyl)-piperazinyliminomethyl]-rifamycin SV; 3-[4-(2,3-dimethylbenzyl)-piperazinyliminomethyl]-rifamicln

SV;

3-[4-(2,4-dimethylbenzyl)-piperazinyliminomethyl]-rifamycin SV and 3-[4-(4-tert-butylbenzyl)-piperazinyliminomethyl]-rifamycin

SV.

To prepare a corresponding sodium salt, equimolar amounts of one of these compounds and sodium bicarbonate are dissolved in a mixture of dioxane and water, and the solution is lyophilized.

Example 14.

Analogous to example 4, the following hydrazones are obtained by reacting 3-formyl-16,17,18,19-tetrahydro-rifamycin SV with correspondingly substituted 1-amino-4-benzylpiperazines at the phenyl ring: 3-[4-(4-methylbenzyl)-piperazine-1iminomethyl ]-16,17,18,19-tetrahydrorifamycin SV;

3-[4-(2,3-dimethylbenzyl)-piperazinyliminomethyl]-16,17,18,19-tetrahydro-rifamycin SV;

3-[4-(2,4-dimethylbenzyl)-piperazinyliminomethyl]-16,17,18,19-tetrahydro-rifamycin SV;

3-[4-(2,6-dimethylbenzyl)-piperazinyliminomethyl]-16,17,18,19-tetrahydro-rifamycin SV as well as

3-[4-(4-tert-butylbenzyl)-piperazinyliminomethyl]-16,17,18,19-tetrahydro-rifamycin SV.

To prepare a corresponding sodium salt, one dissolves equimolar amounts of one of these compounds of sodium bicarbonate in a mixture of dioxane and water and lyophilizes the solution.

Example 15.

Analogous to example 5, the following hydrazones are obtained by reaction of 3-formyl-16,17,18, 19,28,29-hexahydro-rifamycin SV with correspondingly substituted 1-amino-4-benzylpiperazines at the phenyl ring: 3-[4-(4- methylbenzyl)-piperazinyliminomethyl]-16,17,18,19,28,29-hexahydrorifamycin SV;

3-[4-(2,3-dimethylbenzyl)-piperazinyliminomethyl]-16,17,18,19,28,29-hexahydrorifamycin SV;

3-[4-(2,4-dimethylbenzyl)-piperazinyliminomethyl]-16,17,18,19,28,29-hexahydrorifamycin SV;

3-[4-(2,6-dimethylbenzyl)-piperazinyliminomethyl]-16,17,18,19, 28,29-hexahydro-rifamycin SV as well as

3-[4-(4-tert-butylbenzyl)-piperazinyliminomethyl]-16,17,18,19,28,29-hexahydrorifamycin SV.

To prepare a corresponding sodium salt, equimolar amounts of one of these compounds and sodium bicarbonate are dissolved in a mixture of dioxane and water, and the solution is lyophilized.

Example 16.

Capsules, containing 250 mg of 3-[4-(2,4,6-trimethylbenzyl)-piperazinyliminomethyl]-rifamycin SV, can be prepared as follows: Composition (for 1000 capsules): 3-[4-(2,4,6- trimethyl-benzyl)-piperazinyliminomethyl]-rifamycin

The active substance and the maize starch are mixed, moistened with a solution of polyvinylpyrrolidone in 50 g of methanol. The moist mass is pressed through a sieve with a mesh size of 3 mm 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 in portions of 0.320 g in size 0 injection capsules.

Alternatively, the other compounds prepared according to examples 3-15 can also be used as active substance components.

Claims (10)

1. Process for the preparation of compounds of formula I in which Rif means a residue with partial formula wherein A-A-A-A means buta-1,3-diene-1,4-diyl and X-X means vinylene or A-A-A-A tetramethylene and X-X means ethylene or vinylene, and wherein W means a piperazinyl residue of partial formula W in which each of the residues R-^,R<2>,R<3>,R4 and R<5> together with its neighboring residue can mean a divalent aliphatic hydrocarbon residue with 3-10 C atoms, which together with the corresponding two C -atoms of the central phenyl group form an anylated 5- or 6-membered carbocyclic ring, the other residues being hydrogen or C^-Cj-alkyl, or in which R<4>means a C^-C^2~alkyl, phenyl or hydrogen, and R<1>, R<2>, R<3> and R5 independently each mean a Ci-C4 alkyl or hydrogen, at least one of all residues must be different from hydrogen, or a salt thereof, characterized by a) a 3-formylrifamycin of formula in which Rif has the meaning stated in claim 1 and Z means a free or functional modified oxo group, is reacted with an N-aminopiperazine of formula in which W has the meaning stated in claim 1, or b) a hydrazone derived from N'-unsubstituted aminopiperazine with the formula in which Rif has the meaning stated in claim 1, is reacted with a compound of formula in which R<1>, R<2>, R<3>, R<4> and R<5> have the meaning stated in claim 1, and Y means the remainder of a strongly inorganic or organic acid, and if desired, if it is desired with a compound of formula I in quinone form, treat a compound of formula I present in hydroquinone form, with an oxidizing agent and/or when desired, with a compound of formula I In hydroquinone form, treat one in quinone form present compound of formula I with a reducing agent and/or a compound of formula I present in free form is transferred to a salt thereof, or a free compound of formula I is released from a salt thereof. 2. Process according to claim 1 for the preparation of compounds of formula I in which Rif has the meaning stated in claim 1, and in W each of the symbols R<1> and R<2> independently means each C1-C4 alkyl, R<3> and R<5>independently means each hydrogen, or C1-C4-alkyl, and R<4>means phenyl or C1-C4-alkyl» orr<2>means together with R<3>or R<3>together with R <4>an optionally substituted buta-1,3-diene-1,4-diyl, trimethylene or tetramethylene with C₁-C₄ alkyl, R₂ and R<5> together have one of these meanings, or each means individually hydrogen or C1-C4-alkyl, wherein R<4>resp. R<2> means hydrogen or C₁-C₄ alkyl, or a salt thereof. 3. Process according to claim 1 for the preparation of a compound of formula I, in which Rif has the meaning mentioned in claim 1, and in W each of the symbols R-* and R<3>Cj-C^-alkyl, R<4>means hydrogen, a linear C 5 -C 8 alkyl or a C 1 -C 4 alkyl, and R<3> and R<5> are hydrogen or a salt thereof. 4. Process according to claim 1 for the production of compounds of formula I, in which Rif has the meaning stated in claim 1, and in W each of the symbols R'<1>, R<2>, R<3> and R<5> means hydrogen or methyl and R<4> means phenyl, methyl or tert.-butyl, or if at least one of the other residues means methyl, also means hydrogen or a salt thereof. 5. Method according to claim 1 for the production of ■compounds of formula I, in which Rif has the meaning stated in claim 1, and in W the symbols R<2> and R<3> together or R<3> and R<4> together mean buta -1,3-dlene-1,4-diyl, R<1>and R<5> together mean buta-1,3-dien-1,4-diyl or each individual hydrogen or methyl, and R<4>resp . Rg means hydrogen or a salt thereof. 6. Method according to one of claims 1-5 for the preparation of compounds of formula I, in which Rif means one of the residues [Rif SV] or [Rif S], in which A-A-A-A means buta-1,3-diene-1,4-diyl or tetramethylene and X-X means the vinyl. 7. Process according to one of claims 1-6 for the preparation of compounds of formula I, in which Rif means [Rif SC]. 8. Process according to claim 1 for the preparation of compounds of formula I, in which Rif means [Rif SV] and W means 4-(2,4,6-trimethyl)benzyl)-piperazinyl or a salt thereof. 9. Process according to claim 1 for the preparation of compounds of formula I, in which Rif means [Rif SV] and W means 4-(2,6-dimethyl-4-tert-butylphenyl)-piperzinyl, or in which Rif means [Rif SV] and W means 4-(1-naphthylmethyl)-piperazinyl, or wherein Rif is methyl [Rif SV] and W means 4-(9-anthrylmethyl)-piperazinyl, or wherein Rif means [Rif SV] and W means 4-(4-biphenylylmethyl) )-piperazinyl, or a salt thereof. 10. Process for producing a pharmaceutical mixture containing as active substance at least one compound defined in one of claims 1-9, characterized by processing this active substance with at least one pharmaceutical carrier material.