CS244449B2 - Method of new polycyclic hydrazones production - Google Patents

Abstract

Neuartige Hydrazone abgeleitet von 3-Formylrifamycin S oder SV als Aldehydo-Komponente und einem bi- oder tricyclischen N-Aminopiperazin als Hydrazino-Komponente der Formel worin R¹, R², R³, R⁴, R⁵ und R⁶ unabhängig je ein Wasserstoffatom oder C_1-4-Alkyl,

• m und n unabhängig je eine ganze Zahl von 0 bis 5,
• X C_1-5-Alkyliden, Benzyliden oder C_1-4-Alkoxymethylen,
• Y C_1-5-Alkyliden, C_1-4-Alkoxymethylen, Oxy, Thio oder gegebenenfalls substituiertes Imino der Formel -N(R)-, worin R für Wasserstoff, C_1-4-Alkyl, C_3-5-Alkenyl, C_3-12-Cycloalkyl oder Phenyl steht,'oder
• X und Y zusammen ein 1,2-Cycloalkylen oder o-Phenylen, welche durch 1-3 C_1-4-Alkylreste substituiert sein können, und

Rif einen durch die freie Valenz in 3-Stellung sich bindenden Rest von Rifamycin S bzw. SV bedeutet, zeichnen sich durch eine hohe und langdauernde antituberkulotische Wirksamkeit aus. Sie werden in konventioneller Weise, z.B. durch Kondensation ihrer Bildungskomponenten, hergestellt.

Description

(54)

Process for the production of new polycyclic hydrazones

A process for the preparation of novel polycyclic hyrazones of the general formula I _A 6 (CnH _2n ) -Y '/ X

Rif-CH-N-NA 4 - (C _m H 2 _{n 1} ) _{rr 1} H 2 -; R 3 R ^{4 (X)} wherein the general symbols are as defined below. The compounds of the formula I produced have a high and long-lasting antituberculous effect and can be used as medicaments.

The present invention relates to a process for the preparation of novel polycyclic hydrazones derived from 3-formyl mycine S or SV as an aldehyde component and from a bi- or tricyclic N-aminoplperazine as a hydrazino component, in particular a 1-aminopyperazine ring system with a mono- or bicyclic ring position 3,4. In particular, the present invention relates to a process for the preparation of the novel hydrazones of the formula I

(I) in which:

R ^{1, R 2,} R ^{3, R4,} R and ^R6 are hydrogen ^b not exceeding about two of the alkyl group having 1 to 4 carbon atoms,

rn means an integer from 0 to 3, n is an integer from 1 to 4, wherein ring B consists of 5 to 8 ring members, X denotes an alkyl group having from 1 to 5 carbon atoms, a benzylidene group or an alkoxymethylene group having from 1 to 4 carbon atoms in the alkoxy moiety, Ϊ C 1 -C 5 alkylidene, C 1 -C 4 alkoxymethylene, alkoxy; nu, thio, or an optionally substituted amino group of formula -N (R) -, wherein with.. R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, (C 3 -C 5) alkenyl, (C 3 -C 12) cycloalkyl or phenyl; or X and Ϊ together represent a monocyclic 1,2-cycloalkylene group having 5 to 8 ring members or an o-phenyl group, and Rif means a residue of rifmycin S (quinone form) or rifmycin SV (hydroquinone formo) bound by free valence at position 3 of the partial patterns Rf S or Rif SV

O — C - CO

(Rif S) optionally

(Rif SV)

Like their salts.

The compounds produced by the process of the invention have valuable pharmacological properties and can be used as active ingredients of pharmaceutical preparations.

Because of the very close relationship between the 1,4-quinone form and the hydroquinone form (corresponding to rifmycine S and SV) and the ease with which the two forms cross each other, they are intended to be within the scope of this invention, unless specifically indicated otherwise both of these forms.

The (C1-C4) -alkyl group may be ethyl, propyl and butyl, furthermore isopropyl, isobutyl, sec-butyl and tert-butyl, but preferably methyl. Corresponding general and preferred meanings also have this alkyl group in the meaning of an alkoxymethyl group having 1 to 4 carbon atoms in the alkoxy moiety. The (C 5-C má) alkenyl group has an analogous structure with a single double bond, which is preferably located at the 2-position or the 3-position. The preferred alkenyl groups are asyl and methyl. C 1 -C 5 alkylidene is, for example, a heptylidene residue, a butylidene residue, 1- ^ 2- or

A 3-ethylbutyl radical, a 1-ethylpropylidene radical, a 1,2-diethylpropylidene radical, a 1- or 2-methylpropylpropylidene radical, and preferably a propylpropylidene radical, an isopropylidene radical, an ethylidene radical and in particular a methylidene radical.

DroJvazné - ^C m ^H 2 _B - and ^C n ^H 2n> piperazine ring which is the symbol X or X J3ou images alkylated simple line valences (where m is 0), "alkylidene having 1-4 carbon carbon or phenylenoose having from 2 to 4 carbon atoms. Allkpliden - group 3 of 1 to 4 carbon atoms, which separates the piperazino ring A from the radical X or Y with one carbon atom, has one of the general and preferred meanings mentioned above. The C 2 -C 4 -alkylene group which separates the piperazin ring from the radical X 2 to 3 or X 2 to 4 carbon atoms is derived from a branched or preferably straight alkane in which both free valences start from two different, optionally end-chain or mid-chain of sulfur-containing atoms, it is represented by, for example, a tetromethyl group, a 1- or 2-meetyltrimethylene group, an ethylethylenoose group and a 1,1- or 1,2-dimethylethylene group, as well as preferably a trimethylene group, propylene group and ethylene group.

Cyld. o a C 3 -C 12 alkyl group is a monovalent mono- or bicyclic group whose individual rings contain 3 to 8 ring members and one to four alkyl groups of 1 to 4 carbon atoms. methylene groups. Preferred are also symmetric combinations of substituents, i. those whose presence does not give rise to an asymmetric center, such as, in particular, the same (geminal) pairs of the same alkyl groups located on the same carbon atom as in, for example, 4,4-dimethylcyclohexyl or 3,3, 4-4-triethylcyclopentyl group ·

The 1,2-cycloalkylene group is a divalent group analogous to the above-described cycloalkyl group which is monocyclic and contains 5 to 8 ring members, such as 1,2-cyclooctylene and 1,2-cyclopentylene, as well as in particular the 1,2-cycloheptylene group and in particular the 1,2-cyclohexylene group. Cycloalkylene groups may be substituted in an analogous manner as cycloalkyl groups, such as in the case of 4,4-dimethyl-1,2-cyclohexylene or 3,3, 5,5-tetramethyl-1,2-cyclopentylene groups. However, unsubstituted groups are preferred. The phenyl or o-phenylene group may also contain 1 to 4 alkyl groups as defined above having 1 to 4 carbon atoms, in particular methyl groups. Also, this group is preferably unsubstituted.

The ring V fused to the piperazine ring A consists of a total of 5 to 8, in particular 5 or 6, and in particular of 6 ring members.

Each of R ¹ to R 6 individually represents preferably a hydrogen atom. If 1 or 2 of these symbols have a meaning different from hydrogen atoms, then it is one, with a methyl group being particularly preferred. A preferred arrangement consists of two identical substituents which are geminally bonded, i.e. to one and the same carbon atom, and thus do not cause additional center of asymmetry (and consequently a new pair of diastereomers) ·

Preferred compounds of formula I are, for example, those in which v is a number from 0 to 3 and n is a number from 1 to 4, each of the radicals and preferably a straight chain and / or separates the piperazine ring A from X or Y at most 3, preferably at most 2 carbon atoms, at most 1 of R ¹ -R ⁶ are different from hydrogen and are C 1 -C 4 alkyl, such as methyl or ethyl, and one of X and Y is ethylidene or methylene, while the other is C 1 -C 4 alkylidene, C 1 -C 4 alkoxymethylene, alkoxy (-O-), thio (-S-), imino (-NH-) or C 1 -C 4 alkyl C 4 substituted imino or X and Y taken together represent 1,2-cyclohexylene.

Of these compounds, for example, compounds of the formula I are particularly preferred, in which ø is 0 and n is preferably in the direct radical 1 to 4, at most one of R ¹ to R 4 is different from hydrogen and in this case preferably methyl. and one of X and Y is methylene, while the other is ethylidene, propylidene, C1-C4alkoxymethylene or preferably methylene, or X and Y together are a 1,2-cyclohexylene group , 1,2-cycloheptylene, 1,2-cyclooctylene or o-phenylene.

Of these compounds, those compounds in which m is О, z * ^{18 are} methylene, trimethylene or especially ethylene, R ^f is methyl or especially hydrogen, R ² to R 6 are hydrogen, X is ethylidene or in particular methylene and Y is propylidene, isopropylidene, methoxy or ethoxymethylene or in particular methylene or X and Y together represent 1,2-cyclohexylene or o-phenylene.

Correspondingly, particularly preferred N-aminopiperazines having the following backbone, which are optionally substituted by C1-C4 alkyl groups and / or C1-C4 alkoxy groups, are particularly preferred as hydrazine components:

З-а ^ порегГцтУгоруггоЮ 1,2-a) pyrazine,

3-Amino-pyrrolidine-1H-pyrido (1,2-a) pyrazine,

3-Aminopropylproprazino (1,2pa) azrpine nrbp

3-аш1поррг ° уУг ° р1Н-рру ° г1пп (1.2pz) zzocine, optionally

3-aminoprophenylpyozZno (1,2-z) indole,

3 ^ pamnnp1,2,3,4,4a P-hpXEhyrrpppy ° Zinn (L1 ² -z) inrpl,

3-aminoacid (H-pyrazinone ((, 2-a) quinoPine),

3-affinine-2,3,4,4a, 5,6-hppyrropy-1H-pyrazine (1,2-z) quinodium.

Especially particularly preferred are those of the pattern I in which m and n are independently from 1 to 3, wherein the groups _m and m are separated from the X-ring ring from X in each case by X at most by two, preferably one, respectively. ztomrm Uhíku, nrjvýšr jrěrn ^of e R ¹ SZ ^R is other ⁿ R ^z in ^ J ^IK in this ^{EXAMPLE IP ga} is above ^h o ^{n e} metal and X znamrná rthyddenovou group nrbo methylene, while Ϊ means Oxycyclic, thioscyclic or imocyclic, wherein the imino group is optionally substituted preferably in the above-mentioned aryl, with a C1-C4 alkyl group, in particular an isobutyl group or a methyl group.

Of these compounds, it is necessary to emphasize those compounds in which man knows! 1, ^R 'denotes a methyl group nrbo, preferably a hydrogen atom, r2 to R6 denote a hydrogen atom, X represents a m and m represents a oxy group, a thio group, an amino group or a C1-4 alkyl group; carbon atoms, such as isobutyl amino group nrbo eeehydeilPttol ^p Pnu. Especially preferred as the hydrazine component are also N-amylpiperazines having a basic scaffold, optionally substituted by alkyl groups on the nrbp / z carbon atom:

6pzeinppeгlhddroρpгazolp (2pc) ppppχzzil,

6-Amino-piperazino (β, 1-c) -pthizzine as well as 3-morpholin-6-R-perdidiryl-1H-ppyazino (1,2-pz) pyrzzine, wherein R in the latter compounds denotes iminoscopic substituents in particular. hydrogen).

Particularly preferred are all of the compounds of formula (I), which are exemplified in both forms, i.e. both the quinone (S) and hydroquinone (SV) series and the sicr are also marketed, but are explicitly mentioned in the case of the (gGP) form, as well as odoléjc! sed.

Most of the compound patterns can also be present in the form of sod. Those compounds of them that mm)! Sufficient acidity, such as the corresponding hydroquinones of the SV * series, may include sodium with bases, such as less with inorganic bases, preferably physiologically tolerable sodium with sodium metal, such as sodium and potassium salts. These compounds of the formula I which have a sufficient basal content may be present as the acid sodium salt, i.e. as physiologically compactable sodium, with the customary acids from the pharmaceutical compositions, in particular from inorganic acids. phosphoric acids, such as hydrochloric acid, as well as sulfuric acid from phosphoric acid or pyrophosphoric acid. Of the organic acids, the sulfonic acids, for example, and aromatic sulfonic acids, such as benzene or p-trifluorosulfonic acid, emonic acid from sulfanylic acid, or lower sulfonic acid, such as methanesulfonic acid, methanesulfonic acid, may be mentioned. sulfonic acid as well as sulfonic acid, or also aliphatic, cyclic, aromatic or heterocyclic carboxylic acids, such as formic acid, acetic acid, protonic acid, succinic acid, lactic acid, lactic acid, lactic acid, lactic acid, lactic acid, lactic acid, lactic acid, lactic acid, lactic acid acid, citric acid, fujaric acid, maleic acid, hydroxybutyric acid, oxalic acid, pyruvic acid, fenctoacetic acid, benzoic acid, i-amintlenzic acid, anthranilic acid, p-hydroxyl acid benzoic acid, zincicyloite acid and β-γ-2-ynylcyloic acid; Rodeo íyskcУuj.ící alpha j íéintkycsllnc such as glycine, leucine, m ^ e ^ H ^ <^ ^r ^ 1 n ^ ^i, tryptophan, lysine or arginine as well as ascorbic acid. Compounds of formula I which contain both basic and acidic functional groups can also exist in the form of inner salts.

Some hydrazones derived from 3-formylrifmycin SV have been described. Especially in U.S. Pat. No. 3,342,810, among other antimicroactive derivatives, the above-mentioned basic compounds also describe the hydrazones of the formula = NN ^ 2 ^ 3, where Rg and Rj, in addition to a number of meanings for each symbol, individually both together and together with 3 nitrogen heterocyclic ring of 5 to 7 carbon atoms. Except for this definition in Section 6 of the cited patent specification, there are no lower heterocyclic ring heteroatoms in the specification and are merely set forth in the form of a nine example specific individual compound (including magical effects) in Table 3, column 3, compounds 14-14. in the following description (column 6, lines 64 to 75, and column 6, lines 30 to 45), highlights mycine hydrazone SV with 1-amino-4-ethylpiperazine as a result of its potent anti-tumor action, and this compound is particularly protected in 15 of the present invention. Until now, these compounds belong, under the generic name, to the leading therapists in the fight against tuberculosis. Hydrazones with more than one heterocyclic ring were not considered or suggested ·

Although Riiampicin counts as the best agent for the treatment of tuberculosis infections, its relatively short residence time in many cases is a major disadvantage. • The preparation of drugs that would have an effect similar to R.famppcin as an anti-tuberculosis infection but would have a longer duration of action. is therefore one of the most urgent tasks in this area. To date, however, it has not been surprising to find active substances which, in terms of duration of action, have been found to be highly effective in antituberculous activity (in individual cases up to three times that of Rifam?). equivalent to or even exceeded the effect of Rifampicin.

It has now been found that the novel compounds produced by the process of the present invention outweigh both the good anti-puberty effect, in particular in vivo, the effect of RLfomppcin, and in addition the markedly longer residence time in the organism is also significant as evidenced by the results of the following tests.

Legend to Table I:

(1)

H -razones of 3-trifluorophenyl SV; the structure is characterized by ring system B and fused to piperazine ring A;

(IA) -piperazine ring A contains

Tested methyl group in position 2 (3)

Mininminine (4) in vivo organism: McCobaterithm inhibitory concentration in test (myO; p.o. application)

tuberculosis TB HjR _in in vitro assay (5)

Half-life (hours) (7)

Reference substance: 3-formylriamccin SV hydrazone with 1-amino-4-mmthClpiperazine.

(6)

The highest concentration of active substance in blood plasma

Table I

Example Active substance Antituberculous FarmLokinetics number (AND) effect (2) my rat (3) (4) Í5) (n) (5) (6) BALL Ug / ml ≥ 50 mg / kg t / 2 h C max .mu.g / ml t / 2 hr c шах jug / rnl 1 piperidine 0.03 0.8 20 May 27.3 17.0 24.5 2 pyrrolidine 0.1 2.5 9.1 57.7 13.2 4.6 3 6-methylpiperidine 0.4 l t4 22.6 4 5-Ethylpiperidine Isomer A 0.01 0.8 55.1 29.5 В 0.03 1 44.6 26.4 5 piperidine; (IA) isomer A 0.2 3 69.3 t5 58.5 19.7 В 0.4 2 66 38.8 44.7 16.4 C 0.06 3 15 Dec 23.7 D 0.06 3 25.1 33.6 6 perhydroquinoline isomer A 0.03 33.4 56.3 В 0.007 40.9 34 7 1,2,3,4-tetrahydroquinoline 0.06 4,5 32.2 24 8 thiomorpholine 0.2 8 72 9 N * -me thylpiperazine ομ Rifampicin (6) 0.03 5.9 6 24.8 3.8 13.9

The novel compounds of the formula I can be prepared according to the invention in a manner known per se by reacting 3-formylrifamycin of the formula II

Rif-CH = O (II) 'wherein

Rif is as defined above, or a functional derivative thereof, with N-aminopiperazine III

(III) wherein ^r 'to R ®, n, m, X and Ϊ m jí m. where appropriate, if the compound of formula I in quinone form is desired, the compound of formula I present in the hydroquinone form is treated with an oxidizing agent and / or if the compound of formula I in hydroquinone form is desired to the compound of formula I by addition in quinone form of reducing agents, and / or the compound of formula I in free form is converted to a salt or the compound of formula I is released from its salt.

The reaction of 3-foroylrifaoycin of formula II or a reactive functional derivative thereof with hydrazine of formula III is carried out in a manner known per se, for example according to the aforementioned US patent. In particular, the free 3-formflrifmycin SV and N-ia-ananoiperazine of formula III are reacted in an approximately equimolar amount (or a small excess thereof) and preferably in the presence of an organic solvent such as an alcohol such as methanol, ethanol or isopropyl alcohol. an ether, for example diethyl ether, 1,2-dimethoxyethane or 1,2-diethoxyethane, tetratydrofuran or dioxane, an aliphatic ester or amide, for example ethyl acetate or dimethylforaamide, also dimethylsulfoxide and acetooitrile, or a mixture of these solvents, at temperatures from about -20 ° C. ° C to about 50 ° C, preferably between 0 ° C and room temperature. The N-aminoppperazine component of formula III can also be used in the form of an acid addition salt and the base is only released in situ by addition of a basic excipient such as an alkali metal salt, for example sodium or potassium acetate, or a tertiary organic base such as tertiary. an amine such as triethylamine, N-mithyllipptidine or N-ethipipertidine or N-mithiophthaline, or else a cyclic aromatic base of the pyridine type and its mpmoPogs or nitrine. The aldehyde component of formula II can also be used in the form of a functional derivative, for example in the form of an alkali metal salt of the hydro-heating of the starting material of formula II, or preferably in the form of a reactive derivative with a functional aldehydeC2 group.

Rif-CH = Z (IIA) wherein

Rif is as defined above and is especially (Rif S) and

Z is oxyiminosCupiuu, an N-substituted thio group, unstable or

N- (mono- or di-cross-linked hydrazo-ophtalia or thiazoliozoootcup).

Substitutes of imino groups and tydrazpopsCupiol are monovalent hydrocarbon radicals of not more than 8 carbon atoms, in particular alkyl or cycloalkyl radicals of not more than 7 carbon atoms, phenyl or benzyl radicals, or analogous divalent radicals which, together with the nitrogen atom, form a saturated monocyclic ring. the ring optionally having one additional heteroatom, such as oxygen, divalent sulfur, nitrogen or nitrogen, which is once substituted with a C1-C4 alkyl group. Preference is given to those substituents and their combinations which readily volatile amines and / or hydrazines, in particular those which are substantially free of carboxylic acid. a boiling point at atmospheric pressure or at a reduced pressure of not more than 60 ° C, with methyl being particularly preferred.

using such a derivative of the aldehyde component of formula (II), a method analogous to that described above for the free aldehyde is also carried out in a manner known per se. When component II is used in the form of a salt or in the form of a base, it is advantageous to adjust the reaction mixture to a neutral environment, for example by adding diH1 component (N-aminopropaziou III) in acid addition salt form, or also cautiously by adding an acid such as carboxylic acid. , for example acetic acids. When the aldehyde component of formula (II) is used in the form of a derivative having a functionally modified aldehyde group, it is expedient to work in a larger excess of the base component (III), which also serves as a solvent.

The reaction conditions, particularly temperature and pressure, the is adjusted so that the volatile reaction products (e.g., amine, or hydrazine of formula ZH ₂₎ which are released in exchange reactions vzurce starting material II was continuously removed by distillation from the reaction mixture. Suitably, the pressure is reduced such that the distillation temperature does not exceed about 60 ° C, preferably not about 40 ° C. Under the conditions, the exchange can also be carried out in an inert organic solvent, such as in any of the above, for example dimethylsulfoxide.

The rifamycline derivatives of the general formula II which are used as starting materials are known compounds. Also, the compounds of formula (III) are either known or are available by conventional standard synthetic organic chemistry techniques. Thus, the bi- or tricyclic K-aminopiperazines of the formula III can be obtained, for example, by nitrosation (for example by treatment with nitrous acid released in situ or by N ₂ O 4) of the corresponding N-unsubstituted bi- or tricyclic piperazine of the following formula VI and following reduction of the resulting nitroamine, for example by treatment with a complex hydride such as lithium aluminum hydride or by catalytic hydrogenation.

The bi- and tricyclic piperazines of formula VI

(VI) in which:

4

R to R, m, η, X and Y have the above meanings and

W is as defined for and can be obtained either by a simple, generally applicable synthesis, by reacting a nitrogen-containing mono- or bicyclic heterocyclyl-2-carboxylic acid ester of formula VII

-O-CO-Cl

(VII) in which:

R _q is C 1 -C 4 alkyl, in particular methyl or ethyl, am, η, X and Y have the meanings given above, condensed with an optionally substituted ethylene amine of formula VIII

Ю

(VIII) in which:

4

R @ 1 to R @ 2 have the meanings given above, and in the piperazone of the general formula (VI) in which:

R ¹ to R ⁴ , m, η, X and Y are as defined above and W is oxo, this oxo is converted to R ⁶ and R ⁸ in the usual manner. This conversion is performed when R? and R ⁶ are both hydrogen, by reduction, for example, with diborane or a complex hydride such as lithium aluminum hydride. When one of the two symbols and R1 is an alkyl group, the conversion is carried out by treatment with an appropriate organometallic reagent, such as an alkyl lithium or in particular an alkylmagnesium halide, for example an alkylmagnesium chloride or preferably an alkylmagnesium bromide, in a suitable inert organic solvent. As is known, the conditions can be adjusted to obtain a geminal base with two alkyl groups as substituents or to obtain a monoalkyl product. In the latter case, the primary intermediate of formula VI, in which W represents an alkyl group together with a hydroxyl group, must be further reduced, for example, as described above for the oxo group. The reaction is preferably carried out in analogy to the reaction conditions given in the following examples.

In the primary reaction mixture obtained in the process of the present invention, both oxidation stages of the end product, i.e. the 1,4-quinone form of the S-series and the 1,4-hydroquinone form of the SV-series, may be adjacent. However, it is expedient to isolate all the product in only one of the two forms, for example in the hydroquinone form. Suitably, this mixture, as further described below, is converted to a uniform product by the reduction to form the hydroquinone form (derivative of rifamycin SV) or by oxidation to form only the quinone form (derivative of rifamycin S).

Optionally converting the obtained quinone of formula I (Rif S) to the corresponding hydroquinone (Rif SV) or the hydroquinone of formula I (Rif SV) obtained according to the invention to quinone (Rif S) or converting the mixture of both types of compounds to a uniform product according to the invention by reduction or oxidation. This conversion can be carried out with the product already isolated, or more often preferably before the desired product is isolated. The reduction may be carried out by treatment with a reducing agent suitable, in particular, for the reduction of the quinone to the corresponding hydroquinone, such as alkali metal dithionite or bisulfite, such as sodium dithionite or bisulfite, zinc and acetic acid or preferably ascorbic acid. The oxidation may be carried out by treatment with an oxidizing agent suitable for converting the hydroquinone to the corresponding quinone, such as air oxygen, hydrogen peroxide, an alkali metal ferricyanide, for example potassium ferricyanide, a salt persulfate, for example ammonium sulfate. or by treatment with manganese dioxide, the oxidation preferably being carried out under basic conditions. Quinones are mostly compounds that are violet red, while hydroquinones are usually colored yellow and are available due to their easier coating.

Optionally, the salt formation and liberation of the base forms of the compounds of formula I from their salts is carried out in a conventional manner known per se. Thus, hydroquinones are converted to the corresponding alkali metal salts by treatment with an appropriate alkaline reacting compound, in particular a hydroxide, carbonate or bicarbonate. Salts can be converted to the free hydroquinone derivatives by acidification with, for example, inorganic acids, in particular hydrohalic acids. The base-reacting reaction products of formula I may be converted into their acid addition salts, for example by treatment with a salt-forming acid, such as any of the above. Conversely, such basic base form of the compound of formula I is released by the action of base reacting agents such as hydroxides, carbonates and bicarbonates of inorganic compounds, or by organic bases and ion exchangers. The inner salts are formed, for example, by conventional acid-base titration reaching the isoelectric point.

Acid addition salts of the novel compounds, such as picrates. they can also be used to purify the compounds obtained by converting the free compounds into their salts, separating them and recovering the free compounds from the salts. Due to the close relationship between the compounds in the free form and in the form of their salts, the preceding and the following are understood to mean the free compounds according to the meaning and purpose, if appropriate, also corresponding salts.

The reaction products of formula I described above, starting materials of formula III, and intermediates are optionally obtained in the form of racemates (i.e., mixtures of two antipodes), mixtures of racemates (i.e., mixtures of two diastereomeric racemates) and mixtures of diastereomers (i.e. mixtures of two such diastereomers). (which are not antipodes) and can be divided into individual antipodes in a known manner.

In particular, the racemate mixture is formed by reacting the chiral reactant in racemic form with another chiral reactant, which is also present in racemic form. When one of the reactants is used in racemic form and the other is used in the form of a single antipode, such as torne, mainly in the process of the present invention, the result is a mixture of diastereomers. These mixtures of both kinds can be separated by physical methods, in the first case two racemates are isolated, in the latter case two individual diastereomers not belonging together. Among the separation methods, it is necessary to mention in particular fractional crystallization, furthermore also various variants of adsorption chromatography and partition chromatography, in the case of easily volatile mixtures also fractional distillation and especially gas chromatography.

If the racemic starting material is reacted with the achiral reactant in the reactions outlined above, in particular in the preparation of the starting materials of the formula III, then the reaction product is recovered in the form of racemates which, as is known, can only be resolved into individual antipodes using chiral auxiliaries. substances or auxiliaries by methods known per se.

A preferred method is that the racemic free base is converted by treatment with an optically active acid into a mixture of diastereomers of two acid addition salts, separated by suitable physical methods and each individual diastereomer. is separately converted into its basic components, i.e. the acid and the individual antipod base, in a manner known per se, for example by treatment with a stronger acid or base.

Suitable optically active acids are, for example, optically active amino acids, in particular the naturally occurring alpha-amino acids of the L-series and their N-acylated derivatives, optically active tartaric acids, in particular D-tartaric acid and derivatives thereof with esterified hydroxyl groups, D- and L butyric acid, D-camphor-carboxylic acid and also L-camphor-10-sulfonic acid.

The present invention relates to those embodiments of the process wherein the starting material is a compound obtained as an intermediate at any stage of the process and the missing steps are carried out or the starting material is used in the form of a derivative, for example a salt or formed under reaction conditions. conditions.

In the process according to the invention, preference is given to starting materials which lead to compounds which have initially been designated as particularly valuable.

In view of the described pharmacological properties of the novel compounds, the present invention also relates to the use of the active compounds according to the invention alone, for example together with adjuvants or in combination with other active compounds, in particular antibiotics or chemotherapeutics. induced by tuberculosis bacilli, as well as bacteria, in particular coca, as mentioned above, both as medicaments and as disinfectants.

When used as a medicament, the active compounds produced according to the invention are preferably formulated in the form of pharmaceutical preparations together with conventional pharmaceutical carriers or auxiliaries. For example, a warm-blooded animal having a body weight of about 70 kg is administered, depending on the species, body weight, age and individual condition, as well as the daily dose of about 50 to 1000 mg, depending on the mode of administration and in particular the sensitivity of the agent.

The present invention also relates to pharmaceutical compositions comprising as active ingredients the compounds produced by the process of the present invention as well as a process for their preparation.

Pharmaceutical preparations are, for example, pharmaceutical preparations for enteral, such as oral or rectal, as well as parenteral administration by warm-blooded. Corresponding unit dosage forms, in particular for oral administration, for example dragees, tablets or capsules, preferably contain from about 50 to about 500 mg. in particular from about 100 to about 300 mg of active ingredient together with pharmaceutically acceptable carriers or excipients.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, binders such as greasy starch using for example corn starch, wheat starch, rice starch, rice or potato starch, gelatin, tragacanth, methylcellulose and / or optionally disintegrating agents such as the aforementioned starches, further carboxymethylated starch, cross-linked polyrinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate.

The auxiliaries are in particular flow regulators and glidants such as silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearic acid and / or polyethylene glycol.

Dragee cores may be provided with suitable coatings, optionally resistant to gastric juice, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide. b) solutions of lacquers in suitable organic solvents or solvent mixtures, or for producing gastric juice-resistant coatings, solutions of suitable cellulosic preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or dragee core coatings, for example to identify or differentiate different doses of the active ingredient.

Other orally usable pharmaceutical formulations are gelatin insertable capsules as well as soft sealed capsules of gelatin and a plasticizer such as glycerin or sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate salts, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers may also be added.

Possible rectally usable pharmaceutical preparations are, for example, suppositories which consist of a combination of the active ingredient with a suppository base. Suitable bases for suppositories are, for example, natural non-synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. In addition, gelatin rectal capsules can be used which contain a combination of the active ingredient with a matrix. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

Particularly suitable for parenteral administration are aqueous solutions of the active ingredient in water-soluble form, for example in the form of a water-soluble salt, suspensions of the active ingredient, such as corresponding oily injection suspensions, using suitable lipophilic non-media solvents such as fatty oils, e.g. oils or synthetic fatty acid esters, for example ethyl oleic acid ester, neio triglycerides, non-aqueous injection suspensions which increase the viscosity, for example, sodium carboxylic acid, sorbitol neio / a dextran, and optionally withdrawers . The active ingredient, if appropriate together with the auxiliary substances, can also be present in the form of a lyophilisate and, prior to parenteral administration, the latter can be brought into solution by the addition of suitable solvents.

The pharmaceutical preparations of the present invention can be obtained from salts known to those skilled in the art, for example by means of other mixing, granulating, disintegrating, dissolving, dissolving, non-ionizing processes. Thus, for example, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, the resulting mixture optionally granulating the mixture or the granulated mixture, if desired and necessary, after the addition of suitable excipients. those neio nc cores dragees.

The following examples illustrate the invention, but its scope is not in any way limited. Temperatures are given in degrees Celsius, melting points are not corrected for thin layer chromatography. Silica gel adsorbent is used. The solvent mixture is characterized by oily ratios.

Example 1

S-formylrifmycin hyúrazone SV with S-amino-1H-pyrrole-1H-pyrido [1,2-a] plungazin

To a solution of 5 ft. Of S-formyl trifluoride SV in 100 ml. After about 6 minutes, all S-formylrifmycin SV was consumed on the thin layer, according to chrobaarafrafit. For working-up, the reaction solution is concentrated in vacuo and the mixture is removed. The organic phase was washed with dilute aqueous citric acid solution, dried and evaporated. The crude product was crystallized from ethyl acetate to give orange-red crystals of the title compound which did not melt out of decomposition.

^Chhota, Torra '; t · on tlc zc loojitd bethyltnchltriUi c methcnolu mixture in a ratio of 9: 1 as the margin even ^^ ^ Pf adding an organic solvent - 0.6.

limo trios tri spectrum negative): 14 = 862 (baOecial mass calculated for ^C 47 ^C 62 ^C 4 ° 1 ^z ? ·>

A sodium salt of the title compound was obtained by rozpuutí 3 g of the above free hydrazone in 10 ml aitxani To the solution was added a solution of 0.929 g of sodium hy ^dro g®euuilčitcnu in 10 ml of water, the resulting solution was C llofilizujt .

Oxidation of nc. Quinone

Hydrazone solution of 2 g of S-SV lrifbmlciui ftr ^ S-abinoopehhlart1H - ylrdat 1J2-c) pyrazUneb ^(VLR tbený způsoiem described above) in 50 mL bethyltuchloriai after 2 Doiu stirred vigorously at room temperature * AXID manganese powder characterized then the solids are filtered off and the filtrate is evaporated to dryness. 2 g of hydrazone of the 3-form 1H-phenylamine S with 3-aminoperhydro-1H-pyrido (1,2-a) pyrazine are obtained as an amorphous blue-black solid without sharp melting point.

Molecular weight (MH * = 861) by mass spectrum complies with theory for ^C 46 ^H 60 ^N 4 ° 12 ·

The 3-aminoperhydro-1H-pyrido (1,2-a) pyrazine used as starting material can be prepared as follows:

(a) Nitrosation

An aqueous solution of 5.86 g of perhydro-1H-pyrido (1,2-a) pyrazine (cf. E. Freed and AR Day: J. Org. Chem. 25. 2 108 (1960) is treated at 5 ° C by the addition of solution of 3.18 g of sodium nitrite in 5 ml of water is added dropwise while cooling to 0 to 5 ° C, the mixture is stirred for a further 2 hours at 5 to 10 ° C and then treated by the addition of about 58 ml of aqueous 2N sodium hydroxide solution to pH 13. The reaction mixture was extracted with 3 portions of 80 ml of ethyl acetate each time, and the combined organic solutions were dried over sodium sulfate and evaporated to give an oily residue 66.76 g). .

b) Reduction

A solution of 6.76 g of crude 3-nitrosoperhydro-1H-pyrido (1,2-a) pyrazine (produced according to step a) in 30 ml was added dropwise to the stirred suspension of 1.71 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. tetrahydrofuran. The reaction mixture was stirred for an additional 3 hours at room temperature, then 10 ml of aqueous 2N sodium hydroxide solution and then 10 ml of water were added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. The precipitate is filtered off with suction and washed on the filter with hot isopropyl alcohol. The filtrate (all proportions of isopropyl alcohol) was evaporated in vacuo to give the desired 3-aminoperhydro-1H-pyrido (1,2-a) pyrazine (6.68 g) as a pale yellow oil of sufficient purity to produce the hydrazone described above. .

Example 2

3-Fonnylrifamycin SV hydrazone with 3-aminoperhydropyrrolo (1,2-a) pyrazine

To a solution of 2 g of 3-formylrifamycin SV in 200 ml of tetrahydrofuran is added a solution of 1.94 g of 3-aminoperhydropyrrolo (1,2-a) pyrazine in 10 ml of tetrahydrofuran, and the mixture is stirred for 10 minutes at room temperature until thin layer all 3-formylrifamycin consumed. For working up, the reaction solution was concentrated in vacuo and the residue was taken up in methylene chloride. The organic phase was washed twice with aqueous citric acid solution, then dried and evaporated. There remains a crude hydrazone which crystallizes from ether to give orange-red crystals of the title compound. Melting point above 210 ° C with slow decomposition.

TLC (using a 9: 1 mixture of methylene chloride and methanol): Rf = 0.55.

Mass spectrum (DC1 / CH3, negative): M '= 848 (molecular weight calculated for ^C 45 ^H 60 ^N 4 ° 12 = S ⁴⁰ ' ·

In order to produce 3-aminoperhydropyrrolo (1,2-a) pyrazine, which is used as starting material, it is possible to gradually nitrosate and reduce, for example, perhydropyrrolo (1,2-a) pyrazine (cf. E. Freed and AR Day: J. Org. Chem., 25, 2,108 (1960) and RL Peck and AR Day:

J. Heterocyclic Chem. 6, 1 til (1963) according to Example 1, preparation a) and b).

Example 3

3-Amino-3-form ^of lrifimycin SV with 3-amino-e-methylperhydro-1H-pyrido (1,2-a) pyrazine

To a solution of 2 g of 3-formylrffamycin SV in 100 ml of drofurane tetanus is added a solution of 1.86 g of 3-amino-.beta.-methoxy-1-pyrrolo [lo (1,2pa) yyrazil] in 10 ml of tetrahydrofuran and stirred for 10 minutes. The reaction solution is concentrated in vacuo and the residue is taken up in a water bath (100 ml). The organic phase was washed twice with a dilute aqueous citric acid solution, dried and evaporated to give a crude hydrazone, which was separated by chromatography on silica gel into two individual stereoisomers. These stereoisomers were further purified by crystallization from a mixture. acetone, ether and hexane

Both isomers have (FAB, yooitive): MH * (mooelkillar mass analogous to the ^ οο ^^^ ηί spectrum:

= 877 calcd for С47Нб4 ^ 4 ° 12 = 867).

Isomer A: melting point 183-192 chromatotraphia to a thin Rf = 0.58

Isomer B: mp 166-190 ° C (dec.);

layer (9: 1 mixture of methylene chloride and methanol):

° C (gradual decomposition); thin layer chromatography (9: 1 mixture of methylene chloride and methanol): R 1 = 0.55.

For example, in order to prepare the 3-amino-8-methylp (trhydropropyl-1 H -pyrrolidine 1,2pt) yrthrlium used as starting material, the 8-methylperpiperidine (1 H -pyrido1,2pt) yrrthium of Example 1, preparation a) and b) may be sequentially nitrosated and reduced. . The latter compound can be obtained from ethyl 2-methyl-6-yl-pyridine carboxylic acid according to the procedure described above. Freed and Day, J. Org. Chem. 25, 108 (1960).

Example 4

3-formylrifmycin hydrazone SV with 3-αminioP-phylyeryl dr (- IH-pprl · do (1,2pα) yrrazieem

To a solution of 3 g of 3-formylriaamrium SV in 100 ml of tris is added a solution of 1.41 g of pamit-7-yyrhyrdyrrole-1,2-trichloro-1,2-trichloride in 10 ml of triturate and the mixture is stirred at room temperature for a period of time. 20 minutes until all 3-forraylrif mycin SV is consumed according to thin layer chromate. To work up the reaction solution, the reaction solution was concentrated in vacuo and the residue was taken up in methylene chloride. The organic phase is washed twice with dilute aqueous citric acid solution, then dried and evaporated. The crude hydrazone is separated and chromatographed on 200 g to give the title compound as the 2 anthropoic itereoisomer. Both isomers of mail analogous to the UMO (.lititia spectrum).

(FAB, negative): (M-H) ~ = 889 (molar linearity calculated for ¢ 48 ^ 6¾ ° ½ 2 ~ 890).

Isomer A: melting point: 173 chromatograph (rfafle 2: 1): Rf = 177 ° C (dec.);

Thin layer (using a mixture of tri-acetate and cyclohexane at 0.19

Isomer 3: melting point: 173 cyrthms; rafit 2: 1): Rf = up to 180 ° C (decomposition);

thin layer (using a mixture of ethyl acetate and cyclohexane in

For example, in order to prepare the 3-amino-7-ethylperhydro-1H-pyrido (1,2-a) pyrazine which is used as starting material, the 7-ethylperhyrro-1H-pyrido [1,2-a] can be gradually nitrosated and reduced. The pyrazine of Example 1, Preparation a) and b). The latter compound can be obtained from 3-ethyl-6-piperidinecarboxylic acid ethyl ester according to the procedure of Freed and Day, J. Org. Chem. 25, 108 (1960).

Example 5

3-formylrifamycin hydrazone SV and J-amino-2T-methylperhydro-1H-pyrido (1,2-a)

To a solution of 20 g of 3-formylrifamycin SV in 500 ml of tetrahydrofuran is added a solution of 5.8 g of 3-amino-2-methylperhydro-1H-pyrido [1,2-a] pyrazine in 20 ml of tetrahydrofuran and the reaction mixture is stirred for 10 minutes at at room temperature until all 3-formylrifamycin SV is consumed by thin layer chromatography. For working up, the reaction solution was concentrated in vacuo and the residue was taken up in methylene chloride. The organic phase was washed twice with dilute aqueous citric acid solution, dried and evaporated. The crude hydrazone was separated and purified by column chromatography on 1.5 g of silica gel to give 4 stereoisomers (A, V, C and D) of the title compound. All isomers have an analogous mass spectrum (FAB, negative): (M-H) = = 875 (molecular mass calculated for C C yH ^ NN ^O ^ = 076).

These isomers are characterized by the following data. Thin layer chromatography was performed using a 9: 1 mixture of methylene chloride and methanol as the solvent system: Isomer A: mp 176-102 ° C (dec.);

Rf = 0.44

Isomer V: mp 172-178 ° C (dec.);

Rf = 0.41

Isomer C: mp 155-190 ° C (decomposition)

Rf = 0.35

Isomer D: mp 170-190 ° C (dec.)

Rf = 0.32)

The sodium salt of isomer V is formed by adding an aqueous solution of 0.24 g of sodium bicarbonate to a solution of 2.5 g of isomer V and lyophilizing the solution.

In order to prepare the 3-amino-2-methylperhydro-1H-pyrido (1,2-a) pyrazine which is used as the starting material, it can be gradually nitrosated and reduced, for example, 2-methylperhydro-1H-pyrido (1,2-a) pyrazine (cf. C. Winterfeld and G. Gierenz: Chem. Ber. 92, 240 (1959) according to Example 1, preparation a) and b).

Example 6

3-formylrifamycin hydrazone SV with 3-aminoperhydro-1H-pyrazino (1,2-a) quinoline

To a solution of 5 g of 3-formylrifamycin SV in 150 ml of tetrahydrofuran is added a solution of 3.48 g of 3-aminoperhydro-1H-pyrazine (1,2-a) quinoline in 10 ml of tetrahydrofuran and the mixture is stirred at room temperature for 5 minutes according to thin-layer chromatography, all 3-formylrifaroycin SV was consumed. For working up, the reaction solution was concentrated in vacuo and the residue was taken up in methylene chloride. The organic phase was washed twice with dilute aqueous citric acid solution, dried and evaporated. There remains a crude mixture of 4 stereoisomeric hydrazones, from which 2 stereoisomers (A and B) of the title compound are isolated in pure form by column chromatography on 200 g of silica gel. Both isomers have an analogous mass spectrum (FAB, negative): (M-H) - = 915.

(Molecular weight calculated pno = 916).

Isomer A: mp 165-170 ° C (dec.);

Rf = 0.5

Isomer B: mp 168-180 ° C (dec.); .

Rf = 0.42

Thin-layer chromatography is carried out using a 9: 1 mixture of meethylene chloride and methanol as a solvent system.

For the manufacture of 3-1H-aminoperlhyiro ppyraZno (1,2-a) quinoline, used as starting material may nitrosation and reduction eerhydro e.g. 1H-Pey ^ι azine (1,2-a) quinoline according to the procedure of Example 1, Preparation a) and b). The latter compound can be obtained from 2,3,4,4a, 5,6-hexahydro-1H-perraine (1,2-a) quinoline (cf. Swiss Patent Specification 498 849) by catalytic hydrogenation on platinum oxide in ice acetic acid.

Example 7

The hydrazone of 3-foriaylrifmycinu NE 3 aminOlP, 3,4,4a, 5,6-hexthyrrop1H pyrazioo _(l> 2-a) chioll0nem

To a solution of 2.5 g of 3-formylriaamycin SV in 50 ml of tetrahydrofuran is added a solution of 0.57 g of 3-aminoo-2,3,4,4a, 5,6-hexahydro-1H-perraine ((12-a) quinoline) in 10 ml of tetrahydrofuran. and the mixture was stirred for 10 minutes at room temperature until all 3-formylrifamycin SV was consumed by thin-layer chromatography. 173 DEG-180 DEG C. (decomposition) on a thin layer to give a mixture of methylene chloride and methanol, m.p .: 173 DEG-180 DEG C. (decomposition). ratio 9: 1: Rf = 0.60, nmr spectrum (DC1 / OD, negative): M + = 919.

Molar mass calculated for ^C 50 ^H 62 ^C 4 ° 12 = ⁹¹⁰ ·

In order to prepare the 3-aminol-2,3,4,4a, 5,6-hexahydro-1H-pyrazine (1,2pa) chioolium which is used as the starting material, the successive thread is reduced and reduced, for example, by 2.3, 4,4a, 5,6phexahydrop1H-pyrazine (cf. Swiss Patent No. 498,849) according to Example 1, preparation a) and b).

Example 8

Hyyrazzone-formylrifemycline SV with 6-aminolperholyrrolo [2,1-c] pepthiazone

To a solution of 3 g of 3-formylramphamycin SV in 50 ml of tetahydrofuran is added a solution of 1.0 g of 6-aminopiperidine (2,1-c) -β-thiophene in 10 ml of tetrahydrofuran and the reaction mixture is stirred at room temperature for 10 minutes to all 3-foroylfrimcio SV is consumed according to the thin layer chromaao afie. For work-up, the reaction solution is taken up in vacuo and the residue is taken up with methane. The organic phase was washed twice with a dilute aqueous citric acid solution, dried and evaporated. There remains a crude hydrazone which crystallizes from the acetone / ether / hexane mixture to give the title compound. M.p. 173-181 ° C (dec.). Thin layer chromatography using a 9: 1: meetylene chloride / methanol mixture: Rf = 0.71.

H ^ ooooCs! ^ :! Spectrum (FAB, negative): (MH) ~ = 879. Whatsoever the humidity calculated for C45H6qN ₄ ° 12S = 880 ·

For example, in order to prepare rpaminoperhydrleyrazole (2,1-c) -epthiazole which is used as the starting material, it is possible, for example, to gradually nitrosate and reduce eerhydropeyazo (2,1-c) -p-thiazine by the procedure of Example 1, preparation a) ab). The latter compound can be obtained from thiomorpholine-2-carboxylic acid ethyl ester according to the procedure of Freed and Day, J. Org. Chem. $ 2,108 (1960).

Example 9

3-Amino-3-formylrifamycin hydrazone 3-amino-6-methylperhydro-1H-pyrazino (1,2-a) pyrazine

To a solution of 3 g of 3-formylrifamycin SV in 100 ml of tetrahydrofuran is added a solution of 2.04 g of 3T * amino-6-methylperhydro-1H-pyrazino (1,2-a) pyrazine in 10 ml of tetrahydrofuran and the mixture is stirred for 15 minutes at room temperature until all 3-formylrifamycin SV was consumed by thin layer chromatography. For working up, the reaction solution was concentrated in vacuo and the residue was taken up in methylene chloride. The organic phase was washed twice with dilute aqueous citric acid solution, dried and evaporated. The crude hydrazone was obtained, which crystallized from acetone / ether to give a crystalline mixture of two stereoisomers of the title compound, melting at 170 ° C (decomposition). Thin layer chromatography on silica gel using methylene chloride / methanol (9: 1) indicated the presence of two products - 0.47 and Rf _B = 0.41.

Mass spectrum (FAB, negative): (М-Η) ”= 876. Molecular weight calculated for ^С 4б ^Н бЛ ° 12 = ⁸⁷⁷ '

For example, in order to prepare 3-amino-6-methylperhydro-1H-pyrazine (1,2-a) pyrazine, which is used as starting material, 6-methylperhydropyrazine (1,2-a) pyrazine (cf. HJ Beim and AR Day: J. Heterocycklic Chem., 14, 307 (1977) according to the procedure of Example 1, preparation a) and b).

Example 10

3-formylrifamycin hydrazone SV with 3-amino-6-isobutylperhydro-1H-pyrazino (1,2-a) pyrazine

To a solution of 3 g of 3-formylrifamycin SV in 100 ml of tetrahydrofuran is added a solution of 1.73 g of 3-amino-6-isobutylperhydro-1H-pyrazino (1,2-a) pyrazine in 10 ml of tetrahydrofuran and the reaction mixture is stirred at room temperature. over 60 minutes until all of the 3-formylrifamycin SV is consumed by thin layer chromatography. For working up, the reaction solution was concentrated in vacuo and the residue was taken up in methylene chloride. The organic phase was washed twice with dilute aqueous citric acid solution, dried and evaporated. Crude hydrazone is obtained which, by column chromatography on 200 g of silica gel, affords the pure title compound, m.p. 163-170 ° C (dec.). Thin layer chromatography using 9: 1: methylene chloride / methanol Rf = 0.42. Mass spectrum (FAB, negative): (M-H) - = 918.

Molecular weight calculated for ^C 49 ^H 69 ^N 5 ° 12 ^{1 919}

For example, in order to prepare the 3-amino-6-isobutylperhydro-1H-pyrazine (1,2-a) pyrazine used as the starting material, it can be gradually nitrosated and reduced to 6-isobutylperhydro-1H-pyrazine (1,2-a) pyrazine, produced by HJ Beim and AR Day: J. Hetorocyclic Chem. 14. 307 (1977) according to the procedure of Example 1, preparation a) and b).

Example 11

3-formylrifamycin hydrazone SV with 3-amino-6-cyclopentylperhydro-1H-pyrazino (1,2-a) pyrazine

A solution of 1.8 g is added to a solution of 3 g of 3-formylrifamycin SV in 50 ml of tetrahydrofuran

3-Amino-6-cyclopentylperhydro-1H-pyrazino (1,2-a) pyrazine in 10 ml of tetrahydrofuran and the reaction mixture was stirred at room temperature for 15 minutes until all 3-formylrifamycin SV was consumed by thin layer chromatography. For working up, the reaction solution was concentrated in vacuo and the residue was taken up in methylene chloride. The organic phase was washed twice with aqueous citric acid solution, dried and evaporated. The crude hydrazone is obtained which is chromatographed on 200 g of silica gel to give the title compound.

Mass spectrum (FAB, negative): (M-Η) = 930. Molecular weight calculated for 5 5θ 9 9 5 5 12 12 $ $ 31 To produce 3-amino-6-cyclopentylperhydro-1H-pyrazino (1,2-a) pyrazine used as starting material, for example, may be sequentially nitrosated and reduced to 6-cyclopentylperhydro-1H-pyrazino (1,2-a) pyrazine, (ar. HJ Beim and AR.Day: J. Heterocyclic Chem.

14. 307 (1977), following the procedure of Example 1, preparation a) and b).

Example 12

3-Formylrifamycin SV hydrazone with 6-aminoperhydropyrazino (2,1-c) -p-oxazine

To a solution of 3 g of 3-formylrifamycin SV in 100 ml of tetrahydrofuran was added a solution of 1.94 g

6-Aminoperhydropyrazino (2,1-c) -p-oxazine in 10 ml of tetrahydrofuran and stirred for 10 minutes at room temperature until all 3-formylrifamycin SV was consumed by thin layer chromatography. For working up, the reaction solution was concentrated in vacuo and the residue was taken up in methylene chloride. The organic phase is washed twice with dilute aqueous citric acid solution, dried and evaporated. The crude hydrazone is obtained which crystallizes from ethyl acetate / cyclohexane to give the orange red crystals of the title compound. Mass spectrum (FAB, negative): (M-Η) = 863.

Molecular weight calculated for ^C 45 ^H 60 ^N 4 ° 13 = ⁸⁶⁴ *

For example, in order to prepare the 6-amine-perhydropyrazino (2,1-c) -p-oxazine used as starting material, it can be sequentially nitrosated and reduced perhydropyrazino (2,1-c) -p-oxazine by the procedure of Example 1, preparation and ) and b). The latter compound can be obtained from morpholino-2-caboxylic acid ethyl ester according to the procedure of Freed and Day, J. Org. Chem. 21, 2110 (1960).

Example 13

3-formylrifamycin hydrazone SV and 3 = amino-7-methoxyperhydro-1H-pyrido (1,2-a) pyrazine

To a solution of 3 g of 3 * formylrifamycin SV in 100 ml of tetrahydrofuran is added a solution of 1.37 g of 3-amino-7-methoxyperhydro-1H-pyrido (1,2-a) pyrazine in 10 ml of tetrahydrofuran and the mixture is stirred for 60 minutes at at room temperature until all 3-formylrifamycin SV was consumed by thin layer chromatography. For working up, the reaction solution was concentrated in vacuo and the residue was taken up in methylene chloride. The organic phase was washed twice with dilute aqueous citric acid solution, dried and evaporated. The crude hydrazone is obtained which, by column chromatography on 200 g of silica gel, affords the pure title compound. Mass Spectrum (FAB, negative): [nu] MH + = 891.

Molecular weight calculated for «892.

For example, in order to prepare 3-amino-7-methoxyperhydro-1H-pyrido (1,2-a) pyrazine which is used as starting material, 7-methoxyperhydro-1H-pyrido (1,2-a) may be sequentially nitrosated and reduced. ) pyrazine according to the procedure of Example 1, preparation a) and b). The latter compound can be obtained from 2-methoxy-6-piperidinecarboxylic acid ethyl ester as described by Freed and Day, J. Org. Chem. 25, 108 (1960).

Example 14

Capsules containing 250 mg of 3-formylrifamycin SV with 3-aminoperhydro-1H-pyrido (1,2-a) pyrazine can be prepared, for example, as follows:

250 g g

Composition (for 1000 bands):

hydrazone of 3-formylrifamycin SV with 3-aminoperhydro-1H-pyrido (1,2-a) pyrazine maize starch

50.0 polyvinylpyrrolidone

Magnesium salt of stearic acid

5.0 ethanol as needed

The active ingredient and corn starch are mixed and the mixture is moistened with a solution of polyvinylpyrrolidone in 50 g of ethanol. The wet mass is then passed through a 3 mm sieve and dried at 45 ° C. The dry granulate is passed through a 1 mm sieve and mixed with 5 g of magnesium stearate. The mixture is then filled in portions of 0.320 g into size 0 push-fit capsules.

A capsule containing the product of Examples 2 to 13 is prepared in an analogous manner.

the equivalent of the effective dose of each

Claims (16)

SUBJECT LEZU A process for the preparation of novel polycyclic hydrazones of the general formula I (I) wherein: R @ ¹ , R @ ² , R @ 1, R @ 2, _and are hydrogen or at most two and from 1 to 4 carbon atoms, of which alkyl is an integer from 0 to 3, is an integer from 1 to 4; , the ring V consists of 5 to 8 denotes an alkylidene group with a group or alkoxycyclothenylene xyl moiety, carbon atoms, benzylidene 1 to 5; 8 to 1 to 4 carbon atoms in the alkoxy group; (C 1 -C 5) alkoxymethy means an alkylidene group having a (C 1 -C 4) alkylene group, an oxy group, a thio group, or an optionally substituted amino group of the formula -N (R) -, wherein R represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 3 -C 5 alkenyl group, a C 3 -C 12 cycloalkyl group or a phenyl group, or together represent a monocyclic 1,2-cycloalkylene group having 5 to 5 carbon atoms; 8 Ring members or o-phenylene, a Rif is a residue of rifamycin of the partial formulas Rif S or Rif SV CH ₃ (R f S) optionally OH OH CH ₃ CO CH ₃ CH ₃ CH ₃ X I; and CH ₃ O _in OH OH I ^CH 3 i \ * 3 ^С \ o ^x ó-č — со он I ( ₃₎ (Rif SV) as well as 1 salts thereof, characterized in that it is a 3-formylrifamycline of the formula II Rif-CH = O (II) wherein Rif is as defined above, Its functional derivative is treated with an N-aminopiperazine of formula III wherein (III) ^r1 . to ^R6, n, m, X and ^χ are as defined above, whereupon the ^p - .. 'ipad, if desired sloučev Nina formula I in the quinone form, by treating a compound of formula. present in the quinone oxidized form with the reagent and / or if the desired compound is in the hydroquinone form, the compound of formula I present in the quinone form is treated with a reducing agent and / or the compound of formula I present in the free form. converted to a salt or the compound of formula I is released from its salt · 2. A process according to claim 1, wherein the starting materials are corresponding compounds of the formulas II and III to give compounds of the formula I in which m is 0 to 3 and n is 1 to 4, each of the residues and separates the piperazine ring by ayfexilu X or X not more than two carbon uh.íku, no more than one of sym ^b ol ^{of R 1} and ^Z rozdHný ^R6 is hydrogen and the metal is, or e ^thy nominal group ^χ represents ethylidene or methylene; while X is C1 -C4 alkylidene, C1 -C4 alkoxymethylene, alkoxy (-O-), thio (-3-), imino (-NH-), or alkyl Or C1 and 4 together represent a 1,2-cyclohexylene or o-phenylene group, and Rf is as defined in point t. 3. A process according to claim 1, characterized in that the corresponding compounds of the formulas II and III are concealed as starting materials to give compounds of the formula I in which m is ^{0 and} v is less than ¹ and ^{z is 1} . 4 maximum 'jedan of R ¹ to ^R ® declared unto another SKU ^P inu not ^of H · a ratio in these bodies ^a case-represents methyl SKU ^ n ^ one of X and X represents methrleniviu group whilst the other represents ethylidene, propylidene, al (C 1 -C 4) -alkylene (C 1 -C 4) -alkoxy or methylene, or X and X denote together a 1,2-cyclohexylene or i-phenylene group, and Rif has the meaning given in point 1. 4. The process of claim 1, wherein the corresponding compounds of formulas II and III are used as starting materials to produce compounds of formula I wherein m and n are independently 1 to 3, where the radicals (^ H ^% ^ ®2n and ^dd * ° ^ ^lu piperazinvvý ring a or E, X X vžiy one carbon atom, at most one of ^R 'and ^{of R 6} which is other than ^hydrogen and in that ^{d p} fiddle 6 represents a metal group, ^X represents an ethylidene group, or a methylene group, while X represents an oxy group, a thio group or an imino group, the imino group being optionally substituted by an alkyl group having 1 to 2 4 carbon atoms, a C 5 -C 8 cylalkyl group or a phenyl group, and R f is as defined in bv 1. 5. A process according to claim 1, wherein the corresponding compounds of the formulas II and III are used as starting materials to form hyisazone 3-formyltriflucine SV or b. 5 with 3-amino-peroxy-1H-pyrido (1,2-a) pyrazine. 6. A process according to claim 1, characterized in that the corresponding compounds of the formulas II and III are concealed as starting materials to form hydrazone 3-101 .mu.l SV or S with 3-aminepenihriivyrrill (1,2-). (a) pyrazine. 7. The process of claim 1, wherein the corresponding compounds of formulas II and III are used as starting materials to produce 3-amino-8-methylperhydro-1H-pyrido (3-amino-8-methylperhydro-1H-pyrido) hydrazone. 1,2-a) pyrazine. 8. A process according to claim 1, wherein the corresponding compounds of the formulas II and III are used as starting materials to form 1-formylrifamycin hydrazone SV or S with 3-amino-7-ethyl-perhydro-1H-pyrido [1,2-a]. (a) pyrazine. 9. The method according to claim 1, characterized in that as starting materials použjjí Corre- ⁴ .mu.Ci of compounds of the formulas II, III а give the hydrazone of 3-fonnylrifaniycinu SV or S with 3-amino-2-methylperhydro-1 H -pyrido (1 , 2-a) pyrazine. ¹ 10. A process according to claim 1, wherein the corresponding compounds of formulas II and III are used as starting materials to produce 3-formylrifamycin hydrazone SV or S with 3-aminoperhydro-1H-pyrazinof1,2-aquinoline. 11. A process according to claim 1, wherein the corresponding compounds of general formula III are used as starting materials to produce 3-amino-2,3,4,4a, 5,6-hexahydro hydrazone of 3-formylrifamycin SV or S. -1H-pyrazino (1,2-a) quinoline. 12. The process of claim 1, wherein the corresponding compounds of formulas II and III are used as starting materials to form 3-formylrifamycin SV or S hydrazone with 6-aminoperhydropyrazolo (2,1-c) -p-thiazine. 13. A process as claimed in claim 1, wherein the corresponding compounds of the formulas II and III are used as starting materials to form 3-amino-6-R-perhydro-.beta.-pyrazino (3-amino-6-R-perhydro-6-pyrazino) hydrazone. 1,2-a) pyrazine wherein R is methyl, isobutyl or cyclopentyl. 14. The process of claim 1, wherein the corresponding compounds of formulas II and III are used as starting materials to form 3-formylrifamycin hydrazone SV or S with 6- 4-Aminoperhydropyrazolo [2,1-c] -p-oxazine. 15. A process according to claim 1, wherein the corresponding compounds of the formulas II and III are used as starting materials to form 3-formylrifamycin SV hydrazone, or S with 3-amino-7-methoxyperhydro-1H-pyrido (1,2-a) pyrazine. 16. The process of claim 1, wherein the corresponding compounds of formulas II and III are used as starting materials to form the compound of formula I as defined in any one of items 1 to 15 or a pharmaceutically acceptable alkali metal salt thereof derived from: rifamycin SV.